ECR 12.1

European Cardiology Review Volume 12 • Issue 1 • Summer 2017

Volume 12 • Issue 1 • Summer 2017

www.ECRjournal.com

Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Marie Mide Michelsen, Naja Dam Mygind, Daria Frestad and Eva Prescott

Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, Brittany Edgar, Wendy Lin, Maria Auxiliadora Parreiras Martins, Michael K Paasche-Orlow and Jared W Magnani

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Volume 12 • Issue 1 • Summer 2017

www.ECRjournal.com Editor-in-Chief Juan Carlos Kaski

St George’s University of London, London, UK

Associate Editorial Steering Committee Rao Kondapally, Aneil Malhotra, Robin Ray, Nesan Shanmugam St George’s University of London, London, UK

Senior Associate Editors Richard Conti

Wolfgang Koenig

Giuseppe Mancia

Mario Marzilli

Hiroaki Shimokawa

University of Florida, Gainesville, USA

Technical University of Munich, Munich, Germany

University of Milano-Bicocca, Milan, Italy

University of Pisa, Pisa, Italy

Tohoku University, Sendai, Japan

Pablo Avanzas

Michael Fisher

Amir Lerman

Magdi Saba

University Hospital of Oviedo, Oviedo, Spain

Royal Liverpool University Hospital, Liverpool, UK

Mayo Clinic, Minnesota, US

St George’s University of London, London, UK

Cedars-Sinai Heart Institute, Los Angeles, US

Augusto Gallino

José Luis López-Sendón La Paz Hospital, Madrid, Spain

Gianluigi Savarese

Debasish Banerjee

Alberto Lorenzatti

St George’s University of London, London, UK

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Vinayak Bapat

Antoni Bayes-Genis

Angela Maas

Noel Bairey Merz

Columbia University Medical Centre, New York, US

Hospital Germans Trias i Pujol, Barcelona, Spain

Velislav Batchvarov

Robert Gerber

St George’s University of London, London, UK

Conquest Hospital, Hastings, UK

John Beltrame

Bernard Gersh

University of Adelaide, Adelaide, Australia

Mayo Clinic, Minnesota, US

Christopher Cannon

David Goldsmith

Hospital Córdoba, Cordoba, Argentina Radboud University Medical Center, Nijmegen, the Netherlands

Sanjay Sharma St George’s University of London, London, UK

Rosa Sicari Italian National Research Council

Felipe Martinez

Iana Simova

National University of Cordoba, Cordoba, Argentina

Peter Collins

Tommaso Gori

Imperial College, London, UK

Johannes Gutenberg University Mainz, Mainz, Germany

University Hospital of Sabadell, Sabadell, Spain

National Cardiology Hospital, Sofia, Bulgaria

Juan Tamargo University Complutense, Madrid, Spain

Konstantinos Toutouzas

Argyrios Ntalias

University of Athens, Athens, Greece

University of Athens, Athens, Greece

Isabella Tritto

University of Naples Federico II, Naples, Italy

Kim Greaves

Gheorghe Andrei Dan

Sunshine Coast University Hospital, Sunshine Coast, Australia

Denis Pellerin

Eileen Handberg

Carl Pepine

Colentina University Hospital, Bucharest, Romania

Imperial College, London, UK

University of Bologna, Bologna, Italy

Antoni Martínez-Rubio

Alberto Cuocolo

Roxy Senior

Olivia Manfrini

St George’s University of London, London, UK

Harvard Medical School, Boston, US

Karolinska Institute, Stockholm, Sweden

St Bartholomew’s Hospital, London, UK

University of Perugia, Perugia, Italy

Dimitrios Tziakas Democritus University of Thrace, Xanthi, Greece

Ranil de Silva

University of Florida, Florida, US

University of Florida, Florida, USA

Imperial College, London, UK

Thomas Kahan

Piotr Ponikowski

Polychronis Dilaveris

Danderyd University Hospital, Danderyd, Sweden

Wroclaw Medical University, Wroclaw, Poland

Eva Prescott

Koichi Kaikita

Bispebjerg Hospital, København, Denmark

Kumamoto University, Kumamoto, Japan

Axel Pries

Mike G Kirby

Charité Universitätsmedizin Berlin, Germany

University of Hertfordshire, Hatfield, UK; The Prostate Centre, London, UK

Hari Raju

University College, London, UK

Macquarie University, Sydney, Australia

St Thomas’ Hospital, London, UK

Albert Ferro

Patrizio Lancellotti

Giuseppe Rosano

José Luis Zamorano

King’s College London, London, UK

University of Liège, Liège, Belgium

IRCCS San Raffaele, Rome, Italy

Hospital Ramon Y Cajal, Madrid, Spain

Hippokration General Hospital, Athens, Greece

Carlo Di Mario Careggi University Hospital, Florence, Italy

Perry Elliott

Mauricio Wajngarten University of Sao Paulo, Brazil

Hiroshi Watanabe Hamamatsu University School of Medicine, Hamamatsu, Japan

Matthew Wright

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com

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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.

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Established: April 2005 Frequency: Bi-annual Current issue: Summer 2017

Aims and Scope

Submissions and Instructions to Authors

• 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.

• Contributors are identified by the and invited by the Editor-in-Chief with support from the Associate Editors and Managing Editor, and guidance from the Editorial Board.

• Following acceptance of an invitation, the author(s) and Managing Editor, in conjuction with the Editor-in-Chief 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.

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 Associate Editors and the Editorial Board.

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

• Each edition of European 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 Associate Editors and 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.

Reprints All articles included in European Cardiology Review are available as reprints (minimum order 1,000). 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. All manuscripts published in the journal are free-to-access online at www.ECRjournal. com and www.radcliffecardiology.com

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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, Cardiac Failure Review and Interventional Cardiology Review. n

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Contents Foreword

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Juan Carlos Kaski

Cardiovascular Disease in Women

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Ischemic Heart Disease in Women: Not About Religion Angela HEM Maas

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Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma

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Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Marie Mide Michelsen, Naja Dam Mygind, Daria Frestad and Eva Prescott

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Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson

Environment and Cardiovascular Disease

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Noise Pollution and Arterial Hypertension: Can We Remain Mute Anymore?

Sreenivasa Rao Kondapally Seshasai and Juan Carlos Kaski

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Noise Pollution and Arterial Hypertension Thomas Münzel and Mette Sørensen

Cardiovascular Pharmacotherapy

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Key Recent Advances in Atherosclerosis Treatment with Modern Lipid-lowering Drugs: The New Frontier with PCSK9 Inhibitors Antoni Martínez-Rubio and Román Freixa Pamias

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Antiplatelet Therapy in Acute Coronary Syndrome

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Contemporary Management of Stroke Prevention in Atrial Fibrillation Following the European Society of Cardiology Guidelines

Kerry Layne and Albert Ferro

Manav Sohal

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Direct Oral Anticoagulants: A Quick Guide Julia Sikorska and James Uprichard

Ischaemic Heart Disease

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Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions Andrew McNeice, Andrew Ladwiniec, Simon Walsh and Colm Hanratty

Health Literacy

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Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, Brittany Edgar, Wendy Lin, Maria Auxiliadora Parreiras Martins, Michael K Paasche-Orlow and Jared W Magnani

Imaging

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Cardiac Magnetic Resonance in Takotsubo Syndrome Konstantinos Bratis

Cardiology Masters

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Featuring: Prof Carlo Patrono

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© RADCLIFFE CARDIOLOGY 2017

September 16-20 Copenhagen, Denmark

CIRSE 2017 featuring

I M PAC T

TH E

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Get ready f or CIRSE! Visit www.cirse.org/getready for more information

Cardiovascular and Interventional Radiological Society of Europe

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. Prof 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.

Prof Kaski’s research areas include mechanisms of rapid coronary artery disease progression, inflammatory and immunological mechanisms of atherosclerosis, microvascular angina and biomarkers of cardiovascular risk. Prof Kaski has published over 400 papers in peer-review journals, over 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

W

elcome to a new issue of European Cardiology Review (ECR). This issue of the journal coincides with the Annual Congress of the European Society of Cardiology (ESC) in Barcelona. I hope to meet as many of our readers and contributors as possible at the conference, and I also look forward to getting acquainted with the results of the large studies that will be presented

at that esteemed meeting. ECR will have a presence at the conference and I hope that you will visit us at our publisher’s – Radcliffe Cardiology’s – booth N610 during the event.

In this issue, we present a section on cardiovascular disease in women – guest edited by Angela Maas. Professor Mass highlights that “despite impressive progress in treatment over the past 40 years, sex and gender differences in ischemic heart disease are still underrecognized and even ignored in clinical practice”. This is a theme further explored by Tracey Keteepe-Arachi and Sanjay Sharma, who write on how to better understand cardiovascular symptoms and risk factors in women. Eva Prescott and colleagues present a timely review on the assessment of women with stable angina pectoris and no obstructive coronary artery disease. Finally, in the same series, Paul Leeson and colleagues provide an expert viewpoint on the increasing burden of cardiac disease after pregnancy.

