ECR 9.2

European Cardiology Review Volume 9 • Issue 2 • Winter 2014

Volume 9 • Issue 2 • Winter 2014

www.ECRjournal.com

The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification Velislav N Batchvarov

Renal Denervation After Symplicity HTN-3 – Back to Basics.

Review of the Evidence Alexandre Persu, Fadl Elmula M Fadl Elmula, Yu Jin, Ingrid Os, Sverre E Kjeldsen and Jan A Staessen

Hypertension in Chronic Kidney Disease – Role of Arterial Calcification and Impact on Treatment Olivier Phan, Michel Burnier and Grégoire Wuerzner

The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology

LDL-P PCSK9 PC

LDLR

Endosome

ISSN: 1758-3756

For deg

LDLR is recycled

radation

Lysosome

PCSK9, LDL-P and LDL-R Cellular Metabolism

mAB prevents binding of PCSK9 to LDLR

Reduction in systolic blood pressure (mm Hg)

Reynaria N Pitts and Robert H Eckel

50 40 30 20 10 0

PCSK9 is shuttled from Randomisation? the endoplasmic reticulum to How was blood the Golgi network pressure were documented? it enters the secretory Golgi pathway

blinded?

DiagnosticPatient Value of Higher Intercostal Positions

Non-randomised

Randomised

Non-randomised

Doctor, aware of allocation

Blood PressureUnblinded Reduction According to Study Design

Automatic storage

Randomised Doctor, aware of allocation Blinded

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Radcliffe Cardiology

A free-to-access community supporting best practice in cardiovascular care www.radcliffecardiology.com

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05/12/2014 00:02

Volume 9 • Issue 2 • Winter 2014

www.ECRjournal.com

Editor-in-Chief Juan Carlos Kaski Cardiovascular and Cell Sciences Research Institute St George’s, University of London

Editorial Board Luigi Paolo Badano

Department of Cardiac, Vascular and Thoracic Sciences, University of Padua, Italy

Alberto Cuocolo

Department of Advanced Biomedical Sciences, University of Naples Federico II, Italy

Simon Gibbs

National Heart and Lung Institute, Imperial College London, UK

Martin Halle

Technische Universitaet Muenchen, Germany

Sverre E Kjeldsen

Division of Cardiology, Department of Internal Medicine, Ullevaal Hospital, Norway

Steen Dalby Kristensen

Department of Cardiology, Aarhus University Hospital, Denmark

Patrizio Lancellotti

University of Liège, Belgium

Giuseppe Mancia

Department of Clinical Medicine & Prevention, University of Milano-Bicocca, Italy

Zoltan Papp

University of Debrecen, Hungary

Antonio Pelliccia

Institute of Sports Medicine, Italian National Olympic Committee, Italy

Joep Perk

School of Health and Caring Sciences, Linnaeus University, Kalmar, Sweden

Piotr Ponikowski

Centre for Heart Disease, Clinical Military Hospital, Wroclaw, Poland

Fausto Rigo

Mestre-Venice Hospital, Italy

Rosa Sicari

CNR, Institute of Clinical Physiology, Italy

José Luis Zamorano

University Clinic San Carlos, Spain

Design & Production Tatiana Losinska • Publication Manager Michael Schmool Publishing Director Liam O’Neill • Managing Director David Ramsey Managing Editor editor@radcliffecardiogy.com •

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

Cover image

Human heart glowing in chest 3D render CGI © janulla | shutterstock.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved

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Established: April 2005 Frequency: Bi-annual Current issue: Winter 2014

Aims and Scope • European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiology medicine and practice.

• European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• European Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • European Cardiology Review is a bi-annual journal comprising review articles, editorials, and case reports.

• The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the Editorial Board.

• Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion.

• Each edition of E uropean Cardiology Review is replicated in full online at www.ECRjournal.com

Editorial Expertise uropean Cardiology Review is supported by various levels of expertise: E • Overall direction from an Editor-in-Chief, supported by an Editorial Board comprising leading authorities from a variety of related disciplines.

• Invited contributors who are recognised authorities from their respective fields.

• Peer review – conducted by experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

• The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

• Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board.

Following acceptance of an invitation, the author(s) and Managing Editor formalise the working title and scope of the article.

Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.ECRjournal.com.

Reprints All articles included in European Cardiology Review are available as reprints. Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Distribution and Readership European Cardiology Review is distributed bi-annually through controlled circulation to senior professionals in the field in Europe.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in European Cardiology Review unless otherwise stated.

Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

Online All manuscripts published in European Cardiology Review are available free-to-view at www.ECRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review and Interventional Cardiology Review. n

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Lifelong Learning for Cardiovascular Professionals

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Radcliffe Cardiology

© RADCLIFFE CARDIOLOGY 2014

04/12/2014 21:32

Contents

Foreword 64

Juan Carlos Kaski

Coronary Artery Disease Prevention

65 The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology

Reynaria N Pitts and Robert H Eckel

71 Statins: Practical Considerations – A Review Kazeen Abdullah and Anand Rohatgi

76

C urrent Treatment of Familial Hypercholesterolaemia

Risk Assessment and Management

Cameron T Lambert, Pratik Sandesara, Ijeoma Isiadinso, Maria Carolina Gongora,

Danny Eapen, Neal Bhatia, Jefferson T Baer, Laurence Sperling

82

T he Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification

Velislav N Batchvarov

88 Evaluation and Management of ST-elevation Myocardial Infarction and Shock

Lee Chang and Robert Yeh

92 Echocardiographic Evaluation of Aortic Stenosis – Normal Flow and Low Flow Scenarios

Ian G Burwash

Heart Failure

100 Update on Cardiac Resynchronisation Therapy for Heart Failure David D Daly Jr and Michael R Gold

104

Gaps in the Heart Failure Guidelines

Hypertension

Bao Tran and Gregg C Fonarow

110 Renal Denervation After Symplicity HTN-3 – Back to Basics.

Review of the Evidence

Alexandre Persu, Fadl Elmula M Fadl Elmula, Yu Jin, Ingrid Os, Sverre E Kjeldsen and Jan A Staessen

115 Hypertension in Chronic Kidney Disease – Role of Arterial Calcification and Impact on Treatment

Olivier Phan, Michel Burnier and Grégoire Wuerzner

Supported Contribution – Opinion

120 Rhythm Management of the Atrial Fibrillation Patient: Practical Implementation of the 2012 ESC Guidelines

Katrina Mountfort

© RADCLIFFE CARDIOLOGY 2014

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), Honorary Consultant Cardiologist at St George’s Hospital, NHS Trust, London, UK and Director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Professor Kaski is Doctor of Science, University of London, immediate Past-President of ISCP (International Society of Cardiovascular Pharmacotherapy) and editorial board member and associate editor of numerous peer review journals. He is also Fellow of the ESC (FESC), the ACC (FACC), the AHA (FAHA), the Royal College of Physicians (FRCP), and over 30 other scientific societies worldwide.

I

am delighted to take on the editorship of European Cardiology Review.

We have excellent articles in this issue of European Cardiology Review, all reviewing important topics. Amongst these, the review by Robert Eckel looks into the emerging role of PCSK9 inhibitors in preventive cardiology. Velislav Batchvarov meticulously dissects issues related to diagnosis and risk stratification in Brugada syndrome, a topic of major clinical relevance at present. Alexandre Persu discusses the role of renal denervation after the results of SYMPLICITY HTN-3 whilst Ian Burwash’s article tells us about echocardiographic evaluation of aortic stenosis.

Current heart failure guidelines have raised some controversy and this issue features an article from Gregg Fonarow, on “Gaps in the Heart Failure Guidelines”. I’m delighted that European Cardiology Review will also offer its readers excellent articles by Gregoire Wuerzner ‘Hypertension in Chronic Kidney Disease’- and Robert Yeh - ‘The Management of STEMI’, all of which will prove to be of great interest to clinical cardiologists given their practical importance.

Authoritative reviews from Michael Gold on heart failure issues and Anand Rohatgi and Laurence Sperling on practical use of statins and management of familial hypercholesterolemia, respectively, complete the table of contents of this excellent issue of European Cardiology Review.

The issue also includes a sponsored satellite symposium on a topic of utmost clinical importance i.e. ‘Practical Implementation of the 2012 ESC Atrial Fibrillation Guidelines’ - which is relevant for the patient.

I hope you will find this issue enjoyable and useful for your daily clinical practice.n

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Coronary Artery Disease Prevention

The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology R e y n a r i a N Pi t t s a n d R o b e r t H E c k e l Charles A. Boettcher II Chair in Atherosclerosis, University of Colorado Anschutz Medical Campus, Aurora, CO, US

Abstract Low-density lipoprotein cholesterol (LDL-C) is a most important risk factor for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD) and a major focus of CVD risk reduction with lifestyle and statins. Unfortunately residual risk of CVD remains in patients with familial hypercholesterolaemia and/or statin intolerance in whom adequate LDL-C lowering is not accomplished with lifestyle and statins. PCSK9 is a serine protease that binds the LDL receptor (LDL-R) and acts as a chaparone for endocytosis and shuttling the PCSK9-LDLR complex to lysosomes for degradation. In the absence of PCSK9 the LDLR-LDL-C complex dissociates and LDL-R is recycled back to the cell surface. Humanised monoclonal antibodies (evolocumab, alirocumab, bocolicumab) have been developed that increase LDL-R by ~2-fold and lower LDL-C by up to 75 percent. This effect is synergistic to that of statins with the only common adverse effect is a local injection site reaction. At present, ongoing Phase III CVD outcome trials with PCSK9 inhibitors offer promise that patients with LDL-C levels that remain elevated can decrease CVD events and related mortality.

Keywords PCSK9, CHD, CVD, statins, LDL-C, LDL receptor, prevention Disclosure: The authors have no conflicts of interest to declare.

Received: 4 August 2014 Accepted: 30 October 2014 Citation: European Cardiology Review, 2014;9(2):65–70 Correspondence: Robert H Eckel, MD, Division of Cardiology, Charles A Boettcher II Chair in Atherosclerosis, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave, RC1 South, Room 7107, Aurora CO 80045. E: robert.eckel@ucdenver.edu

Elevated levels of low-density lipoprotein cholesterol (LDL-C) have long been established as one of the most important risk factors for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD).1,2 Targeting LDL-C reduction has been effective in lowering cardiovascular risk.3,4 The use of HMGCoA reductase inhibitors (statins) for both primary and secondary cardiovascular disease prevention has become first-line therapy and has resulted in reduction of cardiovascular (CV) events and overall mortality.3 More recent guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) have recommended intensification of statin therapy based on calculated atherosclerotic CVD risk and not based on LDL-C levels alone.5 However, despite reduction in LDL-C by 18–41 % (moderate doses) and 40–60 % (higher doses or more potent statins), there remains significant residual cardiovascular risk. In addition, there are many otherindividuals that have been unable to achieve sufficient LDL-C lowering or have been intolerant to the drug completely.6 Other cholesterol lowering agents (bile acid sequestrants, ezetimibe, niacin, fibrates) have been used in conjunction with statins to achieve historic LDL and/or non-HDL-C goals, however at this time their addition has not been proven to have added value in clinical cardiovascular outcomes.7–10 Due to continued inability to achieve adequate clinical benefit and ongoing incidence of statin intolerance, research for alternative therapies is of utmost priority. The discovery of proprotein convertase subtilisin/kexin Type 9 (PCSK9) has opened the possibility for effective and adjunctive therapy for those who are not optimised with statins while providing therapy in lowering cardiovascular risk in subjects who are intolerant and have little alternatives.

© RADCLIFFE CARDIOLOGY 2014

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LDL Cholesterol Cellular Metabolism Most LDL is cleared from the plasma by LDL receptors on hepatocytes.

At neutral pH, the LDL-receptor (LDL-R) binds to apolipoprotein B-100 (apoB100) on LDL and LDL endocytosis ensues.11 In the acidic environment of the endosome, the LDL-R folds into a closed formation state, thereby releasing LDL.12 LDL-R is then recycled to the cell surface while LDL is transferred to a proteasome targeting it for further processing.13 The inability of LDLR-LDLP complex to dissociate routes the complex for degradation, thereby reducing LDL-R surface concentration. Regulation of the LDL-R is also driven by the intracellular concentration of cholesterol. In the setting of high intracellular cholesterol levels, LDL-R levels decrease and activity of HMG CoA synthase and reductase decrease by more than 90 %. Thus, in the setting of drugs that lower intracellular cholesterol, such as statins, LDL-R levels are increased and serum LDL-C levels are decreased.

Cellular mechanism regulating cholesterol homeostasis is complex and involves balance between intracellular biosynthesis and exogenous uptake of cholesterol. Cholesterol uptake and intracellular biosynthesis is regulated by sterol regulatory element-binding protein (SREBP), a transcription factor located in the endoplasmic reticulum.

When cholesterol levels on the endoplasmic reticulum membrane are low, a sterol sensor binds to SREBP and signals its movement from the endoplasmic reticulum to the Golgi apparatus where SREBP is further activated and transported to the nucleus.14 In the nucleus, SREBP acts as a transcription factor, increasing HMG coA reductase and LDLR gene expression.13

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Coronary Artery Disease Prevention Table 1: Genetic Mutations of the PCSK9 Gene

Type of Mutation Examples Effects

Gain of function mutation

Missense

S127R

Increase levels

F216L

of PCSK9 or

D374Y

affinity for LDL

C161T

receptor

I474V

Loss of function mutation

Y142X

Nonsense

Introduce stop

C679X codon

Missense R46L

Premature termination signal and truncated protein. LDL = low-density lipoprotein.

Figure 1: PCSK9, LDL-P and LDL-R Cellular Metabolism

LDL-P PCSK9 PC

mAB prevents binding of PCSK9 to LDLR

LDLR

a 13 % decrease of LDL-C that was associated with 30 % risk reduction in incidence of ischemic heart disease.20 The higher than expected CVD risk reduction is thought to be from life-long exposure to very low LDL-C levels.

Molecular Mechanism of PCSK9 PCSK9 is a serine protease that belongs to a subfamily of subtilisin proteases responsible for activation or inactivation of other proteins, such as hormones, growth factors and other enzymes. It was initially identified as a seceretory proprotein convertase neural apoptosisregulated convertase-1 (NARC-1) prior to the discovery of its role in cholesterol metabolism.15 PCSK9 proprotein is processed in the endoplasmic reticulum where it undergoes autocatalytic cleavage producing a cleaved, but bound, prodomain and catalytic subunit. The bound prodomain makes the catalytic domain enzymatically inactive, unlike other serine proteases, acting instead as a binding protein when secreted. In the extracellular space, PCSK9 binds to LDL receptor via its catalytic subunit while its C-terminal subunit acts as a chaparone for endocytosis and shuttling the PCSK9-LDLR-LDL complex to lysosomes for degradation.22 In the absence of PCSK9 and in the acidic environment of the clathrin coated endosome, LDLR-LDL complex dissociates and LDLR is recycled back to the cell surface (see Figure 1).23 The PCSK9 gene is located on chromosome 1p32 and its expression is also regulated by intracellular cholesterol, via SREBP-2.24 Synthesis

PCSK 9 enters the secretory pathway through the Golgi network. Circulating PCSK9 binds to LDL-R on cellular surface of hepatocytes. Bound LDL-P to LDL-R is internalised along with PCSK9. In the endosome, the bound PCSK9 targets LDL-R in the endosome for degradation, subsequently lowering LDL-R levels and increasing circulating LDL-P and LDL-C. LDL-R = LDL receptor; LDL-P = LDL particle.

of PCSK9 occurs mostly in the liver, small intestine and kidney and is secreted as a soluble enzyme.25 After secretion, 30–40 % of PCSK9 binds to LDL, a process that may inhibit its uptake of LDL by LDLR.26 Low intracellular levels of cholesterol not only stimulate the synthesis of LDL-R but also PCSK9, serving as a counter-regulatory mechanism to maintain intracellular delivery of cholesterol. In the setting of statin, fibrate and ezetimibe use, PCSK9 expression is up-regulated due to low intracellular cholesterol levels.27 The degree of PCSK9 expression correlates with degree of LDL-C levels in subjects treated with statin, attenuating the cholesterol-lowering effects of statin.28 Thus, PCSK9 inhibition is additive to statin therapy and play a synergistic role in its lipid-lowering effects.

Genetics of PCSK9

Inhibition of PCSK9

PCSK9 was first discovered as a ninth member of the subtilase subfamily,15 Its function was initially largely unknown until its role in hypercholesterolaemia was realised in a group of French families with autosomal dominant familial hyperlipidaemia (FH). These individuals did not exhibit the usual genetic mutations in the LDLR (LDL receptor) or APOB (apolipoprotein B) genes.16 Instead, the genotype of these FH cohorts revealed multiple missense mutations in the PCSK9 gene resulting in defective intracellular PCSK9 processing (see Table 1). A gain of function mutation results from the defective pro-PCSK9 processing and causes either an over expression of PCSK9 or an increased affinity for the LDL receptor.17 These gain of function mutations have shown to significantly decrease LDL receptors by as much as 35 % and consequently increase serum LDL-C levels.18 Targeting PCSK9 as a therapeutic strategy was conceptualised after loss of function mutations were discovered in both African American and Caucasian populations (see Table 1).19,20 Subjects with low LDL-C in the Dallas Heart Study had PCSK9 sequencing that identified two non-sense mutations in 2 % of the African American cohort resulting in low levels of PCSK9 and a marked reduction of plasma LDL-C of 40 %.21 Similarly, missense mutations were also discovered in the Caucasian population that was associated with 30 % decrease in LDL-C.19 Subjects with loss of function mutations and its association with ischaemic heart disease have been evaluated in a meta-analysis. In multiple groups of subjects with loss of function mutations in the PCSK9 gene, there was

PCSK9 inhibition is currently achieved by either preventing PCSK9 synthesis or inhibiting the binding of PCSK9 to LDL-R. The most clinically advanced mechanism by which inhibition of PCSK9 has been achieved is through the development of monoclonal antibodies. Other mechanisms, such as mimetic peptides, antisense RNA inhibition and natural binding inhibitors are mostly in preclinical development (see Table 2).

Endosome

For deg

LDLR is recycled

radation

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Eckel_FINAL.indd 66

Lysosome

PCSK9 is shuttled from the endoplasmic reticulum to the Golgi network were it enters the secretory Golgi pathway

Monoclonal Antibodies In 2009, the first successful development of monoclonal antibody against PCSK9 was developed by Chan et al.29 The fully human monoclonal antibody (mAB) binds to both the catalytic and prodomain sites preventing PCSK9 binding to LDL-R.29 Monoclonal AB was shown to increase LDL receptor levels by 1.7-2.2-fold and had synergistic effects when administered concomitantly with statin.29 Phase I studies showed significant efficacy in reducing LDL-C levels with minimal adverse events. 30,31 Almost simultaneously, multiple monoclonal antibodies have been developed with rapid completion of phase II trials and now ongoing phase III clinical trials.32–34

Alirocumab (REGN727/SAR236553) Initial phase I clinical trials of alirocumab showed a dose-dependent LDL-C lowering effects. In one phase I clinical trial, escalating subcutaneous doses of 50, 100, and 150 mg doses were compared to placebo, lowering

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Emerging role of PCSK9

Table 2: Approaches and Mechanism of PCSK9 Inhibition Approaches to PCSK9 Inhibition Mechanism Example Phase Gene Silencing Antisense oligonucleotide ISIS pharmaceutical1a Preclinical

Small interfering RNA (siRNA) Santaris pharma2a Phase I

Alnylam Pharmaceuticals3a Mimetic Peptides Peptide that mimics EGFA domain of LDLR and binds PCSK94a,5a Genentech, Inc Preclinical

Peptide that mimics PCSK9 and binds LDLR6a Preclinical Small molecule inhibitors Target binds of PCSK9 Natural inhibitor Annexin7a,8a Preclinical

Berberine9a,10a

BMS-96247611a Monoclonal antibodies Targeting catalytic domain of PCSK9 Amgen AMG145 (evolocumab) Phase I - III

Regeneron SAR236553/REGN7270

Pfizer RN316 (bococizumab)

Novartis LGT209

Genentech MPSK3169A LDLR = LDL receptor

LDL-C by 39, 54 and 61 %, respectively (see Table 3).31 Phase II clinical trials have evaluated alirocumab’s use in heterozygous FH and in subjects with hyperlipidaemia on either stable doses of statin or escalating doses of statin (low and high dose atorvastatin). In the phase II clinical trial evaluating the use of alirocumab in the background of stable doses of atorvastatin (low or high dose) in subjects with LDL-C ≥ 100 mg, LDL-C decreased by as much as 72 % with 150 mg administered every two weeks.35,36 This study also showed significant decreases in apolipoprotein B (apoB), non-high density lipoprotein cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)].35 The mechanism by which Lp(a) is lowered is unknown, but maybe related to the decrease in the availability of LDL-apoB [known to decrease Lp(a)] and the increased clearance of apolipoprotein(a).37 In the phase II clinical trial evaluating the safety and efficacy of escalating dose of alirocumab in subjects with heterozygous FH, alirocumab was given either every two (Q2 week) or four (Q4 week) weeks in the background statin use with or without ezetimibe.38 Alirocumab was well-tolerated and effective in adequately treating subjects with FH (68 % reduction in LDL-C with 150 mg SC dose Q2 weeks compared with 11 % in the placebo group).38 The ODYSSEY program is currently underway and is a collection of 14 clinical phase III trials evaluating the efficacy and safety of alirocumab in various patient populations and clinical settings. All trials in the program are designed to treat to goal levels of LDL-C and evaluates efficacy in patient population that are not optimised with current standard therapies. This program involves over 2,000 international sites with over 23,500 subjects.39 The largest study will be evaluating clinical cardiovascular outcomes (ODYSSEYOUTCOMES), which is enrolling subjects with prior history of acute coronary syndrome already on optimised-guideline based therapy.40 In the recent European Society of Cardiology (ESC) scientific meeting, preliminary results from the ODYSSEY program were presented.

Particularly intriguing was a post-hoc analysis of the ODYSSEY LONG TERM trial evaluating LDL-C lowering effects of alirocumab in patients with heterozygous FH or patients with high CV risk. Not surprisingly, alirocumab was shown to decrease LDL-C levels by 61 % compared to placebo. However, after only one year of the intervention post-hoc analysis showed a lower risk for CV events (HR 0.46, CI 0.26-0.82, p = <0.01) (ESC Barcelona Spain 2014).

Evolocumab (AMG 145) Evolocumab, a full human monoclonal antibody, is administered subcutaneously either as every two weeks or every four weeks

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Table 3: Monoclonal Antibodies Dose and LDL-C Reduction Monoclonal Antibodies

Reduction of LDL-C from Baseline

Alirocumab 150 mg every two weeks 300 mg every four weeks

66–72 % 43–48 %

Evolocumab 140 mg every two weeks

51–76 %

420 mg every four weeks

48–71 %

Bococizumab 150 mg every two weeks 300 mg every four weeks

33 % (0.5 mg/kg) – 85 % (18 mg/kg) Mean reduction 53 mg/dL Mean reduction 45 mg/dL

low-density lipoprotein cholesterol

dosing regimen. Koren at al. showed that escalating doses of evolocumab as a monotherapy in both Q2 week or Q4 week dosing administered subcutaneously to subjects with history of hypercholesterolaemia and low cardiovascular risk (Framingham risk score < 10 %) decreased LDL-C from baseline by up to 48 %. 41,42 Stein et al. in the phase II Goal achievement after utilising an antiPCSK9 antibody in statin intolerant subjects (GAUSS) evaluated the efficacy and safety of evolocumab in patients with statin intolerance. 43 Patients receiving escalating doses experienced a significantly reduced LDL-C compared to placebo. At 280 mg dose, LDL-C was reduced by 41 %.43 When escalated to a dose of 420 mg, LDL-C was reduced by 51 %.43 This study was expanded to a phase III trial in subjects with a history of hypercholesterolemia not at previously established National Cholesterol Education Program Adult Treatment Program III (NCEP-ATP III) risk-based goals and intolerant to statins. 44 As in the phase II results, any regimen administered significantly reduced LDL-C compared to ezetimibe, with the highest reduction (61 %) seen with evolocumab 420 mg + ezetimibe 10 mg.

When administered to subjects who were already taking statin, administration of evolocumab further decreased LDL-C by 63–75 % compared to placebo.45 The use of evolocumab was also studied in subjects with heterozygous FH already on maximized tolerated lipid therapy (stable dose of statin with or without ezetimibe).46,47 As in other studies, the largest additional decrease in LDL-C was seen with dose of 420 mg Q4 week (55 % additional LDL-C reduction).44 In subjects with known CAD or CAD risk equivalent and not at NCEP-ATP III goal of LDL-C ≤ 70 mg/dL, evolocumab was studied as an adjunct to stable doses of statin with or without ezetimibe.48 When administered in escalating doses either as a Q2 week or Q4

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Coronary Artery Disease Prevention Table 4: Phase III Clinical Trials in Subjects with Hypercholesterolaemia Treated with Monoclonal Antibodies Monoclonal Antibody Evolocumab

Name of Phase III MENDEL-2

Population Subjects with hypercholesterolaemia, Framingham Risk score < 10%, monotherapy

Statin-intolerant subjects, compared to ezetimibe

GAUSS-2

Subjects with hypercholesterolaemia, statin intolerance, ezetimibe controlled

LAPLACE-2

Subjects treated with evolocumab on high or low dose statin

FOURIER

Evaluating cardiovascular outcomes in subjects with hypercholesterolaemia and elevated

risk cardiovascular risk

Alirocumab

ODYSSEY

Global Phase III program

COMBO-I

subjects treated with maximally tolerated statin therapy

CHOICE I

Alirocumab administered every four weeks compared with placebo

CHOICE II

Alirocumab as monotherapy compared to other non-statin lipid lowering therapies

LONG TERM

Alirocumab use in the background of lipid lowering therapies and long term safety and efficacy

OUTCOMES

Alirocumab effects in cardiovascular outcomes in subjects with acute coronary syndrome

Bocolicumab

SPIRE-1

CV outcomes in subjects with high risk and LDL-C ≤ 70 but ≤ 100 mg dL

SPIRE-2

CV outcomes in subjects with high risk and LDL-C ≥ 100 mg dL

SPIRE-IS

Subjects who are intolerant to statin

SPIRE-HR

Subjects with high or very high risk for CV events

SPIRE-LL

Subjects with primary hyperlipidaemia at high or very high risk

week regimen significant reductions in LDL-C occurred. The Q2 week regimen at 140 mg, achieved the highest LDL-C reduction at 12 weeks (64 %). Each dosing group also significantly achieved NCEPATP III treatment goal when compared to placebo (90 % of those in the Q2 week 140 mg group achieved LDL-C ≤ 70 mg/dL).48 An analysis from this study also showed therapy with evolocumab decreased Lp(a) by 23 % compared to placebo.49 As previously discussed, mechanisms by which this effect occurs is unknown.

The use of evolocumab was also studied in homozygous FH, a rare but severely elevated LDL-C, wherein very high CVD risk with possible death in childhood occurs. In the small study by Stein et al., the effect of evolocumab was studied in both LDL-R negative subjects and LDL-R defective patients. Evolocumab significantly reduced LDL-C by 26 % in only the LDL-R defective subjects. In a larger, randomised controlled trial that enrolled homozygous FH, evolocumab consistently decreased LDL-C by 23 %.50 There are currently phase III clinical trials that have shown safety and efficacy in lowering LDL-C with evolocumab. In a 12-week phase III clinical trial, evolocumab use in combination with moderate or high-intensity statin showed significant reduction in LDL-C (up to 75 % reduction when administered every two or four weeks).45 Another phase III study evaluating evolocumab use as a monotherapy also showed significant decrease in LDL-C (57 % more reduction compared to placebo and 40 % more reduction than ezetimibe).42 In a 12-week phase III study evaluating evolocumab use in subjects with intolerance to statin, those treated with evolocumab had significant reduction of LDL-C compared to ezetimibe (53–56 % vs 37–39 % p< 0.001).44 Patients that were previously enrolled in prior phase II studies (GAUSS, RUTHERFORD, LAPLACE-TIMI 57, and MENDEL) were evaluated in the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) trial. This study showed that subjects who continued to take evolocumab for the duration of the year on a monthly dosing regimen, maintained decreased LDL-C levels, whereas those that discontinued the study drug resumed their baseline levels.51 The Further cardiovascular outcomes research with PCSK9 inhibition in Subjects with Elevated CV Risk (FOURNIER) is currently enrolling to evaluate CV outcomes with evolocumab use in subjects already on guideline-based lipid therapy.

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Bococizumab (RN316/PF04950615) The monoclonal antibody bococizumab has undergone phase I clinical trial and shown that single and escalating intravenous and subcutaneous dose significantly lowered LDL-C by as much as 54 % with 150 mg Q2 week regimen without significant adverse effects.52 Currently, two phase III trials are underway studying bococizumab effects on cardiovascular outcomes in high risk subjects. In one of these outcomes trials, bococizumab use will be evaluated in subjects who are at high risk and have an LDL-C level of 70-100 mg/dL (SPIRE1).

In another CV outcomes study, safety and efficacy of bobocizumab will be evaluated in high risk subjects who have higher than LDL 100 mg/ dL, despite high-dose statin or at the highest tolerated dose (SPIRE2) (see Table 4).

Other Targets for PCSK9 Inhibition Other pharmacologic approaches to PCSK9 inhibition have been proposed; many are still in preclinical development. Direct inhibition of PCSK9 can be attained using small mimetic peptides called adnectins. Mimetic peptides of the PCSK9 binding domain for LDL have been shown to decrease LDL-R degradation.53,54 Mimetic peptides of the binding domain of LDL-R can also bind to PCSK9 and prevent its interaction with LDL-R.53,55 Another approach in PCSK9 inhibition is gene silencing techniques. Antisense oligonucleotides (ASO) are in preclinical development. ASO administration in mice has been shown to increase hepatic LDL-R receptor concentration.56 Antisense RNAs (siRNA) are also being developed to target PCSK9 mRNA, shown in non-human primates to reduce LDL-C by up to 50–70 percent.57 Natural inhibitors, such as annexin A2, a protein expressed in many tissues, inhibit PCSK9 and increase LDL-R.58,59 Berberine, a natural occurring plant alkaloid has been shown to also decrease PCSK9 mRNA expression and increase LDL-R in vitro and animal studies.60,61

Adverse Events Serious adverse events from monoclonal antibodies targeting PCSK9 are rare. The most common adverse reactions are local injection site reactions. In the GAUSS phase II trial evaluating subjects that have intolerance to statin, myalgias were the most common adverse event but had low incidence overall.43 Alirocumab had similar adverse reactions between placebo and treatment groups in its phase II

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Emerging role of PCSK9

trials. In a dose escalating study of alirocumab, one of 152 subjects receiving a dose of alirocumab developed cutaneous leukocytoclastic vasculitis that was successfully treated with prednisone.35 Most common adverse reactions that caused discontinuation of medication in these trials were mild injection site reactions (erythema, pruritis, discoloration, haematoma, swelling). For evolocumab, the most common treatment related adverse reaction was not only injection site reaction (pain), but also headache and skin burning sensation.46

Conclusion PCSK9 Inhibition for Use in Cardiovascular Disease Prevention Although statins have revolutionised lipid therapy and secondary cardiovascular disease prevention, there remains a significant residual risk that can be further targeted. Certain populations may benefit

from additive therapies: those with persistent elevation of LDL-C or residual risk despite optimal guideline-based therapy. Subjects with familial hypercholesterolaemia, for example, have been difficult to treat; despite maximum doses of lipid therapies, many subjects may not achieve sufficient reduction of LDL-C. Intolerance of statin, due to moderate to severe myalgias and/or a 5-fold increase in creatinine kinase have also limited the beneficial use of optimised lipid therapy, and this statin-induced myopathy may represent up to 10 % of treated patients in a primary care setting.62 At present, PCSK9 inhibitors have successfully shown to significantly reduce LDL-C, non-HDL-C and Lp(a) in different patient population and clinical settings. As we look to continued phase III clinical trials, particularly those measuring CV outcomes, PCSK9 inhibitors offer promise to patients with significant residual risk that treatment with PCSK9 inhibitors can further lower cardiovascular outcome events and related mortality. n

Table 2 references 1a. Shan L, Pang L, Zhang R, et al. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun 2008;375:69–73.

2a. McNutt MC, Kwon HJ, Chen C, et al. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem 2009;284:10561–70.

3a. Du F, Hui Y, Zhang M, et al. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 2011;286:43054–61.

4a. Graham MJ, Lemonidis KM, Whipple CP, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res

2007;48:763–7.

5a. Gupta N, Fisker N, Asselin MC, et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PloS One 2010;5:e10682.

6a. Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al.

Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America 2008;105:11915–20.

7a. Mayer G, Poirier S, Seidah NG. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem 2008;283:31791–801.

8a. Seidah NG, Poirier S, Denis M, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PloS one 2012;7:e41865.

9a. Cameron J, Ranheim T, Kulseth MA, et al. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 2008;201:266–73.

10a. Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterollowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10:1344–51.

11a. Lipovsek D. Adnectins: engineered target-binding protein therapeutics. Protein engineering, design & selection: PEDS 2011;24:3–9.

Proceedings of the National Academy of Sciences of the United States of America 2003;100:928–33.

16. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics 2003;34:154–6.

17. Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Human Mutation 2005;26:497.

18. Benjannet S, Rhainds D, Essalmani R, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

J Biol Chem 2004;279:48865–75.

19. Cohen JC, Boerwinkle E, Mosley TH, Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72.

20. Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, lowdensity lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

J Am Coll Cardiol 2010;55:2833–42.

21. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics 2005;37:161–5.

22. Yamamoto T, Lu C, Ryan RO. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor.

J Biol Chem 2011;286:5464–70.

23. Lo Surdo P, Bottomley MJ, Calzetta A, et al. Mechanistic implications for LDL receptor degradation from the PCSK9/ LDLR structure at neutral pH. EMBO reports 2011;12:1300–5.

24. Maxwell KN, Soccio RE, Duncan EM, et al. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 2003;44:2109–19.

25. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 2012;11:367–83.

26. Kosenko T, Golder M, Leblond G, et al. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem 2013;288:8279–88.

27. Careskey HE, Davis RA, Alborn WE, et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 2008;49:394-8.

28. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004;24:1454–9.

29. Chan JC, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America 2009;106:9820–5.

30. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results

from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012;60:1888–98.

31. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108–18.

32. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebocontrolled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809–19.

33. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007–17.

34. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, doubleblind, randomized Phase 3 trial. Int J Cardiol 2014;176:55–61.

35. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/ kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344–53.

36. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891–900.

37. Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278–88.

38. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce lowdensity lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36.

39. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovascular drugs and therapy/sponsored by the International Society of Cardiovascular Pharmacotherapy 2014;28:281–9.

40. Roth EM, Diller P. Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody. Future Cardiology 2014;10:183-99.

41. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2

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2. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–13.

3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.

4. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999;282:2340–6.

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6. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012;14:1–10.

7. Investigators A-H, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–67.

8. Januszkiewicz L. [The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus].

Kardiologia polska 2010;68:853-4; discussion 5.

9. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721–6.

10. Group HTC, Landray MJ, Haynes R, et al. Effects of extendedrelease niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–12.

11. Gent J, Braakman I. Low-density lipoprotein receptor structure and folding. CMLS 2004;61:2461–70.

12. Huang S, Henry L, Ho YK, et al. Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor. J Lipid Res 2010;51:297–308.

13. Brown MS, Goldstein JL. Cholesterol feedback: from Schoenheimer’s bottle to Scap’s MELADL. J Lipid Res 2009;50 Suppl:S15–27.

14. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331–40.

15. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.

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42. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 Monotherapy for Hypercholesterolemia: The MENDEL-2 Randomized, Controlled Phase III Clinical Trial of Evolocumab. J Am Coll Cardiol 2014;63:2531-40.

43. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497–506.

44. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 Antibody Effectively Lowers Cholesterol in Patients With Statin Intolerance: The GAUSS-2 Randomized, Placebo-Controlled Phase 3 Clinical Trial of Evolocumab. J Am Coll Cardiol 2014;63:2541–8.

45. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or highintensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870–82.

46. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408–17.

47. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2014.

48. Desai NR, Giugliano RP, Zhou J, et al. AMG 145, a monoclonal

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antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). J Am Coll Cardiol 2014;63:430–3.

49. Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)Thrombolysis in Myocardial Infarction (TIMI) 57 trial.

Circulation 2013;128:962–9.

50. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebocontrolled trial. Lancet 2014.

51. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234–43.

52. Ling H, Burns TL, Hilleman DE. An update on the clinical development of proprotein convertase subtilisin kexin 9 inhibitors, novel therapeutic agents for lowering lowdensity lipoprotein cholesterol. Cardiovascular Therapeutics 2014;32:82–8.

53. Shan L, Pang L, Zhang R, et al. PCSK9 binds to multiple

receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun 2008;375:69–73.

54. Du F, Hui Y, Zhang M, et al. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 2011;286:43054–61.

55. McNutt MC, Kwon HJ, Chen C, et al. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem 2009;284:10561–70.

56. Graham MJ, Lemonidis KM, Whipple CP, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 2007;48:763–7.

57. Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al.

Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America 2008;105:11915–20.

58. Seidah NG, Poirier S, Denis M, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PloS one 2012;7:e41865.

59. Mayer G, Poirier S, Seidah NG. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem 2008;283:31791–801.

60. Cameron J, Ranheim T, Kulseth MA, et al. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 2008;201:266–73.

61. Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterollowering drug working through a unique mechanism distinct from statins. Nature Medicine 2004;10:1344–51.

62. Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab 2010;95:2015–22.

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LE ATION.

Statins: Practical Considerations – A Review Kazeen Abdullah and Anand Rohatgi Department of Internal Medicine, University of Texas Southwestern Medical Center, Texas, US

Abstract Statins are currently the most efficacious and widely prescribed lipid-lowering medications. The 2013 ACC/AHA cholesterol guidelines provide a dramatic shift in treatment approach with a focus on fixed-dose statins matched to individual risk scores. Statin intolerance is not uncommon and can be challenging to diagnose and manage; however, several therapeutic strategies have been successful in achieving statin tolerance. Statin use is also associated with liver enzyme elevations and increased risk of incident diabetes, but studies show these individuals benefit from statins. Several guidelines exist and statin use is expected to increase with the new cholesterol guidelines bringing along new challenges for prescribers. This review article will provide practical considerations for statin use and management of statin intolerance.

Keywords Statin, cholesterol, guidelines, intolerance, ASCVD, diabetes, CKD, practical, considerations, review Disclosure: Kazeen Abdullah has no conflicts of interest to declare. Anand Rohatgi received a research grant from Merck and served on the Speakers’ Bureau of AstraZeneca.