Also in this issue, we begin to look at the issue of the impact of environmental factors in cardiovascular disease. This is a large and rapidly evolving field that will be explored further in future issues. Here, Sreenivasa Rao Kondapally Seshasai and I introduce Thomas Münzel and Mette Sørensen’s review, in which they examine the effects of noise pollution on the cardiovascular system.

Furthering the exciting partnership between ECR, Radcliffe Cardiology and the International Society of Cardiovascular Pharmacotherapy (ISCP), I am delighted to present our ongoing special section on Cardiovascular Pharmacotherapy – introduced by ISCP President, Antoni Martínez-Rubio and cardiovascular consultant Román Freixa Pamias. The review articles in this section focus on the use of anticoagulants and antiplatelet agents in cardiovascular disease. Kerry Layne and Albert Ferro review the use of antiplatelet therapy in acute coronary syndrome. Manav Sohal discusses current ESC recommendations for stroke prevention in atrial fibrillation and Julia Sikorska and James Uprichard provide a quick guide on the use of direct oral anticoagulants, providing an expert practical haematological view on the topic.

The final three review articles in this issue look at different aspects of cardiology with Colm Hanratty and colleagues discussing an hybrid approach to percutaneous coronary intervention to treat chronic total occlusions, Konstantinos N Aronis and colleagues telling us about health literacy and atrial fibrillation, and Konstantinos Bratis focusing on the use of cardiac magnetic resonance for the assessment and risk stratification of Takotsubo syndrome.

In our ongoing series that highlights the contributions of iconic clinicians and researchers in cardiology – Cardiology Masters – we are delighted that Professor Carlo Patrono has allowed us to profile him. We hope that these Cardiology Masters articles will help readers charting the many routes that lead to excellence in the field of cardiovascular disease.

All articles presented in the current issue deal with extremely important topics in cardiovascular medicine and provide expert views regarding diagnosis, prevention and management of diverse cardiovascular conditions. I extend my thanks to both the ECR Editorial Board and the Steering Committee as well as all the featured authors for their contributions to this issue of the journal. I hope you will enjoy reading it as much as I have enjoyed editing it. n

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the International Society of Cardiovascular Pharmacotherapy Date : May 26 (Sat.) and 27 (Sun), 2018 Venue : The Ritz-Carlton, Kyoto JAPAN for scientific exchange on current topics in evidence-based clinical management

President and Meeting Chair Koji Hasegawa (Leader, Cardiovascular Clinical Research Network, National Hospital Organization) Program Chair Masayuki Yoshida (Director, Life Science and Bioethics Research Center, Tokyo Medical and Dental University) Program Chair Masataka Sata (Professor and Chairman, Cardiovascular Medicine, University of Tokushima Graduate School) Congress Secretariat Division of Translational Research, Kyoto Medical Center Kyoto 612-8555 JAPAN FAX : 81-75-641-9252â&#x20AC;&#x192;E-mail : medical@j-iscp.com Congress website : www.iscp2018.com

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Cardiovascular Disease in Women

Guest Editorial Ischemic Heart Disease in Women: Not About Religion Angela HEM Maas Department of Cardiology, Radboudumc, Nijmegen, The Netherlands

Citation: European Cardiology Review 2017;12(1):8–9. DOI: 10.15420/ecr.2017.12.1.GE1 Correspondence: Angela HEM Maas, MD, PhD, Director Women’s Cardiac Health Program, Department of Cardiology, route 616, Radboudumc, P.O.Box 9101, 6500HB Nijmegen, The Netherlands. E: Angela.Maas@radboudumc.nl

O

ver the past 40 years impressive progress has been made in treating focal, obstructive coronary artery disease (CAD) using percutaneous coronary interventions (PCI) and the most sophisticated surgical bypass techniques. Although women have profited to a great extent from these advancements, sex and gender differences in ischemic heart disease (IHD) are still under-recognised and even ignored in clinical practice.1 The majority of women with

signs and symptoms of IHD are still treated using standards for men. However, this is not in line with the different pattern of IHD in women, with non-obstructive CAD (NOCAD) predominating over obstructive CAD, in combination with functional disorders of the coronary (micro-) circulation.2 Postmortem studies and computed tomography angiograms show clinically relevant sex differences in plaque morphology at all ages, with fewer calcifications, less focal obstruction and a more diffuse pattern of atherosclerosis with ‘outward remodeling’ and ‘soft’ plaques in women compared with men.3,4 Differences in underlying pathophysiology lead to a more distinct presentation of angina symptoms and warrant a more gender-sensitive diagnostic and therapeutic approach than the usual male-oriented diagnostic pathway.

In this edition of European Cardiology Review, several experts provide an excellent overview of our current knowledge on cardiovascular disease – both in women in general and in women after complicated pregnancies. Furthermore, the paper of Michelsen et al. is very helpful in identifying the most appropriate diagnostic tools to assess NOCAD with or without functional coronary (micro-) vascular disease in symptomatic women.5 It is a must read for all professionals working in the field of clinical cardiology.

Why so Reluctant for Change?

For those who are long since familiar with sex and gender differences in the various aspects of IHD, it is striking to observe that there is still a great reluctance among the cardiology community to consider IHD in a broader manner than the traditional stenotic way of thinking.

This tunnel vision impedes optimal care for our female patients and contributes to a considerable waste of resources by repeated inappropriate diagnostic tests and invasive procedures.6 For example, persistent symptoms after coronary interventions – affecting more

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women than men – are often a result of concomitant functional CAD rather than epicardial obstructions.7 Moreover, hypertension is a major trigger for coronary vascular dysfunction and is often poorly treated and interpreted as being stress-related. In most cases, the cardiologist’s reflex to perform another coronary angiogram does not reveal the problem and many women feel disappointed by unsatisfactory explanations and a lack of solutions. While we all believe in ‘black holes’ and ‘gravitational waves’ in space, which we cannot see, we are reluctant to make faster progress in the development of better tools to assess functional CAD in the coronary (micro-) circulation, which we cannot visualize with an angiogram. The topic of IHD in women is still considered to be a ‘women’s affair’ or an issue for those who are ‘believers’. This ignores the accumulating evidence for a different pattern of IHD in women – in both the acute and chronic settings – leading to misdiagnoses and often mistreatment. This also undervalues the importance of female-specific risk factors to identify women at increased risk for premature cardiovascular disease.8 Cardiology for women is not a religion for cardio-feminists, but an evolving scientific field with evidence-based data that need to be implemented in clinical practice.

A Culture Shift is Needed in Cardiology After 40 years of angioplasty, with the development of advanced stents and antithrombotic therapy, it is time to move on and reconsider our patient population. This population is made up of males and females with various ethnic backgrounds and differences in phases of life, risk factors, stress-levels, cardiac and non-cardiac co-morbidities, inflammatory diseases and genetics, and these differences must be taken into consideration in order to provide more tailored care for the broad spectrum of existing IHD manifestations. This needs a cultural change within the cardiology community for whom a specific interest in IHD in women has not been a priority in the past. Our current cardiac care is indebted to women to provide the best possible treatment for IHD. In the US, an alliance of experts has recently established a research agenda for non-obstructive IHD that is equally relevant to our European populations.9 To accelerate improvements, we also need to consider ‘health’ along a horizontally oriented life-course and leave our vertical organ-specific way of thinking behind. Past events such as preeclampsia have serious consequences for future cardiovascular

© RADCLIFFE CARDIOLOGY 2017

Ischemic Heart Disease in Women: Not About Religion disease risk in women, and adequate follow-up requires close collaboration of cardiologists/vascular specialists with obstetricians.

1.

2.

3.

UGenMed; Cardiovascular Clinical Study Group, RegitzE Zagrosek V, Oertelt-Prigione S, Prescott E, et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J 2016;37:24–34.

DOI: 10.1093/eurheartj/ehv598; PMID: 26530104 Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009;54:1561–75. DOI: 10.1016/j.jacc.2009.04.098; PMID: 19833255 Smilowitz NR, Sampson BA, Abrecht CR, et al. Women have less severe and extensive coronary atherosclerosis in fatal cases of ischemic heart disease: an autopsy study.

Am Heart J 2011;161:681–8. DOI: 10.1016/j.ahj.2010.12.022; PMID: 21473966

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Benefits for patients should take precedent, with a shift away from outdated ways of thinking. n

asir K, Gopal A, Blankstein R, et al. Noninvasive assessment N of gender differences in coronary plaque composition with multidetector computed tomographic angiography. Am J Cardiol 2010;105: 453–8. DOI: 10.1016/j.amjcard.2009.09.053; PMID: 20152238 Michelsen MM, Mygind ND, Frestad D, Prescott E. Women with stable angina pectoris and no obstructive coronary artery disease: closer to a diagnosis. European Cardiology Review 2017: XXXXXX Borren N, Maas AH, Ottervanger JP. Stop invasive coronary angiography as the gold standard for the diagnosis of stable angina. Interventional Cardiology 2015;7:415–18.

Kok MM, van der Heijden LC, Sen H, et al. Sex difference in chest pain after implantation of newer generation coronary

8.

9.

drug-eluting stents: A patient-level pooled analysis from the TWENTE and DUTCH PEERS trials. JACC Cardiovasc Interv 2016;9:553–61. DOI: 10.1016/j.jcin.2015.10.043; PMID: 26947384 Elias-Smale SE, Günal A, Maas AH. Gynaecardiology: distinct patterns of ischemic heart disease in middle-aged women.

Maturitas 2015:81:348–52. DOI: 10.1016/j.maturitas.2015.04.012; PMID: 26006301 Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and no obstructive coronary artery disease (INOCA): Developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135:1075–92.

DOI: 10.1161/CIRCULATIONAHA.116.024534; PMID: 28289007

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Cardiovascular Disease in Women

Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma Department of Cardiovascular Sciences, St George’s University of London, London, UK

Abstract Cardiovascular disease (CVD) in women remains under-diagnosed and undertreated due to the diagnostic challenge it presents, as well as the persisting attitude that CVD predominantly affects men. Gender-related risk factors have now been identified but there is a lack of clinical application, leading to the misdiagnosis and poor management of women with CVD. It is necessary to address gender-specific symptomatology and risk factors in order to optimise management and positively influence morbidity and mortality in this cohort of patients.

Keywords Cardiovascular disease, risk factors, microvascular angina, stress cardiomyopathy, Takotsubo, women Disclosure: The authors have no conflicts of interest to declare.

Received: 1 November 2016 Accepted: 2 December 2016 Citation: European Cardiology Review 2017;12(1):10–3 DOI: 10.15420/ecr.2016:32:1 Correspondence: Tracey Keteepe-Arachi, Cardiology Research Fellow and Specialist Registrar, Department of Cardiovascular Sciences, St George’s University of London, Cranmer Terrace, London, SW17 0RE, UK. E: tketeepe28@gmail.com

Globally, cardiovascular disease (CVD) remains the leading cause of mortality in women. Approximately 2.8 million women have been diagnosed with CVD in the UK.1 For many years, the presence of gender-related differences in presentation, risk factors and outcomes have been recognised. Importantly, these discrepancies in presentation and outcomes between the sexes are often associated with inequalities in the detection, referral and management of CVD. There is a lack of gender-specific evidence due to the underrepresentation of women in clinical trials and a long-held myth that CVD is limited to men. Women present with ischaemic heart disease about a decade later than men. This usually occurs in the postmenopausal period, during which time the protective effects of oestrogen are attenuated. Furthermore, population-based risk reduction in women has not resulted in improvements in the incidence of CVD compared to men.

There was a significant decline in the incidence of myocardial infarction (MI) in men between 1979 and 1994, and a comparative increase in the incidence in older women during the same period.2 Further evidence supporting this finding from the National Health and Nutrition Examination Surveys demonstrated an increase in the prevalence of MIs in women in the 35–54 year age range, while a decline in prevalence was observed in age-matched men.3 It follows that early and accurate diagnosis of CVD is pivotal to reduce mortality rates in women.

Gender Differences in the Clinical Presentation of CVD The evaluation of cardiovascular symptoms in women remains challenging due to the atypical nature of presentation. In addition, the use of ‘typical’ angina symptoms in the assessment of females may be imprecise due to the transposition of symptoms derived from male cohorts.4 The Framingham Heart Study initially described the pattern of presentation in women in the 1980s, and demonstrated that females generally develop angina as the initial presentation of ischaemic heart

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disease and are less likely to present with an acute MI compared with men.5,6 In acute coronary syndrome, women also present more commonly with unstable angina, rather than ST-segment elevation myocardial infarction.7,8 In contrast, a study of 246 women and 276 men demonstrated no gender differences in the sensitivity of typical symptoms, defined as chest pain or discomfort, dyspnoea, diaphoresis and arm or shoulder pain, in the diagnosis of acute coronary syndromes.9 Women tend to present less frequently with exertional symptoms of chest pain prior to an acute MI.10 Differences in presentation tend to be more polarised among younger patients compared with older individuals. Supporting this finding, a study of >10,000 patients showed that older women (>65 years) presented with symptoms comparable to men and had a greater frequency of typical angina.11 Current data suggest that in women, symptoms of chest pain are less discriminatory in predicting obstructive coronary artery disease (CAD) than in men.12 This finding has been well documented, and almost 40 years ago Diamond and Forrester suggested that when assessed with coronary angiography for typical or atypical symptoms relating to myocardial ischaemia, women demonstrated lower rates of obstructive CAD compared with men.13 In established CVD, both men and women present with chest pain.

Women report additional, potentially gender-related, non-specific symptoms, however, such as fatigue and sleep disturbance (see Table 1).

The presentation may therefore confound the diagnosis, making dismissal of these symptoms as non-cardiac all the more perilous.14,15

Gender Similarities and Differences in Risk Factors for CVD Despite men and women sharing classic cardiovascular risk factors, the relative importance of each risk factor may be gender specific.

For example, the deleterious impact of smoking is greater in women

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CVD in Women: Symptoms and Risk Factors than men, especially in those <50 years of age.16,17 Smoking also downregulates oestrogen-dependent vasodilatation via biochemical effects on the endothelial wall.18

Table 1: The Influence of Gender on Symptoms of Myocardial Ischaemia

During assessment of CVD risk, typical risk factors must be considered including age >55 years, pre-existing CAD, hypertension, dyslipidaemia and diabetes mellitus, among others (see Figure 1). Risk factors that are specific to women include postmenopausal status, hysterectomy and complications during pregnancy. Women who go on to develop gestational diabetes or pre-eclampsia more than double their risk of developing CVD later in life.19

• Pain, pressure or squeezing in chest • Report milder symptoms • Radiation of pain to neck, shoulder, • Sudden onset of weakness, back, arm, jaw shortness of breath, fatigue, • Palpitations feeling of systemic illness • Difficulty in breathing (without chest pain) • Heartburn, nausea, vomiting, • Mild discomfort in back, Abdominal pain chest, arm, neck or jaw • Cold sweats, clamminess (without chest pain) • Dizziness

Common in both Sexes

Physical inactivity remains a significant risk factor for CVD. The Duke Activity Status Index is a risk stratification tool comprising a 12-item questionnaire measuring functional capacity. When compared to women who engaged in greater levels of physical activity, those performing <4.7 metabolic equivalents of effort in the form of activities of daily living were subject to a 3.7-fold increased risk of death or non-fatal MI.20

The Effects of Menopause on CVD Risk Transition to postmenopausal status is associated with a worsening coronary heart disease (CHD) risk profile in women, conveying the same degree of cardiovascular risk as being male.21,22 The effects of the menopause include an increase in body weight, alteration in fat distribution, centripetal obesity and visceral fat deposition, with an associated increase in other CVD risk factors such as diabetes mellitus.23 In particular, diabetes is a potent risk factor in women. A meta-analysis of 37 studies and almost 450,000 patients revealed a 50 % greater relative risk of fatal CHD compared to men with the disease.24 This substantial gender difference in mortality is associated with a more adverse risk factor profile, smaller coronary vessel diameter and often suboptimal management of diabetes in women.

As oestrogen production wanes in ageing women, systolic blood pressure tends to increase and is modulated by the increase in plasma-renin activity.25–27 In women >75, isolated systolic hypertension is 14 % more prevalent than in men and causes significant morbidity due to left ventricular hypertrophy, diastolic heart failure and cerebrovascular disease.28 In younger women, the relative risk of hypercholesterolaemia is lower compared with men; the postmenopausal state, however, is associated with a more adverse lipid profile, with total cholesterol and low-density lipoprotein (LDL) levels increasing by 10 % and 14 %, respectively, without a significant change in high-density lipoprotein levels.21,29 Postmenopausal reassessment of lipids is therefore an important consideration in women with a borderline premenopausal profile. In women >65 years, mean LDL is higher than in men; however LDL reduction with statins reduces CHD mortality to a similar extent as in men.30

Microvascular Angina This term refers to patients with symptoms of angina, displaying abnormalities on stress testing despite demonstrating normal coronary arteries on angiography. There is a well documented predilection for women to develop microvascular angina, and in a study of 886 patients presenting with chest pain and subsequently undergoing coronary angiography, women were five times as likely to have normal coronary arteries than men.31 The same risk factors leading to atherosclerosis

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More Common in Women

Figure 1: Risk Factors for CVD that are Common to Both Men and Women and those Specific to Women Established risk factors common to both genders

Risk factors specific to women

Psychological stress Smoking

Postmenopausal

Hypertension History of CAD or other atherosclerotic vascular disease

Pregnancy complications: • pre-eclampsia • gestational diabetes

Diabetes mellitus

Hysterectomy

Chronic kidney disease Inflammatory disorders e.g. RA Dyslipidemia: high LDL and/or low HDL Age >55 years Family history of premature CAD CAD = coronary artery disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; RA = rheumatoid arthritis.

may cause microvascular disease, however, with low oestrogen levels in women also implicated. The main aim of treatment is symptom control using calcium-channel blockers and oral nitrates.

Stress (Takotsubo) Cardiomyopathy Stress cardiomyopathy is triggered by intense, unexpected emotional or physical stress and is characterised by temporary apical systolic dysfunction with ballooning of the left ventricle (see Figure 2).

The syndrome predominantly affects postmenopausal women.