Received: 17 October 2014 Accepted: 23 November 2014 Citation: European Cardiology Review, 2014;9(2):71–5 Correspondence: Anand Rohatgi, Department of Internal Medicine, University of Texas Sountwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, US. E: Anand.Rohatgi@utsouthwestern.edu

Statins are currently the most efficacious and widely prescribed lipid-lowering medications.1 Numerous randomised controlled trials across a spectrum of baseline atherosclerotic cardiovascular disease (ASCVD) risk show that a 1.0 mmol/L (~40 mg/dL) reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy is associated with an overall 21 % reduction in major vascular events and 20 % reduction in coronary death.2 Prescribing behaviour of statins has dramatically changed in the last 20 years, with a sixfold increase of statin use in 18–64 year olds and an eightfold increase in adults >65 years old in the US.1 Globally, in the Organisation for Economic Co-operation and Development (OECD) countries, the use of cholesterol-lowering medications including statins has tripled since 2000.3 The recent release of the 2013 ACC/AHA cholesterol guidelines provided a dramatic shift in the treatment approach of cholesterol from the previous Adult Treatment Panel III (ATP III) guidelines, with a focus on fixed dose moderate/high intensity statin treatment.4 According to the new guidelines, the number of eligible individuals for statin treatment is estimated to increase. In comparison, the 2011 ESC/EAS guidelines for cholesterol management risk stratify patients into four risk groups: very high, high, moderate or low risk based on the Systematic Coronary Risk Evaluation (SCORE) risk chart and target specific LDL-C goals.5 The various guidelines and increasing use of statins presents a challenge for providers and a need for practical considerations for use.5,6 It still remains unclear how the ACC/AHA guidelines will affect practice in Europe.

Considerations for Specific Disease States Primary Prevention Current evidence supports the use of statins in individuals without vascular disease at higher ASCVD risk for the primary prevention of future cardiovascular events.7–9 In the most recent meta-analysis which

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included ~60,000 individuals by Taylor et al., authors concluded statin therapy is associated with a 14 % reduction in all-cause mortality and a 35 % reduction in combined fatal and non-fatal cardiovascular disease, coronary heart disease and stroke.8 The 2013 ACC/AHA cholesterol guidelines recommend use of high-intensity or moderate-intensity statins (see Table 1) in individuals with 10 year ASCVD risk of 7.5 % or greater using the pooled cohort equation (PCE). In individuals with a PCE score of 5–7.5 % consideration should be given to treatment with moderate dose statin based on the presence of other risk factors such as family history, LDL-C level, inflammatory markers, coronary calcium score, ankle-brachial index and lifetime risk.6 Decision to choose between high-intensity and moderate-intensity statin can be taken by the individual provider, weighing the risk/benefit ratio of statin side effects. Elderly patients and those with a history of myalgia or risk factors for statin intolerance should be started on moderate-intensity statins.10–13 However, patients with LDL>190 should be on high intensity statins.6 ESC/EAS guidelines recommend treatment with statin for patients in the high-risk group and targeting goal LDL-C levels <70 mg/dL (2.5 mmol/L) for high-risk groups based on SCORE chart or those with LDL-C levels >190 mg/dL (4.9 mmol/L).5

Atherosclerotic Cardiovascular Disease The 2013 ACC/AHA guidelines recommend use of high-intensity statins in individuals with known ASCVD, specifically atorvastatin 80 mg or rosuvastatin 20–40 mg.6 In the Cholesterol Treatment Trialist (CTT) Collaboration meta-analysis including over 170,000 individuals, the authors concluded that more intensive statin therapy and lower LDL-C levels resulted in further reductions in major cardiovascular events.

High-intensity statin therapy demonstrated 15 % reduction in major cardiovascular events as compared to low intensity statins. Overall, authors found that all-cause mortality was reduced by 10 % per

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Coronary Artery Disease Prevention Table 1: Statin Therapy High Intensity Atorvastatin (40†)–80 mg

Moderate Intensity Atorvastatin 10 (20) mg

Low Intensity Simvastatin 10 mg

Rosuvastatin 20 (40) mg

Rosuvastatin (5) 10 mg

Pravastatin 10–20 mg

Simvastatin 20–40 mg

Lovastatin 20 mg

Pravastatin 40 (80) mg

Fluvastatin 20–40 mg

Lovastatin 40 mg

Pitavastatin 1 mg

Fluvastatin XL 80 mg

Fluvastatin 40 mg bid

Pitavastatin 2–4 mg

†Evidence from one randomised controlled trial (RCT) only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL. Boldface indicates statins/doses studied in RCTs. Italics indications statins that are FDA approved but not studied in RCTs. Adapted from Stone, et al., 2013.6

1.0 mmol/L reduction in LDL-C.2 In patients with ASCVD the evidence overwhelmingly supports treatment with high dose statins such as atorvastatin 80 mg or rosuvastatin 20–40 mg daily regardless of baseline LDL-C levels. The ESC/EAS guidelines approach ASCVD as high risk and recommend targeting LDL-C levels <70 mg/dL (<1.8 mmol/L) or at least a 50 % reduction in LDL-C. These guidelines also recommend combination therapy if target cannot be reached with statin only.5

Chronic Kidney Disease Currently under the new ACC/AHA 2013 cholesterol guidelines, chronic kidney disease (CKD) is not classified as a coronary heart disease (CHD) equivalent and does not factor into the risk calculator.6 This differs from ESC/EAS guidelines which place CKD patients into the high risk category.5 Studies have shown increased cardiovascular events and mortality in with patients with decreased estimated glomerular filtration rate (eGFR) and albuminuria.14,15 Independent of lipid effects, a meta-analysis, which included 6,452 CKD patients randomised to statin versus placebo, showed renoprotective effects of statins. Statin therapy was associated with significant reductions in urinary protein excretion (0.77 g/24 h) and creatinine (0.65 mg/ dl), but improvement in creatinine levels was only associated with long-term statin use (>3 years). Significant increase in eGFR was also found between 1–3 years on statin therapy, but this improvement in renal function did not persist beyond three years.16 The Study of Heart and Renal Protection (SHARP) trial directly assessed the cardiovascular benefit of statins in patients with CKD. This study randomised 9,438 adults to the combination simvastatin 20 mg/ ezetimibe 10 mg versus placebo and found a 17 % reduction in cardiovascular events in those allocated to statin/ezetimibe.17 This benefit was not completely from statins, as previous studies have demonstrated the efficacy of ezetimibe added to statins. A recent meta-analysis comparing combination therapy versus statin monotherapy included 11 studies on ezetimibe and concluded an additional 18 % reduction of LDL-C with the addition of ezetimibe.18 These findings are reflected in the new guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) group, which recommends statin/ezetimibe combination therapy for adults >50 years old with eGFR<60 ml/min/1.73 m2 who are not treated with chronic dialysis or kidney transplantation. In adults aged 18–49 with CKD, consideration should be given to statins if they also have risk factors such as known CHD, diabetes mellitus, prior ischaemic stroke or elevated cardiovascular risk score.19 Atorvastatin is recommended in CKD because of its favourable pharmacokinetics and minimal renal excretion negating need for dose adjustment. Rosuvastatin can also be used safely in patients with advanced CKD (GFR<30 ml/ min/1.73 m2), but should be started at 5 mg daily and titrated up to maximum of 10 mg daily if needed.20

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Patients on chronic dialysis have been directly studied in randomised controlled trials and appear not to benefit from statin therapy. In the 4D study, 1,255 patients with diabetes mellitus receiving maintenance haemodialysis were randomised to atorvastatin 20 mg or placebo with no difference in cardiovascular death, stroke or non-fatal myocardial infarction (MI) in the two groups after a median follow-up of four years.21 A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) randomised 2,776 patients on maintenance haemodialysis to rosuvastatin 20 mg versus placebo and again found no benefit in the statin group.22 Therefore, statins should not be initiated in patients on maintenance haemodialysis.

Diabetes Mellitus Diabetes Mellitus (DM) is associated with increased risk of cardiovascular diseases23,24 and early onset is considered a CHD risk equivalent.25 Current guidelines recommend treatment with at least moderate intensity statin for all adults >40 years old and high intensity statin for those with a 10 year risk score >7.5 %.6 ESC/EAS guidelines recommend statins for patients with diabetes only when they develop evidence of end organ damage.5

Dosing, Low-density Lipoprotein levels and Statin Intolerance LDL-C targets have been abandoned in the ACC/AHA guidelines and instead using fixed doses of high and moderate intensity statins are recommended. The intensity of the statin dose is matched to the person’s baseline ASCVD risk. Although these guidelines make no recommendations for or against targeting specific LDL levels, they do suggest follow up assessment of the lipid panel to assess compliance.6,26 In contrast, the ESC/EAS guidelines approach cholesterol management with targeted LDL-C levels for specific disease states and have no specific statin intensity recommendations.5

Statin-associated Myalgias Statin intolerance or the inability to continue statins due to adverse symptoms or abnormal lab values occurs in roughly 5–10 % of patients who use statins. There are only a limited number of studies on statin intolerance creating a diagnostic and therapeutic challenge to prescribers.27 Observational studies like the Prediction of Muscular Risk in Observational conditions (PRIMO) survey, which included 7,924 patients on high dose statins in the outpatient setting found 10.5 % of patients developed muscular symptoms, with the average onset of symptoms being ~1 month after initiation of the statin.28 However, the incidence of reported statin intolerance is greatly variable and thus far randomised clinical trials of statins versus placebo have not shown major differences in symptoms.29,30 Most statin intolerance

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Table 2: Risk Factors for Statin Intolerance Patient Characteristics Advanced age (>80 years)

Co-morbidities Hypothyroidism

Genetics Polymorphisms of CYPD isoenzymes

Medications Drug-drug interactions

Female sex

Chronic kidney disease

Polymorphisms in drug transporter genes

Antidepressant or antipsychotic use

Small body frame and frailty

Diabetes mellitus

Illicit drug use

Asian ancestry (for rosuvastatin)

Multisystem disease

High dose statin use

Grapefruit juice (>1 quart/day)

Alcoholism

Excessive physical activity

Major surgery

History of myopathy

Intercurrent infections

History of CK elevation

Muscle disease

Unexplained cramps Family history of myopathy Family history of statin-induced myopathy Adapted from Ahmad, 2014.27

due to muscle symptoms is related to myalgias, defined as muscle aches without creatinine kinase CK elevation, but rarely patients have developed clinically significant myopathies. Several risk factors have been identified for statin intolerance (see Table 2) and though there is no clear consensus on management of statin intolerance, several small studies have explored this issue. For patients with frank rhabdomyolsis statin therapy should be discontinued.27 For patients with muscle symptoms but normal enzymes the ACC/AHA cholesterol guidelines recommend withdrawal and rechallenge with statin. The patients should be rechallenged with statin only after all muscular symptoms have resolved, which may take >2 weeks.6,27 With regard to rechallenging, Glueck et al.31 found that 60/61 patients enrolled tolerated rosuvastatin 5 or 10 mg daily. Similarly, another study by Stein et al.32 enrolled patients who had discontinued statins in the past due to muscle-related side effects or those who were currently on statin therapy but had impaired quality of life, they found that 97 % of patients tolerated fluvastatin. In addition to switching statin therapy, there has been investigation into alternate doing strategies. A retrospective analysis by Backes et al. found that 72.5 % of the patients tolerated every other day 5–10 mg rosuvastatin.33 Kennedy et al. found that 80 % patients tolerated once weekly 5 or 10 mg of rosuvastatin.34 Simvastatin 80 mg should be avoided in general due to increased risk of myopathy and lack of incremental efficacy compared to lower doses.35 Algorithms for managing patients with statin intolerance may facilitate decision-making in the clinic (see Figure 1).36

Figure 1: Statins and Risk of Diabetes 40 % 28 %

30 %

26 %

20 % TNT

14 % 10 % 0%

0%

0% -5 %

-10 % IDEAL

-13 %

-16 %

-17 %

-20 % -30 %

-33 %

-40 % 0

1

2

Incident DM

3

4

CVE Reduction

Risk score: FBG>100 mg/dL, FTG>150 mg/dL BMI>30, HTN BMI = body mass index; CVE = cardiovascular event; DM = diabetes mellitus; FBG = fasting blood glucose; FTG = fasting triglyceride; HTN = history of hypertension; IDEAL = Incremental Decrease in Events through Aggressive Lipid Lowering; TNT = Treating to New Targets.

Adapted from Waters, et al., 2013.42

Statin-associated Hyperglycaemia Statin-associated Transaminitis Elevations of serum alanine aminotransferase or aspartate aminotransferase up to 3x the ULN transaminitis is also seen with statin users in 0.5–3 % of patients.37 In a post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population, 437 patients with baseline elevation of liver enzymes, thought to be related to fatty liver disease, were randomised to placebo versus statin therapy. The authors found an improvement of liver enzymes and 68 % risk reduction of cardiovascular events in the group treated with statin therapy.38 Similarly in a post hoc analysis of the Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) study, authors found that 1,081 patients with ALT>Upper Limit of Normal (ULN) had a significant risk reduction when treated with high intensity statin versus low intensity statin.39 The current 2013 ACC/AHA Cholesterol guidelines recommend evaluating baseline assessment of liver enzymes but no routine follow up. These observational data support the safety of statins in patient with mild elevations of liver enzymes; however, if LFTs are elevated to >3 times the ULN, with no other explanation, the statin therapy should be discontinued.6,27

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Increased incidence of diabetes is associated with statin use.

A meta-analysis by Sattar et al., which included 91,140 patients found a 9 % increase in incident diabetes with statin use, and in another meta-analysis by Preiss et al., authors were able to show an increased risk with more intensive therapy.40,41 Risk factors for developing diabetes during statin therapy are fasting blood glucose >100 mg/ dL, fasting triglycerides >150 mg/dL, BMI >30 and hypertension. In a recent study, Waters et al. assessed the incidence of diabetes and cardiovascular event reduction from patients in the Treating to New Targets (TNT) and IDEAL studies. They concluded high intensity statins increased the risk of diabetes in patients with 2–4 risk factors but there was no increased risk in patient with 0–1 risk factors. However, in both groups statin therapy was associated with substantial risk reduction with the highest benefit in the patients with the most risk factors for developing diabetes (see Figure 2).42 Analysis from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which randomised 17,603 patients without cardiovascular disease or diabetes to placebo versus rosuvastatin 20 mg demonstrated increased risk of incident diabetes

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Coronary Artery Disease Prevention Figure 2: Algorithm for Management of Statin Intolerance

Statin Intolerance

Rhabdomyolysis

Discontinue statin and identify and treat precipitating factors

Myalgia with CK elevation

Myalgia without CK elevation

Discontinue statin, identify and treat any risk factors

Discontinue statin until all symptoms have resolved

Re-challenge with statin once CK has normalised

Restart statin at same dose or lower dose

If symptoms recur, STOP treatment and restart rosuvastatin 5–10 mg or atorvastatin 20 mg every day, every other day or weekly

Transaminitis

If no other explanation for transaminitis and LFTs >3x ULN discontinue statin

If transaminitis is related to fatty liver disease, continue statin

If symptoms recur consider non-statin treatment options

CK = creatine kinase; LFT = Liver function test; ULN = upper limit of normal. Adapted from Jacobson.36

in the statin group. Ridker et al. concluded overall benefit of statins on cardiovascular events and mortality exceeded the hazard of diabetes.43 A recent meta-analysis studied the effects of two genetic variants of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target enzyme inhibited by statins, on body weight and risk of diabetes.

Authors also updated their previous meta-analysis on association of statins and diabetes. The study concluded that both genetic variants and statin treatment were associated with weight gain and diabetes.44

Conclusions Statin use is expected to increase with the adoption of the new 2013 ACC/AHA Cholesterol guidelines, bringing new challenges for

1. National Center for Health Statistics. Prescription Drug Use by Drug Class. Hyattsville, Maryland. 2014.

2. Baigent C, Blackwell L, Emberson J, et al., Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170,000 participants in 26 randomised trials, Lancet , 2010;376:1670–81.

3. Organization for Economic Co-operation and Development.

Health at a Glance 2013:OECD Indicators, 2013 4. Grundy SM, Cleeman JI, Merz CN, et al., Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines, J Am Coll Cardiol , 2004;44:720–32.

5. Reiner Z, Catapano AL, De Backer G, et al., ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Eur Heart J, 2011;32:1769–818 6. Stone NJ, Robinson JG, Lichtenstein AH, et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atheroscle-rotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol , 2014;63(25 Pt B):2889–934.

7. Taylor F, Ward K, Moore TH, et al., Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev , 2011;1:CD004816.

8. Taylor F, Huffman MD, Macedo AF, et al., Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev , 2013;1:CD004816.

9. Mihaylova B, Emberson J, Blackwell L, et al., The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet , 2012;380:581–90.

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prescribers, with a focus on fixed-dose statins independent of baseline or achieved LDL-C levels. The intensity of statin dose is matched to a person’s baseline ASCVD risk. This is in contrast to the adapted EAS/ESC guidelines in Europe, which recommend tailoring therapy to target specific LDL-C levels. Statin intolerance is not uncommon and can be challenging to manage; however, several therapeutic strategies have been successful in achieving statin tolerance.

Although statin use is associated with liver enzyme elevations and increased risk of incident diabetes, there continues to be a net benefit to statins. Individualised risk assessment and discussion of benefits and risks of statin therapy will likely lead to improved adherence and outcomes. n

10. Gotto AM Jr, Statin therapy and the elderly: SAGE advice?, Circulation , 2007;115:681–3.

11. Deedwania P, Stone PH, Bairey Merz CN, et al., Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE), Circulation , 2007;115:700–7.

12. Spector R, Snapinn SM, Statins for secondary prevention of cardiovascular disease: the right dose, Pharmacology , 2011;87:63–9.

13. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet , 1994;344:1383–9.

14. Matsushita K, van der Velde M, Astor BC, et al., Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative metaanalysis, Lancet , 2010;375:2073–81.

15. van der Velde M, Matsushita K, Coresh J, et al., Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts, Kidney Int , 2011;79:1341–52.

16. Nikolic D, Banach M, Nikfar S, et al., A meta-analysis of the role of statins on renal outcomes in patients with chronic kidney disease. Is the duration of therapy important?, Int J Cardiol , 2013;168:5437–47.

17. Sharp Collaborative Group, Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease, Am Heart J , 2010;160:785–94.

18. Monroe AK, Gudzune KA, Sharma R, et al., Combination Therapy Versus Intensification of Statin Monotherapy: An Update , Rockville

(MD): Agency for Healthcare Research and Quality (US); 2014.

19. Tonelli M, Wanner C, Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline, Ann Intern Med , 2014;160:182.

20. Harper CR, Jacobson TA, Managing dyslipidemia in chronic kidney disease, J Am Coll Cardiol , 2008;51:2375–84.

21. Wanner C, Krane V, März W, et al., Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis, N Engl J Med, 2005;353:238–48.

22. Fellström BC, Jardine AG, Schmieder RE, et al., Rosuvastatin and cardiovascular events in patients under-going hemodialysis, N Engl J Med , 2009;360:1395–407.

23. Lotufo PA, Gaziano JM, Chae CU, et al., Diabetes and allcause and coronary heart disease mortality among US male physicians, Arch Intern Med , 2001;161:242–7.

24. Noto D, Cefalù AB, Barbagallo CM, et al., Hypertension and diabetes mellitus are associated with cardiovascular events in the elderly without cardiovascular disease. Results of a 15-year follow-up in a Mediterranean population, Nutr Metab Cardiovasc Dis , 2009;19:321–6.

25. Wannamethee SG, Shaper AG, Whincup PH, et al., Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors, Arch In-tern Med , 2011;171:404–10.

26. Smith SC Jr, Grundy SM, 2013 ACC/AHA guideline recommends fixed-dose strategies instead of targeted goals to lower blood cholesterol, J Am Coll Cardiol , 2014;64:601–12.

27. Ahmad Z, Statin intolerance, Am J Cardiol , 2014;113:1765–71.

28. Bruckert E, Hayem G, Dejager S, et al., Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study, Cardiovasc Drugs

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Ther , 2005;19:403–14.

29. Guyton JR, Bays HE, Grundy SM, Jacobson TA, An assessment by the Statin Intolerance Panel: 2014 update, J Clin Lipidol , 2014;8:S72–81.

30. Collins R, Armitage J, Parish S, et al., MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial, Lancet , 2003;361:2005–16.

31. Glueck CJ, Aregawi D, Agloria M, et al., Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther, 2006;28:933–42.

32. Stein EA, Ballantyne CM, Windler E, et al., Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol , 2008;101:490–6.

33. Backes JM, Venero CV, Gibson CA, et al., Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance, Ann Pharmacother , 2008;42:341–6.

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34. Kennedy SP, Barnas GP, Schmidt MJ, et al., Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol , 2011;5:308–15.

35. Bulbulia R, Armitage J, Does the benefit from statin therapy extend beyond 5 years?, Curr Atheroscler Rep , 2013;15:297.

36. Jacobson T, Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia, Mayo Clin Proc , 2008;83:687–700.

37. Kashani A, Phillips CO, Foody JM, et al., Risks associated with statin therapy: a systematic overview of randomized clinical trials, Circulation , 2006;114:2788–97.

38. Athyros VG, Tziomalos K, Gossios TD, et al., Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis, Lancet , 2010;376:1916–22.

39. Tikkanen MJ, Fayyad R, Faergeman O, et al., Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-

moderate baseline elevations in alanine aminotransferase levels, Int J Cardiol , 2013;168:3846–52.

40. Sattar N, Preiss D, Murray HM, et al., Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials, Lancet , 2010;375:735–42.

41. Preiss D, Seshasai SR, Welsh P, et al., Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis, JAMA, 2011;305:2556–64.

42. Waters DD, Ho JE, Boekholdt SM, et al., Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes, J Am Coll Cardiol , 2013;61:148–52.

43. Ridker PM, Pradhan A, MacFadyen JG, et al., Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial, Lancet , 2012;380:565–71.

44. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al., HMGcoenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials, Lancet , 2014;pii:S0140–6736(14)61183–1.

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LE ATION.

Current Treatment of Familial Hypercholesterolaemia C a meron T La mbert, P ra t i k S a n d e s a ra , I j e o m a I s i a d i n s o, M a r i a Ca r o l i n a G o n g o ra , Da nny Ea pen, N e a l B h a t i a , J e f f e r s o n T B a e r, L a u r e n c e S p e r l i n g Department of Medicine, Emory University School of Medicine, Atlanta, GA, US

Abstract Familial hypercholesterolaemia is an autosomal-dominant disorder associated with mutations in the LDL receptor gene resulting in markedly elevated plasma low-density lipoprotein cholesterol levels. FH is significantly underrecognised with as many as 1 in 300 having the heterozygous form and 1 in 1 million having the homozygous form of the disease. Early diagnosis and treatment of FH is paramount to reduce the risk of premature atherosclerotic cardiovascular disease and death. The goal of treatment is to reduce LDL-C by 50 % from baseline levels with lifestyle modification, pharmacologic lipid-lowering therapy, LDL apheresis and in rare cases, liver transplantation.

Pharmacologic treatment ranges from statin medications to newer agents such as lomitapide, mipomersin and PCSK9 inhibitors.

Combination therapy is frequently required to achieve goal lipoprotein level reductions and prevent complications.

Keywords Statin, mipomersen, lomitapide, PCSK9 inhibitor, lipoprotein apheresis, cascade screening, lipoprotein receptor Disclosure: The authors have no conflicts of interest to disclose.

Received: 30 October 2014 Accepted: 11 November 2014 Citation: European Cardiology Review, 2014;9(2):76–81 Correspondence: Laurence Sperling, 1365 Clifton Road, NE, Building A, Suite 2200, Atlanta, GA, 30322, US. E: lsperli@emory.edu

Familial hypercholesterolaemia (FH) is an autosomal-dominant disorder associated with mutations in the LDL receptor (LDLR) gene resulting in markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD).

Heterozygous FH (HeFH) (mutation in one allele) is associated with plasma LDL-C levels >190 mg/dl, whereas homozygous FH (HoFH) (mutation in both alleles) is associated with plasma LDL-C levels >500 mg/dl.1,2 As a result, there is a 20-fold increase in risk of premature coronary heart disease (CHD) in untreated patients compared to control.3 HeFH patients usually develop CHD before age 55 and 60 respectively for men and women without treatment.4 HoFH patients, however, develop CHD very early in life and can die before age 20 without treatment.4 In general, an estimated 20 million people worldwide have FH.4 Approximately 1 in 300–500 people have HeFH and 1 in 1 million have HoFH.3 In certain populations, such as French Canadians and Dutch Afrikaners, the prevalence is as high as 1 in 100.3 Despite the high prevalence and increased risk of premature ASCVD in untreated patients, less than 1 % are diagnosed with FH worldwide.4 Family history, physical examination and a lipid profile are essential to establishing a diagnosis of FH. FH should be suspected with fasting LDL-C ≥190 mg/dl in adults and ≥160 mg/dl in children if secondary causes of hypercholesterolaemia such as hypothyroidism, nephrotic syndrome and liver disease are ruled out.2,5 The clinical diagnosis of FH can be established by five criteria: 1) the presence of early coronary artery disease (CAD) in the index case; 2) family history of premature CAD; 3) elevated LDL-C; 4) tendon xanthomas; 5) corneal arcus.2 In addition, validated clinical tools such as US Make Early Diagnosis Prevent Early Death (MEDPED), Dutch Lipid Clinic Network and SimonBroome Registry can assist in the diagnosis of FH.5

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Although genetic screening is not necessary for the diagnosis and clinical management of FH (studies report 5–20 % of FH patients are without identifiable mutation), it can augment screening strategies and help predict cardiovascular risk if a specific genetic anomaly can be identified. 5,6,7 In a large Dutch cohort of nearly 30,000 individuals, finding a pathogenic LDL receptor mutation nearly tripled the cardiovascular risk for that patient (HR 3.64, CI 3.24–4.08, P<0.001).6 Data also show improved sensitivity of a genetic diagnosis compared to one based on epidemiologic LDL distributions. In a study of over 26,000 individuals in the Netherlands, an LDL above the 90th percentile provided a 68.5 % sensitivity while an LDL receptor mutation genetic screen demonstrated a sensitivity of 91.3 %.8 Once an accurate diagnosis is made of FH, cascade screening of all firstdegree relatives is paramount.

Treatment Guidelines Early detection and treatment of FH is recommended to reduce risk of cardiovascular events. The goal of treatment is to reduce LDL-C by 50 % from baseline levels.9 This was based on two trials which showed reduction in CIMT (Carotid Intimal Medial Thickness) in patients who achieved > 50 % reduction of LDL-C on statin therapy.10,11 Lifestyle modification, lipid-lowering therapy, LDL apheresis and in rare cases, liver transplant are the cornerstones of LDL-C lowering in patients with FH. Table 1 summarises the current guidelines for the treatment of FH. It is important for the clinician to be aware of the various treatment options for FH, as combination therapy will likely be required to achieve goal reductions in LDL-C. Investigators have reported as many as 77 % of patients with an FH diagnosis and on cholesterol medication do not achieve goal LDL-C levels within two years of diagnosis.12 The most

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Current Treatment of Familial Hypercholesterolaemia

Table 1: Summary of Guidelines on the Management of Familial Hyperlipidaemia

Guidelines

Recommendation

Therapy

Additional Comments

NLA

Adults: pharmacologic therapy to reduce baseline LDL-C by > 50 % with maximum statin dose tolerated.

Children/Young Adults: Consider initiation of medical therapy in FH pts >8 years old.

Lifestyle modification.

Statin therapy should be initial drug of choice.

If unable to tolerate initial statin, consider alternate statin or alternate day dosing.

If statin contraindicated or poorly tolerated, consider addition of ezetimibe, bile acid sequestrants or niacin.

Additional options: LDL apheresis.

Adults: Reduce LDL-C by >50 %.

Higher risk patients may require more aggressive therapeutic goals (LDL<100 mg/dl).

Children: Treatment goal is >50 % reduction in LDL-C or LDL-C <130 mg/dl.

9,10

NICE11

Children/Young Adults: Cholesterol Lifestyle modification. lowering drugs should be considered in Treatment with high-intensity statin to FH patients by age 10. reduce LDL-C by 50 % should be first line Lipid lowering drugs may be considered medical therapy. before the age of 10 when there is a Ezetimibe is recommended as monotherapy family history of CHD in early adulthood. for patients intolerant of statins. Ezetimibe can be used as adjunctive therapy in heterozygous FH patients on statins with suboptimal TC or LDL-C or when the statin dose cannot be further titrated due to side effects.

Additional options: LDL apheresis.

Adult FH patients at very high risk of coronary heart disease, or with intolerance or contraindication to statins or ezetimibe, should be referred to a FH specialist.

Children and adolescents diagnosed with, or undergoing evaluation for, FH should be referred to a specialist in FH. No published studies to establish target LDL-C target levels in children with FH on lipid lowering therapy.

EAS4,12

Target LDL-C: Children: <135 mg/dl Adults: <100 mg/dl Adults with CHD or Diabetes: <70 mg/dl

Lifestyle modification.

Lipid lowering therapy should be started between ages 8 and 10.

- no safety data on the use of statins before age 8–10.

Ezetimibe should be added as a second line agent if LDL is still above target.

Bile acid resins are third-line agents.

Children: statins, ezetimibe, bile acid resins and LDL apheresis in homozygous FH.4 Adults: maximal potency statins, ezetimibe, bile acid resins, fibrates (specifically fenofibrate), LDL apheresis in homozygous FH and treatment resistant heterozygous FH.4

ACC/AHA13

Recommendation to treat to a target LDL-C level was abandoned due to lack of randomised controlled trials demonstrating that treatment to a specific LDL level improved CVD outcomes.

No specific recommendations for FH patients, but recent guidelines addresses patients with LDL-C >190

Lifestyle modification.

High intensity statin is recommended Addition of nonstatin drugs may be considered.

A reasonable approach would be to reduce LDL-C by > 50 percent.

High potency statins include atorvastatin 40 to 80 mg and rosuvastatin 20 to 40 mg.

NLA = National Lipid Association; NICE = National Institute for Health and Care Excellence; EAS = European Atherosclerosis Society; ACC/AHA = American College of Cardiology/American Heart Association; TC = Total cholesterol.

common reason cited (32 %) for inadequate control of the patients’ cholesterol levels was “acceptance” of a suboptimal LDL-C level by a treating physician.13 Other causes of inadequate control include improper dosing of medications and late age of diagnosis.14

Lifestyle Modifications Lifestyle modification is the foundation in the treatment of FH. Primordial prevention which includes counselling for smoking, avoidance of diabetes and regular physical activity is an integral component for treatment in this population.1 Dietary recommendations from the National Lipid Association and International FH Foundation include are outlined in Table 2.15 These groups’ recommendations also emphasise limiting alcohol intake (one drink daily for women, 1-2 drinks daily for men) and tobacco cessation.16 Referral to appropriately

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qualified nutritionists and dieticians is also recommended.2 Daily physical activity is encouraged, and achieving an optimal weight for overweight patients should be stressed. For every 10 kg of weight lost, there is an 8 mg/dl reduction of LDL-C.17,18 While lifestyle modification is the first step in the treatment of FH patients, this strategy alone will be insufficient as the sole treatment to achieve LDL-C goal. Lifestyle modification will at most reduce LDL-C concentration by 10–15 %19 and most patients will require further pharmacological therapy.

Pharmacologic Treatment Patients with LDL >190 mg/dl are identified within the new ACC/ AHA 2013 Blood Cholesterol Guidelines as requiring pharmacologic intervention.20 The required treatment regimen and the individual’s response to this treatment varies according to the genetic and

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Coronary Artery Disease Prevention Table 2: Dietary Recommendations in the Treatment of Hyperlipidaemia Dietary Recommendations • Total fat intake <25–35 % of total caloric intake • Saturated fat <7 % of total caloric intake • Cholesterol <200 mg/day • Increase intake of monounsaturated and polyunsaturated fats and fibre • Plant sterols and stanols (2 grams of plant sterols daily) may be considered

Bile acid sequestrants, specifically colesevelam (the newest in its class), have been shown to reduce LDL-C levels alone and more significantly when used in combination with ezetimibe and statins.

The combination of these drugs was proven to be safe and well tolerated.31–33 In FH, bile acid sequestrants are considered second line therapy after treatment with statins and ezetimibe.34

Niacin

Statins are first line pharmacologic therapy agents in the treatment

In patients with FH, niacin is considered an alternative agent for patients after treatment with statins, ezetimibe and bile acid sequestrants.

It can be used to further intensify therapy or as replacement when statins are not tolerated.3,35 Its beneficial effects on the lipid profile include increasing HDL-C by 15-30 %, lowering triglycerides up to 35 % and lowering LDL-C about 20 percent.36 Despite these favourable effects, two recent studies showed lack of clinical significance in terms of cardiovascular outcomes. It should be noted however that these two studies were not designed specifically to address the benefit of niacin as adjunct therapy for patients with FH. The recent Atherosclerosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact of Global Health Outcomes (AIM-HIGH) study showed that despite a significant increase in HDL, niacin did not reduce cardiovascular events compared to placebo when added to simvastatin.37 Similar results were demonstrated in the Treatment of HDL to Reduce the Incidence of Vascular Events

of FH; they reduce cardiovascular mortality even in receptor-negative patients.22 Current guidelines recommend maximal statin therapy to reduce LDL-C levels by at least 50 % from baseline.20,23–25 Therapy should be started with a high potency statin at the greatest tolerated dose.

Plasma levels of hepatic transaminases, creatine kinase (CK), glucose and creatinine should be measured before starting drug therapy.

(HPS2-THRIVE) trial in which more than 20,000 patients with known vascular disease were randomised to placebo or niacin in addition to statin or statin/ezetimibe therapy. The trial was stopped prematurely since niacin did not further reduce the risk of the composite endpoint and was found to increase the incidence of nonfatal serious side effects.38

Despite aggressive statin therapy, in the majority of patients with FH, even the highest doses of the most potent statins do not yield more than a 50 % LDL-C reduction. In these patients a combination of lipidmodifying agents enhances efficacy.3,21,22,26–28 Most often, the cholesterol absorption inhibitor Ezetimibe is chosen as second line therapy.3

Newly FDA Approved Agents, Mipomersen and Lomitapide

phenotypic heterogeneity of FH, with autosomal recessive hypercholesterolaemia responding more robustly to treatment.1

Statins Statins inhibit hydroxyl-methylglutaryl coenzyme A reductase (HMGCoAR), a key enzyme in the synthesis of cholesterol in the liver, ultimately decreasing LDL production. Statins also lead to up-regulation of LDL receptors; however this effect is limited due to enhanced compensatory degradation of such receptors. In patients with HoFH, the effectiveness of statins is attenuated given its mechanism of action involves up-regulation of liver LDL receptors. This is the case also for ezetimibe and bile acid sequestrants.21

Cholesterol Absorption Inhibitors Ezetimibe is a selective cholesterol absorption inhibitor that blocks the absorption of dietary cholesterol and delivery of intestinal cholesterol to the liver resulting in up-regulation of hepatic LDL receptors and enhanced clearance of LDL particles from the circulation. Statins and ezetimibe taken together potentiate the LDL reduction. This reduction in LDL-C has been documented between 10–40 percent. The variable response is likely due to differences in the amount of residual functional LDL receptor activity, with those patients with no receptor activity (receptor negative) having limited response to drugs that work through mechanisms involving LDL receptor up-regulation. In one report, ezetimibe added an extra 15 % reduction in LDL levels when added to rosuvastatin 40 mg.29 Despite the added effect of ezetimibe, many patients require further LDL lowering therapy, including bile acid sequestrants, to achieve therapeutic goals.

Bile Acid Sequestrants Bile acid sequestrants bind cholesterol in the gut thereby enhancing cholesterol excretion and reducing the enterohepatic circulation of bile acids and biliary cholesterol. The reduction in bile acids leads to a compensatory increase in conversion of cholesterol to bile acids, up-regulating expression of hepatic LDL receptors and consequently increasing hepatic removal of LDL particles from the circulation.30

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In the last year, two new drugs have been approved by the US Food and Drug Administration (FDA) as adjunct therapy for FH: mipomersen (an apolipoprotein-B [apoB] synthesis inhibitor) (Kynamro–Genzyme) and lomitapide (a microsomal transfer protein inhibitor) (Juxtapid– Aegerion).39 These agents interfere with the production and secretion of apoB-containing lipoproteins respectively, independent of the LDL receptor. These agents are used after statins, cholesterol absorption inhibitors and bile acid sequestrants have been considered.

Mipomersen Mipomersen is an antisense molecule targeting the messenger ribonucleic acid (mRNA) that encodes apoB-100 produced by the liver.

ApoB-100 is the main structural protein of LDL, and its precursor, VLDL. Mipomersen has been tested in four populations: 1) HoFH, 2) HeFH with coronary artery disease, 3) Patients with severe hypercholesterolaemia and 4) Patients at high risk for CAD with hypercholesterolaemia.40–43 All trials were phase 3, randomised, double blind, placebo-controlled and multicentre studies. Mipomersen demonstrated statistically significant reductions in LDL and apoB as a single drug or in combination with statins and other agents.40–45 It is administered weekly by subcutaneous injection with rapid absorption and distribution to tissues. The most common adverse effects observed in clinical studies were erythema or pain at the injection site, which were self-limited, flu-like symptoms and transient elevations in CRP at the beginning of the injections, with no other inflammatory marker elevations. Elevations in hepatic transaminases were less common, largely reversible with no other liver function tests abnormalities or clinical implications. Increase in liver

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fat was also observed, however it stabilised after a year of treatment.

In combination with statin, mipomersen showed a LDL reduction of approximately 25 percent.40,46

Lomitapide Lomitapide binds and inhibits the microsomal triglyceride transfer protein (MTTP). MTTP is critical in the synthesis of cholesterol particles, transferring triglycerides onto apo B in the hepatocyte to form VLDL and in the enterocyte to form chylomicrons.47 Lomitapide is given orally in doses of 5–50 mg daily and is rapidly absorbed with a significant first pass effect in the liver. It is metabolised by CYP3A4 and therefore has the potential for drug interactions with commonly prescribed medications. Ketoconazole can significantly increase levels of lomitapide while simvastatin and warfarin are both increased in concentration when coadministered with lomitapide.48 Gastrointestinal intolerance is the most common adverse effect with patients reporting diarrhoea, nausea and flatulence. These side effects can be ameliorated by slow dose uptitration and adherence to a low fat diet. Vitamin E deficiency is a potential adverse effect. Given patients with FH have higher baseline levels of vitamin E, treatment with lomitapide often results in a normal vitamin level.46 Similar to mipomersen, lomitapide can asymptomatically increase serum transaminases in some patients with no changes in bilirubin and alkaline phosphatase. Transaminase elevations appear to be reversible and transient. Mild increases in liver fat content have been observed and could potentially be counteracted by following a low fat diet.49 The long-term consequences of this induced hepatosteatosis remain unclear and will require future investigation.

Mipomersen and lomitapide were approved with an enclosed warning describing the risk of hepatotoxicity. Due to the overall risk profile, these medications are available only through the restricted Kynamro/ Juxtapid Risk Evaluation and Mitigation Strategy (REMS) Program.

Only certified health care providers can prescribe the medicines and only certified pharmacies may dispense them. Risks considered, mipomersen and lomitapide should be considered as adjunctive therapy to diet and cholesterol-lowering drugs in adults with homozygous FH to further reduce plasma LDL cholesterol, particularly if lipoprotein apheresis (LA) is not available.50

PCSK9 Inhibitors Several new medical therapies are being evaluated in clinical trials for the treatment of FH. The most promising of which are the PCSK9 inhibitors, a completely novel class of medications. PCSK9 is a serine protease that is involved with the degradation of LDL receptors leading to higher circulating plasma LDL-C levels. PCSK9 inhibitors are injectable monoclonal antibodies that bind to PCSK9, thereby decreasing the turnover of LDL receptors, which in turn leads to a decrease in circulating LDL-C levels. Two of the most promising medications in this novel class are evolocumab and alirocumab. Both of these medications have undergone extensive phase II trials and are in the process of completing phases III trials. The DESCARTES phase III trial recently presented 52-week follow up data that compared evolocumab and placebo in patients already treated with standard lipid lowering therapies.51 The investigators’ data show a 57 % reduction in LDL-C in the evolocumab group compared to placebo.