This was demonstrated in a study of 1,750 patients from 26 centres, where almost 90 % of those affected were women with a mean age of 66.4 years.32 Presentation is similar to acute MI, with ST-segment elevation on the ECG and raised cardiac troponin levels. However, angiography does not reveal obstructive coronary disease and the observed regional wall motion abnormality is not limited to the territory supplied by a single coronary artery. The underlying mechanisms are not fully understood but catecholamine toxicity, microvascular dysfunction and coronary artery spasm have all been highlighted as possible pathogenic processes. There may be a genetic component in those predisposed to stress cardiomyopathy, with the identification of familial cases; however more convincing is the finding that 56 % of sufferers had a psychiatric or neurological disorder compared to 26 % of patients with acute coronary syndromes.32

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Cardiovascular Disease in Women Figure 2: Left Ventriculogram Demonstrating the Left Ventricular ‘Ballooning’ seen in Takotsubo Cardiomyopathy

Gender Differences in the Management of CVD Underestimation of cardiovascular risk in women results in delayed or even missed diagnoses of CVD. The use of investigations to detect severe coronary stenosis is often futile, as women have a lower prevalence of obstructive CAD but have greater symptom burden and functional impairment (see Table 2). The management of stable angina in both sexes remains similar, and includes lifestyle modifications, anti-anginal medications and pharmacological secondary prevention, revascularisation and rehabilitation.33

The Role of Cardiac Investigations

Right: diastole; Left: systole.

Table 2: Factors Affecting the Accuracy of Cardiovascular Disease Diagnosis in Women Factor Menopausal Status Premenopausal

Endogenous oestrogen

may cause ST-segment

changes resulting in

false positive ETTs.

Angina and ischaemia

varies with the menstrual cycle.

Functional Capacity

Inability to reach adequate HR may impede diagnosis of ischaemia.

If 5 METs cannot be achieved then pharmacological stress testing should be utilised.

Disease Prevalence

The lower prevalence of disease results in a lower accuracy of stress testing when compared to men.

ECG Changes

Resting ST-T wave changes Reduces the accuracy of identifying changes at peak stress.

ACC/AHA guidelines recommend cardiac imaging in individuals with resting ST-T wave changes on the ECG.

Postmenopausal Higher prevalence of coronary disease.

Lower QRS voltage Affects the diagnostic accuracy of investigations in women.

Table 3: American Heart Association Guidance for the Prevention of Cardiovascular Disease Women 22 Aspirin

• Weight control • Consider low-dose therapy in • Management of hypertension women >65 years if benefits • Increase exercise outweigh risks • Alcohol moderation • Dietary advice Hormone replacement therapy

and selective oestrogen receptor Encourage smoking cessation with modulators are not recommended advice and cessation therapy

Antioxidant supplements, e.g.

Dietary modifications vitamins C and E, should not be • Eat oily fish at least twice a week used for primary/secondary • Limit saturated fat intake prevention of cardiovascular disease

12

Pharmacological stress testing is an accurate diagnostic technique and is preferred for diagnosing CAD in females with lower exercise capacity.37 Stress echocardiography using dobutamine has a sensitivity and specificity of 85 % and 75 %, respectively, for detecting CAD.10,20 Computed tomography coronary angiography has similar diagnostic accuracy in detecting ≥50 % and ≥70 % coronary stenosis in women and men, respectively.38 Of note, in women >55 years with intermediate risk for CHD, the lack of coronary calcium has a high negative predictive value (99 %).39

ACC = American College of Cardiology; AHA = American Heart Association; ETT = exercise tolerance test; HR = heart rate; MET = metabolic equivalent.

Lifestyle Changes

The exercise ECG is of limited use in the evaluation of chest pain in women, owing to lower diagnostic accuracy for CAD compared to men (sensitivity and specificity ~60–70 % versus ~80 %, respectively).34,35 Hormonal variations may contribute to falsepositive rates in premenopausal women and hormone replacement therapy may cause false-negative results due to its vasodilatory properties.36 There are also gender-related difficulties in reaching an adequate level of exercise (>5 metabolic equivalents) to diagnose inducible ischaemia.20

Single-photon emission computed tomography is a highly accurate nuclear imaging technique used to evaluate stress-induced myocardial perfusion defects, although image quality can be affected by breast tissue and obesity, which may result in false-positive outcomes in women.

Gender-dependent Outcomes Recent data suggest that both men and women presenting with stable angina are subject to increased mortality when compared with the general population.40 In fact stable angina is no longer viewed as a benign condition in women, with evidence to support this from the Euro Heart Survey of Stable Angina demonstrating that during the 1-year follow-up period, women had double the risk of death or nonfatal acute MI compared with men.41 The subgroups of CVD also have varying outcomes. Women presenting with ST-segment elevation myocardial infarction have worse outcomes compared to men, but in those presenting with non-ST-segment elevation myocardial infarction no sex-dependent differences in outcome were demonstrated.42

Improvements in the Identification and Management of Women with CVD Despite similar recommendations for men and women, it has been well documented that diagnostic procedures and secondary prevention are not delivered to women with the same intensity. Past clinical trials have predominantly recruited men, making it difficult to determine any gender-specific advantages. Medical management affects men and women in different ways and should therefore be tailored to gender

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CVD in Women: Symptoms and Risk Factors accordingly, for example beta-blockers have been found to provide greater survival benefit in women with acute MI.43 The 2011 American Heart Association guideline for the prevention of cardiovascular disease in women highlights the importance of lifestyle modification, smoking cessation and diet in order to reduce the morbidity and mortality related to CVD (see Table 3).22 These guidelines should form the basis of national strategies aiming to reduce CVD in women.

Conclusion CVD in women continues to be a major public health issue due to the difficulties facing physicians in identifying associated symptoms. There

1. Go AS, Mozaffarian D, Roger VL, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129: e28-e292.DOI: 10.

1161/01.cir.0000441139.02102.80; PMID: 24352519 2. Roger VL, Weston SA, Gerber Y, et al. Trends in incidence, severity, and outcome of hospitalized myocardial infarction. Circulation 2010;121:863–9. DOI: 10.1161/ CIRCULATIONAHA.109.897249; PMID: 20142444 3. Towfighi A, Zheng L, Ovbiagele B. Sex-specific trends in midlife coronary heart disease risk and prevalence. Arch Intern Med 2009;169:1762–6. DOI: 10.1001/archinternmed.2009.318; PMID: 19858433 4. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med 1996;334:1311–5. DOI: 10.1056/ NEJM199605163342007; PMID: 8609950 5. Murabito JM, Evans JC, Larson MG, et al. Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation 1993;88:2548–55.

PMID: 8252666 6. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: A 26-year follow-up of the Framingham population. Am Heart J 1986;111:383–90.

PMID: 3946178 7. Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes IIb Investigators. N Engl J Med 1999;341:226–32. DOI: 10.1056/ NEJM199907223410402; PMID: 10413734 8. Berger JS, Elliott L, Gallup D, et al. Sex differences in mortality following acute coronary syndromes. JAMA 2009;302:874–82.

DOI: 10.1001/jama.2009.1227; PMID: 19706861 9. Milner KA, Funk M, Arnold A, et al. Typical symptoms are predictive of acute coronary syndromes in women. Am Heart J 2002;14:283–8. PMID: 11835032 10. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Part I: Gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 2006;47:S4–S20. DOI: 10.1016/j.jacc.2005.01.072; PMID: 16458170 11. Rosengren A, Wallentin L, K Gitt A, et al. Sex, age, and clinical presentation of acute coronary syndromes. Eur Hear J 2004;25:663–70. DOI: 10.1016/j.ehj.2004.02.023; PMID: 15084371 12. Johnson BD, Shaw LJ, Pepine CJ, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: Results from the NIH-NHLBIsponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J 2006;27:1408–15. DOI: 10.1093/eurheartj/ ehl040; PMID: 16720691 13. Diamond GA, Forrester JS, Hirsch M, et al. Application of conditional probability analysis to the clinical diagnosis of coronary artery disease. J Clin Invest 1980;65:1210–21.

DOI: 10.1172/JCI109776 14. Canto JG, Rogers WJ, Goldberg RJ, et al. NRMI Investigators.

Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012;307:813–22. DOI: 10.1001/jama.2012.199; PMID: 22357832

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are significant gender-specific differences in presentation, response to treatment and outcomes. In 2007, the annual mortality of women secondary to CAD was 4.7 times that of breast cancer, the most common type of cancer in the UK.44 The misconception that women are protected against CVD makes its management all the more challenging. Variation between genders may be related to differences in pathophysiology or merely differences in the detection of CVD. An understanding of these variables is essential in developing gender-specific CVD prevention, and in the identification and management of CVD in women in order to have a beneficial effect on morbidity and mortality. n

15. Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA 2005;293:477–84.

DOI: 10.1001/jama.293.4.477; PMID: 15671433 16. Grundtvig M, Hagen TP, German M, et al. Sex-based differences in premature first myocardial infarction caused by smoking: twice as many years lost by women as by men. Eur J Cardiovasc Prev Rehabil 2009;16:174–9. DOI: 10.1097/ HJR.0b013e328325d7f0; PMID: 19247184 17. Prescott E, Hippe M, Schnohr P, et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ 1998;316:1043–7. PMID: 9552903 18. Vanhoutte PM, Shimokawa H, Tang EHC, et al. Endothelial dysfunction and vascular disease. Acta Physiologica 2009; 196:193–222. DOI: 10.1111/j.1748-1716.2009.01964.x; PMID: 19220204 19. Heida KY, Franx A, Van Rijn BB, et al. Earlier age of onset of chronic hypertension and type 2 diabetes mellitus after a hypertensive disorder of pregnancy or gestational diabetes mellitus. Hypertension 2015;66:1116–22. DOI: 10.1161/ HYPERTENSIONAHA.115.06005; PMID: 26459420 20. Shaw LJ, Olson MB, Kip K, et al. The value of estimated functional capacity in estimating outcome: Results from the NHBLI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol 2006;47:S36–43. DOI: 10.1016/j. jacc.2005.03.080; PMID: 16458169 21. Matthews KA, Meilahn E, Kuller LH, et al. Menopause and risk factors for coronary heart disease. N Engl J Med 1989;321:641–6.

DOI: 10.1056/NEJM198909073211004; PMID: 2488072 22. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women – 2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243–62. DOI: 10.1161/ CIR.0b013e31820faaf8; PMID: 21325087 23. Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women’s Ischemia Syndrome Evaluation (WISE) study. Circulation 2004;109:706–13. DOI: 10.1161/01.CIR.0000115514.44135.A8; PMID: 14970104 24. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332:73–8. DOI: 10.1136/bmj.38678.389583.7C; PMID: 16371403 25. Lima R, Wofford M, Reckelhoff JF. Hypertension in postmenopausal women. Curr Hypertens Rep 2012;14:254–60.

DOI: 10.1007/s11906-012-0260-0 26. Dubey RK, Oparil S, Imthurn B, et al. Sex hormones and hypertension. Cardioavasc Res 2002;53:688–708. PMID: 11861040 27. Burt V, Whelton P, Roccella E, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 1995;25:305–13. PMID: 7875754 28. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291–7. DOI: 10.1056/NEJMoa003417; PMID: 11794147 29. Abbey M, Owen A, Suzakawa M, et al. Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity. Maturitas 1999;33: 259–69. PMID: 10656504 30. 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 [erratum appears in Lancet 2005;366:1358]. DOI: 10.1016/S0140-6736(05)67394-1; PMID: 16214597 31. Sullivan AK, Holdright DR, Wright CA, et al. Chest pain in women: clinical, investigative, and prognostic features. BMJ 1994;308:883–6. PMCID: PMC2539855 32. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–38. DOI: 10.1056/NEJMoa1406761 33. Task A, Members F, Fox K, et al. Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines.

Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27: 1341–81. DOI: 10.1093/eurheartj/ehl001; PMID: 16735367 34. Hlatky MA, Pryor DB, Harrell FE, et al. Factors affecting sensitivity and specificity of exercise electrocardiography.

Multivariable analysis. Am J Med 1984;77:64–71. PMID: 6741986 35. Kwok Y, Kim C, Grady D, et al. Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardiol 1999;83:660–6. PMID: 10080415 36. Grzybowski A, Puchalski W, Zieba B, et al. How to improve noninvasive coronary artery disease diagnostics in premenopausal women? Am Heart J 2016;156:964.e1–964.e5.

DOI: 10.1016/j.ahj.2008.08.014; PMID: 19061713 37. Mulvagh SL, DeMaria AN, Feinstein SB, et al. Contrast echocardiography: current and future applications. J Am Soc Echocardiogr 2000;13:331–42. PMID: 10756254 38. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) Trial. J Am Coll Cardiol 2008;52:1724–32. DOI: 10.1016/j.jacc.2008.07.031; PMID: 19007693 39. Raggi P, Gongora MC, Gopal A, et al. Coronary artery calcium to predict all-cause mortality in elderly men and women. J Am Coll Cardiol 2008;52:17–23. DOI: 10.1016/j.jacc.2008.04.004; PMID: 18582630 40. Hemingway H, McCallum A, Shipley M, et al. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA 2006;295:1404–11. DOI: 10.1001/ jama.295.12.1404; PMID: 16551712 41. Daly C, Clemens F, Lopez Sendon JL, et al. Euro Heart Survey Investigators. Gender differences in the management and clinical outcome of stable angina. Circulation 2006;113:490–8.

DOI: 10.1161/CIRCULATIONAHA.105.561647; PMID: 16449728 42. ISIS Study Group. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet 1986;2:57–66. PMID: 2873379 43. Champney KP, Frederick PD, Bueno H, et al. NRMI Investigators. The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction. Heart 2009;95:895–9. DOI: 10.1136/ hrt.2008.155804; PMID: 19147625 44. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update: a report from the American Heart Association. Circulation 2011;123:e18–e209. DOI: 10.1161/ CIR.0b013e3182009701; PMID: 21160056

13

Cardiovascular Disease in Women

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Ma rie Mide Mic helsen , 1 N a j a D a m M y g i n d , 2 D a r i a Fr e s t a d 3 a n d E v a Pr e s c o t t 1 1. Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; 2. Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 3. Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

Abstract A large proportion of women with chest pain have no obstructive coronary artery disease. Recent studies have demonstrated that these women continue to have symptoms and are at increased risk of cardiovascular morbidity and mortality. Coronary microvascular dysfunction (CMD) leads to an impairment of blood flow regulation to the myocardium and possible transient ischaemia. CMD is a disease entity with several pathophysiologic aspects and diagnostic modalities continue to be developed. However, due to the complexity of the disease, it remains elusive whether CMD is the explanation for the symptoms and the poor prognosis in women with angina and no obstructive coronary artery disease.

Keywords Stable angina pectoris, no obstructive coronary artery disease, coronary microvascular disease, diagnosis, ischaemia, myocardium, women, imaging Disclosure: The authors have no conflicts of interest to declare.

Received: 1 November 2016 Accepted: 11 January 2017 Citation: European Cardiology Review 2017;12(1):14–9 DOI: 10.15420/ecr.2016:33:2 Correspondence: Marie Mide Michelsen, Department of Cardiology, Building 67, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark.

E: marie.m.michelsen@gmail.com

Women have for many years been regarded as being at relatively low risk for the development of ischaemic heart disease (IHD).1,2 Recently this pattern has changed and cardiovascular disease (CVD) is now the leading cause of death for women in Europe.3,4 Under the age of 60 years acute coronary syndrome occurs 3–4 times more often in men; however, after the age of 75 years women represent the majority of the patients. Although coronary artery disease (CAD) develops on average 10 years later in women, CAD is responsible for approximately 20 % of deaths in both men and women.5,6 In regard to mortality, due to CVD women surpass men at 51 versus 42 %7,8 and over the last decades CVD mortality has declined rapidly for men, while the decline has been significantly lower for women.9,10

Chest Pain in Women The typical symptom of CAD is oppressive chest pain radiating to the left arm. Nevertheless, the literature often notes that women tend to present with ’atypical’ symptoms: pain occurring at rest, during sleep or atypically located in the neck and shoulder regions, or fatigue, emotional stress, dyspnoea and general weakness.10,11 Studies have shown that women with characteristic symptoms have a higher likelihood of significant CAD.11,12 This suggests that the main difference between men and women is not so much the presentation of symptoms, but the high proportion of women with angina who have no obstructive CAD. In some studies this proportion has reached 70 % or more.13 Overall, treatment of stable angina pectoris is guided by the presence of obstructive CAD, which leaves patients with angina and no obstructive CAD under-diagnosed with few or no treatment options.1

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Prognosis for Women with Angina and No Obstructive Coronary Artery Disease Women with chest pain and no obstructive CAD were thought to have a benign prognosis, but contrary to previous beliefs, more women than expected may have a cardiac origin to their symptoms. Recent studies have found the condition to be associated with increased cardiovascular (CV) morbidity and mortality, and with a prognosis almost as poor as for subjects with obstructive CAD.13–15 In a study of 4,711 women with stable angina pectoris referred for coronary angiography (CAG) and 3,326 asymptomatic women, the hazard ratio for major CV events (MACE) in women with angina and normal coronary arteries and diffuse non-obstructive stenosis was 1.52 and 1.85, respectively, compared with asymptomatic women. The increased risk was comparable to patients with obstructive CAD and primarily due to CV death, heart failure or myocardial infarction.13 Similarly, the Women’s Ischemia Syndrome Evaluation (WISE) trial demonstrated higher prevalence of CVD events in 540 symptomatic women without CAD compared with 1,000 asymptomatic age- and race-matched women.15 Furthermore, the prognosis might be poorer for women compared with men. A large study (n=13,695) investigated sex differences in outcome after CAG in patients with angina and diffuse non-obstructive CAD and found that women were three-times more likely to experience a cardiac event within the first year compared with men.16

Coronary Microvascular Dysfunction The pathophysiology behind angina with no obstructive CAD remains unknown. Coronary microvascular dysfunction (CMD) has been proposed as a possible explanation for the continued symptoms and higher CV morbidity and mortality. CMD is an impaired coronary

© RADCLIFFE CARDIOLOGY 2017

Women with Angina and No Obstructive Coronary Artery Disease microcirculatory function. Whereas epicardial coronary arteries are conduit vessels, the microcirculation consists of resistance vessels that regulate myocardial blood flow by dilation or contraction according to cardiac demand.17 A dysfunction of the resistance vessels reduces the capability to regulate myocardial perfusion leading to a decreased blood flow, stress-induced ischaemia and altered myocardial metabolism.18–20 The regulation of myocardial perfusion is complex and can be controlled via endothelial-dependent pathways by shear stress and endothelial-independent pathways, including regulation by metabolic substances, auto-regulation, myogenic control in response to increased intraluminal pressure and sympathetic nerve responses.21,22 CMD has multiple pathophysiologic pathways. Vascular causes include functional causes such as endothelial and smooth muscle dysfunction as well as structural causes such as microvascular atherosclerosis, intraluminal microembolism and vascular wall hypertrophy creating stiffness. Extravascular causes might also be a part of the pathogenesis, such as inflammation, structural changes such as ventricular hypertrophy causing vascular compression and impairment of the pathways regulating blood flow, i.e. imbalance of autonomic system with an inappropriate high sympathetic tone.23–25 Presumably, CMD occurs due to a synergy of many causes and it is difficult to isolate and identify the sole responsible cause.