Further supporting this class of medications is the ODYSSEY trial, which randomised heterozygous FH patients on standard lipid-

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lowering therapy to receive alirocumab or placebo.52 The results of this trial showed that alirocumab decreased LDL-C by 49 % from baseline while the placebo group had a 9 % increase in LDL-C. Impressively, in this traditionally very difficult to treat FH population, the percentage of patients reaching goal LDL-C was 70–80 %. Moreover, the post hoc analysis of a separate ODYSSEY Long Term trial was notable for a 54 % reduction in major adverse cardiovascular events in the alirocumab group versus placebo.53 This result was statistically significant.

There are several other medications being evaluated for the treatment of FH but none seem to be as promising as the PCSK9 inhibitors. The MODE trial is a phase II examination of recombinant ApoA1 milano infusions in homozygous FH patients.54 Finally, anacetrapib, a CETP-inhibitor is being studied in homozygous FH patients in a phase III trial.54

Lipoprotein Apheresis When lifestyle modifications prove inadequate and pharmaceutical interventions are either not tolerated or lack adequate response, lipoprotein apheresis (LA) can be used to remove circulating LDL along with other atherogenic particles. All apheresis processes require the removal of blood from a vein (typically the antecubital) and typically involve the separation of that blood into cellular and plasma components. LA sessions typically last three hours and are performed on average every two weeks for HeFH patients and 7–10 days.

Hyperlipidaemia HoFH patients.55 Once the blood is removed, several strategies can be employed to remove atherogenic compounds from the plasma including immunoadsorption, plasmapheresis, direct adsorption, dextran sulfate adsorption, and heparin extracorporeal LDL apheresis. Plasmapheresis was one of the original methods used to remove LDL from serum.

During this process, plasma is separated from the cellular components of the blood and is removed from the body and replaced by albumin infusions. This process was non-selective and removed helpful plasma protein including HDL and immunoglobulins. Immunoadsorption is more selective for the atherogenic particles. In immunoadsorption, the plasma is passed over membranes coated with polyclonal sheep antibodies against apolipoprotein B100 and apolipoprotein B containing lipoproteins thereby removing LDL, VLDL and lipoprotein(a).

Not requiring separation of the plasma and cells, direct lipoprotein adsorption employs polyacrylamide beads within a filter. These beads contain pores of a particular diameter that allows only certain particles to enter and thus be removed from the patient’s serum. Based on the width of the pore, the filters can be more or less selective which is typically determined by disease severity. Typically, these columns can remove LDL, lipoprotein(a) and triglycerides but can also remove fibrinogen in the more non-selective columns.

Dextran sulfate adsorption (DSA) involves separated plasma being passed over two cellulose-bead columns, which contain dextran sulfate. This interaction leads to electrostatic binding of (apolipoproteinB)-containing particles and their removal from circulation. This process, similar to the above-mentioned immunoadsorption, is specific to apolipoprotein-B and does not remove HDL or albumin from circulation. DSA is the most efficient method to remove atherogenic particles from circulation given the quantity of plasma it can filter in a given session. Patients receiving DSA must be anticoagulated with heparin during the session, making heparin hypersensitivity a contraindication to DSA.

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Coronary Artery Disease Prevention The last filtration process, heparin extracorporeal LDL apheresis (HELP), involves the heparinisation and acidification of the patient’s plasma, causing heparin to carry a negative charge and LDL to carry a positive charge. These opposite charges lead to heparin-LDL complex formation, precipitation and eventual filtration. Via this method 60–64 % of LDL, 65–75 % of VLDL and 60-70 % of lipoprotein(a) is removed.55–57 Given the relatively low numbers of patients receiving LA, few randomised clinical trials have been performed to examine its effectiveness.56 The Familial Hypercholesterolaemia Regression Study examined 39 patients randomised to LA and simvastatin or simvastatin and colestipol and found biweekly LA and simvastatin decreased LDL cholesterol levels by 31 % more than the medication only group.58 Similarly, the LDLApheresis Atherosclerosis Regression Study (LAARS) found reductions in the LDL levels of their 42 study subjects randomised to LA.59 Neither study showed a significant difference in coronary atherosclerosis as determined by coronary angiography.55,58,59 Other randomised studies have shown reductions in circulating inflammatory biomarkers such as CRP and lipoprotein-associated phospholipase A2.60,61

complications, immediate organ rejection, and complications from immunosuppressant therapy.62,63,65 Patients who are considered for OLT usually have severe coronary artery disease and valvular insufficiency, which requires simultaneous heart and liver transplant, further increasing postoperative risks and complications. Recent literature supports transplantation in a younger population before the onset of significant coronary artery disease to preclude the need for cardiac transplantation.66–67 Patients with homozygous FH who fail medical therapy and apheresis should be considered candidates for OLT.

Special Populations While statins are the most effective therapy for those with FH, the use of statins is contraindicated during pregnancy. Animal studies have demonstrated conflicting evidence on the teratogenicity of statins during pregnancy.69 There have been studies that have found the lipophilic class of statins (lovastatin, cerivastatin, and fluvastatin) to be associated with skeletal malformations. Atorvastatin and lovastatin have also been associated with developmental toxicity and skeletal defects, but only at supratherapeutic doses that also caused maternal toxicity.69

Given its association with improved LDL control, LA is approved in the United States for HoFH patients with LDL ≥ 500 mg/dL or HeFH patients with LDL ≥ 300 mg/dL or ≥ 200 mg/dL with documented coronary artery disease.55

There is limited data on the teratogenicity of other lipid-lowering agents in humans. Ezetimibe, nicotinic acid, and fibrates have all been associated with teratogenic effects in animal studies.69 Therefore, the only medications currently acceptable to use during pregnancy are

Liver Transplantation

the bile acid binding resins, cholestyramine and colsevelam, as these medications do not pass into the systemic circulation and have not been shown to have any adverse effects thus far.70,71

Orthotopic Liver transplantation (OLT) remains the only curative option for patients with homozygous FH that cannot achieve optimal LDL levels after pharmacological treatment and for those unable to tolerate lipid apheresis.19,50 Liver transplantation replaces dysfunctional hepatic LDL in receptors patients, allowing near normalisation of lipoprotein metabolism.62 While lipid apheresis can reduce or maintain LDL levels at acceptable ranges, it does not prevent development of atherosclerosis.63 The first liver and heart transplant64 for homozygous FH occurred in 1984 in a six-year-old female with severe coronary artery disease. The patient showed significantly improved and sustained lower LDL levels postoperatively, but ultimately died due to cardiac allograft rejection. Since then, over 30 cases with patients ranging from 2–46 years of age have been reported.64–67 The long-term outcomes of OLT are unknown due to paucity of donors, high-risk postsurgical outcomes, and the concern for life-long immunosuppressive therapy. However, a recent update has shown the five-year survival rates after OLT in paediatric patients approaches 90 % in the United States.68 Case reports have shown patients free of coronary artery disease 20 years after transplant, while others have had post-operative

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3. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5:S1–8.

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Conclusion The treatment of FH has evolved considerably with the availability of novel potent LDL-C reducing agents such as lomitapide and mipomersen in addition to plasma lipoprotein apheresis. FH continues to be “hidden in plain sight” with a significant number of children and adults that remain undiagnosed. Initiatives such as the FH foundation and FH registry (http://thefhfoundation.org/) provide a great opportunity to raise awareness and increase the number of patients that are diagnosed and treated with FH. n

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66. Maiorana A, Nobili V, Calandra S, et al. Preemptive liver transplantation in a child with familial hypercholesterolemia.

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67. Malatack JJ. Liver transplantation as treatment for familial homozygous hypercholesterolemia: Too early or too late.

Pediatr Transplant 2011;15:123–25.

68. Kamath BM, Olthoff KM. Liver Transplantation in Children: Update 2010. Pediatr Clin of North Am 2010;57:401–14.

69. Kusters DM, Homsma SJ, Hutten BA, et al. Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy. Neth J Med 2010;68:299–303.

70. Avis HJ, Hutten, Twickler MT, et al. Pregnancy in women suffering from familial hypercholesterolemia: a harmful for both mother and newborn? Curr Opin Lipodol 2009;20:484–90.

71. Eapen DJ, Valiani K, Reddy S, Sperling L. Management of familial hypercholesterolemia during pregnancy: Case series and discussion. J Clin Lipidol 2012;6:88–91.

72. Thorogood M, Seed M, De Mott K. Guideline Development Group, Management of fertility in women with familial hypercholerstolemia: summary of NICE guidance. BJOG 2009;116:478–79.

73. Glueck CJ, Christopher C, Tsang RC, Mellies MJ. Cholesterolfree diet and the physiologic hyperlipidemia of pregnancy in familial hypercholesterolemia. Metabolism 1980;29:949–55.

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LE ATION.

The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification Ve l i s l a v N B a t c h v a r o v Cardiovascular and Cell Sciences Research Institute, St George’s University of London, London, UK

Abstract The Brugada syndrome (BrS) is a hereditary arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals without overt structural heart disease. Currently, its diagnosis is mainly based on the presence of a spontaneous or Na+-channel blocker induced so-called “type 1” Brugada electrocardiographic (ECG) pattern typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal spaces. Presently the main unresolved clinical problem in the BrS is the identification of patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD). Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern and either history of aborted cardiac arrest or documented sustained ventricular tachycardia (class I) or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmias. However, the majority of BrS patients are asymptomatic when diagnosed and have generally low risk (0.5 % annually or lower) and therefore are not indicated for ICD. Most of SCD victims in the BrS have had no symptoms prior to the fatal event and therefore were not protected with an ICD. Currently there are no reliable methods to identify these potential victims of SCD. Although some ECG markers such as QRS fragmentation and infero-lateral early repolarisation have been demonstrated to signify increased arrhythmic risk their value still needs to be confirmed in large prospective studies. Novel risk assessment strategies need to be developed based on computerised quantitative ECG analysis of large digital ECG databases in patients with BrS and their relatives, and combined assessment of the most important factors of ventricular arrhythmogenesis.

Keywords Brugada syndrome, electrocardiogram, sudden cardiac death, risk stratification, heredtary arrhythmic syndromes Disclosure: The author has no conflicts of interest to declare.

Received: 10 November 2014 Accepted: 24 November 2014 Citation: European Cardiology Review, 2014;9(2):82–7 Correspondence: Velislav N Batchvarov, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE E: vbatchva@sgul.ac.uk

Introduction The Brugada syndrome (BrS) is a hereditary arrhythmia syndrome manifesting as recurrent syncope or sudden cardiac death (SCD) due to polymorphic ventricular (VT) or fibrillation (VF) in the absence of overt structural heart disease or myocardial ischaemia.1,2 The prevalence of the syndrome is estimated at around 15 per 10,000 in South East Asia including Japan and around 2 per 10,000 in the Western countries.3,4 The BrS may be responsible for up to 4 % of all sudden cardiac deaths (SCD) and at least 20 % of SCDs in patients with structurally normal hearts.5 It is 8–10 times more prevalent in males than in females6 and males are at considerably higher risk of dying suddenly.7 In South-East Asia, the BrS is the leading cause of non-traumatic death in men younger than 40 years.8 This review will briefly summarise current knowledge about the BrS with emphasis on the methods for diagnosis and risk assessment.

Cellular Mechanisms of the BrS BrS is considered a heritable autosomal dominant disease9 and more than 390 mutations have been identified in the SCN5A gene encoding the α-subunit of the cardiac INa-channel.10 However, presently SCN5A mutations are found only in 11–37 % of the genotyped patients.7,11 Recent data has suggested that heritability may be related to common genetic variation instead of being strictly monogenic.12

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Many patients with the BrS have no family history presumably due to under-diagnosis in the other family members, low penetrance or sporadic disease.13 The cellular basis of the BrS is still not fully understood.14 According to the “repolarisation theory”, reduction of the inward Na+ current leads to unopposed transient outward (Ito) current in some epicardial regions of the right ventricular outflow tract (RVOT), which causes either delayed expression of the action potential (AP) dome and epicardial AP prolongation or loss of the dome and AP shortening. The net effect is a potentially arrhythmogenic magnification of repolarisation dispersion between the RVOT endo- and epicardium, and between different RVOT epicardial regions. The repolarisation theory was initially promoted on the basis of experimental studies15,16,17 and was later supported by clinical data such as “spike and dome” configuration with deep notching of monophasic action potentials (MAP) from the RVOT epicardium but not endocardium,18 paradoxical shortening of the RVOT epicardial activation-recovery intervals (ARI) during augmentation of Brugada-type ST segment elevation,19 steep AP duration restitution (slope >1) in the RVOT20,21,22 (both clinically and experimentally), longer ARI in the RVOT epicardium recorded from the conus branch of the right coronary artery than in the endocardium of patients with BrS and type 1 ECG pattern but not in controls23 and others.

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There is also mounting evidence from experimental,22 histopathological,24 computational,25 clinical electrophysiological23,25 and imaging26 studies for the presence of conduction abnormalities in the RVOT and their importance for the genesis of ventricular arrhythmias in BrS22,23 (“depolarisation theory”). Delay of the RVOT activation relative to the rest of the RV has also been proposed as a mechanism of the Brugada type ECG changes on the surface ECG.27 The presence of late potentials and prolonged filtered QRS duration on signal-averaged ECG (SAECG) as well as increased notching and fragmentation of the QRS on the standard ECG are linked to increased arrhythmic risk in BrS.28,29,30,31 The reported cases of patients presenting with both arrhythmogenic right ventricular cardiomyopathy (ARVC) and BrS with SCN5A mutations,32 further attest to the likely role of conduction abnormalities in the BrS. A third hypothesis unifying the above two explains the BrS with abnormal expression of the neural crest cells during the embryological development of the RVOT. This defect in the embryogenesis of the RVOT leads to both abnormally augmented electrical gradients during repolarisation as well as to delayed activation of the RVOT.33

Figure 1: Brugada Type ECG Patterns

Brugada Type 1 (A), Type 2 (B) and Type 3 (C) ECG Pattern On this figure and all subsequent figures, the ECGs are presented at 25 mm/s, 1 cm/mV. See the text for details.

Figure 2: Diagnostic Value of Higher Intercostal Positions

From electrocardiographic point of view, the characteristic elevation of the J point and ST segment of the type 1 Brugada ECG pattern (see below) results from early relative (intracellular) positivity of the unaffected zone (RVOT endocardium according to the “repolarisation theory” or normally activated myocardium outside the RVOT according to the “depolarisation theory”), whereas the negative T wave is an expression of late epicardial relative (intracellular) positivity in the affected RVOT zone due to either prolongation of the epicardial APs or its delayed activation.

Clinical Manifestations of the BrS The symptoms associated with the BrS are due to re-entry ventricular arrhythmias typically arising in the affected zone of the RV. If they last briefly (seconds) and terminate spontaneously they can be asymptomatic or cause palpitations; longer arrhythmias lead to syncope or nocturnal agonal respiration, or can degenerate into VF and cardiac arrest. The duration of the arrhythmia is unpredictable with currently available methods and every arrhythmic episode can be fatal. Therefore, the assessment of the degree of arrhythmic risk and the need for prophylactic treatment is by far the most important aspect of the management of these patients.

The Electrocardiogram – a Key to the Diagnosis of the Brugada Syndrome The standard 12-lead ECG (with some additional modifications, as explained below) is crucial for the diagnosis and likely also for determining the prognosis (i.e. the level of arrhythmic risk) in the BrS. The diagnostic hallmark of syndrome is the so-called “coved” or “type 1 Brugada ECG pattern” characterised by J-point elevation with slowly descending or concave ST segment elevation merging into a negative or reaching the isoelectric line symmetric T wave7,34 (see Figure 1A). The type 1 Brugada ECG pattern is observed most frequently in leads V1 and V2, much less frequently in lead V3.35 When type 1 Brugada ECG pattern is observed in lead V3 it is always accompanied by the same ECG pattern in at least one more right precordial lead (unpublished observations).

In patients investigated for the BrS, leads V1 and V2 should always be recorded both from the 4th intercostal (i.c.) space as well as from the 3rd and 2nd i.c. space, because the “high” positions increase the

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Recording Leads V1 to V3 from One or Two Intercostal (i.c.) spaces higher than their standard positions (i.e. 3rd or 2nd i.c. space for leads V1 and V2) increases their sensitivity for detecting the diagnostic type 1 Brugada ECG pattern. Note the transition of the ECG complexes in lead V3 from a normal morphology (in the standard position) to type 2 (one i.c. space higher) and type 1 Brugada ECG pattern (two i.c. spaces higher). V1-III, V2-III, V1-II, V2-II = leads V1 and V2 from the 3rd and 2nd i.c. spaces, respectively; V3-III, V3-II = lead V3 recorded one and two spaces higher, respectively. ECG = electrocardiogram.

sensitivity of leads V1 and V2 for detecting type 1 pattern without loss of specificity36 (see Figure 2). This has been noted already in 1960,37 long before the discovery of the Brugada syndrome. Since the exact anatomic relation between RV and the thoracic cage is individually specific and any of the three i.c. spaces could be closest to the RVOT, it is best to record simultaneously leads V1 and V2 in the 4th, 3rd and 2nd i.c. space. One small study with cardiovascular magnetic resonance imaging found that the maximum RVOT area was most frequently in the 3rd followed by the 4th and 2nd i.c. space.38 In our experience, when type 1 Brugada pattern is observed in the 4th i.c. space it is always also observed in the 3rd or 2nd i.c. space whereas the converse is not the case (unpublished observations). Positioning lead V3 one or two i.c. spaces higher also increases its sensitivity to detect type 1 pattern (unpublished data) (see Figure 2). Bipolar precordial leads between the V2 electrode (positive pole) and V4 or V5 electrodes (negative pole) which can be computed from the standard unipolar leads V2, V4 and V5 seem to be more sensitive and equally specific compared to the unipolar lead V2 for detecting the diagnostic type 1 Brugada ECG pattern.39 Type 1 Brugada ECG pattern sometimes also can be observed in the inferior40,41,42,43 or lateral44,45 leads (the so-called “atypical” BrS).

Another ECG pattern of J point and ST segment elevation with a positive T wave in the right precordial leads, the so-called “saddleback” pattern, is considered suspicious but not diagnostic of BrS, unless converted into type 1 pattern following administration of Na+

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Risk Assessment and Management channel blocking agents. Traditionally the “saddle back” patterns are further divided into “type 2” and “type 3” Brugada ECG pattern depending on the level of J point and ST segment elevation2 (see Figure 1B,C). A recently published expert Consensus Report on the ECG characteristics of the BrS proposed “type 2” and “type 3” patterns to be unified into one “saddle-back” Brugada pattern because, according to the authors’ opinion, the small morphological differences between the two patterns had no diagnostic or prognostic significance.34 In the latest HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes published in December 2013,7 however, type 2 and type 3 Brugada ECG patterns are still mentioned separately.

Up to 40 % of patients with the BrS present with normal or nondiagnostic resting ECG.46 In these patients, the diagnostic “coved” ECG pattern can be elicited by i.v. administration of sodium channel blocker (ajmaline, procainamide, flecainide).47,48 Currently the BrS is definitely diagnosed when type 1 pattern is observed in at least one of leads V1 and V2 recorded from the 4th, 3rd or 2nd i.c. space either spontaneously or following administration of Na+channel.7 The presence of gene mutations is not considered essential for the diagnosis.2,7

as a first line treatment of such episodes.60 Patients with BrS have increased incidence (10–53 %) of atrial fibrillation (AF).61,62 Additional ECG findings which support the diagnosis of the BrS in asymptomatic patients with spontaneous or induced by Na-channel blockers type 1 pattern include the presence of atrial fibrillation, atrio-ventricular or intraventricular conduction abnormalities (first degree A-V block, fragmented and/or prolonged QRS, abnormal signal-averaged ECG (SAECG), left axis deviation of the QRS complex, prolonged HV interval), ventricular ectopic beats with left bundle branch block (LBBB) morphology and short (<200 ms) ventricular effective refractory period.7

Assessment of the Arrhythmic Risk – the Most Important Clinical Problem in the Brugada Syndrome The identification of BrS patients with high arrhythmic risk especially among those without previous history of arrhythmia-related symptoms is currently the most important and yet unresolved clinical problem in the BrS. In some aspects, this problem is similar to one of the main (also still not fully resolved) problems of modern cardiology – the identification of patients with ischaemic heart disease (IHD) at high risk of dying suddenly who need prophylactic implantable cardioverter-defibrillator (ICD).

It is important to distinguish between type 2 Brugada ECG pattern and the r’or R’-pattern (incomplete right bundle branch block (iRBBB) pattern) in leads V1 and V2 (especially when recorded from the 3rd or 2nd i.c. space) which can be observed in healthy subjects (frequently in athletes49). It has been reported that a broader angle between the ascending and descending limb of the r’/R’-wave50 or a broader base of the triangle formed by the two limbs of the r’/R’-wave measured at 5 mm from the highest point51,52 can reliably distinguish type 2 Brugada ECG pattern from IRBBB pattern. The classical diagnostic type 1 Brugada ECG pattern needs to be distinguished from similar “Brugadalike” patterns caused by RBBB, septal hypertrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC), pectus excavatum and other conditions, and also from the transient appearance of typical Brugada pattern in the cause of various acute processes such as acute ischaemia, Prinsmetal angina, pulmonary embolism, pericarditis, metabolic disorders, various medications and others (the so-called “Brugada phenocopies”,53 see www.brugadaphenocopy.com). The ECG characteristics of the BrS and the methods to distinguish them from other conditions presenting with similar ECG changes are reviewed in great detail in the above mentioned ECG Consensus Report.34 ECG acquisition with inappropriate high-pass filtering (e.g. non-linear phase high-pass filter of 0.5 Hz instead of the recommended 0.05 Hz)54 can cause considerable ST segment distortion and even mimic type 1 or 2 Brugada pattern.34,55,56 The ECG in BrS characteristically shows considerable dynamic variability; it can be completely normal at one time and demonstrate diagnostic type 1 pattern at another. Vagal influences (slow heart rate, post-prandial state, nighttime) tend to augment the J point and ST segment elevation and the type 1 pattern,57 whereas exercise and catecholamine infusion tend to have the opposite effect (however, in some BrS patients the ST segment elevation might become more prominent during exercise).58 Autonomic influences play important role also in the genesis of malignant arrhythmias because most of the arrhythmic events in BrS occur at night, two long RR intervals often precede episodes of VT/VF,59 whereas catecholamine infusion is used

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In BrS patients with a previous history of arrhythmic syncope or aborted cardiac arrest the annual event rate of sustained VT or VF is relatively high – between 1.9 %63 and 8.8 %64 and between 7.7 %62 and 13.8 %63, respectively. It is universally accepted that those with aborted cardiac arrest or documented spontaneous sustained VT (with or without syncope) should receive an ICD which is the single therapy with proven efficacy (Class I indication, “…is recommended”).6 There is also evidence that patients with spontaneous type 1 pattern and syncope judged to be of arrhythmic origin (“intermittent risk” group) also are indicated for ICD implantation (currently class IIa indication, “…can be useful.”), whereas asymptomatic patients with spontaneous type 1 pattern are currently considered to represent a “low risk” group (class IIb indication, “…may be considered” depending on the presence or absence of other, not yet fully established risk factors, see below).6 A very recently published Japanese multicentre study confirmed the difference in the level of risk between the latter two patient groups (2.2 % vs 0.5 % during a mean follow-up of 62 months).65 However, the decision to offer an ICD even to a BrS patient with a syncope of presumably arrhythmic origin often is difficult because unlike IHD patients, most of them are relatively young, apparently healthy and without any previous awareness of cardiac problems.

Most importantly, it is often very difficult to exclude non-arrhythmic cause of the syncope. In addition, the rate of ICD-related complications (20–30 % annually including inappropriate shocks) is higher than the rate of appropriate activation of the device (2.6–8 % annually).66,67,68 This suggests that novel, better methods of risk-stratification could benefit even some symptomatic BrS patients (i.e. those with the current class IIa indications).6 The majority of BrS patients (64 % in the largest reported series of 1029 BrS patients, the France, Italy, Netherlands, Germany (FINGER) study62 and 63 % in the report of the Brugada syndrome investigators in Japan69) have no symptoms at the time of establishment of the diagnosis.

The annual rate of SCD or sustained VT in these patients is low – between 0 %70,71 and 0.872 (0.5 % in the FINGER study62 and the

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Japanese multicentre study,66 0.4–1 % in several Japanese studies73,74,75) and cannot justify ICD implantation in all of them. On the other hand, the majority of the patients in this heterogeneous group have generally structurally normal hearts and are young or middle aged when diagnosed (median age 45 years in the FINGER study), and therefore the low annual risk can translate into a considerable cumulative arrhythmic risk for the next several decades of their life expectancy. In fact, the majority of victims of SCD in BrS come from this “low risk” (according to current standards) population. One study showed that among patients with the BrS who have died suddenly 68 % had no previous history of arrhythmia-related symptoms and therefore had not been protected by ICD.13 Currently, there are no firmly established reliable methods for the identification of these patients. Similarly, the largest absolute number of patients with IHD who die suddenly also comes from a large patient population considered to have generally low risk (i.e. post-myocardial infarction patients with relatively preserved left ventricular ejection fraction).76

Figure 3: QRS Notching in the Brugada Syndrome

Marked fractionation of the QRS complex in lead V2(2nd i.c. space) during positive diagnostic ajmaline test in a 20-year old man with aborted cardiac arrest and a non-diagnostic resting ECG (not shown).

Figure 4: Early Repolarisation in the Brugada Syndrome

While some studies77,78,79 reported increased occurrence of arrhythmic events in BrS patients with SCN5A mutations these findings have not been confirmed by other studies.80 The genetic analysis is expensive, time-consuming and available only in specialised centres. The role of programmed ventricular stimulation (PVS) during EPS for induction of VT has been an object of controversy and debate since the 1990s.

While some early studies supported its value for risk stratification mainly due to its high negative predictive value,81,82 most recent studies failed to confirm its independent predictive value.66,83,84 In the FINGER study,62 inducibility during EPS also did not predict arrhythmic events in multivariate analysis whereas in the multicentre PRELUDE study which tested uniform protocol of PVS during EPS in all 308 patients, the rate arrhythmic events during an average follow-up of three years was not significantly different between the 126 inducible (3.9 %) and the 182 non-inducible patients (4.9 %).85 Currently its role of EPS for risk stratification is accepted only as a Class IIb (“may be considered”) indication.7,86 The method is inherently limited by its invasive character and probably also by the labile nature of the underlying electrophysiologic substrate.87

ECG-derived Parameters for Risk Assessment Similarly to other diseases with intraventricular conduction abnormalities such as IHD and cardiomyopathies, the presence of notched or fragmented QRS,31,83 (see Figure 3) has been consistently demonstrated to indicate increased arrhythmic risk independently of other clinical and ECG variables (HR 4.9, 95 % CI 1.6-15.4 in the PRogrammed ELectrical stimUlation preDictive valuE (PERLUDE) study).85 However, currently the presence of notching/fractionation is assessed only visually using arbitrary descriptive criteria (e.g. number of QRS peaks). The presence of late potentials on the signal-averaged ECG (SAECG) is another marker of intraventricular conduction disturbances which also indicates increased arrhythmic risk in BrS30 independently of QRS fractionation. The standard time-domain SAECG, however, cannot detect conduction abnormalities within the QRS complex, has uncertain value in patients with bundle branch block, and uses only a single-lead ECG complex which is derived from the XYZ orthogonal leads and does not contain any regional information.

Among asymptomatic BrS patients, those with Brugada ECG pattern in the infero-lateral leads in addition to the right precordial leads,88 (increased “spatial Brugada burden”) were recently demonstrated to have several times higher risk of VF compared to those with Brugada

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Lateral early repolarisation (ER) in a 34-year-old man with aborted cardiac arrest and Brugada syndrome. A: Standard 12-lead ECG. Note the ER changes in leads V4-V6 as well as, less pronounced, in leads I and AVL. B: Leads V1 and V2 recorded in the standard positions, in the 3rd and 2nd i.c. space at baseline (left panel) and 7 minutes after the start of ajmaline administration (right panel). Note the appearance of diagnostic type 1 Brugada ECG pattern in leads V1(3rd and 2nd i.c. space) and lead V2 (2nd i.c. space) after ajmaline administration.

There were no Brugada-like changes in the peripheral leads following ajmaline administration (not shown).The abbreviations are the same as in Figure 2.

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Risk Assessment and Management type 1 changes only in the right precordial leads.89 On the other hand, the number of right precordial leads displaying type 1 pattern and the degree of J-point or ST-segment elevation do not seem to correlate with the arrhythmic risk.35,36 The “high” (3rd or 2nd i.c. space) positions of leads V1 and V2 are diagnostically more sensitive than their standard positions in the 4th i.c. space90,91,92 but prognostically their value is the same.93 Infero-lateral early repolarisation (ER) (see Figure 4) is not only more common (up to 15 %94) in BrS patients,70,94,95 but also carries up to 4-fold increased risk of spontaneous VF67,70 and even higher risk if the ER has “malignant” morphology,96 i.e. is associated with horizontal/descending (as opposed to rapidly ascending) ST segment after the J point.68,75 The combination of infero-lateral ER and fractionated QRS complex seems to indicate indicate a particularly high arrhythmic risk.97

indication they require the presence of at least two of the following risk factors: history of syncope, family history of sudden cardiac death and inducible VF during EPS.104 Obviously, these guidelines do not offer solution to the problem of identifying the high risk asymptomatic patients with the BrS. Strict adherence to the HRS/EHRA/APHRS guidelines means that each year in the UK alone, approximately 40 asymptomatic BrS patients are likely to experience their first and potentially lethal arrhythmic event without ICD protection (assuming 0.5 % annual rate in asymptomatic patients [approximately 2/3 of all BrS patients] × estimated 12,600 (2 per 10,000) BrS patients in the UK).

Clearly, there is a pressing need to develop novel, easily applicable (e.g. ECG based) risk stratifiers (or combinations thereof) and to confirm prospectively the value of the most promising available ones (e.g. QRS fractionation, infero-lateral ER, possibly others).

Currently there are only limited data suggesting that other ECG parameters may indicate increased arrhythmic risk. These parameters include changes in repolarisation dynamics (QT/RR and Tpeak-Tend/RR intervals relations),98 deep negative T wave in lead V1,99 QTc interval more than 460 ms in lead V2 and prolonged Tpeak-Tend interval,100 dynamic alterations in the amplitude of the ST elevation,101 prolonged PR-interval,93 presence of atrial arrhythmias,60,61,102 and augmentation of the ST segment elevation during the early recovery phase of exercise test.103

Obvious obstacles along the path to this goal are the low rate of arrhythmic events (i.e. end-point events in prospective studies), the small number of patients in the individual centres (since the prevalence of the disease outside South-East Asia is generally low), difficult organisation of big multicentre prospective studies and, possibly, inherent differences between various patient populations (e.g. Western vs Japanese).66 Less appreciated obstacle is the fact that currently ECG research studies (as well as everyday clinical practice) still use mainly 12-lead paper ECGs (or digital ECG images) which are amenable only

Summary – Risk Stratification in the Brugada Syndrome – Current Status and Future Diretions

to visual assessment and simple manual measurement. Computerised mathematical methods for quantitative assessment of QRS and ST-T wave abnormalities have been developed and successfully tested in various cardiac diseases105,106 but they require the availability of digital ECGs (digital files containing the raw ECG signal and not just digital image files). Finally, the development of sustained VT/VF in the BrS is likely a complex event resulting from interaction between the arrhythmic substrate (repolarisation and depolarisation abnormalities) and various triggering and modifying factors (e.g. ventricular ectopic beats, atrial arrhythmias, autonomic modulations such as vagal surge, fever, etc.).14,107,108 Therefore a successful ECG-based risk stratification in BrS should likely involve the combined quantitative assessment of several most important elements of arrhythmogenesis. n

Whereas the diagnosis of the BrS is relatively straightforward with currently available ECG-based methods, the identification of high risk patients who need prophylactic ICD implantation is still an unresolved issue. Currently the only class I indications for ICD implantation in patients diagnosed with the BrS endorsed by the 2013 HRS/EHRA/ APHRS Expert Consensus Statement7 is history of aborted cardiac arrest or documented spontaneous sustained VT, whereas syncope judged to be likely of arrhythmic origin is only a Class IIa indication which mainly reflects the difficulty of excluding a non-cardiac origin of syncope. The guidelines of the Japanese Cardiac Society of 2011 accept practically the same Class I indications whereas for Class IIa

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24. Coronel R, Casini S, Koopmann TT, et al. Right Ventricular Fibrosis and Conduction Delay in a Patient With Clinical Signs of Brugada Syndrome. A Combined Electrophysiological, Genetic, Histopathologic, and Computational Study. Circulation 2005;112:2769–77.

25. Nagase S, Kusano KF, Morita H, et al. Epicardial Electrogram of the Right Ventricular Outflow Tract in Patients With the Brugada Syndrome. Using the Epicardial Lead. J Am Coll Cardiol 2002;39:1992–5.

26. Tukkie R, Sogaard P, Vleugels J, et al. Delay in Right Ventricular Activation Contributes to Brugada Syndrome. Circulation 2004;109:1272–7.

27. Meregalli PG, Wilde AAM, Tan HL. Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367–78.

28. Ikeda T, Sakurada H, Sakabe K, et al. Assessment of Noninvasive Markers in Identifying Patients at Risk in the Brugada Syndrome: Insight Into Risk Stratification.

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29. Furushima H, Chinushi M, Hirono T, et al. Relationship Between Dominant Prolongation of the Filtered QRS Duration in the Right Precordial Leads and Clinical Characteristics in Brugada Syndrome. J Cardiovasc Electrophysiol 2005;16:1311–7.

30. Huang Z, Patel C, MD, et al. Role of signal-averaged electrocardiograms in arrhythmic risk stratification of patients with Brugada syndrome: A prospective study. Heart

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The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification

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31. Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a Marker of Conduction Abnormality and a Predictor of Prognosis of Brugada Syndrome. Circulation 2008;118:1697-704.

32. Peters S. A second case with arrhythmogenic cardiomyopathy, provocable Brugada ECG and SCN5A mutation. Int J Cardiol 2014;171:e117–8.

33. Elizari MV, Levi R, Acunzo RS, et al. Abnormal expression of cardiac neural crest cells in heart development: A different hypothesis for the etiopathogenesis of Brugada syndrome. Heart Rhythm 2007;4:359–65.

34. Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G, Goldwasser D, Lambiase P, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433–42.

35. Richter S, Sarkozy A, Paparella G, et al. Number of electrocardiogram leads displaying the diagnostic covedtype pattern in Brugada syndrome: a diagnostic consensus criterion to be revised. Eur Heart J 2010;31:1357–64.

36. Govindan M, Batchvarov VN, Raju H, et al. Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada Syndrome. Heart 2010;96:1904–8.

37. Roesler H. An electrocardiographic study of high take-off of the R(R’)-T segment in right precordial leads. Am J Cardiol 1960;6:920–8.

38. Veltmann CT, Papavassiliu T, Konrad T, Insights into the location of type I ECG in patients with Brugada syndrome: Correlation of ECG and cardiovascular magnetic resonance imaging. Heart Rhythm 2012;9:414–21.

39. Batchvarov VN, Govindan M, Macfarlane PF, et al. Diagnostic Utility of Bipolar Precordial Leads During Ajmaline Testing for Suspected Brugada Syndrome. Heart Rhythm 2010; 7:208–15.

40. Takagi M, Aihara N, Takaki H, et al. Clinical Characteristics of Patients With Spontaneous or Inducible Ventricular Fibrillation Without Apparent Heart Disease Presenting with J Wave and ST Segment Elevation in Inferior Leads.

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41. Chinushi M, Izumi D, Furushima H, et al. Multiple Premature Beats Triggered Ventricular Arrhythmias During Pilsicainide Infusion in a Patient with Inferior ST-Segment Elevation.

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42. Kalla H, Yan G-X, Marinchak R. Ventricular Fibrillation in a Patient with Prominent J (Osborn) Waves and ST Segment Elevation in the Inferior Electrocardiographic Leads: A Brugada Syndrome Variant? J Cardiovasc Electrophysiol 2000;11:95–8.

43. Batchvarov VN, Govindan M, Camm AJ, Behr ER. BrugadaLike Changes in the Peripheral Leads During Diagnostic Ajmaline Test in Patients With Suspected Brugada Syndrome.

Pacing Clin Electrophysiol 2009;32:695–703.

44. Van den Berg MP, Wiesfeld ACP. Brugada Syndrome with ST-Segment Elevation in the Lateral Leads. J Cardiovasc Electrophysiol 2006;17:1.

45. Bonakdar H, Haghjoo M, Sadr-Ameli MA. Brugada Syndrome Manifested by the Typical Electrocardiographic Pattern both in the Right Precordial and the High Lateral Leads. Ind Pacing Electrophysiol J 2008;8:137–40.

46. Rivero-Ayerza M, Brugada R, Brugada J, et al.

Electrocardiogram of Brugada Syndrome and its Dynamic Patterns. In: Malik M, Camm AJ (editors), Dynamic Electrocardiography , Futura/Blackwell Publishing, NY; 2004;417–24.

47. Brugada R, Brugada J, Antzelevitch C et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510–5.

48. Rolf S, Bruns H-J, Wichter T, et al. The Ajmaline challenge in Brugada syndrome: Diagnostic impact, safety, and recommended protocol. Eur Heart J 2003;24:1104–12.

49. Chung EH, McNeely DE, Gehi AK, et al. Brugada-type patterns are easily observed in high precordial lead ECGs in collegiate athletes. J Electrocardiol 2014;47:1–6.

50. Chevallier S, Forclaz A, Tenkorang J, et al. New Electrocardiographic Criteria for Discriminating Between Brugada Types 2 and 3 Patterns and Incomplete Right Bundle Branch Block. J Am Coll Cardiol 2011;58:2290–8.

51. Serra G, Baranchuk A, Bayes de Luna A, et al. New electrocardiographic criteria to differentiate the Type-2 Brugada pattern from electrocardiogramof healthy athletes with r′-wave in leads V1/V2. Europace 2014;16:1639–45.

52. García-Niebla J, Baranchuck A, Bayés de Luna A. True Brugada pattern or only high V1-V2 electrode placement?

J Electrocardiol 2014;47:756–8.

53. Baranchuk A, Nguyen T, Ryu MH, et al. Brugada Phenocopy: New Terminology and Proposed Classification. Ann Noninvas Electrocardiol 2012;17:299–314.

54. Kligfield P, Gettes LS, Bailey JJ, et al. AHA/ACC/HRS Ssinetific Statements. Recommendations for the Standardization and Interpretation of the Electrocardiogram Part I: The Electrocardiogram and Its Technology. J Am Coll Cardiol 2007;49:1109–27.

55. García-Niebla J, Serra-Autonell G, Bayés de Luna A. Brugada syndrome electrocardiographic pattern as a result of improper application of a high pass filter. Am J Cardiol 2012;110:318–20.