Whether CMD explains both symptoms and the increased CVD risk in patients with angina and no obstructive CAD remains elusive due to diagnostic difficulties and lack of evidence-based intervention.

Diagnostic Methods to Assess Coronary Microvascular Dysfunction A single method may not be sufficient to rule out CMD since each method may assess different aspects of the pathophysiology.26

Vasodilator Stimuli Myocardial perfusion can be examined by using various vasodilator stimuli. Administration of adenosine, A 1–A3 receptor agonists, leads to coronary microvascular dilatation by acting directly on the vascular smooth muscle cells. Dipyridamole inhibits reuptake of adenosine and has a similar effect.27,28 Like adenosine, the selective A2a receptor agonist, regadenoson, dilates the coronary and peripheral arterial microvessels by acting on the smooth muscle cells.28 These vasodilators assess endothelial-independent coronary microvascular function27 in the absence of epicardial coronary artery stenosis.29 Microvascular function is expressed as a flow reserve calculated as the ratio between flow during stress and rest. Although CMD should be seen as a continuum,30 European guidelines suggest a flow reserve <2 as a strong indicator of CMD,31 but studies have used both higher and lower cut-off values depending on the method of assessment.19,20,32–34 Endothelium-dependent dysfunction and both macrovascular and microvascular spasm can be assessed by an intracoronary acetylcholine provocation test.35 Vascular response to acetylcholine is predominantly caused by the release of nitric oxide (NO) from endothelial cells causing vasodilation.36 In patients with vascular dysfunction, examination with infusion of acetylcholine shows a diminished vasodilation, a paradoxical vasoconstriction or in larger doses coronary artery spasms may be elicited. This reaction has been suggested as part of the definition of vasospastic angina. 37 The cold pressor test, the submersion of the patient’s hand in ice

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water, is also used to assess endothelial-dependent function. This procedure induces sympathetic stimulation, thereby increased heart rate, blood pressure and blood flow. The proposed mechanism is through adrenergic receptors releasing NO. 38 However, for both acetylcholine and cold pressor tests, a direct effect on smooth muscle cells cannot be excluded and the response is not solely endothelial dependent.39

Invasive Assessment by Angiography Epicardial blood flow can be measured by intracoronary Doppler flow where the tip of the guidewire has ultrasound capabilities measuring resting and peak velocities at maximal hyperaemia. To investigate resistance changes in the distribution of the epicardial coronary arteries, coronary vascular resistance can be calculated as mean arterial pressure divided by coronary blood flow.40 Additionally, quantitative vasomotor response in epicardial coronary arteries can be evaluated as a change in vessel diameter. Measurements are usually repeated using increasing concentrations of acetylcholine. Endothelial dysfunction is defined as vasoconstriction, lack of coronary blood flow increase and/or vasospasm as a result of direct activation of muscarinic receptors on vascular smooth muscle cells.37,41 Endothelial-independent function can also be assessed during vasodilator infusion with adenosine, dipyridamole or regadenoson with calculation of the coronary flow velocity reserve (CFVR). 29 Flow velocity changes in the coronary arteries are assumed to be representative of changes in flow volume due to dilation of the smaller resistance vessels, based on the assumption that coronary artery diameters remain constant during hyperaemia. However, dilation of the epicardial coronary arteries during hyperaemia may occur.

Therefore, intracoronary NO to achieve maximum dilation of the epicardial coronary arteries before CFVR measurement can be used as well as quantification of the cross-sectional area of the measuring point in the coronary artery calculating volumetric blood flow.42 Invasive CFVR measurement has been extensively used and validated and is at present considered the gold standard for assessment of endothelial-independent CMD. Corrected thrombolysis in myocardial infarction (TIMI) frame counts can also be used as an invasive measure of CMD. The ratio between number of angiographic frames for the contrast to reach a distal landmark at maximal hyperaemia and rest reflects coronary microvascular function and has shown good correlation with invasive CFVR.29,43,44 CMD may also be assessed through thermodilution, although this method is less widely used.45

Positron Emission Tomography Positron emission tomography (PET) can assess absolute myocardial blood flow (ml/min/g) by a dynamic imaging protocol calculating the rate of tracer uptake into the myocardium at rest and during stress.46 Rubidium (Rb)-82, oxygen (O)-water-15 and nitrogen (N)-13-ammonia are the most widely used tracers. Focusing on endothelial-dependent function, cold pressor testing can be used to induce stress by sympathetic stimulation calculating the absolute flow difference between rest and stress.34,47 The use of endothelial-independent vasodilators allows for calculation of the myocardial blood flow reserve (MBFR) for the assessment of coronary microvascular function.34,48 The few studies investigating the repeatability of MBFR have not been able to produce convincing results.49–51 However, one study found PET MBFR valid against invasively measured CFVR calculated by the volumetric

15

Cardiovascular Disease in Women Figure 1: Overview of the Diagnostic Process for Coronary Microvascular Dysfunction

Echocardiographic Assessment

CAD

Transthoracic Doppler echocardiography (TTDE) can visualise the left anterior descending artery and peak coronary flow velocities at rest and maximum hyperaemia during vasodilator infusion with adenosine, dipyridamole or regadenoson can be measured by pulsed wave Doppler technique. The resulting CFVR reflects coronary microvascular function but may be affected by the possible dilation of the epicardial coronary arteries. The method can be technically challenging, but is highly reproducible in experienced hands with good agreement with invasively measured CFVR.52–58 However, agreement with PET measured MBFR is only modest in both women with no obstructive CAD (n=107) and patients with CAD (n=35).26,57 Advantages of the TTDE assessment is that it is easily accessible, non-invasive and radiation-free.59 Another method to assess CMD is myocardial perfusion echocardiography.60

>50 % coronary artery stenosis

Examination with CAG/CT angiography

Patient experience angina-like chest pain

blood flow method, where the cross-sectional area of the coronary artery was quantified to calculate blood flow volume.42

<50 % coronary artery stenosis

No non-cardiac explanation certain (gastro-oesophageal reflux disease, musculoskeletal pain etc.)

No obstructive CAD

Cardiac Magnetic Resonance

Positive acetylcholine or cold pressor test

Epicardial vasospastic angina

Coronary flow reserve <2.0 with adenosine, dipyridamole or regadenoson test

Endothelialdependent CMD/ microvascular spasm

Endothelialindependent CMD

Both test positive

No positive test

Both endothelialindependent and dependent dysfunction

Unknown

CAD = coronary artery disease; CAG = coronary angiography; CMD = coronary microvascular dysfunction; CT = computer tomography.

Table 1: Diagnostic Tests for Coronary Microvascular Dysfunction

The microvasculature can be assessed by cardiac magnetic resonance (CMR) perfusion with images acquired immediately after the injection of gadolinium contrast.61 Contrast signal intensity gives an estimate of myocardial perfusion. The myocardial perfusion reserve index is the ratio of contrast signal intensity/upslope during pharmacologically induced hyperaemia and at rest. Use of CMR perfusion imaging in diagnosing CMD has not yet been standardised but having in mind that perfusion defects in CAD are visible even before angina, it is likely that women with CMD in the absence of obstructive CAD could have inducible perfusion abnormalities detectable by CMR. The reproducibility of perfusion CMR has been assessed in healthy volunteers with a coefficient of variation of 13.7 % for resting values and 12.9 % for stress values. Furthermore, inter- and intra-observer agreement was good.62 In patients with obstructive CAD, perfusion CMR correlated significantly with CFVR by Doppler flow guidewire.63

Computed Tomography Angiography Examination for whether patients have CMD Type Endothelial-

Vasodilator stimuli Adenosine

Potential methods Intracoronary Doppler

independent CMD

Dipyridamole

flow guidewire

Regadenoson

corrected TIMI frame

counts

Invasive thermo-

dilution method

Transthoracic Doppler

echocardiography

Positron emission

tomography

Cardiac magnetic

resonance perfusion

Computer tomography

perfusion

Endothelial- Acetylcholine

Intracoronary

dependent CMD

Doppler flow

Cold pressor test

guidewire

Positron emission

tomography

Transthoracic Doppler

echocardiography

CMD = coronary microvascular dysfunction; TIMI = thrombolysis in myocardial infarction.