56. García-Niebla J, Serra-Autonell G, Fiol M, Bayés de Luna A. Brugada electrocardiographic pattern: Reality or fiction?

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57. Mizumaki K, Fujiki A, Nishida K, et al. Bradycardia-dependent ECG changes in Brugada syndrome. Circ J 2006;70:896–901.

58. Amin AS, de Groot EA, Ruijter JM, et al. Exercise-induced ECG changes in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2:531–9.

59. Matsuo K, Shimizu W, Kurita T, et al. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:508–12.

60. Veerakul G, Nademanee K. Treatment of electrical storms in Brugada syndrome. J Arrhythmia 2013;29:117–24.

61. Morita H, Kusano-Fukushima, Nagase S, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol 2002;40:1437–44.

62. Kusano KF, Taniyama MK, Nakamura K, et al. Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol 2008;51:1169–75.

63. Probst V, Veltmann C, Eckardt L, et al. Long-Term Prognosis of Patients Diagnosed With Brugada Syndrome: Results from the FINGER Brugada syndrome Registry. Circulation 2010;121:635–43.

64. Brugada J, Brugada R, Antzelevitch C, et al. Long-term followup of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation 2002;105:73–8.

65. Takagi M, Sekiguchi Y, Yokoyama Y, et al. for the Japan Idiopathic Ventricular Fibrillation Study (J-IVFS )Investigators.

Long-term prognos is inpatients with Brugada syndrome based on Class II indication for implantable cardioverterdefibrillator in the HRS/EHRA/APHRS Expert Consensus Statement: Multicenter study in Japan. Heart Rhythm 2014;11:1716–20.

66. Sacher F, Probst V, Iesaka Y, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation 2006;114:2317–24.

67. Sarkozy A, Boussy T, Kourgiannides G, et al. Long-term follow-up of primary prophylactic implantable cardioverterdefibrillator therapy in Brugada syndrome. Eur Heart J 2007;28:334–44.

68. Rosso R, Glick A, Glikson M, et al. Outcome after implantation of cardioverter defibrillator [corrected] in patients with Brugada syndrome: a multicenter Israeli study (ISRABRU). Isr Med Assoc J 2008;10:435–9.

69. Kamakura S, Ohe T, Nakazawa K, et al. Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1– V3. Circulat Arrhythmia Electro-Physiol 2009;2:495–503.

70. Letsas KP, Weber R, Efremidis M, et al. Long-term prognosis of asymptomatic individuals with spontaneous or druginduced type 1 electrocardiographic phenotype of Brugada syndrome. J Electrocardiol 2011;44:346–9.

71. Champagne J, Philippon F, Gilbert M, et al. The Brugada syndrome in Canada: a unique French-Canadian experience.

Can J Cardiol 2007;23(Suppl B):71B. 72. Eckardt L, Probst V, Smits JP, et al. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation 2005;111:257.

73. Atarashi H, Ogawa S. Idiopathic Ventricular Fibrillation Investigators. New ECG criteria for high-risk Brugada syndrome. Circ J 2003;67:8.

74. Takagi M, Aonuma K, Sekiguchi Y, et al, The Japan Idiopathic Ventricular Fibrillation Study. The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: Multicenter study in Japan (J-IVFS) Investigators. Heart Rhythm 2013;10:533–9.

75. Yokokawa M, Noda T, Okamura H, et al. Comparison of longterm follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. Am J Cardiol 2007;100:649.

76. Huikuri HV, Castellanos A, Myerburg RJ. Sudden Death Due to Cardiac Arrhythmias. N Engl J Med 2001;345:1473–82.

77. Sommariva E, Pappone C, Martinelli Boneschi F, et al.

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification. Eur J Human Genetics 2013;21:911–7.

78. Nishii N,Ogawa M,Morita H, et al.SCN5A mutation is associated with early and frequent recurrence of ventricular fibrillation in patients with Brugada syndrome. Circ J 2010;74:2572–8.

79. Meregalli PG, Tan HL, Probst V, et al. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm 2009;6:341–8.

80. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7.

81. Brugada J, Brugada R, Brugada P. Electrophysiologic testing predicts events in Brugada syndrome Patients. Heart Rhythm 2011; 8:1595–7.

82. Sarkozy A, Paparella G, Boussy T, et al. The usefulness of the consensus clinical diagnostic criteria in Brugada syndrome.

Int J Cardiol 2013;167:2700–4.

83. Gasparini M, Priori SG, Mantica M, et al. Provocative tests in the Brugada syndrome: do we have the right tools?

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84. Eckardt L, Kirchhof P, Schulze-Bahr E, et al.

Electrophysiologic investigation in Brugada syndrome. Yield of programmed ventricular stimulation at two ventricular sites with up to three premature beats. European Heart Journal 2002;23:1394–401.

85. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome results of the PRELUDE (Programmed Electrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37–45.

86. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines. Circulation 2006;114:e385–484.

87. Wichter T, Matheja P, Eckardt L, et al. Cardiac Autonomic Dysfunction in Brugada Syndrome. Circulation 2002;105:702–6.

88. Rollin A, Sacher F, Gourraud JB, et al. Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome.

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89. Viskin S, Adler A, Rosso R. Brugada burden in Brugadasyndrome: The way to go in risk stratification? Heart Rhythm 2013;7:1019–20.

90. Shimizu W, Matsuo K, Takagi M, Tanabe Y, Aiba T, Taguchi A, Suyama K, Kurita T, Aihara N, Kamakura S: Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-sevenlead body surface potential mapping and its application to twelve-lead electrocardiograms.

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91. Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, Sitthisook S, et al: New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J 2001;22:2290–6.

92. Teijeiro R, Garro HA, Acunzo RS, et al. Recording of High V1-V3 Precordial Leads May Be Essential to the Diagnosis of Brugada Syndrome During the Ajmaline Test.

J Cardiovasc Pharmacol and Therapeutics 2006;11:153–5.

93. Miyamoto K,Yokokawa, M,Tanaka K, et al. Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome. Am J Cardiol 2007;99:53–7.

94. Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardio-graphic repolarization abnormalities in Brugada syndrome. Circulat Arrhythmia Electrophysiol 2009;2:154–61.

95. Bastiaenen R, Raju H, Sharma S, et al. Characterization of early repolarisation during ajmaline provocation and exercise tolerance testing. Heart Rhythm 2013;10:247–54.

96. Rosso R, MD, Glikson E, Belhassen B, et al. Distinguishing “benign” from “malignant early repolarization”: The value of the ST-segment morphology. Heart Rhythm 2012;9:225–9.

97. Tokioka K, Kusano KF, Morita H, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol 2014;63:2131–8.

98. Sangawa M, Morita H, Nakatsu T, et al. Abnormal transmural repolarization process in patients with Brugada syndrome.

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99. Miyamoto A, Hayashi H, Makiyama T, et al. Risk determinants in individuals with a spontaneous type 1 Brugada ECG. Circ J 2011;75:844–51.

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Tpeak–Tend and Tpeak–Tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol 2006;47:1828–34.

101. Take Y, Morita H, Wu J, et al. Spontaneous electrocardiogram alterations predict ventricular fibrillation in Brugada syndrome. HeartRhythm 2011;8:1014–21.

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103. Makimoto H, Nakagawa E,Takak I H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol 2010;56:1576–84.

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107. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol 2006;47:2074–85.

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Risk Assessment and Management

LE ATION.

Evaluation and Management of ST-elevation Myocardial Infarction and Shock L e e Ch a n g 1 a n d R o b e r t Ye h 2 1. Department of Medicine; 2. Cardiology Division, Massachusetts General Hospital, Boston, US

Abstract Cardiogenic shock is the deadliest complication of acute ST-elevation myocardial infarction. Prompt recognition and intervention are critical for patient survival. The diagnosis of cardiogenic shock is primarily a clinical one based on signs and symptoms of low cardiac output and heart failure, and can be confirmed with placement of a pulmonary arterial catheter. Vasopressor and inotropic therapies are typically required, and in severe cases, an intra-aortic balloon pump can provide additional haemodynamic support. Although mortality for cardiogenic shock associated with ST-elevation myocardial infarction remains high, early reperfusion strategies primarily via percutaneous coronary intervention or coronary artery bypass graft surgery have led to improved outcomes.

Keywords Cardiogenic shock, STEMI, intra-aortic balloon pump, PCI, CABG, rescue PCI Disclosure: The authors have no conflicts of interest to declare.

Received: 9 October 2014 Accepted: 19 November 2014 Citation: European Cardiology Review, 2014;9(2):88–91 Correspondence: Robert Yeh, Cardiology Division, Massachusetts General Hospital, GRB800, 55 Fruit St, Boston, MA 02114, US. E: RYEH@mgh.harvard.edu

Cardiogenic shock is the leading cause of death in patients with acute ST-elevation myocardial infarction (STEMI). Characterised by a state of low cardiac output leading to end-organ hypoperfusion, cardiogenic shock complicates approximately 5–8 % of STEMIs and is associated with a mortality rate approaching 50 percent.1–3 Prompt recognition and therapeutic intervention for cardiogenic shock due to STEMI are critical for patient survival.

Aetiology Ischaemic dysfunction of cardiac myocytes during STEMI can impair systolic and diastolic function of the right, left or both ventricles. When ischaemic injury is extensive, ventricular function can be impaired to such a degree that cardiogenic shock occurs, whereby cardiac output falls and elevated ventricular filling pressures lead to heart failure.4 The decreased cardiac output then propagates a vicious cycle of progressively worsening coronary perfusion, myocyte dysfunction, and ultimately end-organ hypoperfusion.5 This review focuses on ventricular dysfunction as the cause of shock, but cardiogenic shock can also occur from mechanical complications of STEMI such as papillary muscle, ventricular septum or free wall rupture.

Left ventricular dysfunction is implicated in the majority of cases of cardiogenic shock associated with STEMI.6 Often, the infarction involves the anterior territory of the left ventricle. Predominant right ventricular dysfunction comprises approximately 5 % of cases and is usually due to an inferior MI with proximal occlusion of the right coronary artery.7 In addition to the acute infarction, patients in cardiogenic shock often have suffered prior infarcts and tend to have severe three-vessel coronary disease, all of which leaves them prone to extensive ischaemic injury and subsequent ventricular dysfunction.4,7

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Presentation and Diagnosis Patients suffering from STEMI and cardiogenic shock present with signs and symptoms of hypoperfusion and heart failure. The diagnosis is made clinically and can be confirmed with placement of a pulmonary arterial catheter (PAC).

Common symptoms include chest pain and dyspnoea. On physical examination, patients are hypotensive and may show evidence of systemic hypoperfusion such as altered mental status or poor urine output. Laboratory studies may show an elevated lactate level and a rising creatinine, which may be due to both decreased renal perfusion and venous congestion. Classically, cardiogenic shock has been associated with cool extremities due to low cardiac output and compensatory systemic vasoconstriction. In practice, however, systemic vascular resistance is often not elevated and may even be low. This may be due to concomitant septic shock, particularly as the hypoperfusion from cardiogenic shock places patients at high risk for ischaemic bowel and subsequent translocation of gut microbes. In addition, myocardial infarction alone can lead to a systemic inflammatory response.8 Most STEMI patients who develop cardiogenic shock do so not on arrival to the hospital, but within the first 24 hours of admission.9 Patients may also demonstrate signs of volume overload. Decreased oxygen saturation and rales due to pulmonary oedema may be present in patients with predominantly left ventricular dysfunction and may necessitate intubation, but up to one-third of such patients present without pulmonary congestion and chest X-ray may be clear.10 Patients with mainly right-sided involvement tend to have clear lungs but may have distended neck veins and peripheral oedema or ascites.

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Risk factors for cardiogenic shock associated with STEMI include older age, diabetes mellitus, ongoing angina, heart failure, low systolic blood pressure, tachycardia and left bundle branch block.11,12 Of these risk factors, age appears to be most predictive. An increase in age by 10 years has been shown to be associated with a nearly 50 % higher probability of developing cardiogenic shock.12 Echocardiography should be performed to assess ventricular function and to exclude mechanical complications of STEMI. Echocardiography findings in cardiogenic shock include severe impairment of ventricular function, which may be predominantly right or left-sided or both and may be either systolic or diastolic or both. While a low left ventricular ejection fraction (LVEF) is a poor prognostic indicator, it does not completely correlate with the presence of cardiogenic shock. Often the LVEF is only moderately depressed and occasionally can be preserved.13–16 Placement of a PAC can both provide a definitive diagnosis of cardiogenic shock and guide resuscitative efforts. PAC haemodynamic measurements confirm the diagnosis of cardiogenic shock by showing a low cardiac index (<2.2 L/min/m2) and elevated ventricular filling pressures. Mixed venous oxygen saturation is typically low, reflecting the decreased cardiac output and increased oxygen extraction from peripheral tissues. In addition, PACs can distinguish between left ventricular or right ventricular dysfunction as the primary cause of shock by demonstrating a corresponding pulmonary capillary wedge pressure (PCWP) greater than 15–18 or right ventricular end diastolic pressure (RVEDP) greater than 10–15 mmHg, respectively.10 From the haemodynamic parameters provided by a PAC, systemic vascular resistance can be calculated to determine the potential co-existence of other types of shock. While PACs have not been proven to confer mortality benefit or lead to shorter hospitalisations, their utility specific to cardiogenic shock has not been evaluated.17–19 In practice, they provide haemodynamic measurements that can prove invaluable in both diagnosis and management of cardiogenic shock.20

Therapy The management for cardiogenic shock due to STEMI centres on early revascularisation and the provision of pharmacological and mechanical haemodynamic support. Re-establishing coronary perfusion can reverse the ischaemic injury to cardiac myocytes and potentially recover ventricular function. Therefore, revascularisation via percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) should be attempted on an urgent basis.

Early presentation and early intervention are associated with significantly lower mortality rates at six months and 12 months as seen in the SHOCK trial.14,21 It is the widespread adoption of early revascularisation that has led to the steady improvement in survival for cardiogenic shock over the last two decades, which previously was almost always fatal.1,21 Revascularisation should be attempted even for delayed presentations of cardiogenic shock.

Survival benefit has been demonstrated for PCI performed within 48 hours of STEMI onset and 18 hours after onset of shock.22 In settings where PCI and CABG are unavailable, fibrinolysis should be performed, although the mortality benefit conferred is modest and inferior to PCI or CABG.23,24 If fibrinolysis does not achieve reperfusion, often considered “primary failure” of thrombolytic therapy, then rescue PCI should be undertaken as soon as possible, ideally within 12 hours of initial chest pain.25–27 Among patients for whom fibrinolysis initially appears successful, a substantial proportion will develop recurrent

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ischaemia caused by threatened reocclusion of their coronary artery.28 These patients, similarly to those who undergo rescue PCI, also derive survival benefit from early revascularisation with PCI.29,30 A comparison of outcomes between PCI and CABG in the setting of cardiogenic shock found no difference in survival at 30 days and one year. Notably, the patients in the CABG group were more likely to have three-vessel disease or left main disease.31 Overall for patients in cardiogenic shock due to STEMI, PCI is performed much more commonly than CABG, particularly if a culprit lesion is found. Rarely, in cases involving multi-vessel or left main disease, PCI may be necessary to stabilise patients prior to CABG. In addition to revascularisation, patients should be started on antithrombotic therapy including aspirin, heparin, P2Y12 inhibitors, and potentially glycoprotein IIb/IIIa inhibitors whereas beta blockers and other drugs with negative inotropic effects should be withheld. Although aspirin and heparin have not been specifically studied in cardiogenic shock, they should be continued given their established benefit in acute coronary syndromes and lack of obvious contraindication.32,33 Antiplatelet therapy with P2Y12 inhibitors like clopidogrel, ticagrelor, or prasugrel are also indicated.34–36 Glycoprotein IIb/IIIa inhibitors have been shown to independently reduce the 30-day mortality rate for patients in cardiogenic shock and should be considered particularly when P2Y12 inhibitors are not used.37 In combination with antithrombotic therapy, the risk of major periprocedural bleeding is nontrivial and should be weighed carefully.

For PCI, the risk has been reported as high as 5 %, although the increasing use of radial access has lowered the rate of vascular and bleeding complications.38–42 Beta blockers and calcium channel blockers should be avoided given their negative inotropic effects and potential to prolong or worsen cardiogenic shock.43 While revascularisation is the definitive therapy for cardiogenic shock in STEMI, inotropic and vasopressor support is critical to maintain perfusion of vital organs. The ideal choice of first-line agent is not well-established, likely reflecting the complex physiology of cardiogenic shock. PACs are useful for tailoring vasopressor and inotropic therapy given the often uncertain and dynamic haemodynamic parameters in these settings. For patients who are severely hypotensive, norepinephrine is a reasonable first choice that exerts both inotropic and vasopressor activity. Dopamine at doses >10 mcg/kg/min is similar in effect, although it is associated with more arrhythmias and possibly higher mortality compared to norepinephrine. 44 However, the increased systemic vascular resistance brought on by both norepinephrine and dopamine raises afterload so that the heart must work harder to maintain cardiac output. For patients whose hypotension is less severe, inotropes such as dobutamine and milrinone should be considered. The vasodilation caused by both of these inotropes may be prohibitive in the severely hypotensive patient. In patients with milder cardiogenic shock, however, the vasodilatory effect and reduction in afterload may improve cardiac output such that on balance blood pressure may not actually decrease. The minimum required dose should be used for all of these agents as escalating doses increase the chance of arrhythmia and impose increased demand on an already struggling heart.

In addition to determining the optimal choice of inotropic or vasopressor support, a PAC can also guide fluid management.20 The

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Risk Assessment and Management overall goal of fluid management is to maximise cardiac output and minimise ventricular filling pressures. The optimal filling pressures are often a moving target and must be individualised to each patient in cardiogenic shock. Some patients in cardiogenic shock may be hypovolaemic with relatively low PCWP shown on PAC and these patients may benefit from a small volume challenge. Other patients present with pulmonary oedema with evidence of high filling pressures on PAC and require intravenous diuresis. Typically the goal PCWP ranges from 18–25 mmHg.10 Placement of an intra-aortic balloon pump (IABP) should also be considered to provide mechanical support of cardiac function, particularly for severe cardiogenic shock. The balloon pump is inserted into the proximal aorta and inflates during diastole to augment coronary perfusion and deflates in systole to reduce afterload by a vacuum effect. In the IABP SHOCK II trial, patients in cardiogenic shock from acute MI were randomised to either undergo IABP placement or not. There was no mortality difference between the two groups both at 30 days and at one year.45,46 Nonetheless, the study authors acknowledge that their patient population represented primarily mild to moderately severe cardiogenic shock. IABP may provide mortality benefit for patients in rapidly decompensating and severe cardiogenic shock.

Early experience with other forms of mechanical support such as the percutaneous or surgically implanted left ventricular assist device (LVAD) has been relatively inconclusive thus far.

The ventricular assist devices appear to result in more rapid

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3. Fox KA, Steg PG, Eagle KA, et al., Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006, JAMA, 2007;297:1892–900.

4. Alonso DR, Scheidt S, Post M, Killip T, Pathophysiology of cardiogenic shock. Quantification of myocardial necrosis, clinical, pathologic and electrocardiographic correlations, Circulation, 1973;48:588–96.

5. Hollenberg SM, Kavinsky CJ, Parrillo JE, Cardiogenic shock, Ann Intern Med, 1999;131:47–59.

6. Hochman JS, Boland J, Sleeper LA, et al., Current spectrum of cardiogenic shock and effect of early revascularization on mortality. Results of an International Registry. SHOCK Registry Investigators, Circulation, 1995;91:873–81.

7. Reynolds HR, Hochman JS, Cardiogenic shock: current concepts and improving outcomes, Circulation, 2008;117:686–97.

8. Kohsaka S, Menon V, Lowe AM, et al., Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock, Arch Intern Med, 2005;165:1643–50.

9. Webb JG, Sleeper LA, Buller CE, et al., Implications of the timing of onset of cardiogenic shock after acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?, J Am Coll Cardiol, 2000;36:1084–90.

10. Menon V, White H, LeJemtel T, et al., The clinical profile of patients with suspected cardiogenic shock due to predominant left ventricular failure: a report from the SHOCK Trial Registry.

SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK?, J Am Coll Cardiol, 2000;36:1071–6.

11. Lindholm MG, Køber L, Boesgaard S, et al., Cardiogenic shock complicating actue myocardial infarction; prognostic impact of early and late shock development, Eur Heart J, 2003;24:258–65.

12. Hasdai D, Califf RM, Thompson TD, et al., Predictors of cardiogenic shock after thrombolytic therapy for acute myocardial infarction, J Am Coll Cardiol, 2000;35:136–43.

13. Picard MH, Davidoff R, Sleeper LA, et al., Echocardiographic predictors of survival and response to early revascularization in cardiogenic shock, Circulation, 2003;107:279–84.

14. Hochman JS, Sleeper LA, Webb JG, et al., Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock, N Engl J Med, 1999;341:625–34.

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haemodynamic improvement than IABPs but have not been shown to provide additional mortality benefit and yet are more invasive and associated with more complications.47,48 Patients with predominantly right ventricular dysfunction also derive benefit from early revascularisation and haemodynamic support but there are distinctive aspects to their management. These patients are highly preload dependent and often require large volume fluid resuscitation.49,50 Fluids should be administered until the jugular venous pressure is greater than 15 mmHg and there is no longer improvement in blood pressure.51 Nitrates and diuretics should generally be avoided as they both reduce preload of the right ventricle. If inotropic support is needed, dopamine and dobutamine are first-line agents.52 Both agents also provide chronotropic support that is often necessary given the high frequency of bradycardia associated with right ventricular STEMIs. As low heart rates in this setting may substantially impair cardiac output, atropine or placement of a temporary pacemaker may also be required.53,54

Conclusion Although cardiogenic shock remains a deadly complication of STEMI, early diagnosis and intervention have led to improved outcomes. The diagnosis of cardiogenic shock is primarily based on clinical signs and symptoms of low cardiac output and heart failure and confirmed with placement of a PAC. Vasopressor and inotropic therapies are typically required and in severe cases, an IABP can provide additional haemodynamic support. Ultimately, early revascularisation performed via PCI or CABG offers patients the greatest chance for survival. n

15. Ramanathan K, Harkness SM, Nayar AC, et al., 887-2 Cardiogenic shock in patients with preserved left ventricular systolic function: Characteristics and insight into mechanisms, J Am Coll Cardiol, 2004;43:A241.

16. Reynolds HR, Anand SK, Fox JM, et al., Restrictive physiology in cardiogenic shock: observations from echocardiography, Am Heart J, 2006;151:890.e9–15.

17. Binanay C, Califf RM, Hasselblad V, et al., Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial, JAMA, 2005;294:1625–33.

18. Harvey S, Harrison DA, Singer M, et al., Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial, Lancet, 2005;366:472–7.

19. Cohen MG, Kelly RV, Kong DF, et al., Pulmonary artery catheterization in acute coronary syndromes: Insights from the GUSTO IIb and GUSTO III trials, Am J Med, 2005;118:482–8.

20. Mueller HS, Chatterjee K, Davis KB, et al., ACC expert consensus document. Present use of bedside right heart catheterization in patients with cardiac disease. American College of Cardiology, J Am Coll Cardiol, 1998;32:840–64.

21. Hochman JS, Sleeper LA, Webb JG, et al., Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction, JAMA, 2006;295:2511–5.

22. Zeymer U, Vogt A, Zahn R, et al., Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI); Results of the primary PCI registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK), Eur Heart J, 2004;25:322–8.

23. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group, Lancet, 1994;343:311–22.

24. French JK, Feldman HA, Assmann SF, et al., Influence of thrombolytic therapy, with or without intra-aortic balloon counterpulsation, on 12-month survival in the SHOCK trial, Am Heart J, 2003;146:804–10.

25. Gershlick AH, Stephens-Loyd A, Hughes S, et al., Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction, N Engl J Med, 2005;353:2758–68.

26. Carver A, Rafelt S, Gershlick AH, et al., Longer-term followup of patients recruited to the REACT (Rescue Angioplasty Versus Conservative Treatment or Repeat Thrombolysis) trial, J Am Coll Cardiol, 2009;54:118–26.

27. Wijeysundera HC, Vijayaraghavan R, Nailamoth BK, et al., Rescue angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for ST-segment myocardial infarction: a meta-analysis of randomized trials, J Am Coll Cardiol, 2007;49:422–30.

28. Armstrong PW, Fu Y, Chang WC, et al., Acute coronary

syndromes in the GUSTO-IIb trial: prognostic insights and impact of recurrent ischemia. The GUSTO-IIb Investigators, Circulation, 1998;98:1860–8.

29. Gibson CM, Karha J, Murphy SA, et al., Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolyis in Myocardial Infarction trials, J Am Coll Cardiol, 2003;42:7–16.

30. Barbash GI, Birnbaum Y, Bogaerts K, et al., Treatment of reinfarction after thrombolytic therapy for acute myocardial infarction: an analysis of outcome and treatment choices in the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (gusto I) and assessment of the safety of a new thrombolytic (assent 2) studies, Circulation, 2001;103:954–60.

31. White HD, Assmann SF, Sanborn TA, et al., Comparison of percutaneous coronary intervention and coronary artery bypass grafting after acute myocardial infarction complicated by cardiogenic shock: results from the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial, Circulation, 2005;112:1992–2001.

32. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group, Lancet, 1988;2:349–60.

33. Cohen M, Gensini GF, Maritz F, et al., The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial, J Am Coll Cardiol, 2003;42:1348–56.

34. Yusuf S, Zhao F, Mehta SR, et al., Effects of clopidogrel in addition to aspirin in patients with acute coronoary syndromes without ST-segment elevation, N Engl J Med, 2001;345:494–502.

35. Wiviott SD, Braunwald E, McCabe CH, et al., Prasugrel versus clopidogrel in patients with acute coronary syndromes, N Engl J Med, 2007;357:2001–15.

36. Wallentin L, Becker RC, Budaj A, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med, 2009;361:1045–57.

37. Hasdai D, Harrington RA, Hochman JS, et al., Platelet glycoprotein IIb/IIIa blockade and outcome of cardiogenic shock complicating acute coronary syndromes without persistent ST-segment elevation, J Am Coll Cardiol, 2000;36:685–92.

38. Kinnaird TD, Stabile E, Mintz GS, et al., Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions, Am J Cardiol, 2003;92:930–5.

39. Doyle BJ, Ting HH, Bell MR, et al., Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from

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Evaluation and Management of ST-elevation Myocardial Infarction and Shock

1994 to 2005, JACC Cardiovasc Interv, 2008;1:202–9.

40. Jolly SS, Amlani S, Hamon M, et al., Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials, Am Heart J, 2009;157:132–40.

41. Jolly SS, Yusuf S, Carins J, et al., Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial, Lancet, 2011;377:1409–20.

42. Feldman DN, Swaminathan RV, Kaltenbach LA, et al., Adoption of radial access and comparison of outcomes to femoral access in percutaneous coronary intervention: an updated report from the national cardiovascular data registry (2007-2012), Circulation, 2013;127:2295–306.

43. Chen ZM, Jiang LX, Chen YP, et al., Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial, Lancet, 2005;366:1607–21.

44. De Backer D, Biston P, Devriendt J, et al., Comparison of

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dopamine and norepinephrine in the treatment of shock, N Engl J Med, 2010;362:779–89.

45. Thiele H, Zeymer U, Neumann FJ, et al., Intraaortic balloon support for myocardial infarction with cardiogenic shock, N Engl J Med, 2012;367:1287–96.

46. Thiele H, Zeymer U, Neumann FJ, et al., Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial, Lancet, 2013;382:1638–45.

47. Thiele H, Sick P, Boudriot E, et al., Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock, Eur Heart J, 2005;26:1276–83.

48. Seyfarth M, Sibbing D, Bauer I, et al., A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction, J Am Coll Cardiol, 2008;52:1584–8.

49. Goldstein JA, Pathophysiology and management of right heart ischemia, J Am Coll Cardiol, 2002;40:841–53.

50. Dell’Italia LJ, Starling MR, Crawford MH, et al., Right ventricular infarction: identification by hemodynamic measurements before and after volume loading and correlation with noninvasive techniques, J Am Coll Cardiol, 1984;4:931–9.

51. Ferrario M, Poli A, Previtali M, et al., Hemodynamics of volume loading compared with dobutamine in severe right ventricular infarction, Am J Cardiol, 1994;74:329–33.

52. Müllner M, Urbanek B, Havel C, et al., Vasopressors for shock, Cochrane Database Syst Rev , 2004;(3):CD003709.

53. Goodfellow J, Walker PR, Reversal of atropine-resistant atrioventricular block with intravenous aminophylline in the early phase of inferior wall acute myocardial infarction following treatment with streptokinase, Eur Heart J, 1995;16:862–5.

54. Topol EJ, Goldschlager N, Ports TA, et al., Hemodynamic benefit of atrial pacing in right ventricular myocardial infarction, Ann Intern Med, 1982;96:594–7.

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Risk Assessment and Management

Echocardiographic Evaluation of Aortic Stenosis – Normal Flow and Low Flow Scenarios Ian G Burwash University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada

Abstract The echocardiographic evaluation of the patient with aortic stenosis (AS) has evolved in recent years, beyond confirming the diagnosis and measuring the resting mean pressure gradient or valve area. New echocardiographic approaches have developed to address the clinical dilemmas related to discordant haemodynamic data, asymptomatic haemodynamically severe AS and low-flow, low-gradient AS in order to better evaluate the disease severity, enhance the risk stratification of patients and provide important prognostic information. This article reviews the echocardiographic evaluation of the AS patient and focuses on the echocardiographic assessment of the haemodynamic severity, the prediction of clinical outcome and the use of echocardiography to guide patient management in the presence of normal flow and low flow scenarios.

Keywords Aortic stenosis, echocardiography, stress echocardiography, exercise echocardiography, dobutamine echocardiography, low-flow aortic stenosis, low-gradient aortic stenosis Disclosure: The author has no conflicts of interest to declare.

Received: 10 October 2014 Accepted: 11 November 2014 Citation: European Cardiology Review, 2014;9(2):92–9 Correspondence: Ian G Burwash, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada E: iburwash@ottawaheart.ca

Aortic stenosis (AS) is a progressive disease of worsening left ventricular outflow obstruction. In the early stage of the disease, the prognosis is excellent with a very small risk of sudden death (<1 % per year).1–3 However, the development of a haemodynamically severe stenosis and the onset of symptoms herald a dramatic deterioration in prognosis. At this point, aortic valve replacement (AVR) provides symptomatic and survival benefits that generally outweigh the associated surgical risks.4–10 Echocardiography plays a critical role in the management of patients with suspected and documented AS by confirming the diagnosis, quantifying the haemodynamic severity and providing prognostic information important for predicting the clinical course and guiding management.9–11 Resting transthoracic echocardiography provides the mainstay technique for these purposes; however, transoesophageal and stress echocardiography can provide additional important information when encountering patients with discordant haemodynamic data, apparently asymptomatic haemodynamically severe AS and severe low-flow, low-gradient AS with or without a reduced left ventricular ejection fraction (LVEF). The purpose of this article is to review the echocardiographic assessment of the AS patient, highlighting important issues related to the assessment of haemodynamic severity, the prediction of clinical outcome and the use of echocardiography to guide patient management in both normal flow and low flow scenarios.

severity of the valve disease.9,10 Haemodynamic severity is used to decide whether symptoms are likely attributable to the valve and dictate the frequency of follow-up evaluations. Numerous haemodynamic indices have been proposed for this purpose; however, transvalvular velocity (VAS), transvalvular mean gradient (MG) and aortic valve area (AVA) derived by the continuity equation are the parameters recommended for routine clinical use due to their ability to predict clinical outcome.9–11 Haemodynamically severe AS has been defined by VAS≥4 m/s, MG≥40 mmHg and AVA≤1.0 cm2, because these findings are associated with a poor prognosis.9–11 The fulfilment of all three criteria essentially confirms the presence of severe AS; however, discordant findings occur in at least 30 % of AS patients with a normal LVEF, casting doubt about the disease severity.12–14 In patients with a reduced LVEF, discordant findings are even more common.15–19 In both groups, the vast majority of the discordance relates to an AVA in the severe range, but MG or VAS in the non-severe range. In only a small minority of cases (<10 %), AVA is in the non-severe range, but MG or VAS is severe.12,14

Sorting Out Discrepant Haemodynamic Data – Aortic Valve Area is Severe, but the Mean Gradient is Not! The Normal Left Ventricular Ejection Fraction Patient Technical Reasons (Measurement Error)

Criterion for Haemodynamically Severe Aortic Stenosis Management of the AS patient is critically dependent on an accurate evaluation of the patient’s symptomatic status and the haemodynamic

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Accurate measurement of the left ventricular outflow tract (LVOT) velocity, LVOT diameter and VAS are critical to the calculation of AVA using the continuity equation. Underestimation of the LVOT time velocity integral or diameter can lead to an erroneously small

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stroke volume (SV) and underestimation of AVA. Optimal LVOT velocity signals require the ultrasound beam to be aligned parallel to left ventricular (LV) outflow, the sample volume to be positioned immediately inferior to the aortic valve (5–10 mm) and the signal to show laminar flow with minimal spectral dispersion.11 The LVOT diameter measurement should be acquired on a zoomed parasternal long-axis image in mid-systole and measured 5 mm below cusp insertion.11 While measurements obtained at the annulus improve reproducibility, they tend to result in a larger AVA. The circular assumption used to derive the LVOT area from the diameter measurement is an important cause for underestimation of AVA as many patients have an elliptically shaped LVOT.20 The LVOT long-axis diameter often approximates the minor axis diameter and can lead to a 26 % underestimation of SV and AVA.21,22 Identification of the highest VAS is required to accurately measure MG and AVA, and Doppler interrogation of the aortic valve should be performed from the apical, right parasternal and suprasternal windows.23 Failure to identify the highest VAS will lead to an underestimation of MG, an overestimation of AVA and an underestimation of AS severity that tends to have a concordant rather than discordant MG and AVA. When discrepant data are encountered, the initial approach should be to rule out measurement error. Echocardiographic images should be carefully reviewed for proper data acquisition and repeated if improper technique was used. The SV measurement should be confirmed by using another technique such as three-dimensional (3D)-echocardiography, or corroborating the continuity equation AVA by planimetry of the anatomic orifice using two-dimensional (2D) or preferably 3D-transoesophageal echocardiography. 22,24 An AVA≤1.0 cm 2 on planimetry confirms the presence of severe AS. However, an AVA slightly greater than 1.0 cm 2 does not definitively exclude severe AS since the effective orifice area derived by continuity equation is usually slightly smaller than the anatomic AVA.

Patient Body Size Cardiac output and AVA requirements are dependent on body size.

In a small individual, an AVA≤1.0 cm2 may be relatively adequate for the cardiac output and generate a VAS<4 m/s or MG<40 mmHg. Conversely, an AVA>1.0 cm2 may be inadequate for a large individual, resulting in severe obstruction and a VAS≥4 m/s or MG≥40 mmHg. Current guidelines suggest that indexing AVA for body surface area (aortic valve area index [AVAi]) to account for different body sizes may be helpful and propose an AVAi≤0.6 cm2/m2 to identify severe AS.9–11 However, prognostic studies supporting this approach are limited.25 Indexing AVA to body surface area increases the prevalence of severe AS, but also increases the prevalence of discrepant haemodynamic data.12,14,26,27 In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, AVAi did not improve the prediction of aortic valve events or cardiovascular death compared to AVA.26,27 A linear relationship between AVA and body surface area may not be the optimal correction factor and likely oversimplifies the different implications of body size, overweight status and obesity that might require different correction factors.14,28 Nevertheless, body size should be considered when confronted with discordant haemodynamic data.

Inconsistencies Between Different Criteria for Severe Aortic Stenosis in the Valve Guidelines Inherent in the definition of severe AS is that a MG of 40 mmHg equates to an AVA of 1.0 cm2. However, the relationship between

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MG and AVA is a function of cardiac output, heart rate and systolic ejection period. A patient with a cardiac output of 6 l/min, a heart rate of 70 bpm and a systolic ejection period of 330 msec would have a MG of 34 mmHg if AVA was 1.0 cm2, not 40 mmHg as suggested by the guidelines. Potentially, MG could be as low as 26 mmHg with an AVA of 1.0 cm2 despite a normal cardiac output.29

Low Flow State MG is directly proportional to the squared function of transvalvular flow and can be small (<40 mmHg) despite an AVA≤1.0 cm2 if transvalvular flow is significantly reduced.16,18,19 Low flow is usually considered when the LVEF is reduced, but should not be excluded when the LVEF is normal. Low flow has been defined as an indexed stroke volume (SVi)<35 ml/m2;19,30 however, measures that account for the systolic ejection period (i.e. mean transvalvular flow rate <200–250 ml/s) are theoretically likely more appropriate.

Hypertension, significant mitral or tricuspid valve disease, pulmonary artery hypertension and atrial fibrillation are clinical entities often co-existing with AS and associated with low flow despite a normal LVEF. Elevated blood pressure can reduce transvalvular flow and result in a smaller MG, smaller AVA and discordant measurements.31 In patients with uncontrolled hypertension, low flow and discordant data, blood pressure should be corrected and the echocardiogram repeated as normalisation of flow may resolve the discrepancy.

Low transvalvular flow can also be present in AS patients without concomitant valve disease or pulmonary artery hypertension, a clinical entity often referred to as paradoxical low flow AS, because of the paradoxical association of a low flow state despite a preserved LVEF.30 These patients tend to be older, female and have associated hypertension, metabolic syndrome, diabetes or atrial fibrillation.19,30,32–34 They also tend to have smaller left ventricular cavities with concentric remodeling, myocardial fibrosis, reduced compliance and restrictive physiology.19,34,35 Despite the preserved LVEF, they have evidence of intrinsic systolic dysfunction with impaired longitudinal shortening.34–37

The Reduced Left Ventricular Ejection Fraction Patient The presence of a low flow state is often the first assumption when encountering discrepant haemodynamic data in the AS patient with a reduced LVEF. However, not all patients with a reduced LVEF have a low flow state. SVi or mean transvalvular flow rate (<35 ml/m2 and <200–250 ml/s, respectively) should be calculated to confirm the presence of low flow and measurement error excluded.

Additional Complementary Investigations Discordant measurements can usually be resolved by systematically considering the above issues. However, multi-detector computed tomography (MDCT), magnetic resonance imaging (MRI) and cardiac catheterisation can be helpful when the cause for the discrepancy is not apparent and the patient has symptoms or unexplained left ventricular dysfunction. AVA, LVOT area and SV can be obtained non-invasively using MDCT or MRI and compared with the echocardiography data.22,38–40 Aortic valve calcification (AVC) can be quantified using MDCT and may help clarify discordant data. AVC>~1,250 Agatston units (AU) in women and >~2,050 AU in men suggests the presence of severe AS.41 Cardiac catheterisation provides a direct measurement of MG or AVA by Gorlin equation, and can evaluate for coronary artery disease as an alternate explanation for symptoms or left ventricular dysfunction.39

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Risk Assessment and Management Figure 1: Survival of Medically Managed (Censored at Aortic Valve Replacement) Severe Aortic Stenosis Patients with Left Ventricular Ejection Fraction ≥50 % (n=1,704) Based on the Flow Pressure Gradient Classification

Flow Pressure Gradient Classification Patients with AVA≤1.0 cm2 and a normal LVEF can be classified into four subtypes based on the presence of: • normal flow (NF) or low flow (LF) (SVi≥ or <35 ml/m2); and • high MG (HG) or low MG (LG) (MG≥ or <40 mmHg).36,37

100

Survival (%)

80 60 40 20 0 0

1

2

3

Years LF/HG LF/HG LF/LG NF/HG NF/LG

LF/LG 80.8(8) 82.5(23) 83.0(223) 91.0(190)

NF/HG 80.8(5) 44.1(8) 66.9(108) 82.3(112)

NF/LG 60.6(1) 27.6(3) 52.7(56) 72.7(65)

The NF/LG group had the best survival and the LF/LG group had the worst (p<0.0001).