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Computer tomography (CT) perfusion is a rapidly developing noninvasive diagnostic test evaluating the haemodynamic significance of coronary artery stenosis.64 Studies are currently establishing whether semi-quantitative measures, including the myocardial perfusion reserve (hyperaemic versus resting myocardial blood flow) and transmural perfusion ratio (subendocardial to subepicardial attenuation density) can identify patients with CMD.

The Coronary Microvascular Dysfunction Diagnosis In summary, patients with no obstructive CAD can be diagnosed with either endothelial-dependent and/or endothelial-independent CMD depending on the choice of vasodilator using several methods (see Figure 1 and Table 1). However, there are multiple methods assessing coronary microvascular function and some seem to diverge and may be assessing different aspects of the complex pathophysiological mechanisms of both the endothelial independent and dependent part of CMD.26

Is Coronary Microvascular Dysfunction the Cause of Angina in Women with No Obstructive Coronary Artery Disease?

CMD is highly prevalent in a population of women and men with angina and no obstructive CAD. In a cross-sectional study of 159 women with no obstructive CAD examined invasively with CFVR,

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Women with Angina and No Obstructive Coronary Artery Disease 47 % had CMD (CFVR <2.5).65 Another cross-sectional study of 1,439 patients with angina and no obstructive CAD found that 1,171 (81 %) had CMD with angiographic testing and infusion of both acetylcholine and adenosine: 19 % had both endothelial dependent and independent CMD; 12 % only endothelial-independent CMD and 33 % only endothelial-dependent CMD.66 In prospective and cross-sectional TTDE studies, CMD (CFVR <2.0) prevalence has been reported lower ranging from 22 to 40 %.33,67,68 In a prospective study of 1,218 patients assessed by PET more than 50 % of women were diagnosed as having endothelial-independent CMD (MBFR <2.0).69 Focusing on endothelial-dependent function, a prospective study of 470 patients with angina and no obstructive CAD found CMD defined as ≤50 % increase in myocardial blood flow to acetylcholine measured angiographically to be present in 56 %.70 Similarly 95 out of 147 patients (66 %) had CMD in a prospective study using >20 % diameter reduction in response to acetylcholine measured angiographically as criterion for CMD.71 Classification of angina symptoms, frequency, stability and treatment satisfaction were not associated with CMD assessed by TTDE CFVR in a cohort study of 919 women with angina. Burden of symptoms in terms of physical limitation and self-perception of disease was related to CMD, although differences between CFVR level were small.68 In accordance, PET MBFR (study n=1,218) was not different for patients with typical or atypical angina, compared with symptoms classified as non-cardiac or no symptoms.69 The WISE study compared CMR perfusion in women with angina and no obstructive CAD (n=53) to healthy controls (n=12) and found that the symptomatic women had a significantly lower myocardial perfusion reserve index but the burden of risk factors was also lower in the controls.72 Furthermore, trials (n=51 and n=46) have failed to show that improvement of symptoms are related to changes in coronary microvascular function.73,74 This questions whether CMD and the burden of symptoms are actually related; although symptoms are generally hard to study being indeed subjective.

Cardiovascular Risk Factors in Women with No Obstructive Coronary Artery Disease A proportion of patients with angina and no obstructive CAD have IHD caused by insignificant atherosclerosis, vasospastic angina or CMD. Prevalence of CV risk factors in women with angina and no obstructive CAD is relatively high compared with the general population of women at similar ages and comparable to patients with coronary heart disease13,65,68,75 and independently predicts cardiovascular mortality.76,77 In recent large studies from the US and Denmark, approximately 50 % of women with angina and no obstructive CAD had hypertension, hyperlipidaemia and a family history of CAD, one-fifth had diabetes mellitus and generally these women had a high body mass index (BMI). However, active smoking varied from 16 %, 20 % and 30 % probably due to a general decline in smoking in the recent years.13,65,68 In comparison, around 35 % women in a Danish general population had hypertension, 8 % had diabetes and 20 % were actively smoking in the year 2013.75 CMD has been found to be associated with CV risk factors such as age,32,33,65,67–69,78,79 hypertension,33,68,69,79,80 diabetes mellitus,68,69,79,80 smoking,68,78 heart rate,68,81 HDL cholesterol,68,78 BMI,69,81 menopause and absence of hormone therapy post-menopause.65 However, not all studies identify the same CV risk factors and the contribution of risk factors explaining variation in CFR assessing CMD is low.66,68,82 The fact that prevalence of CV risk factors is high in women with angina and no obstructive CAD may play a role in the increased risk of CV events and possible CMD in this population.13,65,68,76

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Signs of Myocardial Affection/Ischaemia CMD is thought to be global or to involve random patchy areas of hypoxia, which might lead to transient myocardial ischaemia.83

Cardiac Exercise Stress Testing Even in the absence of CAD, a large percentage of patients with persistent chest pain present with transient ischaemia on electrocardiogram due to regional myocardial hypoperfusion.18 However, ST-segment depression during an exercise test is thought to be less accurate in identifying CAD in women compared with men.84 Presence of impaired CFVR and endothelial dysfunction consistent with CMD is a plausible explanation for perfusion abnormalities sufficient to produce electrocardiogram changes and angina during stress testing. However, two large studies found no association between presence of CMD and results from diagnostic stress testing prior to CAG in women with angina and no obstructive CAD.66,68 The explanation may lie in the size and the possible patchy distribution of the affected, ischaemic myocardium, undetectable by present techniques in cardiac stress testing. Decreased exercise tolerance, vasospastic angina and oestrogen levels have also been suggested as causes for ST-depression in women with no obstructive CAD.84,85

Markers of Inflammation Chronic inflammation, expressed as elevated C-reactive protein levels, has been found associated with endothelial dysfunction and CMD in patients with no obstructive CAD.86,87 Patients with angina and a normal CAG were in one study (n=137) found to have elevated C-reactive protein levels and reduced PET measured MBFR compared with controls.88

Prognosis for Patients with Coronary Microvascular Dysfunction Epicardial and microvascular coronary endothelial dysfunction assessed invasively by acetylcholine predict long-term risk of CV events in patients with no obstructive CAD (study n between 147 and 470), independently of traditional risk factors.70,71,89,90 In a study of 72, cold pressor testing in PET imaging can be used to predict CV outcome.47 Endothelial-independent CMD assessed both invasively (n=152) by PET (n=1,218) and by Doppler echocardiography (n=394) has been shown to be strongly associated with adverse CV outcome in several prospective studies of patients with no obstructive CAD.32,33,69 Large prognostic studies of perfusion CMR in patients without obstructive CAD are lacking, but in one study of 103 patients with angina and normal stress perfusion CMR no patient with a normal CMR experienced events, whereas 16 events occurred in 14 patients with abnormal CMR during follow-up.91 In the WISE study, global perfusion abnormalities reflecting CMD could also predict adverse events.92

Continued Symptoms Patients with angina pectoris and no obstructive CAD are costly for society due to continued symptoms resulting in multiple hospital re-admissions and re-assessments for obstructive CAD.93 Angina is persistent in 45–61 % of patients after 1–3 years.94–97 Persistent angina has been reported to be associated with non-fatal myocardial infarction and stroke.95 Frequent angina was furthermore found to be associated with lower physical functioning, angina stability, treatment satisfaction and quality of life.94 Patients with angina and no

17

Cardiovascular Disease in Women obstructive CAD have increased risk of hospitalisation primarily due to stable and unstable angina, repeat CAG, heart failure and stroke compared with healthy controls. Furthermore, higher rates of followup consultations at the general practitioners have been reported.93,98 Besides high healthcare costs, patients with angina and no obstructive CAD often exit the workforce prematurely requiring disability pension.

Surprisingly, costs are comparable to patients with obstructive CAD.97,99 Cumulative costs over a five-year period has, in an American study, been estimated to be lower, though still very high, for women with no obstructive CAD (US$32,239; 95 % confidence interval [CI], US$29,496–US$34,982) than for patients with obstructive CAD (increasing to US$53,398; 95 % CI, US$43,854–US$62,942 for patients with three-vessel disease).93

Treatment Strategies Currently, there are no evidence-based treatment strategies for women with no obstructive CAD. However, guideline-based management of the relative high burden of risk factors in all patients with IHD, including women with no obstructive CAD, is important. Further

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approaches are lifestyle modification (smoking cessation, exercise and a healthy diet).100 Moreover, large clinical trials are lacking for those diagnosed with any aspect of CMD. Small clinical trials indicate that anti-ischaemic and antianginal medication (such as treatment with angiotensin-converting enzyme inhibitor, statins and NO modulators) could have a role in improving CMD. However, the trials conducted have been of moderate or poor quality and/or with too few subjects (n from 6 to 13) to have an impact on guidelines.24

Closer to a Diagnosis?