AVR = aortic valve replacement; HG = high gradient; LF = low flow; LG = low gradient; NF = normal flow. Source: Eleid et al., 2013,32 reproduced with permission from the publisher (Wolters Kluwer Health).

Risk Stratification and the Prediction of Outcome Using Echocardiography Asymptomatic Aortic Stenosis with Normal Left Ventricular Ejection Fraction Peak Aortic Stenosis Velocity and the Rate of Haemodynamic Progression VAS is the strongest predictor of clinical outcome, even in the subgroup with severe AS.1,2,42–45 For asymptomatic AS patients with VAS<3m/s, 3–4 m/s and >4 m/s, approximately 15 %, 35 % and 75 % of patients, respectively, will develop symptoms requiring AVR within three years.1–3,42,45 VAS>5.5 m/s is associated with a poor three year event-free survival of only 11 %,44 and the European Society of Cardiology (ESC) and American Heart Association (AHA)/ American College of Cardiology (ACC) valve guidelines consider AVR reasonable in these asymptomatic patients if the surgical risk is low (IIa recommendation).9,10 AVA also predicts event-free survival, although the relationship is not as robust as VAS.1,42,43,46 This may relate in part to an inherent bias by which clinicians may be more likely to refer patients with a higher VAS or MG for AVR. Rapid haemodynamic progression, defined as an increase in VAS≥0.3 m/s/yr, identifies patients at increased risk for clinical events.1,3,45 Severe AS patients with rapid haemodynamic progression have an event rate as high as 80 % in two years,3 and according to the ESC and AHA/ACC valve guidelines, AVR may be considered in an asymptomatic patient at low surgical risk (IIa and IIb recommendation, respectively).9,10

Valve Calcification Valve calcification is best evaluated clinically using MDCT. However, valve calcification assessed by echocardiography is a strong predictor of haemodynamic and clinical progression across the spectrum of disease severity, and independent of the haemodynamic severity.3,45 Calcification can be graded as none, mild (isolated small spots), moderate (multiple bigger spots) and severe (extensive thickening/calcification of all cusps).

Severe AS patients with moderate or severe valve calcification have an event rate of 80 % at four years, but only 25 % with no or mild calcification.3

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Most patients (52–73 %) have the NF/HG pattern, in which MG and AVA are concordant for severe AS and SVi is normal.30,32,36,37 The NF/ LG pattern is present in 15–31 %, and encompasses patients with inherent inconsistencies in the cut-points for severe AS, small body size and prolonged ejection times in which SVi is normal but transvalvular flow rate may be reduced. The LF/HG pattern is observed in 3–13 %, and includes patients with concordant indices but intrinsic left ventricular dysfunction despite a normal LVEF. The LF/LG pattern is present in 3–19 % of patients, a group characterised by discordant haemodynamic indices and a low flow state.

The flow pressure gradient classification provides important prognostic information for severe AS patients with a normal LVEF. The NF/LG pattern has the highest event-free survival, while the LF/LG pattern has the worst outcome.32,34,37,47 The NF/HG and LF/HG patterns have intermediate survival. In Eleid et al.,32 survival with medical management (censored at AVR) at two years was 82 % in NF/LG patients, 81 % in LF/HG patients, 67 % in NF/HG patients and 44 % in LF/LG patients (p<0.0001) (see Figure 1). AVR conferred a strong survival benefit in LF/LG and NF/HG patients, but no benefit in NF/LG patients. However, other investigators have observed a survival benefit of AVR in both symptomatic LF/LG and NF/LG patients.48–51 SVi appears to be an important marker of prognosis and has a graded association with mortality in severe low gradient AS patients with preserved LVEF.52,53

Left Ventricular Function Only a minority of severe AS patients present with a reduced LVEF and the prognosis is poor without AVR.9,54 However, a large proportion of severe AS patients with normal LVEF have intrinsic systolic dysfunction with abnormal global longitudinal strain on speckle tracking imaging.55–57 Patients with moderate or severe AS and global longitudinal strain ≤15 % have a poor two-year event-free survival of ≈30 %, as compared with 65 % if >15 %.56,57 There are no data to justify AVR in asymptomatic patients with impaired longitudinal strain, although close follow-up is likely warranted.

Valvular Arterial Impedance Valvular arterial impedance (Zva) provides a measure of global LV load due to the valve stenosis and vascular afterload. Zva is calculated as (SBP+MG)/SVi, where SBP is the systolic blood pressure.58 In asymptomatic patients with moderate or severe AS, Zva>4.5–5.0 mmHg/ml/m2 predicts reduced event-free survival and a 2.8-fold increased risk of death;56,58 however, Zva does not identify the relative contributions of the valve and vasculature that is necessary to guide management (i.e. AVR versus blood pressure [BP] control).

Exercise Echocardiography More than 50 % of patients with asymptomatic severe AS develop symptoms within three years, and the subsequent prognosis is poor without timely AVR.1–3,8 Exercise testing can unmask symptoms in as many as one third of patients and a positive exercise test predicts the need for AVR or death.59–61 The ESC and AHA/ACC valve guidelines

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Exercise echocardiography may provide additional prognostic information beyond the exercise test. An exercise increase in MG>18–20 mmHg potentially identifies severe AS patients at increased risk for symptoms, AVR or death, even with a normal exercise test (see Figure 2).62,63 The adverse prognosis of patients with greater increases in MG likely reflects a more severely stenotic or non-compliant valve with minimal opening reserve. In the ESC guidelines, AVR may be considered in these patients if the surgical risk is low (IIb recommendation).10 Failure of LVEF to increase with exercise is also associated with an abnormal exercise test and reduced event-free survival (event-free survival <40 % at two years).64 Although not specifically addressed in either valve guidelines, these patients should at a minimum be observed closely for surgical indications.

Resting and exercise changes in global longitudinal strain are associated with an abnormal stress test and reduced event-free survival; however, their incremental prognostic value requires further study.55,65 Pulmonary hypertension is associated with poor outcomes and higher complication rates with valve intervention.66,67 The prevalence of pulmonary hypertension at rest in asymptomatic AS patients is low; however, exercise-induced pulmonary hypertension may develop in >50 % of severe AS patients.68 Pulmonary systolic pressure >60 mmHg with exercise is associated with a twofold increased risk of cardiac events and a reduced cardiac event-free survival at three years (22 ± 7 versus 55 ± 9 %; p=0.014), independent of the change in MG with exercise.68 Exercise pulmonary hypertension appears to unmask a severe impairment of diastolic function. Close follow-up of these patients is likely warranted.

Low-flow, Low-gradient Aortic Stenosis Low-flow, Low-gradient Severe Aortic Stenosis with Reduced Left Ventricular Ejection Fraction Definition Low-flow, low-gradient severe AS with reduced LVEF, or classical low-flow, low-gradient AS,19 is defined by a MG<40 mmHg or VAS<4 m/s, AVA≤1.0 cm2, and a LVEF<40–50 %.9–11 Inherent in the definition is that flow is reduced, although no specific criteria are included in the guidelines. Individual studies have used a cardiac index <3.0 l/min/m2 or SVi <35 ml/m2,18,19 although measures such as transvalvular flow rate (<200–250 ml/s) may be more appropriate.

These patients represent a diagnostic and management challenge since the severity of the underlying valve stenosis is often unclear, AVR is associated with a high operative risk and the benefits of AVR to alleviate symptoms or significantly improve prognosis may be limited in some patients.16–19,54,69–71

Figure 2: Event-free Survival (Cardiovascular Death or Aortic Valve Replacement) of Aortic Stenosis Patients with a Normal Exercise Test (n=135) Based on the Rest Mean Gradient and Exercise Increase in Mean Gradient C 100 Rest MG≤35 & Exer. ∆MG>20

80 Event-free Survival (%)

consider AVR indicated in asymptomatic severe AS patients with symptoms on exercise testing (Class I recommendation) or a drop in BP (IIa recommendation).9,10

Rest MG≤35 & Exer. ∆MG≤20

60 Rest MG>35 & Exer. ∆MG≤20

40 20 P<0.0001 0 0

6

12

18

24

Rest MG>35 & Exer. ∆MG>20

Follow-up (months) Number of patients at risk 9 9 9 59 57 49 47 34 27 20 11 6

8 38 24 3

8 29 13 0

AVR = aortic valve replacement; Exer. MG = exercise-induced increase in mean pressure gradient; MG = mean pressure gradient. Source: Marechaux et al., 2010,63 reproduced with permission from Oxford University Press.

encountering the patient with low-flow, low-gradient severe AS with reduced LVEF is to distinguish the patient with ‘true’ severe AS (TSAS), where the valve is severely stenotic and afterload mismatch exists, from the patient with ‘pseudo-severe’ AS (PSAS), where the underlying valve is only mild or moderately stenotic, but appears severe due to low flow and the inability of a poorly functioning ventricle to sufficiently open the valve. AVR is likely beneficial in the TSAS patient, but may not be beneficial in the PSAS patient since the valve is not the primary problem.

PSAS is reported to be present in 5–35 % of these patients depending on the specific diagnostic criteria used.69,70,80–82

True Versus Pseudo-severe Aortic Stenosis

TSAS and PSAS can be distinguished by augmenting transvalvular flow using dobutamine stress echocardiography (DSE) and re-evaluating the valve haemodynamics at a normal flow state. A commonly used DSE protocol employs an initial infusion of 2.5–5.0 ug/kg/min, followed by incremental infusions of 2.5–5.0 ug/kg/min at 5–8 minute stages to a maximum dose of 20 ug/kg/min.71,82 This low dose, longer stage protocol minimises the potential for myocardial ischaemia and allows for steady state acquisition of LVOT and transvalvular velocities.

Patients with TSAS and an underlying ‘fixed’ valve stenosis would be expected to have little change in AVA and a large increase in MG during DSE. In contrast, patients with PSAS would be expected to have an increase in AVA outside of the severe range and only a small increase in MG due to the larger AVA.

AVA, whether measured by continuity equation or orifice planimetry, is affected by flow and becomes smaller when transvalvular flow is reduced.72–74 This phenomenon has been attributed to flow dependence of the flow convergence,75–77 flow-mediated effects on the vena contracta spatial velocity profile,76 reductions in anatomic orifice area due to smaller flow-mediated forces,78,79 or a combination of these factors.

The potential effect is that AVA may appear only mild or moderately stenotic when assessed under normal flow conditions, but potentially severe when assessed under low flow conditions. The challenge when

Criteria used to diagnose TSAS have included a DSE peak MG>30–40 mmHg, an AVA increase <0.3 cm2, and/or a DSE peak AVA≤1.0–1.2 cm2.18,19,69,70,80–82 PSAS is suggested if the DSE peak AVA is >1.0–1.2 cm2 and the peak MG is ≤30 mmHg or the AVA increase is ≥0.3 cm2. In the AHA/ACC valve guidelines, AVR is considered reasonable in symptomatic patients with low-flow, low-gradient severe AS with reduced LVEF if VAS is ≥4.0 m/s or MG is ≥40 mmHg with an AVA≤1.0 cm2 at any time during DSE (IIa recommendation).9 While this criteria is specific for TSAS, many

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Risk Assessment and Management Figure 3: Survival Curves for Low-flow, Low-gradient Aortic Stenosis Patients with Reduced Left Ventricular Ejection Fraction (n=136) and Contractile Reserve (Group I) or No Contractile Reserve (Group II) Based on Whether They Underwent Valve Replacement or Medical Treatment

Figure 4: Survival Curves for Low-flow, Low-gradient Aortic Stenosis Patients with Reduced Left Ventricular Ejection Fraction Based on (A) Dobutamine Stress Echocardiography Peak Left Ventricular Ejection Fraction ≤35 or >35 % (n=101) and (B) Dobutamine Stress Echocardiography Peak Global Longitudinal Strain Rate ≤-0.5s -1 or >-0.5s -1 (n=47)

Group I, Valve Replacement

75

80 LVEF peak >35 %

50

Group II, Valve Replacement Group I, Medical Treatment

25

Group II, Medical Treatment 0

A 100

Survival (%)

Patient Survival (%)

100

60 LVEF peak ≤35 %

40 p=0.03 20

0

50

100

54

45

41

31

27

19

13

47

29

24

17

15

12

10

6

12

18

24

30

36

0

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0

Source: Monin et al., 2003,70 reproduced with permission from Wolters Kluwer Health.

Follow-up (month)

A significant limitation to distinguishing TSAS and PSAS patients relates to the marked inter-individual variability to which flow augmentation occurs with DSE.74,82 Some patients have very little increase in transvalvular flow during DSE and a low flow state persists.

Other patients have a large increase in transvalvular flow with supranormal flow rates. Since the increase in MG and AVA are largely dependent on the magnitude of flow augmentation, interpretation of the underlying AS severity without consideration of the transvalvular flow is problematic. To address this issue, the projected AVA (AVAproj) at 250 ml/s has been proposed to standardise the calculation of AVA at a normal flow rate and better distinguish TSAS and PSAS.82,83 Transvalvular flow rate and AVA generally display a linear relationship in AS patients with the slope varying between patients.72,74 AVAproj can be calculated by measuring AVA and transvalvular flow rate at a minimum of two different flow rates during DSE using the equation: AVAproj = AVArest + VC x (250-Qrest) where AVArest is the resting AVA, Qrest is the resting mean transvalvular flow rate and VC is the ‘valve compliance’ or slope of the valve area – transvalvular flow relationship.82

B 1.0

0.8 Survival probability

patients with TSAS have a MG<40 mmHg during DSE because of poor contractile reserve or inherent inconsistencies in the criteria for severe AS.69,82,83 A lower cut-point for MG (i.e. >30 mmHg) may be justified to avoid underdiagnosing TSAS patients in whom the prognosis without AVR is extremely poor.69–71,82,83

p=0.0021 0.6

0.4

0.2

0.0 0

Patients at risk: 23 21

21

21

20

24

20

15

10

9

6

12

18

24

Survival time (months) peak stress PLSR≤-0.5s-1

peak stress PLSR>-0.5s-1

DSE = dobutamine stress echocardiography; LVEF = left ventricular ejection fraction; PLSR = peak global longitudinal strain rate. Source for Figure 4A: Clavel et al., 2008,71 reproduced with permission from Wolters Kluwer Health. Source for Figure 4B: Bartko et al. 2013,86 reproduced with permission from Wolters Kluwer Health.*

In an initial 23 patients undergoing surgical inspection, AVAproj≤1.0 cm2 and an AVAproj≤0.55 cm2/m2 correctly classified 83 % and 91 % of patients, respectively.82 In a larger study of 52 patients, a simplified approach was used to calculate VC that only required the measurement of resting and peak DSE transvalvular flow rate and AVA:

Quantitation of AVC by MDCT may provide an additional technique to potentially distinguish TSAS from PSAS, and be especially helpful in those patients in whom the DSE is non-diagnostic or the augmentation of transvalvular flow is minimal. In 18 patients with classical low-flow, low-gradient AS, AVC≥1,651 AU correctly classified 89 % of patients as having either TSAS or PSAS.84 Gender specific thresholds for identifying TSAS are likely warranted based on studies in AS patients with preserved LVEF (~1,250 AU in woman and ~2,050 AU in men), although this has not been studied in classical low-flow, low-gradient AS.41

VC = (AVApeak - AVArest)/(Qpeak - Qrest)

Prediction of Clinical Outcome

AVAproj≤1.0 cm2 correctly classified 92 % of patients, and was superior to DSE peak AVA<1.2 cm2 (77 %), peak MG>30 mmHg (73 %) and AVA increase <0.3 cm2 (60 %).83 However, AVAproj needs to be interpreted cautiously if the increase in transvalvular flow rate is <15 % due to inaccuracies in calculating VC.82

Contractile or flow reserve, defined as a 20 % increase in SV with DSE, is a strong predictor of peri-operative mortality rate and long-term survival.69,70 AVR is associated with a peri-operative mortality rate as high as 33 % in patients with no contractile reserve, but only 5–8 % in patients with contractile reserve.54,69,70 In the European Multicentre study, three-year survival of patients with contractile

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Echocardiographic Evaluation of Aortic Stenosis

Patients with no contractile reserve have a high operative mortality rate and poor long-term survival; however, their survival is better with AVR than medical therapy when tested using propensity matched analysis.54 Furthermore, patients with no contractile reserve have similar improvements in LVEF and New York Heart Association (NYHA) functional class following AVR as patients with contractile reserve.85 In essence, absence of contractile reserve identifies patients with a high operative mortality rate and reduced long-term survival who may still benefit from AVR. In the ESC guidelines, AVR should be considered in symptomatic patients with evidence of flow reserve (IIa recommendation) and may be considered in symptomatic patients without flow reserve (IIb recommendation).10

Figure 5: Event-free Survival of Low-flow, Low-gradient Severe Aortic Stenosis Patients with Left Ventricular Ejection Fraction >50 % (n=55) Based on (A) AVAproj and (B) Indexed AVAproj A 100 AVAproj>1 CM2

80 Event-free Survival, %

reserve undergoing AVR was 79 %, significantly better than the 35 % survival observed in patients with no contractile reserve (see Figure 3).70 Patients with contractile reserve did significantly better with AVR than medical management (three-year survival <25 %).

60 AVAproj≤1 CM2

40 HR=1.25; p=0.008 HR=132; p=0.002

20

18

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37

22

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0 0

contractile reserve in TOPAS and the European Multicentre Study may have related to different DSE protocols or differences in the study population (TOPAS had a greater prevalence of concomitant diseases such as coronary artery disease).70,71 Additionally, DSE peak LVEF is essentially a composite measure of both resting LVEF and ‘contractile reserve’, and may explain the better predictive value of this parameter.

Longitudinal strain parameters are severely impaired in low-flow, low-gradient severe AS with reduced LVEF, but may improve with DSE in a substantial proportion of patients. In a substudy of TOPAS, patients with a DSE peak global longitudinal strain rate (PLSR) <-0.5 s-1 had a two-year survival of 91 %, but only 40 % if DSE PLSR was ≥-0.5 s–1 (see Figure 4B).86 DSE PLSR was the strongest predictor of overall survival and added incremental prognostic information to DSE peak LVEF.

Low-flow, Low-gradient Severe Aortic Stenosis with Preserved Left Ventricular Ejection Fraction Definition The criteria for low-flow, low-gradient severe AS with preserved LVEF include a VAS<4 m/s or MG<40 mmHg, AVA≤1.0 cm2, LVEF>50 % and SVi<35 ml/m2.9–11,19

True Versus Pseudo-severe Aortic Stenosis Patients with low-flow, low-gradient severe AS with preserved LVEF have similar transvalvular flow rates as classical low-flow, low-gradient severe AS.83,87 Since transvalvular flow is reduced, the small AVA may reflect underlying TSAS or PSAS. The prevalence of PSAS is reported to be ≈30 % in these patients, similar to what is observed in classical low-flow, low-gradient severe AS.87 DSE and exercise echocardiography have been used to distinguish TSAS and PSAS in one small study.87 AVAproj≤1.0 cm2 was 94 % accurate in distinguishing the two conditions when compared to surgical inspection, and performed better than DSE peak MG≥30 mmHg (75 %) or ≥40 mmHg (81 %) and DSE peak AVA≤1.0 cm2 (69 %) or ≤1.2 cm2 (63 %). In the AHA/ACC and ESC valve guidelines, AVR is reasonable in symptomatic patients if the clinical, haemodynamic and

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Follow-up time (months) B Indexed AVAproj>0.55 cm2/m2

100 80 Event-free Survival, %

In the True or Pseudo Severe Aortic Stenosis (TOPAS) study of 101 patients with low-flow, low-gradient severe AS with reduced LVEF, independent echocardiographic predictors of reduced survival were AVAproj≤1.2 cm2 and DSE peak LVEF≤35 % (see Figure 4A).71,83 Contractile reserve was not an independent predictor of survival.71 The conflicting findings regarding the predictive value of

6

60 Indexed AVAproj≤0.55 cm2/m2 40 HR=1.55; p=0.002 HR*=1.59; p=0.002 20 19

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6

Follow-up time (months) AVAproj = projected aortic valve area; HR = hazard ratio. * on Figure 5B is hazard ratio (HR) adjusted for age and sex. Source: Clavel et al., 2013,87 reproduced with permission from Elsevier.

anatomic data support valve obstruction as the most likely cause of the symptoms (IIa recommendation).9,10 Reserving surgical intervention only for symptomatic TSAS patients appears theoretically sound, although this management strategy has not been tested.

Measurements of AVC using MDCT may have a role in identifying TSAS and PSAS in patients with low-flow, low-gradient severe AS with preserved LVEF. In 451 patients with at least moderate AS, preserved LVEF, normal SVi and concordant MG and AVA measurements, an AVC threshold of 1,274 AU in women and 2,065 AU in men correctly classified 87 % of patients as having moderate AS or severe AS.41 A similar 87 % accuracy was obtained using an AVC indexed to aortic annulus area threshold of 292 AU/cm2 for women and 476 AU/cm2 for men. In a further 172 patients with preserved LVEF and discordant AS measurements (MG<40 mmHg and AVA≤0.6 cm2/m2), ~50 % of patients had an AVC score consistent with moderate rather than severe AS.41 Low flow (SVi <35 ml/m2) was present in ~16 % of these patients; however, results for this subgroup were not provided and DSE results were not reported. Further studies are warranted to determine whether AVC thresholds can be used to distinguish TSAS and PSAS in low-flow, low-gradient severe AS with preserved LVEF.

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Risk Assessment and Management Prediction of Clinical Outcome

Conclusion

AVAproj and indexed AVAproj are strong predictors of adverse outcome in patients with low-flow, low-gradient severe AS with preserved LVEF (hazard ratio: 1.32 and 1.59, respectively, for each 0.1 cm2 decrease in AVAproj and indexed AVAproj) and is superior to traditional parameters of stenosis severity for predicting outcome.87 More than 90 % of patients with AVAproj>1.0 cm2 or indexed AVAproj>0.55 cm2/m2 remain free of death or AVR at 12 months, whereas only 50 % of patients with AVAproj≤1.0 cm2 or AVAproj≤0.55 cm2/m2 will be free of death or AVR (see Figure 5).87

The role of echocardiography in the evaluation of AS patients has progressed beyond the measurement of resting MG and AVA. Challenging situations in which patients have discordant haemodynamic data, asymptomatic haemodynamically severe AS or severe low-flow, low-gradient AS have resulted in new approaches to improve the haemodynamic evaluation, risk stratification and prediction of clinical outcome for patients with both normal-flow and low-flow AS. Integration of these advances will help ensure that AS patients receive the most appropriate management. n

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65. Donal E, Thebault C, O’Connor K, et al., Impact of aortic stenosis on longitudinal myocardial deformation during exercise, Eur J Echocardiogr, 2011;12:235–41.

66. McHenry MM, Rice J, Matlof HJ, Flamm MD Jr, Pulmonary hypertension and sudden death in aortic stenosis, Br Heart J, 1979;41:463–7.

67. Carnero-Alcázar M, Reguillo-Lacruz F, Alswies A, et al., Short- and mid-term results for aortic valve replacement in octogenarians, Interact Cardiovasc Thorac Surg, 2010;10:549–54.

68. Lancellotti P, Magne J, Donal E, et al., Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis, Circulation, 2012;126:851–9.

69. Nishimura RA, Grantham A, Connolly HM, et al., Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function. The clinical utility of the

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Echocardiographic Evaluation of Aortic Stenosis

dobutamine challenge in the catheterization laboratory, Circulation, 2002;106:809–13.

70. Monin JL, Quéré JP, Monchi M, et al., Low-gradient aortic stenosis: operative risk stratification and predictors for longterm outcome: a multicenter study using dobutamine stress hemodynamics, Circulation, 2003;108:319–24.

71. Clavel MA, Fuchs C, Burwash IG, et al., Predictors of outcomes in low-flow, low gradient aortic stenosis: results of the multicenter TOPAS Study, Circulation, 2008;118(14suppl):S234–42.

72. Burwash IG, Thomas DD, Sadahiro M, et al., Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis, Circulation, 1994;89:827–35.

73. Burwash IG, Pearlman AS, Kraft CD, et al., Flow dependence of measures of aortic stenosis severity during exercise, J Am Coll Cardiol, 1994;24:1342–50.

74. Burwash IG, Hay KM, Chan KL, Hemodynamic stability of valve area, valve resistance, and stroke work loss in aortic stenosis: a comparative analysis, J Am Soc Echocardiogr, 2002;15:814–22.

75. Segal J, Lerner DJ, Miller C, et al., When should Doppler determined valve area be better than the Gorlin formula?

Variation in hydraulic constants in low flow states, J Am Coll Cardiol, 1987;9:1294–305.

76. DeGroff CG, Shandas R, Valdes-Cruz L, Analysis of the effect

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of flow rate on the Doppler continuity equation for stenotic orifice area calculations: a numerical study, Circulation, 1998;97:1597–605.

77. Kadem L, Rieu R, Dumesnil JG, et al., Flow-dependent changes in Doppler derived aortic valve effective orifice area are real and not due to artifact, J Am Coll Cardiol, 2006;47:131–7.

78. Montarello JK, Perakis AC, Rosenthal E, et al., Normal and stenotic human aortic valve opening: in vitro assessment of orifice area changes with flow, Eur Heart J, 1990;11:484–91.

79. Chambers JB, Sprigings DC, Cochrane T, et al., Continuity equation and Gorlin formula compared with directly observed orifice area in native and prosthetic aortic valves, Br Heart J, 1992;67:193–9.

80. deFilippi CR, Willett DL, Brickner ME, et al., Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients, Am J Cardiol, 1995;75:191–4.

81. Schwammenthal E, Vered Z, Moshkowitz Y, et al., Dobutamine echocardiography in patients with aortic stenosis and left ventricular dysfunction: predicting outcome as a function of management strategy, Chest, 2001;119:1766–77.

82. Blais C, Burwash IG, Mundigler G, et al., Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (Truly or Pseudo-Severe

Aortic Stenosis) study, Circulation, 2006;113:711–21.

83. Clavel MA, Burwash IG, Mundigler G, et al., Validation of conventional and simplified methods to calculate projected valve area at normal flow rate in patients with low flow, low gradient aortic stenosis: the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study, J Am Soc Echocardiogr, 2010;23:380–6.

84. Cueff C, Serfaty JM, Cimadevilla C, et al., Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction, Heart, 2011;97:721–6.

85. Quere JP, Monin JL, Levy F, et al., Influence of preoperative left ventricular contractile reserve on postoperative ejection fraction in low-gradient aortic stenosis, Circulation, 2006;113:1738–44.

86. Bartko PE, Heinze G, Graf S, et al., Two-dimensional strain for the assessment of left ventricular function in low flow-low gradient aortic stenosis, relationship to hemodynamics, and outcome: a substudy of the multicenter TOPAS study, Circ Cardiovasc Imaging, 2013;6:268–76.

87. Clavel MA, Ennezat PV, Maréchaux S, et al., Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF, JACC Cardiovasc Imaging, 2013;6:175–83.

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Heart Failure

Update on Cardiac Resynchronisation Therapy for Heart Failure David D Daly Jr and Michael R Gold Medical University of South Carolina, Charleston, South Carolina, US

Abstract Cardiac resynchronisation therapy (CRT) is well accepted therapy for the treatment of symptomatic systolic heart failure in defined patient subgroups. Large clinical trials over the past 20 years have shown that patients with a left ventricular (LV) systolic dysfunction and interventricular conduction delay benefit from this therapy. Recent advances in this field include the expansion indications for CRT to patients with mild heart failure and to those with a mildly depressed ejection fraction that require frequent right ventricular pacing. In addition, although CRT guidelines have included indications in atrial fibrillation, it is now clear that this is most effective when pacing is utilised nearly 100 % of the time, often requiring atrioventricular (AV) junction ablation. Strategies for optimising LV lead placement based on identifying late mechanical contraction or electrical delay are promising for maximising CRT response. Finally, the role of routine AV delay optimisation is no longer recommended based on the results of multicentre trials.

Keywords Cardiac resynchronisation therapy, heart failure, pacing Disclosure: David Daly has no conflicts of interest to declare. Michael Gold has received research grants and served as a consultant to Boston Scientific, St Jude and Medtronic.

Received: 10 October 2014 Accepted: 11 November 2014 Citation: European Cardiology Review, 2014;9(2):100–3 Correspondence: Michael R Gold, Division of Cardiology, Medical University of South Carolina, 25 Courtenay St, ART 7031, Charleston, SC 29425, US. E: goldmr@musc.edu

Interventricular conduction delay is common in patients with systolic heart failure (HF) and has been associated with a poor prognosis amongst these patients.1 Abnormal ventricular depolarization results in prolonged ventricular activation time and increased myocardial tension thus increasing myocardial oxygen consumption and decreasing ventricular diastolic filling time. In addition, asynchronous ventricular contraction caused by conduction delay induces ventricular remodeling and has been shown to increase the duration of mitral regurgitation.2,3 Cardiac resynchronisation therapy (CRT) has been investigated as a therapy to reverse the deleterious effects of conduction delay by improving electrical and mechanical synchrony.

The first attempt CRT was performed over thirty years ago by placing an epicardial lead on the left ventricular lateral wall in patients with a left bundle branch block undergoing aortic valve replacement.4 Subsequently, Bakker, Gold and others assessed the role of epicaridal pacing in HF. Later, Daubert et al. reported the first case series of patients undergoing left ventricular pacing by transvenous lead placement into the coronary sinus.5 During the early years of CRT, a haemodynamic benefit of improved interventricular synchrony was shown setting the stage for future study. Since that time, multiple large, randomised clinical trials have been performed and demonstrated that CRT improves mortality and clinical outcomes in severe HF patients who are symptomatic despite optimal medical therapy.6–9

Expanding Indications for Cardiac Resynchronisation Therapy In Heart Failure The indications for CRT were recently updated in the European and American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines due

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in part to recent clinical trials on the subject.1,10 Subsequently, the Resynchronization Reverses Remodeling in Systolic left Ventricular Dysfunction (REVERSE) and Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trials demonstrated that subjects with New York Heart Association (NYHA) class I or II HF had better outcomes with CRT.11–13 The Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) extended these findings with a longer follow-up showing that CRT with implantable defibrillator (ICD) backup (CRT defibrillator [CRT-D]) prolongs survival compared with ICD alone, in NYHA class II subjects.14 Post hoc analysis of the patients included in the MADIT-CRT and REVERSE trials revealed that the mildly symptomatic patients with only mild left ventricular systolic dysfunction also benefitted from CRT, suggesting that a larger population of patients may benefit from CRT.15 After the revision of the guidelines, the Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block (Block-HF) trial was published showing benefit of CRT in patients with an indication for pacing and a mildly depressed ejection fraction. The BLOCK-HF trial randomised 691 patients with an indication for pacemaker placement and an ejection fraction ≤50 % to biventricular (BiV) or right ventricular (RV) pacing. The primary endpoint was a composite of death from any cause, HF care requiring intravenous therapy or evidence of adverse cardiac remodeling as measured by an increase in left ventricular end-systolic volume index of ≥15 %. There were statistically improved outcomes with CRT for both the composite primary outcome as well as a secondary outcome of HF hospitalisation.16,17 The Block-HF trial supports the previously published Dual Chamber and VVI Implantable Defibrillator

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(DAVID) and Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) trials suggesting that frequency of right ventricular pacing leads to adverse clinical outcomes and adverse ventricular remodeling.18,19 Despite the Block-HF trial, concern has been raised about the composite endpoint being driven mostly by adverse ventricular remodeling rather than ‘harder’ clinical outcomes, and that the control arm also received a LV lead that was programmed not to pace thus neutralising procedural complications.20 These concerns were further heightened by the recent preliminary report of the Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BIOPACE) trial. The BIOPACE trial was designed to randomise subjects with an indication for permanent ventricular pacing, but no guideline indication for CRT pacing, to standard right ventricular pacing device verses BiV device. Primary endpoints include the combination of time-to-death or first HF admission and secondary endpoints include quality of life, six-minute hall walk and echocardiographic signs of adverse remodeling.21 Preliminary results presented at the ESC Congress 2014 were notable for a non-significant 13 % reduction in the primary endpoint with CRT.22 The inconsistent results from this and other studies may reflect some of the challenges of designing trials for implantable devices. Many of these design issues are evident comparing the REVERSE study, which had an implanted, double-blind design and MADIT-CRT, which was unblinded with one arm receiving CRT-D devices and the other arm ICD. The challenges of performing a device-based trial in HF have been discussed elsewhere.23

Cardiac Resynchronisation Therapy in Atrial Fibrillation Despite the abundant data on CRT among patients in sinus rhythm, this therapy in patients with atrial fibrillation (AF) has been less well studied. AF was excluded from most of the clinical trials. In RAFT, which included the largest number of AF patients randomised to CRT, the outcomes of CRT in AF were non-significant, which may be due to the relatively low BiV pacing percentage in this cohort.24 The PAVE trial showed benefit of CRT in patients with a depressed left ventricular ejection fraction undergoing atrioventricular junction (AVJ) ablation secondary to refractory, symptomatic atrial fibrillation.1,19 CRT is also recommended in permanent AF patients that have symptomatic HF with a severely depressed ejection fraction and significant interventricular conduction delay.1 Currently, AVJ ablation is recommended after the inability to achieve complete BiV pacing.1 Recent studies have indicated that a very high pacing percentage is required to achieve full CRT benefit. One large cohort of patients followed by remote telemetry monitoring suggested over 98 % of conducted beats must be paced beats in order to confer all of the mortality benefits of CRT, and that AF limited the percentage of paced beats.25 The RAFT randomised to CRT without ablation, required patients to be aggressively rate controlled before trial enrolment, with a resting heart rate <60 and a heart rate of <90 after six-minute walk, but still only achieved greater than 95 % BiV pacing in one-third of patients.24 Initial registry and meta-analysis data shows similar outcomes for patients that undergo AVJ ablation to the sinus rhythm group, but worse outcomes for patients in AF who are treated with medical rate control.26–28 Randomised controlled trials are needed to identify the optimal timing of AVJ ablation in the permanent AF population, but the emerging consensus is that more aggressive use of this technique is needed in CRT.

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Cardiac Resynchronisation Therapy Non-Responders Despite the overall benefit demonstrated by CRT, a clinical non-response is noted in approximately one-third of patients throughout the literature, although this estimate varies based on the clinical outcome used to define response.29,30 CRT is an expensive and invasive therapy thus significant interest in understanding, predicting and reducing non-responders has been evaluated. The reason for the clinical non-response is complicated and likely multifactorial in most patients with irreversibly advanced HF, myocardial scar, lead placement, lack of clinically significant dyssynchrony and lack of AV and VV optimisation all thought to play a role in certain cases.31 The remainder of this review will highlight some of the proposed methods to decrease the CRT non-response rate.

Improved Patient Selection for Cardiac Resynchronisation Therapy (Electrocardiography and Beyond) Subgroup analyses from multiple studies have shown that the greatest response to CRT is noted with QRS prolongation and left bundle branch block (LBBB). Patients with LBBB and QRS duration >150 ms receive the most benefit from therapy and have a Class I indication in the current guidelines, whereas patients with a non-LBBB and QRS duration of 120–150 ms receive only a Class IIB in severe HF and are not indicated in mild HF.1 Given the expense of large randomised clinical trials and the number of trials that have already addressed these issues in the past, it is unlikely that a trial will be designed with enough power to further tease out the clinical and electrocardiography (ECG) factors that are the best predictors in HF patients in sinus rhythm that do not require RV pacing. Recently a large individual patient meta-analysis of the Cardiac Resynchronization in Heart Failure (CARE-HF), Multicenter InSync Randomized Clinical Evaluation (MIRACLE), REVERSE, MIRACLE ICD and RAFT studies was performed to evaluate the further predictors for CRT response. In this large cohort, QRS duration but not QRS morphology (i.e. LBBB) predicted survival or HF hospitalisations. In addition, CRT response rates did not differ based on ejection fraction including the groups of patients with a left ventricular ejection fraction over 35 %, males and females appeared to respond similarly to CRT, and there were no differences in response rates in patients with a diagnosis of ischaemic or non-ischaemic cardiomyopathy.8,9,14,24,32 There was much early enthusiasm for the use of echocardiography to identify mechanical dyssynchrony to predict CRT response.

However, subsequent prospective multicentre trials failed to support this strategy. The Predictors of Response to CRT (PROSPECT) trial assessed several echocardiographic parameters (including several tissue Doppler parameters and M-mode parameters) to predict CRT response rate, and none of these parameters were found to have clinically useful value.29 More recently, the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) trial was a randomised trial designed to determine if mechanical dyssnchrony as identified by tissue Doppler or colour tracking radial stain predicted CRT response in patients with a QRS duration <130 ms and NYHA class III or IV HF. All patients were implanted with CRT devices with the control group having CRT turned off. The trial was stopped early by the safety monitoring board due to futility with a trend towards increased mortality at the time of trial stoppage.33 These trials further reinforced the importance of QRS duration as a predictor of CRT response.

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Heart Failure Left Ventricular Lead Position The traditional strategy for left ventricular lead placement was based on early haemodynamic studies indicating that the best acute response was achieved with lateral wall positions. Such strict anatomic criteria have not been validated in multicentre studies. Specifically, post hoc analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study showed no significant impact of lead position on outcomes including mortality and HF hospitalisations.34 Subsequently, apical lead position was shown to be associated with increased risk of HF death or hospitalisation in a post hoc analysis of the MADIT-CRT, but this and other studies indicated significant heterogeneity in the ideal left ventricular pacing site to achieve optimal haemodynamic and clinical response.35–37 Furthermore, LV pacing on the site of transmural scar has been associated with an adverse haemodynamic response and scar burden has been associated with poor clinical response to CRT.38–41 Non-invasive methods, such as echocardiography, to identify the site of latest ventricular activation and avoid significant myocardial scar have become the focus of recent randomised trials. The Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) trial randomised 220 consecutive CRT patients to standard based LV lead placement or echocardiogram derived radial strain based LV lead placement. In the echocardiography group the LV lead was placed at the site of latest ventricular activation without evidence of significant myocardial scarring defined by decreased amplitude of contraction. There was a significant increase in the primary endpoint of positive left ventricular remodeling by echocardiogram as well as a decrease in a combined clinical endpoint of death and hospitalisation.42 Long-term follow-up of the TARGET study data at a mean of 39 months has suggested decreased mortality and improved LV remodeling.43 These results have been reinforced by the recently published Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) study.44 The Empiric Versus Imaging Guided Left Ventricular Lead Placement in Cardiac Resynchronization Therapy (ImagingCRT) trial should be complete in the near future and will further evaluate echocardiogram speckle tracking combined with cardiac and single photon emission computed tomography-computed tomography (SPECT CT) to guide lead implant site.45 In addition to late mechanical contraction to guide lead placement, there are accumulating data to show that electrical delay at the site of LV pacing is a strong predictor of CRT response. The most commonly used measure is the QLV interval, which is the time from the onset of the QRS complex to the peak of the local electrogram at the LV electrode. The QLV is a strong predictor of acute haemodynamic response, both with BiV and LV only pacing.46 In addition, QLV is a strong independent predictor of echocardiographic remodeling response as well as quality of life improvement with QLV.47 An analysis of the RV–LV interval, another measure of electrical delay, from the Pacing Evaluation-Atrial Support Study in Cardiac

1. Brignole M, Auricchio A, Baron-Esquivias G, et al., 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA), Eur Heart J, 2013;34:2281–329.

2. Xiao HB, Lee CH, Gibson DG, Effect of left bundle branch

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Resynchronization Therapy (PEGASUS CRT) trial showed that this was an independent measure of HF events.48

Device Optimisation AV delay programming has been shown to have haemodynamic effects in left ventricular pacing but its use is controversial and routine optimisation is not recommended in the current guidelines based on recent trial results.1,49 Despite this fact, almost all trials studying CRT in HF used an echocardiographic method to attempt to improve AV synchrony.50 The method of left ventriculoventricular (VV) optimisation has also been controversial. VV optimisation was somewhat limited in the past as early devices allowed only simultaneous BiV pacing. Current devices are much more complex and diverse allowing individualised programming of the VV intervals and proprietary device algorithms are designed to optimise VV synchrony making programming more complex.

Unfortunately, manual VV optimisation is time-consuming and requires an understanding of both interventricular (left ventricular relative to right ventricular contraction) and the intraventricular (septa-to-posterior delay of the LV) dyssnchrony.50 Methods to measure dyssnchrony have included time-consuming echocardiographic measures as well as left ventricular outflow tract (LVOT) velocity time integral (VTI) measurement at different device settings for optimisation.

More recent large clinical trials such as the SmartDelay determined AV Optimization: A Comparison of AV Optimization Methods Used in Cardiac Resynchronization Therapy (SMART-AV) trial and Frequent Optimization Study using the QuickOpt Method (Freedom) trial used device algorithms for AV and VV optimisation and did not show benefit in clinical endpoints resulting in the current guidelines recommending against routine AV or VV optimisation.1,51,52 The SMART-AV trial randomised CRT patients to a fixed AV delay, echocardiographic mitral inflow based AV delay, or an automated device algorithm based AV delay and found no difference in clinical outcomes or left ventricular end-systolic volume at six months.51 A substudy of the SMART-AV trial using the QLV interval at the LV pacing site showed that the SmartDelay method improved remodeling at six months among patients with long QLV intervals and the LV pacing site.53 The recently published ADAPTIVE trial randomised patients with a normal intrinsic AV interval to left ventricular fusing pacing verses echocardiography optimised BiV pacing and demonstrated non-inferiority in the left ventricular pacing cohort. Higher percent left ventricular pacing was associated with improved clinical outcomes.54 Using AV and VV optimisation in non-responders to CRT and in specific patient populations needs further review.

Conclusion Over the last twenty years the use of CRT has expanded and evolved considerably. The indications for CRT implant now include subjects with mild HF as well as those with mild LV dysfunction and frequent RV pacing. New techniques help to identify optimal sites for LV pacing. Finally, the role of AV optimisation is less clear with routine optimisation discouraged. n

block on diastolic function in dilated cardiomyopathy, Br Heart J, 1991;66:443–7.

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4. de Teresa E, Chamorro JL, Pulpón LA, et al., An Even More Physiological Pacing: Changing the Sequence of Ventricular Activation. In: Steinbach K, editor, Proceedings of the VIIth World Symposium on Cardiac Pacing , Darmstadt, Germany: Steinkoopff,

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5. Daubert JC, Ritter P, Le Breton H, et al., Permanent left ventricular pacing with transvenous leads inserted into the coronary veins, Pacing Clin Electrophysiol, 1998;21:239–45.

6. Abraham WT, Fisher WG, Smith AL, et al., Cardiac resynchronization in chronic heart failure, N Engl J Med, 2002;346:1845–53.

7. Higgins SL, Hummel JD, Niazi IK, et al., Cardiac resynchronization

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therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias, J Am Coll Cardiol, 2003;42:1454–9.

8. Cleland JG, Daubert JC, Erdmann E, et al., Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase], Eur Heart J, 2006;27:1928–32.

9. Young JB, Abraham WT, Smith AL, et al., Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial, JAMA, 2003;289:2685–94.

10. Tracy CM, Epstein AE, Darbar D, et al., 2012 ACCF/AHA/ HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2012;60:1297–313.

11. Daubert C, Gold MR, Abraham WT, et al., Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial, J Am Coll Cardiol, 2009;54:1837–46.

12. Reynolds CR, Gold MR, Cardiac resynchronization therapy in mild heart failure: a review of the REVERSE and MADIT-CRT trials, Curr Cardiol Rep, 2010;12:367–73.

13. Moss AJ, Hall WJ, Cannom DS, et al., Cardiacresynchronization therapy for the prevention of heart-failure events, N Engl J Med, 2009;361(14):1329–38.

14. Linde C, Abraham WT, Gold MR, et al., Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms, J Am Coll Cardiol, 2008;52:1834–43.

15. Kutyifa V, Kloppe A, Zareba W, et al., The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy), J Am Coll Cardiol, 2013;61:936–44.

16. Curtis AB, Worley SJ, Adamson PB, et al., Biventricular Pacing for Atrioventricular Block and Systolic Dysfunction, N Engl J Med, 2013;368:1585–93.

17. Elguindy AM, Elmaghawry M, BLOCK-HF: CRT gains new ground, Glob Cardiol Sci Pract, 2013;2013:361–3.

18. Wilkoff BL, Cook JR, Epstein AE, et al., Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial, Jama, 2002;288:3115–23.

19. Doshi RN, Daoud EG, Fellows C, et al., Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study), J Cardiovasc Electrophysiol, 2005;16:1160–5.

20. Witte KK, BLOCK-HF: a game changer or a step too far?, Heart, 2014;100:361–2.

21. Funck RC, Blanc JJ, Mueller HH, et al., Biventricular stimulation to prevent cardiac desynchronization: rationale, design, and endpoints of the ‘Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace)’ study, Europace, 2006;8:629–35.

22. Funck RC, Blanc JJ, Mueller HH, et al., Biopace Trial Preliminary Results, Presented at: ESC Congress Meeting, Barcelona, Spain, 1 September 2014.

23. Hauptman PJ, Gottlieb SS, Clinical trial design in contemporary device studies in heart failure: is there a gold

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standard?, J Card Fail , 2014;20:223–8.

24. Healey JS, Hohnloser SH, Exner DV, et al., Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT), Circ Heart Fail, 2012;5:566–70.

25. Hayes DL, Boehmer JP, Day JD, et al., Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival, Heart Rhythm, 2011;8:1469–75.

26. Yin J, Hu H, Wang Y, et al., Effects of Atrioventricular Nodal Ablation on Permanent Atrial Fibrillation Patients With Cardiac Resynchronization Therapy: A Systematic Review and Meta-analysis, Clin Cardiol, 2014 [Epub ahead of print].

27. Gasparini M, Leclercq C, Lunati M, et al., Cardiac resynchronization therapy in patients with atrial fibrillation: the CERTIFY study (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry), JACC Heart Fail, 2013;1:500–7.

28. Gasparini M, Auricchio A, Metra M, et al., Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation, Eur Heart J, 2008;29:1644–52.

29. Chung ES, Leon AR, Tavazzi L, et al., Results of the Predictors of Response to CRT (PROSPECT) trial, Circulation, 2008;117:2608–16.

30. Foley PWX, Leyva F, Frenneaux MP, What is treatment success in cardiac resynchronization therapy?, Europace , 2009;11 Suppl 5:v58–-65.

31. Gorcsan J 3rd, Finding pieces of the puzzle of nonresponse to cardiac resynchronization therapy, Circulation, 2011;123:10–2.

32. Cleland JG, Abraham WT, Linde C, et al., An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure, Eur Heart J, 2013;34:3547–56.

33. Ruschitzka F, Abraham WT, Singh JP, et al., Cardiacresynchronization therapy in heart failure with a narrow QRS complex, N Engl J Med, 2013;369:1395–405.

34. Saxon LA, Olshansky B, Volosin K, et al., Influence of left ventricular lead location on outcomes in the COMPANION study, J Cardiovasc Electrophysiol, 2009;20:764–8.

35. Singh JP, Klein HU, Huang DT, et al., Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial, Circulation, 2011;123:1159–66.

36. Derval N, Steendijk P, Gula LJ, et al., Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites, J Am Coll Cardiol, 2010;55:566–75.

37. Butter C, Auricchio A, Stellbrink C, et al., Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients, Circulation, 2001;104:3026–9.

38. Bleeker GB, Kaandorp TA, Lamb HJ, et al., Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy, Circulation, 2006;113:969–76.

39. de Roest GJ, Wu L, de Cock CC, et al., Scar tissueguided left ventricular lead placement for cardiac resynchronization therapy in patients with ischemic cardiomyopathy: an acute pressure-volume loop study, Am Heart J, 2014;167:537–45.

40. Adelstein EC, Tanaka H, Soman P, et al., Impact of scar burden by single-photon emission computed tomography

myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy, Eur Heart J, 2011;32:93–103.

41. Ypenburg C, Roes SD, Bleeker GB, et al., Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy, Am J Cardiol, 2007;99:657–60.

42. Khan FZ, Virdee MS, Palmer CR, et al., Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial, J Am Coll Cardiol, 2012;59:1509–18.

43. Kydd AC, Khan FZ, Watson WD, et al., Prognostic benefit of optimum left ventricular lead position in cardiac resynchronization therapy: follow-up of the TARGET Study Cohort (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy), JACC Heart Fail, 2014;2:205–12.

44. Adelstein E, Alam MB, Schwartzman D, et al., Effect of echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy on mortality and risk of defibrillator therapy for ventricular arrhythmias in heart failure patients (from the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region [STARTER] trial), Am J Cardiol, 2014;113:1518–22.

45. Sommer A, Kronborg MB, Poulsen SH, et al., Empiric versus imaging guided left ventricular lead placement in cardiac resynchronization therapy (ImagingCRT): study protocol for a randomized controlled trial, Trials, 2013;14:113.

46. Gold MR, Leman RB, Wold N, et al., The effect of left ventricular electrical delay on the acute hemodynamic response with cardiac resynchronization therapy, J Cardiovasc Electrophysiol, 2014;25:624–30.

47. Gold MR, Birgersdotter-Green U, Singh JP, et al., The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy, Eur Heart J, 2011;32:2516–24.

48. Martin DO, Day JD, Lai PY, et al., Atrial support pacing in heart failure: results from the multicenter PEGASUS CRT trial, J Cardiovasc Electrophysiol, 2012;23:1317–25.

49. Auricchio A, Stellbrink C, Block M, et al., Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group.

The Guidant Congestive Heart Failure Research Group, Circulation, 1999;99:2993–3001.

50. Brabham WW, Gold MR, The role of AV and VV optimization for CRT, Journal of Arrhythmia, 2013;29:153–61.

51. Ellenbogen KA, Gold MR, Meyer TE, et al., Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy, Circulation, 2010;122:2660–8.

52. Abraham WT, Gras D, Yu CM, et al., Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial, Am Heart J, 2010;159:944–8 e1.

53. Gold MR, Yu Y, Singh JP, et al., The effect of left ventricular electrical delay on AV optimization for cardiac resynchronization therapy, Heart Rhythm, 2013;10:988–93.

54. Birnie D, Lemke B, Aonuma K, et al., Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial, Heart Rhythm, 2013;10:1368–74.

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Heart Failure

LE ATION.

Gaps in the Heart Failure Guidelines B a o Tr a n a n d G r e g g C F o n a r o w Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, Los Angeles, California, US

Abstract There are still many aspects of heart failure care for which gaps remain in the evidence base, resulting in gaps in the guidelines. We aim to highlight these guideline gaps including areas that warrant further research and other areas where new data are forthcoming.

Keywords Heart failure, guidelines, quality of care Disclosure: Bao Tran has no conflicts of interest to declare. Gregg C Fonarow is a consult for Amgen, Bayer, Gambro, Janssen, Medtronic and Novartis.

Received: 15 September 2014 Accepted: 4 November 2014 Citation: European Cardiology Review, 2014;9(2):104–9 Correspondence: Gregg C Fonarow, Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, 10833 LeConte Ave, Room 47-123 CHS, Los Angeles, CA 90095-1679, US. E: gfonarow@mednet.ucla.edu

Heart failure (HF) remains a major public health problem resulting in substantial morbidity, mortality and healthcare expenditures globally. The European Society of Cardiology (ESC) 2012 Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure and the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) 2013 Guideline for the Management of Heart Failure both provide comprehensive evidence-based recommendations in caring for patients with HF.1,2 Both guidelines use similar predefined scales for strength of recommendation and level of evidence for particular treatment options.

The classes of recommendations range from Class I (where a given treatment is beneficial) to Class III (where a given treatment is not useful and in some cases may be harmful). The levels of evidence (LOE) range from Level A (where data have been derived from multiple randomised clinical trials [RCTs]) to Level C (where recommendations are based on consensus of expert opinions). The ACCF/AHA Guideline also emphasises the concept of optimal treatment, termed guideline-directed medical therapy (GDMT). Although guidelines do not substitute individual clinical judgment, improved adherence to HF guidelines translates to improved clinical outcomes in real world patients. It has been shown that each 10 % improvement in ACCF/AHA HF guideline recommended composite care was associated with a 13 % lower odds of 24-month mortality.3 However, there are still many aspects of HF care for which gaps remain in the evidence base, resulting in gaps in the guidelines. Only 19.5 % of the ACCF/AHA Guideline recommendations are considered well established

by RCTs – 24 Level of Evidence A recommendations compared with 99 Level B or C. Similarly, only 34.4 % of the ESC Guideline recommendations are considered well established – 43 Level A compared with 82 Level B or C. Additionally, there are areas where new evidence has emerged but has not yet been incorporated into the guidelines. We aim to highlight these guideline gaps including areas that warrant further research, areas where data are conflicting and other areas where new data are forthcoming (see Table 1).

Gaps in Pharmacological Therapy Substantial progress has been made in pharmacological therapy for HF with reduced ejection fraction (HFrEF) including

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angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and aldosterone antagonists, and novel agents continue to be developed.

However, uncertainty remains with some of the oldest class of drugs.

The vasodilator combination hydralazine and isosorbide dinitrate (H-ISDN) is the first therapy proven in a RCT to improve outcome in HFrEF. The initial Vasodilator-Heart Failure Trial 1 (V-HeFT I) showed 28 % mortality reduction compared with placebo, although this finding only reached borderline statistical significance (p=0.053).4 The follow-up V-HeFT II actually showed 28.2 % higher mortality with H-ISDN when compared with enalapril (p=0.016).5 Definitive mortality benefit of H-ISDN was finally established with the subsequent African-American Heart Failure Trial (A-HeFT) that enrolled self-identified African Americans with symptomatic HFrEF who were already on modern GDMT.6 The study terminated early as the H-ISDN arm showed 43 % decrease in all-cause mortality (p=0.01) and 33 % reduction in rate of hospitalisation (p=0.001) compared with placebo.

However, the role of H-ISDN in non-African American patients with HFrEF in the modern era remains uncertain and warrants further research. The ESC Guideline currently gives H-ISDN an equivocal recommendation of Class IIb/LOE B in patients with HFrEF. The ACC/ AHAF Guideline recognises the differential treatment effect and gives H-ISDN Class I/LOE A in African Americans with HFrEF and Class IIa/ LOE B in other patients with HFrEF who cannot tolerate ACE inhibitor or angiotensin receptor blocker (ARB).

The use of digoxin, the oldest compound in cardiovascular medicine, declined after the disappointing Digitalis Investigation Group (DIG) trial, which showed a 28 % reduction in hospitalisations (p<0.001) but no difference in mortality.7,8 This trial, however, was done in an era where the current GDMT and device therapy were not commonly part of background therapy. Subsequent meta-analysis, retrospective studies and post-hoc analysis of more contemporary clinical databases have yielded conflicting conclusions, suggesting potential benefit as well as harm.9–13 Prospective RCT data would help clarify the role of digoxin in modern clinical practice in HFrEF with and without atrial fibrillation (AF).

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The benefit of anticoagulation for stroke prevention in patients with AF is well established. However, in patients with very depressed ejection fraction (EF) who are at risk for intracardiac thrombi, anticoagulation has not been shown to be beneficial. Two RCTs of patients with HFrEF in sinus rhythm showed no clinical benefit and increased bleeding with warfarin when compared with aspirin.14,15 Given the improved safety and efficacy of the new oral anticoagulants (dabigatran, apixaban and rivaroxaban), these agents should be studied in subsets of patients with HFrEF in sinus rhythm that are at highest risk for thromboembolism.

Newer agents, ivabradine, aliskiren and LCZ696, are still establishing their roles in HF. The ESC Guideline gives ivabradine a Class IIa/LOE B recommendation in patients with symptomatic HFrEF and heart rate >70 beats per minute (BPM) based on the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), which showed 26 % decrease in HF hospitalisations (p<0.0001) and a previous trial, which established its safety.16,17 In the US, ivabradine is still awaiting US Food and Drug Administration (FDA) approval and has not received formal recommendation in the ACCF/AHA Guideline. Aliskiren is a novel agent that targets the renin–angiotensin–aldosterone system (RAAS) to reduce blood pressure. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) investigated aliskiren in patients with HFrEF and acute decompensated heart failure (ADHF). It showed increased rates of adverse effects, such as hyperkalaemia (relative risk [RR] 1.19 [0.98–1.46]), hypotension (RR 1.36 [1.07–1.72]) and renal failure (RR 1.37 [1.08–1.75]) in the aliskiren arm without benefit in mortality or hospitalisation.18 An ongoing RCT is investigating the role of aliskiren or aliskiren/enalapril combination in patients with chronic HFrEF (NCT00853658). Aliskiren has not received formal recommendation by the ACCF/AHA or ESC guidelines and its role in HF appears uncertain. In contrast to this is LCZ696, a novel dual-acting angiotensin receptor–neprilysin inhibitor (ARNI), which has the potential to shift the foundation of HFrEF therapy. The recent Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was stopped early with LCZ696 demonstrating significant reduction in all-cause mortality (hazard ratio [HR] 0.84, 95 % confidence interval [CI] 0.76–0.93) and HF hospitalisations (HR 0.79, 95 % CI 0.71–0.89) as well as improvement in quality of life compared with enalapril.19 Based on these findings, we anticipate expedited approval of LCZ696 by both US and European regulatory agencies, and the addition of ARNI in the next ESC and ACCF/AHA Guideline update.

Table 1: Gaps in Heart Failure Guidelines Diagnosis • Unified diagnostic criteria for HFpEF • Classification of borderline systolic dysfunction and HF with recovered EF • Utility of advanced imaging and biomarkers Pharmacological Therapy • Values of digoxin, H-ISDN, IV vasodilators and inotropes in the modern era • Novel agents ivabradine, aliskiren and LCZ696 for chronic HF • Novel agents serelaxin, ularitide and omecamtiv mecarbil for ADHF • Effective therapy for HFpEF Device Therepy • Role of CRT in non-LBBB or AF and approach to CRT non-responders • Transcatheter mitral valve repair for secondary MR • Long-term role of ventricular assist devices in advanced HF Other Non-pharmacological Therapy • Viability testing and revascularisation in CAD and severely reduced EF • Sodium and fluid restriction • Ultrafiltration in ADHF • Remote clinical management interventions Co-morbidities • Optimal HF therapy for patients with significant co-morbidities • Optimal treatment of underlying co-morbidities Variation of Care • Generalizability of HF therapy to women and underrepresented minorities • Ideal therapy and role of palliative care for patients with end-stage HF • Strategies to improve guideline implementation and patient adherence ADHF = acute decompensated heart failure; CAD = coronary artery disease; CRT = cardiac resynchronisation therapy; EF = ejection fraction; HF = heart failure; HFpEF = HF with preserved ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; IV = intravenous; LBBB = left bundle branch block; MR = mitral regurgitation.

Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) that evaluated CRT in patients with mild-to-moderate HF, subsets of patients with permanent AF had no clinical benefit with CRT.24 An ongoing RCT is evaluating the strategy of atrioventricular junction ablation to increase CRT response in patients with permanent AF (NCT01522898). Finally, although up to 30–45 % of CRT-implanted patients receive little benefit, the management of these CRT non-responders remains controversial.25 A meta-analysis suggests small improvement in left ventricular ejection fraction (LVEF) with CRT optimisation procedures, but it is unclear whether this would translate into hard outcomes, and the ideal optimisation protocol remains undefined.26

Gaps in Device Therapy Cardiac resynchronisation therapy (CRT) has played an important role in the past decade in decreasing hospitalisations and increasing survival of patients with HFrEF. Though benefits are clear for symptomatic patients in sinus rhythm with typical left bundle branch block (LBBB) (particularly with QRS width >150 ms), there are some populations where data are equivocal.20 Post-hoc analysis of the major CRT trials showed no significant benefit in subgroups with non-LBBB morphology or subgroups with QRS duration <150 msec.21,22 Results are pending of the recently completed Pacing Affects Cardiovascular Endpoints in Patients with Right Bundle-Branch Block (PACE-RBBB) trial, which is evaluating whether univentricular right ventricular (RV) pacing can restore synchronisation in patients with right bundle branch block (RBBB) (NCT01169493). The benefits of CRT are also unclear in patients with AF where efficient CRT delivery is compromised by underlying conduction. Thus these patients have been excluded from most major CRT trials.23 In the

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Device-based clinical management interventions for HF have shown mixed results. Previous trials of thoracic impedance monitoring and remote monitoring systems have failed to show improvement in outcomes.27,28 More recently, however, the Influence of Home Monitoring on Mortality and Morbidity in Heart Failure Patients with Impaired Left Ventricular Function (IN-TIME) trial showed that an implantable cardioverter defibrillator (ICD)-based telemonitoring system dramatically reduced mortality when compared with standard care (HR 0.37, 95 % CI 0.16–0.83).29 Another device, an implantable pulmonary artery pressure monitor, was shown in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Functional Class III Heart Failure Patients (CHAMPION) trial to decrease HF hospitalisation (HR 0.72, 95 % CI 0.60–0.85).30 However, in both these positive trials the contribution of additional patient–physician interaction on outcomes cannot be underestimated.

Notably there was a delay in FDA approval of the pulmonary

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Heart Failure artery pressure monitoring device over question of potential bias in preferential support of treatment group.31 Neither the ACCF/AHA nor the ESC Guideline endorses a remote monitoring strategy.

From a structural standpoint, new data about transcatheter mitral valve repair is encouraging. Secondary mitral regurgitation (MR) is a common consequence of left ventricular (LV) enlargement and dysfunction, but surgical repair has not been proven to be superior to medical therapy for functional MR.32 Two recent non-randomised trials reported results of transcatheter mitral valve repair MitraClip in patients with severe MR who were deemed too high-risk for surgery.33,34 In both studies more than 70 % of patients had functional MR. After mitral valve repair using MitraClip device, patients experienced improved clinical symptoms, decreased LV dimensions, and in one of the trials decreased mortality compared with a propensity matched cohort. Further prospective controlled trials are ongoing to define transcatheter mitral valve repair’s role in patients with symptomatic functional MR (NCT01626079 and NCT01772108). Pending results from these RCTs, the ACCF/AHA Guideline gives transcatheter mitral valve repair for functional MR an ambivalent Class IIb/LOE B recommendation, and the ESC Guideline does not give a specific class of recommendation about this topic.

Gaps in Non-pharmacological Therapy Coronary artery disease (CAD) is the most common aetiology of HFrEF.35 While revascularisation with concurrent use of viability studies in severe ischaemic cardiomyopathy is logically sound, recent studies have challenged this dictum. The Surgical Treatment for Ischemic Heart Failure (STICH) trial showed no mortality benefit with coronary artery bypass grafting (CABG) when compared to medical therapy in patients with EF <35 %.36 Though notably, after taking into account patient crossover from the medical therapy arm, the ‘as-treated’ analysis showed decreased mortality with CABG (HR 0.70, 95 % CI 0.58–0.84). An imaging substudy of STICH showed that viability assessment by single-photon emission computed tomography (SPECT) or dobutamine echocardiography did not identify patients who would benefit from CABG.37 Cardiac magnetic resonance and position emission tomography imaging promise improved sensitivities and specificities in identifying viable myocardium, but their impact on clinical outcomes has not been rigorously tested.38 Thus the roles of viability testing and revascularisation in patients with CAD and severely reduced EF remain debatable. The ESC Guideline gives a viability testing Class IIa/LOE C recommendation and recommends against revascularisation in patients without viable myocardium (Class III/LOE C). The ACCF/AHA Guideline gives viability testing and revascularisation in patients with LVEF <35 % a Class IIa/ LOE B recommendation.

Though sodium and fluid restriction in patients with HF appears intuitive, its role is controversial. Even though sodium restriction is endorsed by many guidelines, small RCTs have shown worse neurohormonal profiles and increase in HF admissions for patients with HFrEF assigned to low-sodium diet.39–41 Similarly, other small trials have shown no significant benefit with fluid restriction in patients with HF.42,43 More recently, one RCT showed New York Heart Association (NYHA) class improvement in patients with chronic HF randomised to modest sodium and fluid restriction,44 while another RCT showed no clinical benefit with aggressive sodium and fluid restriction in hospitalised patients with ADHF.45 Despite conflicting data, the ACCF/ AHA Guideline gives sodium restriction and fluid restriction Class IIa/

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LOE C recommendation, and the ESC Guideline gives only a general recommendation supporting sodium restriction and fluid restriction for symptomatic HF. Well-powered outcome trials are needed. Given the complexity of sodium and fluid homeostasis, perhaps the answer may be individualised targets based on the patient’s clinical status.

Other non-pharmacological interventions, such as self-management counselling, telephone support and home visitation have been advocated. However, there is no definitive evidence supporting an individual approach.46 While intensive multidisciplinary programmes have been found to reduce mortality and hospitalisation, the resources required to maintain this strategy have limited its ability to reach a wide spectrum of patients.47

Gaps in Acute Heart Failure Therapy Despite significant advances in understanding the pathophysiology of HF, treatment of ADHF has changed little in the past decade. The mainstays of parenteral pharmacological treatments, such as diuretics, vasodilators and positive inotropes, improve haemodynamics but have not been shown to improve outcomes.48 The optimal diuretic regimen remains at the discretion of the clinician as the Diuretic Optimization Strategies Evaluation (DOSE) trial did not show clear benefits for low-dose or high-dose diuretics and bolus or continuous infusion.49 Contemporary trial of a common clinical practice, low-dose dopamine in ADHF, failed to show clinical benefits in the Renal Optimization Strategies Evaluation (ROSE) trial.50 Though intravenous nitrates and nitroprusside are widely used in practice, data demonstrating their safety and efficacy are sparse. The vasodilator nesiritide was widely used based on improvement in dyspnoea from the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, but it fell out of favour after safety concerns were raised.51 Confirmatory trials demonstrated safety but also no significant clinical benefits.50,52 Ironically, given the number of trials, nesiritide has one of the largest bodies of evidence demonstrating safety compared with other pharmacological therapies for ADHF. Novel agents for ADHF that improve outcomes are urgently needed. The most promising of these is serelaxin, a peptide hormone with vasodilatory effect. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin significantly reduced the primary endpoint of dyspnoea in patients with both HFrEF and HF with preserved ejection fraction (HFpEF).53,54 Unexpectedly there was a large reduction in the non-predefined endpoint of mortality (HR 0.63, 95 % CI 0.42–0.93), and a larger trial is looking to confirm this finding (NCT01870778). Another phase III trial is ongoing to evaluate ularitide, a synthetic natriuretic peptide, in ADHF (NCT01661634). Omecamtiv mecarbil, a novel inotrope-like agent, is awaiting phase III trial though phase II did not achieve the primary endpoint of reducing dyspnoea.55 From a non-pharmacological standpoint, contemporary ultrafiltration devices used for rapid fluid removal promised rapid decongestion in treatment of ADHF. The Ultrafiltration versus intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) and Continuous Ultrafiltration for Congestive Heart Failure (CUORE) trials showed reduced readmission rates with ultrafiltration compared with diuretics (HR 0.56, 95 % CI 0.28–0.51 and HR 0.14, 95 % CI 0.04–0.48, respectively).56,57 However, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial evaluating patients with ADHF and renal dysfunction showed only excess adverse events in the ultrafiltration group (72 versus 57 %, p=0.03), driven by worsened renal function, bleeding complications and intravenous catheter-related complications.58 Unfortunately, a

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larger trial to evaluate the role of ultrafiltration on readmissions for HF has been terminated due to patient recruitment challenges (NCT01474200). The ESC Guideline does not provide specific recommendation for ultrafiltration, and the ACCF/AHA Guideline gives it an equivocal Class IIB/LOE B recommendation. The ideal patient population who would benefit from ultrafiltration remains uncertain until more definitive data from larger trials are available.

Future clinical trials of therapies for ADHF should target HFpEF and HFrEF separately in addition to stratifying patients based on severity of decompensation and co-morbidities. Pressure to expand inclusion criteria to enrol enough patients to power studies for mortality benefits may ultimately dilute findings by increasing patient heterogeneity.

Gaps in Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction The management of HFrEF has made substantial gains over the past three decades. In contrast, despite the high prevalence, mortality and morbidity of HFpEF, little progress has been made in establishing unified diagnostic criteria.59 The treatment of HFpEF remains largely opinion-based with little good evidence to guide therapy. Though promising in theory, trials of beta-blocker, ACEI, ARB, aldosterone antagonists, digoxin and phosphodiesterase type 5 (PDE-5) inhibitors have all shown largely disappointing results.60 Establishing broadly applicable therapies is hampered by the heterogeneity of the syndrome.

LCZ696, discussed previously in HFrEF, was found to reduce N-terminal pro-brain natriuretic (NT-proBNP) and left atrial size in patients with HFpEF when compared with valsartan in a phase II RCT.61 The followup phase III trial powered to evaluate mortality has recently started recruiting patients (NCT01920711). Future studies should more distinctly subclassify different clinical phenotypes of HFpEF to target the dominant pathophysiology. And while mortality and hospitalisation are important clinical endpoints, they may be too insensitive for this heterogeneous population with multiple co-morbidities. There should be more focus on using health-related quality of life and other measures of health status as part of clinical trial endpoints to elicit meaningful results.

Additional ambiguity is seen in the intermediate group with EF between 40 and 50 %. These patients are often treated with therapy recommended for patients with HFrEF despite being underrepresented or excluded from most HFrEF trials.1 Finally, patients with a history of HFrEF where EF have recovered represent another subset where little is known about the natural history and prognosis. They likely represent a distinct phenotype in the spectrum of HFrEF and HFpEF and need further characterisation to determine the need for continued therapies.62

Gaps in Treatment of Co-morbidities Common non-cardiac co-morbidities, such as anaemia, lung disease, kidney disease, diabetes and depression, likely play important roles in progression of HF and may interfere with diagnosis and therapy.

Anaemia and chronic obstructive pulmonary disease (COPD) may confound the diagnosis of worsening HF. Depression may interfere with a patient’s ability to self-manage. Kidney disease often limits the use of ACEI/ARB, and severe lung disease may limit the use of beta-blocker. Frailty, cancer, gout, obesity and other co-morbidities may also directly affect HF therapy. The long-term safety and efficacy of many treatments for these co-morbidities in patients with HF are unknown. Moreover, as HF trials commonly exclude patients with significant co-morbidities, it is not clear whether GDMT have differential effects in these particular patients.63

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Chronic obstructive pulmonary disease (COPD) can co-exist and confound the diagnosis of HF. Unfortunately, patients with severe COPD are often excluded from HF trials, so data are limited in this population.64 Despite concern about beta-blockers exacerbating COPD, it has been shown that even non-selective beta-blockers, such as carvedilol, are not associated with worse outcomes in patients with chronic HF and COPD.65 However, in the setting of an acute COPD exacerbation, the role of beta-blockers remains unknown. Additionally, the use of beta-2 agonist bronchodilators have been implicated in worsening HF, though this finding is limited by the observational nature of the data.66 Anaemia is a common finding in patients with HF and is independently associated with increased mortality risk.67 However, It is unclear whether anaemia is simply a marker of disease severity or a direct mediator of poor outcomes. Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF), the largest RCT to evaluate erythropoiesis-stimulating agents in patients with HFrEF and anaemia, showed no difference in death or HF hospitalisation but increased thromboembolic events in the darbepoetin alfa group (13.5 % versus 10.0 %, p=0.009).68 In patients with HF and iron deficiency, however, the Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial showed that Intravenous (IV) ferric carboxymaltose improved NYHA class, six-minute walk distance and quality of life.69 A multicentre RCT evaluating oral iron in patients with HFrEF and iron deficiency is expected to start soon (NCT02188784).

Diabetes mellitus (DM) is highly associated with poor clinical status in patients with HF.70 The interaction between these two clinical syndromes is complex, and patients with DM have been shown to respond differently to HFrEF therapy compared with non-diabetics.71 From a DM therapy standpoint, while thiazolidinedione has clearly been shown to increase HF, the safety of newer therapies for DM – glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT-2) inhibitors – are unknown for patients with HF. Even insulin, an established treatment, has been associated with higher mortality in patients with advanced HF, though this may be more related to severity of diabetes.72 Chronic kidney disease (CKD) and the associated cardiorenal syndrome portend poorer prognosis and significantly impact management of HF patients.73 Significant renal dysfunction may preclude the use of ACEIs, ARBs and mineralocorticoids in patients with HFrEF. In addition, patients with advanced kidney disease (stage 4 and stage 5 CKD) and end-stage renal disease are frequently excluded from HF trials.74 In the setting of ADHF, no effective therapy for cardiorenal syndrome has been found, perhaps mirroring the lack of progress in ADHF care in the last decade.

Depression is also highly prevalent in patients with HF and independently predicts increased hospitalisation and mortality.75 However, there has been surprisingly little work done on defining the interaction between the two diseases and finding effective therapy. Although data have contested conventional wisdom that beta-blocker is associated with depression, beta-blocker’s effect on patients with concomitant HF and depression is unclear.76 While tricyclic antidepressants should be avoided in patients with HF due to known risks of QT interval prolongation and ventricular arrhythmia, the ideal antidepressant in HF patients is unknown. Sertraline Against Depression and Heart Disease in Chronic Heart Failure

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Heart Failure (SADHART-CHF), one of the few RCTs to date on this topic, found no benefit with sertraline in patients with HF and depression.77 Finally, pulmonary hypertension (PH) is a common complication of HF and is independently associated with poor prognosis.78 Unfortunately, there is no validated treatment for PH due to left heart disease.

Perhaps due to patient heterogeneity, clinical trials have not shown benefits with prostanoids, endothelin-1 antagonists or guanylate cyclase stimulators in patients with HFrEF.79 For patients with HFpEF and PH, one small placebo-controlled trial showed that sildenafil increased exercise capacity and improved haemodynamic status.80 However a larger trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), evaluated sildenafil in HFpEF and showed no difference in clinical outcomes compared to placebo.81 Ongoing trials are evaluating the role of sildenafil (NCT01616381) and tadalafil (NCT01910389) in patients with PH and HFrEF, and the role of riociguat in patients with PH and HFpEF (NCT01172756). Neither the ACCF/AHA nor the ESC Guideline specifically addresses patients with HF and PH.

data from the Get With The Guidelines®-Heart Failure registry shows that a concerted national quality improvement programme can deliver equally effective care across racial and ethnic groups.83 In clinical trials, the impact of therapy on quality of life can sometimes be deemed less important than the primary endpoint of mortality.

This issue is particularly relevant for very elderly patients or patients with poor long-term prognosis, where symptom control may be more valuable than mortality benefits. Additionally, palliative services and hospice remain underutilised in patients with advanced HF, especially when compared with patients with cancer.84 Determining the optimal timing and palliative care approach is difficult in HF because of the undulating course of disease and availability of advanced therapies for end-stage HF, such as heart transplantation and ventricular assist devices.

Conclusion

In negative trials, the clinical heterogeneity of patient population is sometimes invoked as a reason why a therapy does not reach statistical significance. However, from a population perspective,

The economic burden of HF continues to grow and HF is one of the single most expensive and deadly healthcare problems. Additional clinical and comparative effectiveness research studies are urgently needed, along with development of new and innovative therapies.

Significant gaps remain in the evidence base and guidelines for HF, particularly in the care of patients with HFpEF, patients with ADHF and patients with HF, and multiple co-morbidities. Other gaps in

most RCTs that form the current evidence base do not randomise a sufficient number of women and underrepresented minorities, thus limiting their generalizability. Women and various racial and ethnic groups have significant differences in aetiology of HF and response to treatment due to underlying biological differences and disparities in healthcare utilisation.82 Future trials should strive to enrol higher proportions of these underrepresented populations. Encouragingly,

evidence that we did not address include the increasing use of ventricular assist devices, novel cardiac biomarkers and advanced cardiac imaging techniques. Along with encouraging novel devices and pharmacological therapies, it remains important to refine the roles of established therapies. When such evidence-based, guideline-directed therapies exist or emerge, every effort should be made to effectively implement these HF therapies to optimise care and outcomes. n

Gaps in Variation of Heart Failure Care

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2. McMurray JJ, Adamopoulos S, Anker SD, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur J Heart Fail, 2012;14:803–69.

3. Fonarow GC, Albert NM, Curtis AB, et al., Associations between outpatient heart failure process-of-care measures and mortality, Circulation, 2011;123:1601–10.

4. Cohn JN, Archibald DG, Ziesche S, et al., Effect of vasodilator therapy on mortality in chronic congestive heart failure.

Results of a Veterans Administration Cooperative Study, N Engl J Med, 1986;314:1547–52.

5. Cohn JN, Johnson G, Ziesche S, et al., A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure, N Engl J Med, 1991;325:303–10.

6. Taylor AL, Ziesche S, Yancy C, et al., Combination of isosorbide dinitrate and hydralazine in blacks with heart failure, N Engl J Med, 2004;351:2049–57.

7. Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure, N Engl J Med, 1997;336:525–33.

8. Ambrosy AP, Butler J, Ahmed A, et al., The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions, J Am Coll Cardiol, 2014;63:1823–32.

9. Turakhia MP, Santangeli P, Winkelmayer WC, et al., Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study, J Am Coll Cardiol, 2014;64:660–8.

10. Ahmed A, Rich MW, Love TE, et al., Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial, Eur Heart J, 2006;27:178–86.

11. Hood WB Jr, Dans AL, Guyatt GH, et al., Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis, J Card Fail, 2004;10:155–64.

12. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al., Lack of evidence of increased mortality among patients

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with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial, Eur Heart J, 2013;34:1489–97.

13. Whitbeck MG, Charnigo RJ, Khairy P, et al., Increased mortality among patients taking digoxin--analysis from the AFFIRM study, Eur Heart J, 2013;34:1481–8.

14. Homma S, Thompson JL, Pullicino PM, et al., Warfarin and aspirin in patients with heart failure and sinus rhythm, N Engl J Med, 2012;366:1859–69.

15. Massie BM, Collins JF, Ammon SE, et al., Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, Circulation, 2009;119:1616–24.

16. Fox K, Ford I, Steg PG, et al., Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial, Lancet, 2008;372:807–16.

17. Swedberg K, Komajda M, Böhm M, et al., Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study, Lancet, 2010;376:875–85.

18. Gheorghiade M, Böhm M, Greene SJ, et al., Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial, JAMA, 2013;309:1125–35.

19. McMurray JJ, Packer M, Desai AS, et al., Angiotensinneprilysin inhibition versus enalapril in heart failure, N Engl J Med, 2014;371:993–1004.

20. Prinzen FW, Vernooy K, Auricchio A, Cardiac resynchronization therapy: state-of-the-art of current applications, guidelines, ongoing trials, and areas of controversy, Circulation, 2013;128:2407–18.

21. Sipahi I, Carrigan TP, Rowland DY, et al., Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials, Arch Intern Med, 2011;171:1454–62.

22. Sipahi I, Chou JC, Hyden M, et al., Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials, Am Heart J, 2012;163:260–7.e3.

23. Dickstein K, Vardas PE, Auricchio A, et al., 2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy.

Developed with the special contribution of the Heart Failure

Association and the European Heart Rhythm Association, Eur J Heart Fail, 2010;12:1143–53.

24. Healey JS, Hohnloser SH, Exner DV, et al., Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT), Circ Heart Fail, 2012;5:566–70.

25. Zacà V, Mondillo S, Gaddi R, Favilli R, Profiling cardiac resynchronization therapy patients: responders, nonresponders and those who cannot respond--the good, the bad and the ugly?, Int J Cardiovasc Imaging, 2011;27:51–7.

26. Kosmala W, Marwick TH, Meta-analysis of effects of optimization of cardiac resynchronization therapy on left ventricular function, exercise capacity, and quality of life in patients with heart failure, Am J Cardiol, 2014;113:988–94.

27. van Veldhuisen DJ, Braunschweig F, Conraads V, et al., Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure, Circulation, 2011;124:1719–26.

28. Anker SD, Koehler F, Abraham WT, Telemedicine and remote management of patients with heart failure, Lancet, 2011;378:731–9.

29. Hindricks G, Taborsky M, Glikson M, et al., Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial, Lancet, 2014;384:583–90.

30. Abraham WT, Adamson PB, Bourge RC, et al., Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial, Lancet, 2011;377:658–66.

31. Loh JP, Barbash IM, Waksman R, Overview of the 2011 Food and Drug Administration Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting on the CardioMEMS Champion Heart Failure Monitoring System, J Am Coll Cardiol, 2013;61:1571–6.

32. Wu AH, Aaronson KD, Bolling SF, et al., Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction, J Am Coll Cardiol, 2005;45:381–7.

33. Glower DD, Kar S, Trento A, et al., Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study, J Am Coll Cardiol, 2014;64:172–81.

34. Swaans MJ, Bakker AL, Alipour A, et al., Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients, JACC Cardiovasc Interv, 2014;7:875–81.

35. Gheorghiade M, Bonow RO, Chronic heart failure in the

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United States: a manifestation of coronary artery disease, Circulation, 1998;97:282–9.

36. Velazquez EJ, Lee KL, Deja MA, et al., Coronary-artery bypass surgery in patients with left ventricular dysfunction, N Engl J Med, 2011;364:1607–16.

37. Bonow RO, Maurer G, Lee KL, et al., Myocardial viability and survival in ischemic left ventricular dysfunction, N Engl J Med, 2011;364:1617–25.

38. Srichai MB, Jaber WA, Viability by MRI or PET would have changed the results of the STICH trial, Prog Cardiovasc Dis, 2013;55:487–93.

39. Parrinello G, Di Pasquale P, Licata G, et al., Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure, J Card Fail , 2009;15:864–73.

40. Paterna S, Gaspare P, Fasullo S, et al., Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?, Clin Sci (Lond), 2008;114:221–30.

41. Paterna S, Parrinello G, Cannizzaro S, et al., Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure, Am J Cardiol, 2009;103:93–102.

42. Holst M, Stromberg A, Lindholm M, Willenheimer R, Liberal versus restricted fluid prescription in stabilised patients with chronic heart failure: result of a randomised cross-over study of the effects on health-related quality of life, physical capacity, thirst and morbidity, Scand Cardiovasc J, 2008;42:316–22.

43. Travers B, O’Loughlin C, Murphy NF, et al., Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability, J Card Fail, 2007;13:128–32.

44. Philipson H, Ekman I, Forslund HB, et al., Salt and fluid restriction is effective in patients with chronic heart failure, Eur J Heart Fail, 2013;15:1304–10.

45. Aliti GB, Rabelo ER, Clausell N, et al., Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial, JAMA Intern Med, 2013;173:1058–64.

46. Bui AL, Fonarow GC, Home monitoring for heart failure management, J Am Coll Cardiol , 2012;59:97–104.

47. McAlister FA, Stewart S, Ferrua S, McMurray JJ, Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials, J Am Coll Cardiol, 2004;44:810–9.

48. Selby VN, Teerlink JR, What’s new in the treatment of acute heart failure?, Curr Cardiol Rep, 2013;15:393.

49. Felker GM, Lee KL, Bull DA, et al., Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med, 2011;364:797–805.

50. Chen HH, Anstrom KJ, Givertz MM, et al., Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial, JAMA, 2013;310:2533–43.

51. Topol EJ, Nesiritide - not verified, N Engl J Med, 2005;353:113–6.

52. O’Connor CM, Starling RC, Hernandez AF, et al., Effect of nesiritide in patients with acute decompensated heart failure,

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N Engl J Med, 2011;365:32–43.

53. Teerlink JR, Cotter G, Davison BA, et al., Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial, Lancet, 2013;381:29–39.

54. Filippatos G, Teerlink JR, Farmakis D, et al., Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial, Eur Heart J, 2014;35:1041–50.

55. Teerlink J, Hot Line IV: Late breaking trials on heart failure and acute coronary syndrome, Presented at: European Society of Cardiology Congress, Amsterdam, 3 September 2013.

56. Costanzo MR, Guglin ME, Saltzberg MT, et al., Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure, J Am Coll Cardiol, 2007;49:675–83.

57. Marenzi G, Muratori M, Cosentino ER, et al., Continuous ultrafiltration for congestive heart failure: the CUORE trial, J Card Fail, 2014;20:9–17.

58. Bart BA, Goldsmith SR, Lee KL, et al., Ultrafiltration in decompensated heart failure with cardiorenal syndrome, N Engl J Med, 2012;367:2296–304.

59. Butler J, Fonarow GC, Zile MR, et al., Developing therapies for heart failure with preserved ejection fraction: current state and future directions, JACC Heart Fail, 2014;2:97–112.

60. Senni M, Paulus WJ, Gavazzi A, et al., New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes, Eur Heart J, 2014;35:2797–815.

61. Solomon SD, Zile M, Pieske B, et al., The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial, Lancet, 2012;380:1387–95.

62. Basuray A, French B, Ky B, et al., Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes, Circulation, 2014;129:2380–7.

63. Boyd CM, Vollenweider D, Puhan MA, Informing EvidenceBased Decision-Making for Patients with Comorbidity: Availability of Necessary Information in Clinical Trials for Chronic Diseases, PLoS One, 2012;7:e41601.

64. Hawkins NM, Petrie MC, Macdonald MR, et al., Heart failure and chronic obstructive pulmonary disease the quandary of Beta-blockers and Beta-agonists, J Am Coll Cardiol, 2011;57:2127–38.

65. Mentz RJ, Wojdyla D, Fiuzat M, et al., Association of betablocker use and selectivity with outcomes in patients with heart failure and chronic obstructive pulmonary disease (from OPTIMIZE-HF), Am J Cardiol, 2013;111:582–7.

66. Mentz RJ, Fiuzat M, Kraft M, et al., Bronchodilators in heart failure patients with COPD: is it time for a clinical trial?, J Card Fail, 2012;18:413–22.

67. Groenveld HF, Januzzi JL, Damman K, et al., Anemia and mortality in heart failure patients a systematic review and meta-analysis, J Am Coll Cardiol, 2008;52:818–27.

68. Swedberg K, Young JB, Anand IS, et al., Treatment of anemia with darbepoetin alfa in systolic heart failure, N Engl J Med,

2013;368:1210–9.

69. Anker SD, Comin Colet J, Filippatos G, et al., Ferric carboxymaltose in patients with heart failure and iron deficiency, N Engl J Med, 2009;361:2436–48.

70. Khan SS, Butler J, Gheorghiade M, Management of comorbid diabetes mellitus and worsening heart failure, JAMA, 2014;311:2379–80.

71. Maggioni AP, Greene SJ, Fonarow GC, et al., Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial, Eur Heart J, 2013;34:3117–27.

72. Smooke S, Horwich TB, Fonarow GC, Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure, Am Heart J, 2005;149:168–74.

73. Heywood JT, Fonarow GC, Costanzo MR, et al., High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database, J Card Fail, 2007;13:422–30.

74. Damman K, Tang WH, Felker GM, et al., Current evidence on treatment of patients with chronic systolic heart failure and renal insufficiency: practical considerations from published data, J Am Coll Cardiol, 2014;63:853–71.

75. Albert NM, Fonarow GC, Abraham WT, et al., Depression and clinical outcomes in heart failure: an OPTIMIZE-HF analysis, Am J Med, 2009;122:366–73.

76. Ko DT, Hebert PR, Coffey CS, et al., Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction, JAMA, 2002;288:351–7.

77. O’Connor CM, Jiang W, Kuchibhatla M, et al., Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial, J Am Coll Cardiol, 2010;56:692–9.

78. Grigioni F, Potena L, Galiè N, et al., Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure, J Heart Lung Transplant, 2006;25:1241–6.

79. Vachiéry JL, Adir Y, Barberà JA, et al., Pulmonary hypertension due to left heart diseases, J Am Coll Cardiol, 2013;62:D100–8.

80. Guazzi M, Vicenzi M, Arena R, Guazzi MD, Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study, Circulation, 2011;124:164–74.

81. Redfield MM, Chen HH, Borlaug BA, et al., Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial, JAMA, 2013;309:1268–77.

82. McLean RC, Jessup M, The challenge of treating heart failure: a diverse disease affecting diverse populations, JAMA, 2013;310:2033–4.

83. Thomas KL, Hernandez AF, Dai D, et al., Association of race/ ethnicity with clinical risk factors, quality of care, and acute outcomes in patients hospitalized with heart failure, Am Heart J, 2011;161:746–54.

84. Lemond L, Allen LA, Palliative care and hospice in advanced heart failure, Prog Cardiovasc Dis, 2011;54:168–78.

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Hypertension

Renal Denervation After Symplicity HTN-3 – Back to Basics.

Review of the Evidence Alex a ndre P ersu, 1 , 2 Fa d l E l m u l a M Fa d l E l m u l a , 3, 4 Yu J i n , 5 I n g r i d O s, 3, 4 Sv err e E Kj e l d s e n 3, 4 a n d Ja n A S t a e s s e n 5, 6 1. Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; 2. Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 3. Departments of General Internal Medicine, Cardiology and Nephrology, Ullevaal University Hospital; 4. Faculty of Medicine, University of Oslo, Oslo, Norway; 5. Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; 6. Vitak Development and Research, Maastricht University, Maastricht, The Netherlands

Abstract Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment resistant hypertension, a condition defined as office blood pressure elevation despite prescription of at least three antihypertensive drugs including a diuretic. However, the impressive fall in blood pressure reported after RDN in Symplicity HTN-2, the first randomised study, and multiple observational studies has not been confirmed in the US sham-controlled trial Symplicity HTN-3 and four subsequent prospective randomised studies, all published or presented in 2014. The blood pressure reduction documented in earlier studies may be largely due to non-specific effects such as improvement of drug adherence in initially poorly adherent patients (Hawthorne effect), placebo effect and regression to the mean. The overall blood pressure lowering effect of RDN seems rather limited and the characteristics of true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparent drug-resistant hypertension, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment and with true resistant hypertension who may respond to RDN.

Keywords Resistant hypertension, renal denervation, ambulatory blood pressure, white coat effect, Hawthorne effect, regression to the mean, drug adherence, drug monitoring Disclosure: Sverre Kjeldsen has received lecture and consultancy honoraria from AZ, Bayer, Medtronic, MSD, Novartis, Serodus, and Takeda, unrestricted grants from AZ, Hemo Sapiens and Pronova and royalty payments from Gyldendal (publisher). Fadl Elmula M Fadl Elmula has received speaker honorarium from Medtronic and Hemo Sapiens. Alexandre Persu, Ingrid Os, Yu Jin and Jan A Staessen declare that they have no conflict of interest.

Received: 6 October 2014 Accepted: 9 November 2014 Citation: European Cardiology Review, 2014;9(2):110–14 Correspondence: Prof. Alexandre Persu, MD-PhD, Division of Cardiology, Cliniques Universitaires Saint-Luc (UCL), 10 Avenue Hippocrate, 1200, Brussels, Belgium.

E: alexandre.persu@uclouvain.be

Renal sympathetic denervation (RDN) has been introduced as a novel approach to treat patients with so-called resistant hypertension.1–3 The first randomised clinical trial showed an impressive 32/12 mmHg fall in blood pressure after six months in the intervention group (n=52) compared to the control group (n=54). However, with the recent publication of the Symplicity HTN-3 study in the US4 the world has become in doubt whether RDN lowers blood pressure. An editor of distinguished journal5 published his reflections and stated that the Symplicity HTN-3 results came as a shock to the world; a single but large and properly designed prospective randomised clinical trial could on its own neutralise hundreds of mostly observational studies, case reports and other enthusiastic publications emphasising the amazing effect of RDN, not only in patients with resistant hypertension, but also in a host of other diseases and conditions.

The initial enthusiasm followed by the setback of RDN can probably be summarised by a handful of explanations: 1) The role of the sympathetic system in the pathophysiology of hypertension is

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substantiated by a wealth of experimental and clinical arguments.6–12 On this background, enthusiasm surged when an intervention in this system seemed to drastically lower blood pressure; 2) Market-driven industry took control and exerted unprecedented influence on the medical community; 3) Subsequently, pitfalls in apparent treatmentresistant hypertensive patients, which are simple but well-known for decades, were suddenly forgotten including well described phenomena such as the placebo effect, regression to the mean, poor drug adherence13–15 and the Hawthorne effect.

The history of the rise and decline of RDN deserves a more in-depth analysis. The first and for long the only prospective randomised clinical trial in this field, the Symplicity HTN-2 study2, was monitored

by Ardian (Medtronic) who collected and processed the data.2 Usually, when such a task is given to industry, all measures are taken to secure confidence and trials are prospective, randomised and double-blinded.16–19 However, in this case, everything was open, making the trial particularly vulnerable to patients, physicians and

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effect as office blood pressure.

Despite the major limitations and potential biases of Symplicity HTN-2, a small open study with suboptimal design including only 106 patients followed up for six months, RDN was adopted in hundreds of centres worldwide. Medtronic Inc® (Minneapolis, Minnesota) paid $800 million to purchase Ardian® (Mountain View, California), the company that had developed the technology5, and more than ten companies developed their own RDN systems, five of which obtained the CE mark. The procedure was quickly reimbursed in Germany, and later on in Switzerland, Sweden and the Netherlands. While RDN remained an investigational procedure in the US, at least 8,00031, possibly 15,000 to 20,000 procedures were performed in Europe and in the rest of the world in less than four years, most of them using the Ardian-Medtronic® catheter. It may be hypothesised that the massive incomes generated by selling the Symplicity catheter to enthusiastic Europeans contributed to the expenses of the Symplicity HTN-3 study4, required by the Food and Drug Administration (FDA) before approval of RDN in the US. In Symplicity HTN-34, blinding of patients through the use of a sham procedure and wider use of ambulatory blood pressure measurement balanced and limited the differential impact of the Hawthorne, white coat, placebo and regression to the mean effects in both treatment arms. This disclosed to the world the true size of blood pressure decrease attributable to RDN, at least in patients meeting the Symplicity criteria; it was less than 3 mmHg systolic based on ambulatory blood pressure monitoring (Table 1). Sham-procedure is however not feasible in clinical practice but was required by FDA in the Symplicity HTN-3 Study to overcome all the pitfalls in hypertension research mentioned above in order to investigate whether RDN has a true blood pressure lowering effect and the procedure may be characterised as “evidence based medicine”. Taken together with another four prospective and randomised clinical trials published or presented in 2014, discussed below, RDN as of today obviously does not fulfill these criteria and should not be used outside research protocols.

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Figure 1: Blood Pressure Reduction According to Study Design Reduction in systolic blood pressure (mm Hg)

sponsor-related biases.19 As indicated by Shun-Shin et al. in a recent editorial,20 “measurement of a noisy variable by unblinded optimistic staff is a known recipe for calamitous exaggeration”. This is illustrated in Figure 1. It is unfortunate that selection of patients enrolled in Symplicity HTN-2 and evaluation of efficacy were based on office rather than ambulatory blood pressure (ABPM), which is state-ofthe art,21 particularly in resistant hypertension.22 ABPM reduces observer bias and measurement error, minimises the white-coat effect and has greater reproducibility, and therefore provides a better estimate of a patient’s usual blood pressure and cardiovascular prognosis.23,24 Notwithstanding the well-known, major contribution of poor drug adherence to apparently resistant hypertension13–15,25–27, drug adherence was not monitored, either at baseline or during follow-up.

This made the study vulnerable to the Hawthorne effect, i.e. patients changing behaviour – in this case starting taking their drugs as prescribed – in response to the intervention and massive attention devoted to them. The lack of blood pressure decrease in the control group also raised concerns. One would indeed suspect that patients in the control group had not taken their medications properly, in order to keep their blood pressure at a higher level that made them eligible for cross-over to RDN group.28,29 Finally, placebo effect and regression to the mean must also be taken into account. Noteworthy, the placebo effect is small by using ambulatory blood pressures21,30; however ambulatory blood pressures remain as sensitive to the Hawthorne

50 40 30 20 10 0

Randomisation? Non-randomised Randomised How was blood pressure documented?

Non-randomised

Doctor, aware of allocation

Patient blinded?

Randomised

Automatic storage

Doctor, aware of allocation

Unblinded

Blinded

The figure shows reported reductions in systolic blood pressure according to whether there was randomisation, whether blood pressure was documented automatically or by a physician, and whether there was blinding. Each point represents the point estimate of reduction in systolic blood pressure from one trial report. As the quality of the trial design increased, the reported effect size decreased. The Symplicity HTN-3 trial was unique in being randomised, blood pressure being documented by a blinded member of staff, and the patient being blinded using a placebo (sham) procedure. The trial failed to meet its primary endpoint.

The mathematical prediction (20) was that its effect size would be in the dotted area. The figure is reproduced with permission from Shun-Shin et al., 2014.20

Figure 2: Overview of the ENCOReD Network P1: KU Leuven, Belgium P2: UMCU, Netherlands P3: AP-HP HEGP and URCEco, France P4: CHUV, Switzerland P5: MHH, Germany P6: UniSR, Italy P7: UJ, Poland P8: CU, Czech Republic P9: UHO, Norway P10: UNN, Norway P11: KI, Sweden P12: AUH, Denmark P16 P13: OUH, Denmark P14: UCD, Ireland P14 P15: WHRI, England P16: UG, Scotland P15 P17: UCL, Belgium P18: HUS, Finland

P10

P9

P18

P11

P12 P13

P3

P2 P1 P17

P5

P7 P8

P4 P6

The figure gives an overview of the European Network COordinating research on Renal Denervation (ENCOReD) network with investigational sites in 15 countries. The ENCOReD network is set up to include hundreds of patients in randomised protocols, observational studies and registries independent of industry.

For all aforementioned reasons, and in view of the complexity and multifactorial character of hypertension, the failure of RDN to normalise or substantially reduce blood pressure in all patients with apparently resistant hypertension was a reasonable working hypothesis for us, even before the Medtronic announcement that Symplicity HTN-3 had failed to meet its primary endpoint (http://www.tctmd.com/show. aspx?id=123265 ). We32–34 and others19,28 had predicted that the true effect of RDN might have been overestimated and may considerably shrink in properly designed studies.19,29 In particular, in preliminary analysis of the European Network COordinating research on Renal Denervation (ENCOReD) network,35 we were struck by the imbalance between the 17.6 mmHg decreases in office blood pressure, vs only 5.9 mmHg for 24-h ambulatory blood pressure.

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Hypertension The ENCOReD site in Oslo, with longstanding traditions for randomised research in hypertension36, applied a simple and practical way to deal with pitfalls in the recruitment of patients with resistant hypertension. After extensively ruling out secondary hypertension, and improving drug treatment in the run-in phase, patients had to qualify for the RDN protocols by having elevated daytime ambulatory blood pressures after witnessed oral intake of their prescribed blood pressure medication.33 This was a convenient way to identify the true treatment-resistant hypertensive patients and to exclude patients with white coat hypertension or those non-adherent patients whose blood pressure normalised after witnessed drug intake. Meanwhile a centre in Germany37 published a small but well documented series of patients whose blood pressure remained unchanged after RDN. We were thus not surprised when the Oslo activity found no change in either office or ambulatory blood pressures following RDN, first in an open series of six patients33 and later followed by a randomised study, the Oslo-RDN trial.38 Patients who were randomly assigned to further improvement of drug treatment guided by noninvasive haemodynamic monitoring had normalised blood pressures.

In contrast, patients exposed to RDN experienced only a small and probably partly placebo-induced fall in office and ambulatory blood pressures (see Table 1). The decreases averaged 20 mmHg more for office and 9 mmHg more for ambulatory systolic blood pressure in the haemodynamically guided drug treatment group compared to

of Symplicity HTN-3 by showing a difference in blood pressure were post hoc and speculations. Besides, also this study was overseen by procedure experts (proctors) from the sponsoring company, namely Medtronic. Furthermore, the Symplicity HTN-3 results are diluted by non-scientific comparisons with the Medtronic® registry45 which is hampered by all the weaknesses touched upon in this commentary, and even more as it is a pure industry-ran activity. Finally, while RDN will not become available in the US, and ongoing research in Asia was stopped, Medtronic and other companies continued making their catheters available for clinical use in Europe and did not restrain from heavily promoting the technique, for example at the Euro PCR conference in Paris in May 2014 (www.medscape.com/author/shelley-wood).

the RDN group.

pressure reductions six months following RDN (Δ systolic blood pressure: 17.7 mm Hg, P<0.001). The non-crossover group also had large reductions in office pressure one year post randomisation (Δ systolic blood pressure: 21.4 mm Hg, P<0.001) (http://congress365. escardio.org/). In the summary session of the ESC meeting the keynote speaker (Bryan Williams, London, U.K.) on September 3 pointed out the uncertain future of RDN based on the recent randomised studies performed in Oslo38 and in the US.4

In the absence of solid evidence of efficacy, how can we explain the uncontrolled deployment of RDN in Europe and worldwide (with the notable exception of the US where RDN remained an investigational procedure)? Of course, publications of the Symplicity studies and of multiple observational studies, and enthusiastic reports, editorials and reviews1–3,39,40 had a substantial impact, and the lack of strict rules for introduction of device-based therapies in Europe facilitated the large-scale implementation of the technique. However, this phenomenon would have remained limited without the huge promotion by device-producing industry. Medical journals were swamped by reviews and meta-analyses showing the powerful blood pressure lowering effects as recorded in observational studies and in the single available randomised study, Symplicity HTN-2. Comments pointing out the defects and inconsistencies in such meta-analysis encountered great delay in getting published.41 Many never questioned whether RDN should be implemented, but when it should start in an institution.

By all means, the purpose was to disseminate the enthusiasm for RDN from the technically-oriented invasive radiologists and cardiologists who usually had little interest or experience in the treatment of hypertension to the “hypertension establishment.” The European Society of Hypertension issued specific guidelines,42,43 but maintained reservations that more data was needed, and eventually it had to be proven that RDN would lower morbidity and mortality before being generally accepted in the treatment of true or apparent treatment- resistant hypertension.

Unfortunately, the most enthusiastic proponents of RDN do not seem to have fully accepted the lessons of Symplicity HTN-3. In the aftermath of Symplicity HTN-3, a campaign has been set up to criticise the study because of including inexperienced investigators, who did not appropriately document the delivery of ablation energy in the renal arteries, and enrolling too many African American patients who improved their drug adherence in the course of the trial.31,44 Symplicity HTN-3 may have had its weaknesses, however, no subgroup analysis was statistically significant4 and all the hypotheses explaining the failure

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One-year results of Symplicity HTN-34 were presented at the European Society of Cardiology (ESC) meeting in Barcelona in end of August 2014. Following the six-month evaluation all subjects and clinicians were unblinded and antihypertensive medications changes were allowed. Of the 171 original sham control group subjects, 101 who still fulfilled all of the baseline inclusion and exclusion criteria, and agreed to receive the procedure, crossed over to RDN. The remaining 70 sham control subjects did not cross over and were not treated with RDN. At one year post-procedure, both office and 24 hour mean ambulatory systolic blood pressure continued to demonstrate a decrease in the original RDN group. Similarly, the crossover group showed blood

The key message of Symplicity HTN-34 is simple and we should be wise enough to accept it: the true overall benefit of RDN on systolic blood pressure is modest, <3 mmHg, without evidence of a favourable impact on morbidity-mortality so far. The results of three other recent rigorously designed randomised controlled trials, Oslo RDN38 (see Table 1), DENER-HTN46, and PRAGUE-1547 including a smaller number of well-trained operators are in line with those of Symplicity HTN-34, and confirm that the failure of RDN to achieve superiority over medical treatment in the latter cannot be merely explained by inclusion of a high proportion of African Americans or insufficient degree of renal nerve ablation. Along the same lines, a fourth randomised shamcontrolled study performed in mild resistant hypertension (daytime systolic blood pressure between 135 and 149 mmHg and/or diastolic blood pressure between 90 and 94 mmHg on ≥ 3 drugs classes including a diuretic), Symplicity Flex48, failed to show an advantage of RDN compared to drug treatment alone.

Does the failure of Symplicity HTN-3 mean the end of RDN? Not necessarily. Indeed, as already mentioned, RDN is based on a solid rationale substantiated by over fifty years of meticulous research of the sympathetic nervous system and its involvement in the pathophysiology of hypertension.6–12 Furthermore, it has been shown in cohorts recruited from the third (The effect of progressive sympathectomy on blood pressure, Walter Bradford Cannon 1931, http://www.ncbi.nlm.nih.gov/ pubmed/2204236) until the fifth decade of the last century49,50 that abdominal sympathectomy associated to splanchnicectomy is effective in the treatment of severe hypertension. Finally, many centres report

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Renal Denervation After Symplicity HTN-3 – Back to Basics

Table 1: Characteristics and Results of Three Prospective and Randomised Studies of Blood Pressure Lowering Effects of Renal Sympathetic Denervation with Symplicity Catheters Variable Year

SYMPLICITY HTN-2 2010

Oslo RDN 2014

SYMPLICITY HTN-3 2014

Design

Open

Open

SHAM single-blind

Drug adherence

Patient diary

Witnessed intake

Patient diary

RDN Control

RDN

Control

RDN

Control

N° of patients

52

54

9

10

364

171

N° of drugs

5.2

5.3

5.1

5.0

5.1

5.2

Intervention

RDN

no active

RDN

drug adjustment

RDN

no active

Office SBP Baseline, mmHg

178

178

156

160

180

180

Δ FU – six month, mmHg

–32

+1

–8

–28

–14.13

–11.74

Δ RDN – control, mmHg

–33

Ambulatory SBP Baseline, mmHg Δ FU – six month, mmHg

+20

–2.39

?* –11

Δ RDN – control, mmHg

?* –3

–8**

152

152

159

160

–10

–19

–6.75

–4.79

+9

–1.96

SBP = Systolic blood pressure; RDN= Renal denervation; six month = six-month follow-up; - ΔRDN-control in favour of renal denervation group; +Δin favour of control group; ?* = Baseline ambulatory BPs values were not given in this study; -8** results are provided only for the difference between 20 patients in renal denervation group and 25 patients in control group.

major responses to RDN in a minority of patients.33,35,38 Accordingly, research should go on to find out the minority of patients who are true responders to RDN, and identify predictors of effective RDN. The

In a substantial proportion of patients, resistant hypertension may reflect resistance to taking medications rather than true treatment resistance.54 In this perspective, therapeutic drug monitoring may prove

ENCOReD network (see Figure 2) is set up to include hundreds of patients in randomised protocols, observational studies and registries independent of industry. Some early results35,51 from this joint effort have already been published and suggest that it may be worthwhile searching for potential predictors of response to RDN.

an effective strategy, not only for detecting poor drug adherence but also for improving blood pressure control. Indeed, when non-adherent patients are confronted with their low or undetectable drug levels and provided additional counselling to overcome barriers of adherence, blood pressure control improves considerably without intensification of therapy.55 Along the same lines, a recent analysis based on German data and life statistics showed that therapeutic drug monitoring is a cost-effective health care intervention in patients diagnosed with apparent drug-resistant hypertension, and this finding is valid for a wide range of patients, irrespective of age and sex.56 Even in truly resistant hypertensive patients with demonstrated drug adherence, blood pressure control may be achieved in a substantial proportion of patients by skilful drug treatment adjustment.33,38 While RDN deserves more in depth research, in the present state of knowledge, initiatives aiming at diagnosing and improving poor drug adherence56,57 and optimisation of drug treatment51 may prove much more cost-effective, both at the individual and public health level. n

As of now, the modest overall benefits and high cost of RDN should be balanced with its potential risks. In particular, more than 20 cases of de novo renal artery stenosis have been reported after RDN,52 most of them after the announcement that Symplicity HTN-3 failed to meet its primary endpoint. RDN deserves further investigation but is not ready for clinical deployment and its use should be restricted to research protocols. Accordingly, in Germany, the insurances companies which were the first in Europe to reimburse the procedure have terminated their coverage, and even well-known proponents of the technique acknowledge that RDN “should be returned back to the academic arena”53 before further clinical deployment.

1. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81.

2. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.

Lancet 2010;376:1903–9.

3. Krum H, Schlaich MP, Böhm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622–9.

4. Bhatt DL, Kandzari DE, O’Neill WW, et al. SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med . 2014;370:1393-1401.

5. Demaria AN. Reflections on renal denervation. J Am Coll Cardiol 2014;63:1452–3.

6. Von Euler US, Hellner S, Purkhold A. Excretion of noradrenaline in urine in hypertension. Scand J Clin Lab Invest 1954;6:54–9.

7. Julius S, Esler M. Autonomic nervous cardiovascular regulation in borderline hypertension. Am J Cardiol 1975;36:685–96.

8. Esler M, Zweifler A, Randall O, et al. Agreement among three different indices of sympathetic nervous system activity in essential hypertension. Mayo Clin Proc . 1977;52:379–82.

9. Esler M, Jackman G, Leonard P, et al. Determination of noradrenaline uptake, spillover to plasma and plasma concentration in patients with essential hypertension.

Clin Sci (Lond) 1980;59 Suppl 6:311s–3s.

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10. Kjeldsen SE, Flaaten B, Eide I, et al. Increased peripheral release of noradrenaline and uptake of adrenaline in essential hypertension? Clin Sci (Lond) 1981;61(Suppl 7):215s–7s.

11. Kjeldsen SE, Zweifler AJ, Petrin J, et al. Sympathetic nervous system involvement in essential hypertension: increased platelet noradrenaline coincides with decreased betaadrenoreceptor responsiveness. Blood Press 1994;3:164–71.

12. Manolis AJ, Poulimenos LE, Kallistratos MS, et al.

Sympathetic overactivity in hypertension and cardiovascular disease. Curr Vasc Pharmacol 2014;12:4–15.

13. Gifford RW. An algorithm for the management of resistant hypertension. Hypertension 1988;11:I-171–5.

14. Klein LE. Compliance and blood pressure control.

Hypertension 1988;11:I-161–4.

15. Ceral J, Habrdova V, Vorisek V, et al. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate nonresponsiveness from non-adherence to recommended therapy.

Hypertens Res 2011;34:87–90.

16. Staessen JA, Fagard R, Thijs L, et al. Randomised doubleblind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–64.

17. Dahlöf B, Devereux RB, Kjeldsen SE, et al. for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.

18. Julius S, Kjeldsen SE, Weber M, et al. Cardiac events, stroke and mortality in high-risk hypertensives treated with valsartan or amlodipine: Main outcomes of The VALUE Trial.

Lancet 2004;363:2022–31.

19. Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4,121 patients with focus on trial design: the CONVERGE report. Heart 2013;99:1579–87.

20. Shun-Shin MJ, Howard JP, Francis DP. Removing the hype from hypertension. Symplicity HTN-3 illustrates the importance of randomisation and blinding for exciting new treatments. BMJ 2014;348:g1937.

21. O’Brien E, Parati G, Stergiou G, et al. European society of hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013;31:1731–68.

22. Persu A, O’Brien E, Verdecchia P. Use of ambulatory blood pressure measurement in the definition of resistant hypertension: a review of the evidence. Hypertens Res 2014;37:967-972.

23. Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, Richart T, et al., IDACO investigators.

Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Blood Press Monit 2007;12:393–5.

24. Salles GF, Cardoso CR, Muxfeldt ES. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med 2008;168:2340–6.

25. Jung O, Gechter JL, Wunder C et al. Resistant hypertension?

Assessment of adherence by toxicological urine analysis.

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26. Rosa J, Zelinka T, Petrák O, et al. Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically? J Hum Hypertens 2014 Feb 6. [Epub ahead of print] 27. Tomaszewski M, White C, Patel P, et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart 2014;100:855–61.

28. Azizi M, Steichen O, Frank M, et al. Catheter-based radiofrequency renal-nerve ablation in patients with resistant hypertension. Eur J Vasc Endovasc Surg 2012;43:293–9.

29. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension.

Hypertension 2012;60:596–606.

30. Staessen JA, Thijs L, Bieniaszewski L, et al. Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Hypertension 1996;27:414–20.

31. Lüscher TF, Mahfoud F. Renal nerve ablation after SYMPLICITY HTN-3: confused at the higher level? Eur Heart J 2014;35:1706–11.

32. Persu A, Azizi M, Burnier M, Staessen JA. Residual effect of renal denervation in patients with truly resistant hypertension. Hypertension 2013;62:450–2.

33. Fadl-Elmula FEM, Hoffmann P, Fossum E, et al. Renal sympathetic denervation in patients with treatmentresistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension 2013;62:526–32.

34. Persu A, Renkin J, Asayama K, et al. Renal denervation in treatment-resistant hypertension: the need for restraint and more and better evidence. Expert Rev Cardiovasc Ther 2013;11:739–49.

35. Persu A, Jin Y, Azizi M, et al. on behalf of the European Network Coordinating research on REnal denervation (ENCOReD). Blood pressure changes after renal denervation at 10 European expert

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centers. J Hum Hypertens 2014;28:150–6.

36. Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Am J Medicine 1980:69:725–32.

37. Brinkmann J, Heusser K, Schmidt BM, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: Prospective case series. Hypertension 2012;60:1485–90.

38. Fadl Elmula FE, Hoffman P, Larstorp AC, et al. Adjusted drug treatment is superior to sympathetic renal denervation in patients with true treatment resistant hypertension.

Hypertension 2014;63:691–9.

39. Mahfoud F, Ukena C, Schmieder RE, et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013;128:132–40.

40. Ott C, Mahfoud F, Schmid A, et al. Renal denervation in moderate treatment-resistant hypertension. J Am Coll Cardiol 2013;62:1880–6.

41. Jin Y, Persu A, Staessen JA. Letter by Jin et al. regarding article, “ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension”. Circulation 2014;129:e499.

42. Schmieder RE, Redon J, Grassi G, et al. ESH Position Paper: Renal Denervation - an Interventional Therapy of Resistant Hypertension. J Hypertens 2012;30:837–41.

43. Schmieder RE, Redon J, Grassi G, et al. Updated ESH position paper on interventional therapy of resistant hypertension.

Euro Intervention 2013;9:R58–66.

44. Schmieder RE. How should data from SYMPLICITY HTN 3 be interpreted? Nat Rev Cardiol . Advance online publication 20 May 2014;doi:10.1038/nrcardio.2014.70.

45. Pathak A, Ewen S, Fajadet J, et al. From SYMPLICITY HTN-3 to the Renal Denervation Global Registry: where do we stand and where should we go? Euro Intervention 2014;10:21–3.

46. Azizi M, Monge M, Pereira H, Sapoval M on behalf of DENER-HTN investigators. The French DENER-HTN Trial: renal denervation + standardized antihypertensive treatment vs. standardized antihypertensive treatment alone in

patients with resistant hypertension. J Hypertens 2014; 32(e-Supplement 1):e89. http://www.hypertension2014.org/ wordpress/wp-content/uploads/2014/06/ESH-ISH-2014Abstract-Book-Oral.pdf.

47. Widimsky J, Rosa J, Tousek P, et al. Renal denervation versus intensified medical treatment including spironolactone in patients with true resistant hypertension: 6-months results of multicenter randomized Prague. J Hypertens 2014;32(e-Supplement 1):e87. http://www.hypertension2014. org/wordpress/wp-content/uploads/2014/06/ESH-ISH-2014Abstract-Book-Oral.pdf 48. http://www.tctmd.com/show.aspx?id=126422 Accessed 2nd October 2014.

49. Longland CJ, Gibb WE. Sympathectomy in the treatment of benign and malignant hypertension; A review of 76 patients.

Br J Surg 1954;41:382-392.

50. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension, results in 1,266 cases. JAMA 1953;152:1501–4.

51. Persu A, Jin Y, Baelen M, et al; European Network Coordinating research on REnal Denervation (ENCOReD) Consortium. Eligibility for renal denervation: experience at 11 European expert centers. Hypertension 2014;63:1319–25.

52. Persu A, Sapoval M, Azizi M, et al. Renal artery stenosis following renal denervation: a matter of concern. J Hypertens 2014;32:2101–5.

53. Böhm M, Mahfoud F. SYMPLICITY HTN-3 trial: what is it and what does it mean? Eur Heart J 2014;35:1697–8.

54. Brown MJ. Resistant hypertension: resistance to treatment or resistance to taking treatment? Heart 2014;100:821–2.

55. Brinker S, Pandey A, Ayers C, et al. Therapeutic drug monitoring facilitates blood pressure control in resistant hypertension. J Am Coll Cardiol 2014;63:834–5.

56. Chung O, Vongpatanasin W, Bonaventura K, et al. Potential cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension. J Hypertens 2014 Sep 24.

57. Kjeldsen SE, Os I. Cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension and improving patients’ adherence. J Hypertens 2014. In press.

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Hypertension

LE ATION.

Hypertension in Chronic Kidney Disease – Role of Arterial Calcification and Impact on Treatment Oliv ier P ha n , 1 M i c h e l B u r n i e r 1 a n d G r é g o i r e Wu e r z n e r 1 ,2 1. Service of Nephrology; 2. Clinical Research Center, Lausanne University Hospital, Lausanne, Switzerland

Abstract Hypertension contributes to the progression of kidney diseases as well as to the occurrence of cardiovascular events such as myocardial infarction, heart failure and stroke. The prevalence of hypertension is elevated in patients with kidney disease, and increases progressively as glomerular filtration rate falls. A better understanding of the mechanisms leading to hypertension in renal diseases has been gained in recent years; in this article we will review the pathogenesis of hypertension in chronic kidney disease (CKD) with a special focus on vascular calcification because calcification is associated with an increased incidence of cardiovascular morbidity in CKD patients. Although calcification of large arteries and blood pressure increase with age, few studies have specifically investigated a possible connection between these two factors as determinants of the severity of hypertension in CKD. Finally, we will review the trends in hypertension treatment in CKD patients. Expanded understanding of the role of CKD as both a cause and a target of hypertension highlights key points of pathophysiology of hypertension and may contribute to the identification of new strategies for its prevention and treatment.

Keywords Hypertension, chronic kidney disease, vascular calcification, proteinuria, treatment Disclosure: The authors have no conflicts of interest to declare.

Received: 7 October 2014 Accepted: 19 November 2014 Citation: European Cardiology Review, 2014;9(2):115–20 Correspondence: Olivier Phan, Service of nephrology, Lausanne University Hospital, Rue du Bugnon 17, 1011 Lausanne, Switzerland. E: olivier.phan@chuv.ch

Chronic kidney disease (CKD) is characterised by progressive nephron loss leading to increased intraglomerular pressure, glomerular permeability, proteinuria and systemic hypertension. The prevalence of CKD defined as estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m2 ranges from 2 to 12 % in Europe and in the US.1,2 CKD is an independent risk factor for the development of cardiovascular diseases (CVDs), showing a graded risk of cardiovascular events as eGFR declines, with a sharp rise in events as eGFR falls <45 mL/min per 1.73 m2.3 Hypertension prevalence increases as renal function declines and may be present in more than 80 % of patients with stage 4 to 5 CKD.4 Hypertension contributes to progression of kidney disease as well as to cardiovascular (CV) events such as myocardial infarction, congestive heart failure and stroke.

In Western countries, approximately 20–30 % of incident end-stage renal disease (ESRD) cases are attributed to hypertension.1,2 One characteristic of hypertension is the remodelling of the arterial wall in response to the increase in blood pressure (BP).

Moreover, with time, significant modifications in extracellular matrix composition and in vascular cell phenotype occur in the vasculature.5 Vascular tissue remodelling associated with hypertension, might actually create an environment for calcium deposition within the arteries.6 This phenomenon is particularly important in CKD patients.

Indeed, in CKD, vascular calcifications are clearly associated with a higher CV morbidity and mortality.3 Although calcification of large arteries and BP increase with ageing, only a few studies specifically investigated the interaction between these two factors as aggravating mechanisms of hypertension and CV events, and as promoters of a

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more rapid decline of renal function in CKD. In this review, we will focus on accelerated vascular calcification and its association with CKD and hypertension.

Accelerated Vascular Calcification in Chronic Kidney Disease and Hypertension – Implications for New Concepts The risk of CV diseases in patients with chronic renal disease appears to be far greater than in the general population.3 Among patients treated by dialysis, the prevalence of coronary artery disease is approximately 40 % and the prevalence of left ventricular hypertrophy is approximately 75 %. CV mortality of dialysis patients has been estimated to be approximately 9 % per year.3 Even after stratification by age, gender, race and the presence or absence of diabetes, CV mortality in dialysis patients is 10–20 times higher than in the general population.3 These findings have prompted most hypertension guidelines to include the presence of CKD as a CV risk factor.7 Premature arterial calcification in CKD patients is one factor possibly increasing the CV risk. The natural history of coronary artery calcification has been studied in 22 young adults with ESRD by electron-beam computed tomography (EBCT).8 After a baseline assessment, computed tomography (CT) scanning was repeated at a mean of 22 ± 7 months later. Among 12 patients who had no evidence of coronary artery calcification on the initial scan, two had evidence of calcification on follow-up scanning. Among 10 of these 22 patients who had evidence of coronary artery calcification on the initial scan, nine had a higher calcification score on follow-up

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Hypertension scanning; the values nearly doubled (from 125 ± 104 to 249 ± 216) over a mean period of 20 ± 3 months (p=0.02).

Pulse Wave Velocity, Systolic Hypertension and Vascular Calcification in Chronic Kidney Disease Patients

The mechanisms responsible for vascular calcifications in CKD patients remain uncertain, and the relation between arterial wall calcification and the atherosclerotic process is not fully understood. The factors involved in these complications are complex. Numerous metabolic and endocrine abnormalities involving calcium and phosphorus metabolism are found in CKD. Furthermore, CKD is believed to be a state of inflammation and oxidative stress. Most of these abnormalities occur early in the course of CKD and may contribute to the development and progression of vascular calcification and atherosclerosis. The mechanisms regulating the process of vascular calcification and the factors involved are subject to continued investigation. Both calcium and phosphorus directly stimulate vascular smooth muscle cell transformation into osteoblast-like cells and abnormal mineralization in vitro. The mechanisms whereby smooth muscle cells calcify appears to result from a complex interplay between factors that activate and inhibit tissue calcification.9 Matrix vesicles initiate mineral nucleation during skeletogenesis; similar vesicular structures are deposited at sites of pathologic vascular calcification. In vitro studies have shown that elevated levels of extracellular calcium and phosphorus can induce mineralization of vascular smooth muscle cells.10 In addition, numerous other factors have been shown, both in vitro and in vivo, to promote

Pulse wave velocity (PWV) is the gold standard method for evaluating arterial stiffness non-invasively. It depends on the arterial wall structure and function but is mainly influenced by age-associated alterations and BP.17 Temmar et al. studied the temporal link between PWV and aortic and coronary calcifications in a cohort of 150 patients with different stages of CKD.18 They found that both vascular stiffness and vascular calcification appeared early in CKD patients. Age, mean arterial BP, diabetes and aortic calcification score were all independent determinants of increased PWV. The relationship between measures of arterial stiffness PWV and the extent of calcification in the coronary arteries was also examined by Haydar et al. in a small population of 66 haemodialysis patients.19 The mean age of the 55 patients was 56.4 years and the mean duration of dialysis was 65.4 months; they demonstrated that PWV is strongly related to the degree of EBCT-derived coronary artery calcium score in CKD patients. The next step in validating PWV as a useful tool for the risk assessment of CKD patients was to study the effect of pharmacological intervention.

Clinical studies involving essential hypertension and CKD patients have shown that angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists decreased aortic PWV to a large extent in response to BP lowering.20 The results indicate that independent of BP changes, survival

this process, in part through the production and activity of proteins like osteopontin, osteoprotegerin, osteocalcin, bone morphogenetic proteins and matrix Gla protein.8

was substantially better for those subjects whose aortic PWV decreased in response to decreased BP. Guerin et al. hypothesised that the PWV is partly dependent on BP.21 They evaluated if the changes in PWV in response to decreases in BP can predict mortality in dialysis patients.

They showed that the loss of aortic PWV sensitivity to BP was predictive of adverse outcome, indicating that arterial stiffness is not only a risk factor contributing to the development of CV disease but also a marker of more advanced, less reversible arterial damage. Taken together, these results support the hypothesis that measurement of arterial parameters exploring both structural and functional properties, such as quantification of arterial calcium deposit and determination of PWV, could help in stratifying the risk but also in evaluating the risk reduction strategies by monitoring these arterial parameters under different drug regimens. Significant alterations of the aortic PWV appear at an early stage of the disease; mild-to-moderate renal insufficiency, an elevated stiffness of the central arteries seems to be significantly associated with a reduced creatinine clearance, independent of BP and other standard CV risk factors.22 These results suggest that alterations of the viscoelastic properties of the arterial wall are significantly connected to renal alterations, and that this association is present long before the appearance of ESRD and macrovascular complications.23

Calcium deposits are found, however, in a large proportion of atherosclerotic lesions, providing the basis for the use of EBCT to screen for coronary artery disease.11 Arterial layers are more frequently and more intensively calcified in uraemic patients than in non-uraemic patients, and participated to the progression of CKD.12 Both the intima and media arterial layers are more frequently and more intensively calcified in uraemic patients than in non-uraemic individuals, and vascular and valvular calcification are both predictors of increased CV mortality and morbidity.13 In the atheromatous plaque, the most marked difference between uraemic and non-uraemic patients is not in its size but its composition, with a marked increase in calcium content in CKD patients.14

Vascular Calcification – Role of Vitamin D and Vitamin D Analogues Calcitriol and various analogues are commonly used to suppress secondary hyperparathyroidism in CKD but may also exacerbate vascular calcification in experimental models; the mechanisms by which high doses of vitamin D or its derivatives induce vascular calcification include an increase in serum calcium and phosphate, the formation of fetuin-A mineral complexes in association with a decrease in free serum levels of fetuin-A.15 Some active vitamin D derivatives, when given in high amounts to animals with CKD, are not endowed with the same calcification-inducing capacity. For example, paricalcitol has been shown to be less pro-calcifying in uraemic rats than calcitriol or doxercalciferol.

However, there are no prospective randomised controlled trials in CKD patients comparing the effect of native vitamin D or active vitamin D derivatives with placebo on vascular calcification. So far, the results of the PRIMO study (Paricalcitol capsules benefits in Renal failure Induced cardiac MOrbidity in subjects with chronic kidney disease Stage 3/4) that failed to show a beneficial effect of long-term paricalcitol administration over placebo on cardiac structure and function in CKD patients confirms the need for further intervention studies with firm outcomes.16

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High BP and proteinuria are major factors in the progression of CKD.24 Weir et al. have evaluated whether PWV was associated with increased risk of proteinuria in CKD patients.24 Systolic BP was important as an explanatory factor for variations in proteinuria, whereas PWV incrementally accounted for a significant portion of variation in proteinuria beyond that explained by brachial artery systolic BP in diabetics but not in non-diabetic patients.

Importance of Blood Pressure Control and Antihypertensive Therapy The main goal of BP reduction in CKD patients is to reduce the risk of CV events and to slow the decline of GFR. Most of the evidence for reducing BP comes from large randomised controlled trials in the general population. These trials showed that treatment of BP

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reduces CV outcomes. In CKD patients with proteinuria, it has been shown that BP reduction is associated with a slower decline of renal function.25,26 The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the management of BP in CKD acknowledges that no single BP target is optimal for all CKD patients and encourages individualisation of treatment depending on age, the severity of albuminuria and co-morbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mmHg systolic and ≤90 mmHg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 hour (i.e. those with both micro- and macroalbuminuria), a lower target of ≤130 mmHg systolic and ≤80 mmHg diastolic is suggested.26,27 In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged in all guidelines.

Blocking the renin-angiotensin-aldosterone system (RAAS), using ACE inhibitors or angiotensin receptor blockers (ARBs), is the current gold standard pharmacological treatment approach for hypertension and proteinuria in CKD. Numerous randomised controlled trials in diabetic and non-diabetic CKD patients have shown that these agents slow the decline of CKD compared with placebo or with other antihypertensive agent.28–33 The beneficial effect was confirmed in a meta-analysis.34 These agents act not only to lower BP but also through a BP-independent effect on proteinuria. The most recent analysis of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) have documented that the initial treatment-induced reduction in albuminuria is highly predictive of reduction of fatal and non-fatal renal and CV events.35 This predictive effect of the decrease in proteinuria prompted trials, which studied the effect of intensive blockade of the renin-angiotensin system (RAS). Unfortunately, the results from ONTARGET showing a lack of an additional benefit of double blockade (ramipril–telmisartan) over monotherapy (ramipril or telmisartan alone), with an increased risk of hyperkalaemia, renal failure, discourage the use of ACE inhibitors/ ARBs combination in patients at high-risk of CV events. Aliskiren, the first direct renin inhibitor to receive approval for hypertension treatment, was thought to provide additional renoprotective effects over standard treatment.36,37 The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), which included 8,606 patients with type 2 diabetes, compared the effects of aliskiren or placebo added to standard treatment of RAS blockade. This study was terminated prematurely due to higher adverse events occurring in patients receiving aliskiren in addition to the standard care, such as an increased incidence of a non-fatal stroke, renal failure, hyperkalaemia and hypotension. The use of a single drug to block the RAAS is therefore recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 hour.

In order to achieve BP targets, more than one drug is often necessary, particularly in CKD.38 Therefore, the question arising is which is the best antihypertensive drug to combine with a RAS blocker? In the Avoiding Cardiovascular Events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a randomised controlled trial comparing fixed-dose combination of the ACE inhibitor benazepril and the dihydropyridine calcium channel blocker amlodipine with the combination of benazepril and hydrochlorothiazide in reducing CV morbidity and mortality, the progression of CKD was a prespecified endpoint. This study, which included 11,506 high-risk hypertensive patients, showed that events of CKD defined as double serum creatinine or ESRD were lower in the benazepril–amlodipine group

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compared with the benazepril–hydrochlorothiazide group (hazard ratio [HR] 0.52, 0.42–0.65). A possible explanation may come from the differential effect of calcium channel blockers compared with thiazides on vascular calcification.

In fact, no study has really investigated the effect of treatment on vascular calcifications and BP and the progression of renal diseases. A substudy of the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Therapy (INSIGHT) trial,39 which compared the effect of nifedipine once-daily versus co-amilozide (hydrochlorothiazide 25 mg, amiloride 2.5 mg) on mortality and morbidity in high-risk hypertensive patients, was interested in progression of coronary calcification in a subgroup of patients (n=201). While the main study failed to show any difference in mortality and morbidity between the two arms, the substudy showed a slower progression of coronary calcification in the nifedipine versus the co-amilozide group.40 This finding may be of relevance since even CKD patients with mild renal dysfunction have accelerated coronary calcifications independently of other risk factors.41 However, it is worth mentioning that the use of calcium channel blockers is associated with more peripheral oedema that might limit its use in CKD.39,42 As salt and fluid retention are largely responsible for the high BP in CKD patients, it is not surprising that diuretics still play an important role in the control of hypertension in these patients. Most guidelines recommend using loop diuretics over thiazides for the treatment of hypertension once CKD reaches stage 4 (eGFR<30 ml/min/1.73 m2).

However, recent evidence from small trials suggest that thiazides may still be useful in advanced CKD.43 The combined use of blockers of the RAS, diuretics and a low sodium diet appears to be particularly useful in reducing BP and proteinuria.44 The use of beta-blockers may be particularly useful in patients with CKD and systolic heart failure. Indeed, a meta-analysis reported that compared with placebo the risk ratio of all-cause mortality (relative risk [RR] 0.72, 95 % confidence interval [CI] 0.64–0.80) and CV mortality (RR 0.66, 95 % CI 0.49–0.89) was reduced.45 Beta-blockers, however, are not the preferred first-line drugs because it has be shown that if peripheral (brachial) BP is lowered similarly by atenolol and amlodipine, central BP is decreased more intensively by amlodipine.46 This may be of importance because in the same cohort, central BP was significantly associated with a composite outcome of total CV events/procedures and the development of renal impairment.

Finally, as renal function declines, the pharmacokinetics of drugs due to impaired renal clearance may be affected. It is important to adapt the dose of antihypertensive drugs to the eGFR in order to avoid accumulation, which may result in serious side effects.

Lifestyle interventions are recommended in most hypertension or renal disease guidelines. If restriction of sodium intake makes sense from a pathophysiological point of view (reduced capacity to excrete sodium in CKD, effect on proteinuria, effect on nocturnal BP, increased effectiveness of RAS blockade), the level of sodium intake that should be targeted in CKD remains a matter of debate since recent post hoc analysis have shown that a J-curve may exist.47 This indicates that a restriction in sodium intake that is too strict may actually be deleterious. Well-designed prospective trials targeting sodium intake are needed to confirm this phenomenon. In addition to sodium intake, moderate alcohol intake, regular exercise,48 weight

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Hypertension loss in those with a body mass index >25 kg/m2 and reduced amount of saturated fat help to reduce BP.49

Is Accelerated Renal Calcification a Reason for the Failure of Renal Denervation to Lower Blood Pressure in Chronic Kidney Disease?

There is a current surge in research investigating renal denervation as a potential treatment for resistant hypertension, as an overactive renal sympathetic system is known to exert an influence on the underlying pathophysiology of both hypertension and CKD. In a uraemic rat model, Campese et al. have shown in subtotally nephrectomised rats that BP rapidly increases after surgery, which was abolished by afferent denervation.50 Interestingly, renal afferent denervation has also prevented the progression of renal disease in this model.51 They have also showed that a small lesion in one kidney by an intrarenal phenol injection, not affecting kidney function, increases sympathetic activity and leads to a long-term increase in noradrenaline secretion and to hypertension. These effects are also abolished by afferent denervation. In humans, it has been show that the activity of the sympathetic nervous, assessed by microneurography, increases as renal function declines.52 Taken together, these results indicate that the sympathetic nervous system is a logical target for intervention.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic BP reductions. Prior unblinded studies have suggested that catheter-based renal artery denervation reduces office BP in patients with resistant hypertension;41 the results of the SYMPLICITY HTN-3 study, a single-blind, randomised, sham-controlled trial, failed to show a significant reduction of systolic BP six months after renal artery denervation as compared with a sham control.53 Interestingly, subgroup analysis suggested that patients with eGFR

1. Coresh J, Selvin E, Stevens LA, et al., Prevalence of chronic kidney disease in the United States, JAMA, 2007;298:2038–47.

2. Zoccali C, Kramer A, Jager KJ, Epidemiology of CKD in Europe: an uncertain scenario, Nephrol Dial Transplant, 2010;25:1731–3.

3. Foley RN, Parfrey PS, Sarnak MJ, Epidemiology of cardiovascular disease in chronic renal disease, J Am Soc Nephrol, 1998;9(12 Suppl):S16–23.

4. Centers for Disease Control and Prevention (CDC), Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004, MMWR Morb Mortal Wkly Rep, 2007;56:161–5.

5. Chen NX, Moe SM, Vascular calcification in chronic kidney disease, Semin Nephrol, 2004;24(1):61–8.

6. Moe SM, O’Neill KD, Duan D, et al., Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins, Kidney Int, 2002;61(2):638–47.

7. Mancia G, Fagard R, Narkiewicz K, et al., 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), Eur Heart J, 2013;34(28):2159–219.

8. Goodman WG, Goldin J, Kuizon BD, et al., Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis, N Engl J Med, 2000;342:1478–83.

9. Moe SM, O’Neill KD, Duan D, et al., Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins, Kidney Int, 2002;61:638–47.

10. Scialla JJ, Astor BC, Isakova T, et al., Mineral metabolites and CKD progression in African Americans, J Am Soc Nephrol , 2013;24(1):125–35.

11. Fiorino AS, Electron-beam computed tomography, coronary artery calcium, and evaluation of patients with coronary artery disease, Ann Intern Med, 1998;128(10):839–47.

12. Shanahan CM, Cary NR, Salisbury JR, et al., Medial localization of mineralization-regulating proteins in association with Mönckeberg’s sclerosis: evidence for smooth muscle cellmediated vascular calcification, Circulation, 1999;100(21):2168–76.

13. Massy ZA, Ivanovski O, Nguyen-Khoa T, et al., Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice, J Am Soc Nephrol, 2005;16(1):109–16.

14. Raggi P, Boulay A, Chasan-Taber S, et al., Cardiac

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<60 ml/min/1.73 m2 were less responsive (between-group difference in change in office BP 0.54 [-8.29–9.37, 95 % CI]) than patients with eGFR ≥60 ml/min/1.73 m2 (between-group difference in change in office BP -5.22 [-10.51–0.06, 95 % CI]).54 The effect of renal function in response to renal denervation is consistent with an earlier report showing that higher baseline creatinine was associated with lower probability of 24 hour BP improvement (odds ratio for each 20 µmol/L increase, 0.60; p=0.05). The degree of renal artery calcification may limit the efficacy of renal denervation; however, this remains to be proven. Recently, a study was conducted to investigate the proportion of patients eligible for renal denervation and the reasons for non-eligibility at 11 expert centres participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD).55 The most frequent cause of ineligibility (approximately half of cases) was BP normalisation after treatment adjustment by a hypertension specialist.

These results highlight that hypertension centres with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.56 Further evaluation in rigorously designed clinical trials will be necessary to bring evidence that renal denervation may a therapeutic option for CKD patients.

In conclusion, the burden of hypertension in CKD patients is high.

These patients are at increased risk of target organ damages and CV events. Vascular lesions due to hypertension-induced remodelling and vascular calcifications play an important role in the development of CV and renal complications. In the absence of specific treatment of arterial stiffness and calcifications, reduction of BP using non-pharmacological or/and pharmacological interventions is crucial to reduce these risks. Most of the time, several drugs are necessary to reach the targeted BP. Today, the combination of drugs including a blocker of the RAS and a calcium channel blocker appear to be one of the most effective associations in high-risk patients. n

calcification in adult hemodialysis patients: A link between end-stage renal disease and cardiovascular disease?, J Am Coll Cardiol, 2002;39(4):695–701.

15. Price PA, Williamson MK, Nguyen TM, Than TN, Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat, J Biol Chem, 2004;279(3):1594–600.

16. Thadhani R, Appelbaum E, Pritchett Y, et al., Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial, JAMA, 2012;307(7):674–84.

17. Avolio AP, Chen SG, Wang RP, et al., Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community, Circulation, 1983;68(1):50–8.

18. Temmar M, Liabeuf S, Renard C, et al., Pulse wave velocity and vascular calcification at different stages of chronic kidney disease, J Hypertens, 2010;28(1):163–9.

19. Haydar AA, Covic A, Colhoun H, et al., Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients, Kidney Int, 2004;65(5):1790–4.

20. London GM, Marchais SJ, Guerin AP, et al., Salt and water retention and calcium blockade in uremia, Circulation, 1990;82(1):105–13.

21. Guerin AP, Blacher J, Pannier B, et al., Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure, Circulation, 2001;103(7):987–92.

22. Mourad JJ, Pannier B, Blacher J, et al., Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension, Kidney Int, 2001;59(5):1834–41.

23. Covic A, Haydar AA, Bhamra-Ariza P, et al., Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients, J Nephrol, 2005;18(4):388–96.

24. Weir MR, Townsend RR, Fink JC, et al., Hemodynamic correlates of proteinuria in chronic kidney disease, Clin J Am Soc Nephrol, 2011;6(10):2403–10.

25. Appel LJ, Wright JT Jr, Greene T, et al., Intensive bloodpressure control in hypertensive chronic kidney disease, N Engl J Med, 2010;363(10):918–29.

26. Peterson JC, Adler S, Burkart JM, et al., Blood pressure control, proteinuria, and the progression of renal disease.

The Modification of Diet in Renal Disease Study, Ann Intern Med, 1995;123(10):754–62.

27. Sarnak MJ, Greene T, Wang X, et al., The effect of a lower

target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study, Ann Intern Med, 2005;142(5):342–51.

28. Lewis EJ, Hunsicker LG, Clarke WR, et al., Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes, N Engl J Med, 2001;345(12):851–60.

29. Fried LF, Emanuele N, Zhang JH, et al., Combined angiotensin inhibition for the treatment of diabetic nephropathy, N Engl J Med, 2013;369(20):1892–903.

30. Agodoa LY, Appel L, Bakris GL, et al., Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial, JAMA, 2001;285(21):2719–28.

31. Maschio G, Alberti D, Janin G, et al., Effect of the angiotensinconverting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-ConvertingEnzyme Inhibition in Progressive Renal Insufficiency Study Group, N Engl J Med, 1996;334(15):939–45.

32. Brenner BM, Cooper ME, de Zeeuw D, et al., Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, N Engl J Med, 2001;345(12):861–9.

33. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group, N Engl J Med, 1993;329(20):1456–62.

34. Jafar TH, Schmid CH, Landa M, et al., Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease, A meta-analysis of patient-level data, Ann Intern Med, 2001;135(2):73–87.

35. Yusuf S, Diener HC, Sacco RL, et al., Telmisartan to prevent recurrent stroke and cardiovascular events, N Engl J Med, 2008;359(12):1225–37.

36. White WB, Bresalier R, Kaplan AP, et al., Safety and tolerability of the direct renin inhibitor aliskiren in combination with angiotensin receptor blockers and thiazide diuretics: a pooled analysis of clinical experience of 12,942 patients, J Clin Hypertens (Greenwich), 2011;13(7):506–16.

37. ONTARGET Investigators, Yusuf S, Teo KK, et al., Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med, 2008;358(15):1547–59.

38. Bakris GL, Williams M, Dworkin L, et al., Preserving renal function in adults with hypertension and diabetes:

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Hypertension in Chronic Kidney Disease

a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group, Am J Kidney Dis, 2000;36(3):646–61.

39. Brown MJ, Palmer CR, Castaigne A, et al., Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT), Lancet, 2000;356(9227):366–72.

40. Motro M, Shemesh J, Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics, Hypertension, 2001;37(6):1410–3.

41. Bursztyn M, Motro M, Grossman E, Shemesh J, Accelerated coronary artery calcification in mildly reduced renal function of high-risk hypertensives: a 3-year prospective observation, J Hypertens, 2003;21(10):1953–9.

42. Bakris GL, Sarafidis PA, Weir MR, et al., Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial, Lancet, 2010;375(9721):1173–81.

43. Agarwal R, Sinha AD, Thiazide diuretics in advanced chronic

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kidney disease, J Am Soc Hypertens, 2012;6(5):299–308.

44. Vogt L, Waanders F, Boomsma F, et al., Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan, J Am Soc Nephrol, 2008;19(5):999–1007.

45. Badve SV, Roberts MA, Hawley CM, et al., Effects of betaadrenergic antagonists in patients with chronic kidney disease: a systematic review and meta-analysis, J Am Coll Cardiol, 2011;58(11):1152–61.

46. Williams B, Lacy PS, Thom SM, et al., Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study, Circulation, 2006;113(9):1213–25.

47. Burnier M, Wuerzner G, Chronic kidney disease: Should sodium intake be restricted in patients with CKD?, Nat Rev Nephrol, 2014;10(7):363–4.

48. Wuerzner G, Bochud M, Zweiacker C, et al., Step count is associated with lower nighttime systolic blood pressure and increased dipping, Am J Hypertens, 2013;26(4):527–34.

49. Redon J, Cifkova R, Laurent S, et al., The metabolic syndrome in hypertension: European society of hypertension position statement, J Hypertens, 2008;26(10):1891–900.

50. Campese VM, Kogosov E, Renal afferent denervation prevents hypertension in rats with chronic renal failure, Hypertension, 1995;25(4):878–82.

51. Campese VM, Kogosov E, Koss M, Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat, Am J Kidney Dis, 1995;26(5):861–5.

52. Grassi G, Quarti-Trevano F, Seravalle G, et al., Early sympathetic activation in the initial clinical stages of chronic renal failure, Hypertension, 2011;57(4):846–51.

53. Bhatt DL, Kandzari DE, O’Neill WW, et al., A controlled trial of renal denervation for resistant hypertension, N Engl J Med, 2014;370(15):1393–401.

54. Persu A, Jin Y, Azizi M, et al., Blood pressure changes after renal denervation at 10 European expert centers, J Hum Hypertens, 2014;28(3):150–6.

55. Persu A, Jin Y, Baelen M, et al., Eligibility for renal denervation: experience at 11 European expert centers, Hypertension, 2014;63(6):1319–25.

56. Wuerzner G, Muller O, Erne P, et al., Transcatheter renal denervation for the treatment of resistant arterial hypertension: the Swiss expert consensus, Swiss Med Wkly, 2014;144:w13913.

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Supported Contribution – Opinion

Rhythm Management of the Atrial Fibrillation Patient: Practical Implementation of the 2012 ESC Guidelines K a t rina Mou n t f o r t , M e d i c a l Wr i t e r , R a d c l i f f e Ca r d i o l o g y R ev iewed for a c c u r a c y b y : K a r l - H e i n z Ku c k 1 a n d Ri c h a r d S c h i l l i n g , 2 1. Asklepios Klinik St Georg, Hamburg, Germany; 2. St Bartholomew’s and Queen Mary University, London, UK

Abstract A symposium at the 2014 European Society of Cardiology (ESC) congress reviewed the 2012 update of the ESC guideline on rhythm management of atrial fibrillation (AF) patients. The guidelines now include catheter ablation of AF as first-line therapy in selected patients with symptomatic, paroxysmal AF. A panel comprising electrophysiologists and cardiologists discussed four clinical cases that illustrated the challenges faced in the day-to-day treatment of AF patients and how these guidelines can help inform treatment decisions. Among the key discussions were the importance of early treatment of AF and the dilemma faced in treating AF patients with recently implanted stent, where the risk of stroke must be balanced against the risk of stent thrombosis. The panel considered that among selected patients with paroxysmal AF and no structural heart disease, catheter ablation is reasonable as first-line therapy.

Keywords Atrial fibrillation, catheter ablation Disclosure: Prof. Kuck has received research grants from Biosense Webster, Stereotaxis, Medtronic, St Jude, Cardiofocus and Abbott, and speakers bureau honoraria from Biosense Webster, Medtronic, St Jude, Cardiofocus, Abbott, and Biotronik. Prof. Schilling has received research grants from Biosense Webster, Medtronic, St Jude Medical, Biotronik and Boston Scientific, and speakers bureau honoraria from Daiichi Sankyo and Boehringer-Ingelheim.

Received: 17 September 2014 Accepted: 20 November 2014 Citation: European Cardiology Review, 2014;9(2):120–2 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. E: katsmountfort@virginmedia.com

Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased risk of stroke, heart failure and mortality.1 Following increased therapeutic options for AF, an update in guidelines for management of AF has been published. A symposium, chaired by KarlHeinz Kuck, Hamburg, Germany, was held at the European Society of Cardiology (ESC) congress in Paris on the 2nd September 2014. It aimed to inform cardiologists of the 2012 ESC guidelines and also to foster a “shared care” approach between electrophysiologist and cardiologists.

An update of the 2010 ESC guidelines for the management of AF, developed with the European Heart Rhythm Association, was published in 2012.2 The definitions of AF are: paroxysmal AF (PAF) is AF of duration 48 hours or less but a maximum of 7 days. Permanent AF is AF that persists for at least 7 days or requires a cardioversion,

or long standing persistent AF lasting more than a year, as well as permanent AF in which physician and patient accept that AF should not be converted.3 The ESC guidelines have incorporated patient choice into the treatment paradigm (see Figure 1). In addition, for the first time, the guidelines state that catheter ablation is recommended in patients who have symptomatic recurrences of AF on antiarrythmic drug therapy and who prefer further rhythm control therapy (class I recommendation). Catheter ablation should be considered as first-line therapy in selected patients with symptomatic PAF as an alternative to antiarrhythmic drug therapy (class IIa). These recommendations follow a clinical trial that demonstrated that, among patients with PAF without previous antiarrhythmic drug treatment, radiofrequency ablation resulted in a lower rate of recurrent atrial tachyarrhythmias at 2 years compared with antiarrhythmic drugs.4 n

Application of the ESC Guidelines to Real Life Cases Presented by Richard Schilling, London, UK

In order to illustrate the challenges of AF management, Professor Schilling presented four real-world cases for discussion by a panel of expert cardiologists.

Case 1 Case 1 was a 55 year-old man with symptomatic PAF. The patient had

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no previous history of cardiovascular disease (CVD) or other relevant medical history. Professor Schilling proposed a thyroid function test (TFT) but not an echocardiogram; the latter would not, in his opinion, have a significant impact on patient management. The patient had a CHA2DS2-VASc score of 0 and therefore did not need anticoagulation.

However, the panel considered that an echocardiogram was essential

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to assess the size of the left atrium, left ventricular function and whether mitral stenosis is present. If the patient had mitral stenosis, the CHA2DS2-VASc score would be irrelevant because anticoagulation would be required. Despite consensus of the panel and the audience that an echocardiogram is mandatory in this patient, this is not reflected in the guidelines.

Figure 1: 2012 update: management of AF No or minimal structural heart disease

Paroxysmal

In terms of treatment, the panel agreed that patient choice was important. Options include rate control. Depending on the frequency of AF, a conservative pill-in-pocket strategy may be preferred. The guidelines state that regular antiarrhythmics should be the first choice. Most would consider catheter ablation but would involve the patient in the decision-making process.

Persistent

Patient choice a

Catheter ablation

Dronedarone, flecainide, propafenone, sotalol

Case 2 Case 2 was a 35 year-old man diagnosed with AF during a routine medical examination. He was asymptomatic with no history of CVD. Professor Schilling proposed a TFT and 24-hour Holter tape to determine whether the AF was persistent rather than paroxysmal, followed by an echocardiogram to assess possible structural defects.

No stroke prevention was required: the CHADSVasc score was 0.

In terms of treatment, rate control is a reasonable option. Rhythm control would not be offered because cardioversion and drugs offer no prognostic benefit. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial showed that management of AF with rhythm control offers no survival advantage over rate control and that the latter has potential advantages, such as a lower risk of adverse effects.5 Remaining in sinus rhythm was associated with reduced mortality but the use of rhythm control drugs was associated with increased mortality.6 However, if this patient had a normal heart and PAF, catheter ablation may be a better option. A registry study showed that restoration of sinus rhythm by catheter ablation was associated with lower rates of stroke and death compared with medical treatment.7 Furthermore, ablation was more successful in PAF than in persistent AF. Further clinical trial data are needed to support this.

The panel considered that clinical trial data were not applicable to this patient: he is not representative of study populations. Most agreed that a discussion explaining but not encouraging catheter ablation, would be appropriate. A significant proportion of the audience would perform cardioversion, despite the fact that there is no evidence for its benefits and evidence of harm. The panel considered that recurrence rate following cardioversion is high; it should be used in emergencies only.

Case 3 Case 3 was a 76 year-old man who presented with a transient ischaemic attack (TIA), was in sinus rhythm and had no history of CVD. Professor Schilling proposed an ECG, carotid Doppler test and echocardiogram. He would not recommend a 24-hour Holter tape; instead he would advise keeping a pulse diary. Depending on the findings of the latter, he would consider prolonged monitoring or an event recorder. A 24-hour tape has poor sensitivity and specificity for AF screening.8 Monitoring by the patient or a family member may be equally as effective at detecting an irregularity. A study of patients aged ≥55 years following a cryptogenic stroke or TIA, found that AF lasting ≥30 seconds was detected in 16.1 % of patients fitted with a 30-day event-triggered recorder, compared with 3.2 % in the control group, who were fitted with a 24-hour monitor.9

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b

Patient choice

Amiodarone

The Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial (ASSERT) study showed that, in patients with hypertension but no history of AF, episodes of atrial tachycardia >6 minutes were seen in approximately one-third of patients and were associated with a 2.5-fold increase in the risk for ischemic stroke.10 However, these patients were all fitted with a pacemaker and there is no evidence that that successful catheter ablation reduces risk of stroke.

In terms of treatment, if AF or AF triggers were found, an anticoagulant may be recommended.

Case 4 Case 4 was a 68 year-old man with shortness of breath coinciding with new onset palpitations, a week prior to admission to the emergency room. A diagnosis of persistent AF was made. An echocardiogram would be useful to assess LV function, mitral regurgitation and left atrial size. If the patient had been experiencing AF for several years, a conservative management strategy would be advised. The echocardiogram should be performed only when the rate is controlled: a fast heart rate would impede assessment of LV function. Echocardiography can also indicate AF duration: a small left atrium is associated with short duration of AF.11 The guidelines recommend rate control and, if still symptomatic, either cardioversion and amiodarone for at least a year or catheter ablation.12 Professor Schilling prefers the latter option. He then introduced a complication: the patient had a myocardial infarction (MI) 2 weeks previously, with subsequent implantation of a coated stent. This raises issues about the use of anticoagulation. The ESC guidelines in terms of anticoagulant therapy are based on risk profiles for AF patients.

However, this case presents a dilemma in how to balance the risk of stroke and stent thrombosis. An electrophysiology specialist would assess risks from the viewpoint of AF and reduce dual antiplatelet therapy, but in doing so would increase the risk of stent thrombosis.

The guidelines do not address these issues. This case illustrates the importance of clinician judgement.

Discussion and Concluding Remarks Dr Kuck began his discussion by stating that the progression from PAF to persistent AF should be a new endpoint in AF treatment and,

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Supported Contribution – Opinion to illustrate this point, returned to case 2. If this patient is allowed to remain in AF for 5 years and subsequently becomes symptomatic, he will be more difficult to treat as he may have structural changes including remodelling of the left atrium. This led to the question: when should catheter ablation be performed? In Dr Kuck’s opinion, as early as possible, ideally at the time of PAF to prolong the time to progression to chronic forms of AF. The ongoing Early treatment of Atrial fibrillation for Stroke prevention (EAST) Trial will determine whether rhythm control therapy, when applied early after initial diagnosis of AF, can prevent cardiovascular complications associated with AF.13 In order to demonstrate the importance of early treatment, Dr Kuck presented a study that investigated the long-term procedural success of catheter ablation in patients with symptomatic PAF and normal left ventricular function. After a median 1 procedure, stable sinus rhythm was achieved in 80 % of patients.14 By contrast, in a study of the 5-year efficacy of catheter ablation for long-standing persistent AF, success rates for single and multiple ablation procedure were 20 % and 45 %, respectively.15 Patients with a total AF duration <2 years had a significantly higher ablation success rate than patients with AF duration ≥2 years (76.5 % vs. 42.2 %, respectively). These data show

1. Peters NS, Schilling RJ, Kanagaratnam P, et al., Atrial fibrillation: strategies to control, combat, and cure, Lancet , 2002;359:593-603.

2. Camm AJ, Lip GY, De Caterina R, et al., 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association, Europace , 2012;14:1385-413.

3. European Heart Rhythm A, European Association for CardioThoracic S, Camm AJ, et al., Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC), Eur Heart J , 2010;31:2369-429.

4. Morillo CA, Verma A, Connolly SJ, et al., Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial, JAMA , 2014;311:692-700.

5. Wyse DG, Waldo AL, DiMarco JP, et al., A comparison of rate control and rhythm control in patients with atrial fibrillation, N Engl J Med , 2002;347:1825-33.

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that prolonging the decision to undergo catheter ablation may not be best for the patient.

In RecordAF, a worldwide prospective study, patients with recent onset AF were allocated to rate or rhythm control.16 AF progression (paroxysmal to persistent) at 12 months occurred in 15 % of patients.

Patients treated with rhythm control were less likely to show progression than those treated only with rate control (11 % vs 26 %; p<0.001).

Independent predictors of AF progression included history of heart failure, history of hypertension and rate control rather than rhythm control.16 In the absence of large randomized controlled trials, these data may help inform clinical decision-making. The ongoing ATrial FibrillaTion ProgrESsion Trial (ATTEST) aims to determine whether early radiofrequency ablation treatment in subjects with PAF delays AF progression compared with drug therapy (rate or rhythm control).17 This seminar has stimulated discussion between electrophysiologists and cardiologists and highlighted the need for large clinical trials to inform early treatment decisions. It may be concluded that among selected patients with PAF and no structural heart disease, catheter ablation is reasonable as first-line therapy. n

6. Corley SD, Epstein AE, DiMarco JP, et al., Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study, Circulation , 2004;109:1509-13.

7. Hunter RJ, McCready J, Diab I, et al., Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death, Heart , 2012;98:48-53.

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