Women with angina pectoris and no obstructive CAD have continued symptoms and a poor CV prognosis. CMD is an entity comprising several pathologic pathways. New invasive and non-invasive diagnostic modalities for identifying CMD are being developed and accumulating research points to CMD as a cause of poor prognosis in women with angina and no obstructive CAD. Whether CMD directly causes angina cannot be decisively concluded at present, for this we must await intervention studies showing simultaneous improvement in CMD and angina symptoms. Furthermore, evidence-based treatment strategies for women with no obstructive CAD are lacking. ■

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World J Cardiol 2015;7 (12):861–74. DOI:10.4330/wjc.v7.i12.861; PMCID:PMC4691812 61. Shehata ML, Basha TA, Hayeri MR, et al. MR myocardial perfusion imaging: insights on techniques, analysis, interpretation, and findings. Radiographics 2014;34 (6):1636–57.

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62. Larghat AM, Maredia N, Biglands J, et al. Reproducibility of first-pass cardiovascular magnetic resonance myocardial perfusion. J Magn Reson Imaging 2013;37 (4):865–74.

DOI:10.1002/jmri.23889; PMID:23335425 63. Kurita T, Sakuma H, Onishi K, et al. Regional myocardial perfusion reserve determined using myocardial perfusion magnetic resonance imaging showed a direct correlation with coronary flow velocity reserve by Doppler flow wire.

Eur Heart J 2009;30 (4):444–52. DOI:10.1093/eurheartj/ehn521; PMID:19098020 64. Rochitte CE, George RT, Chen MY, et al. Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study. Eur Heart J 2014;35 :1120–30. DOI:10.1093/eurheartj/eht488; PMID:24255127 65. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J 2001;141 (5):735–41.

PMID:11320360 66. Sara JD, Widmer RJ, Matsuzawa Y, et al. Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC Cardiovasc Interv 2015;8 (11):1445–53. DOI:10.1016/ j.jcin.2015.06.017; PMID:26404197 67. Sade LE, Eroglu S, Bozbas¸ H, et al. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis 2009;204 (2):580–5.

DOI:10.1016/j.atherosclerosis.2008.09.038; PMID:19019370 68. Mygind ND, Michelsen MM, Pena A, et al. Coronary Microvascular Function and Cardiovascular Risk Factors in Women With Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study. J Am Heart Assoc 2016;5 (3):e003064. DOI:10.1161/JAHA.115.003064; PMID:27068634; PMCID:PMC4943278 69. Murthy VL, Naya M, Taqueti VR, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129 (24):2518–27. DOI:10.1161/ CIRCULATIONAHA.113.008507; PMID:24787469; PMCID:PMC4076200 70. Reriani M, Sara JD, Flammer AJ, et al. Coronary endothelial function testing provides superior discrimination compared with standard clinical risk scoring in prediction of cardiovascular events. Coron Artery Dis 2016;27 (3):213–20.

DOI:10.1097/MCA.0000000000000347; PMID:26882018; PMCID:PMC4823151 71. Sánchez-Recalde A, Galeote G, Moreno R, et al. Long-term prognostic value of endothelial dysfunction in patients with chest pain and angiographically normal coronary arteries. Rev Port Cardiol 2009;28 (7–8):785–91. PMID:19894657 72. Shufelt CL, Thomson LEJ, Goykhman P, et al. Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls. Cardiovasc Diagn Ther 2013;3 (3):153–60. DOI: 10.3978/j.issn.2223-3652.2013.08.02; PMCID: PMC3839208 73. Di Franco A, Villano A, Di Monaco A, et al. Correlation between coronary microvascular function and angina status in patients with stable microvascular angina. Eur Rev Med Pharmacol Sci 2014;18 (3):374–9. PMID:24563437 74. Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol 2013;112 (1):8–13. DOI:10.1016/ j.amjcard.2013.02.045; PMID:23558043 75. The National Institute of Public Health. The National Health Interview Surveys. 2013. Available at: www. sundhedsprofil2010.dk (Accessed 13 January 2016).

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JAMA 2003;290 (7):898–904. DOI:10.1001/jama.290.7.898; PMID:12928466 78. Lee DH, Youn HJ, Choi YS, et al. Coronary flow reserve is a comprehensive indicator of cardiovascular risk factors in subjects with chest pain and normal coronary angiogram. Circ J 2010;74 (7):1405–14. PMID:20484824 79. Tuccillo B, Accadia M, Rumolo S, et al. Factors predicting coronary flow reserve impairment in patients evaluated for chest pain: an ultrasound study. J Cardiovasc Med (Hagerstown) .

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82. Wessel TR, Arant CB, McGorray SP, et al. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE). Clin Cardiol 2007;30 (2):69–74. DOI:10.1002/clc.19; PMID:17326061 83. Pries AR, Reglin B. Coronary microcirculatory pathophysiology: can we afford it to remain a black box? Eur Heart J 2016; DOI:10.1093/eurheartj/ehv760; PMID:26843279; epub ahead of press.

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PMID:14613736 87. Cosín-Sales J, Pizzi C, Brown S, Kaski JC. C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms. J Am Coll Cardiol 2003;41 (9):1468–74. PMID:12742283 88. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 2013;6 (6):660–7. DOI:10.1016/j.jcmg.2012.12.011; PMID:23643286 89. Halcox JPJ, Schenke WH, Zalos G, et al. Prognostic Value of Coronary Vascular Endothelial Dysfunction. Circulation 2002;106 (6):653–8. PMID:12163423 90. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;109 (6):722–5.

DOI:10.1161/01.CIR.0000115525.92645.16; PMID:14970106 91. Lerakis S, McLean DS, Anadiotis A V, et al. Prognostic value of adenosine stress cardiovascular magnetic resonance in patients with low-risk chest pain. J Cardiovasc Magn Reson 2009;11 :37. DOI:10.1186/1532-429X-11-37; PMID:19772587; PMCID:PMC2758876 92. Doyle M, Weinberg N, Pohost GM, et al. Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study. JACC Cardiovasc Imaging 2010;3 (10):1030–6. DOI:10.1016/j.jcmg.2010.07.008; PMID:20947048; PMCID:PMC3278772 93. Shaw LJ, Merz CNB, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women’s Ischemia Syndrome Evaluation. Circulation 2006;114(9): 894–904. DOI:10.1161/CIRCULATIONAHA.105.609990; PMID:16923752 94. Jespersen L, Abildstrøm SZ, Hvelplund A, Prescott E. Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin Res Cardiol 2013;102 (8):571–81. DOI:10.1007/s00392-013-0568-z; PMID:23636227 95. Johnson BD, Shaw LJ, Pepine CJ, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J 2006;27 (12):1408–15. DOI:10.1093/eurheartj/ehl040; PMID:16720691 96. Pasternak RC, Thibault GE, Savoia M, et al. Chest pain with angiographically insignificant coronary arterial obstruction.

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Cardiovascular Disease in Women

Viewpoint Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson Oxford Cardiovascular Clinical Research Facility, University of Oxford, Oxford, UK

Abstract Pregnancy complications, such as hypertensive disorders or preterm delivery, identify families predisposed to cardiovascular problems at other times in life. Whether the pregnancy complication induces cardiac disease or whether the pregnancy stress unmasks an underlying predisposition remains unclear. However, improved survival following severe pregnancy complications for both the mother and, in particular, the offspring – who is often born preterm – has resulted in a growing cohort of individuals who carry this increased cardiovascular risk. Research to understand the underlying pathological mechanisms that link these conditions might ultimately lead to novel therapeutic or prevention strategies for both cardiovascular and pregnancy disease.

Keywords Pregnancy, cardiovascular disease, preeclampsia, preterm birth, mothers, offspring Disclosure: The authors have no conflicts of interest to declare.

Received: 21 April 2017 Accepted: 1 May 2017 Citation: European Cardiology Review 2017;12(1):20–3. DOI: 10.15420/ecr.2017:4:1 Correspondence: Prof Paul Leeson, Cardiovascular Clinical Research Facility, BHF Centre for Research Excellence, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E: paul.leeson@cardiov.ox.ac.uk

Historically pregnancy has been viewed as only clinically relevant to women and for the relatively brief time from conception to the puerperium. However it is now clear that events during pregnancy have much longer-term implications, particularly for cardiovascular health, both for the mother and her offspring.

Pregnancy complications such as hypertension and preterm birth appear to serve as a key early indicator of cardiovascular risk for both mother and child. For example, pregnancy complicated by de novo hypertension (preeclampsia or gestational hypertension) is frequent and affects 6–10 % of pregnancies.1–4 It is now well established that a diagnosis of hypertensive disorder of pregnancy is associated with an increased risk of maternal cardiovascular disease: almost 1.5-times increase in ischaemic heart disease, fivefold risk of hypertension, threefold risk of cardiovascular death, almost twofold risk of heart failure and twofold risk of stroke.5–8 There is also evidence of a correlation between the severity of hypertensive disorder of pregnancy and the risk of cardiac disease.9 Similarly preterm delivery (birth before 37 weeks gestation), which occurs in 11 % of births worldwide, is increasing in incidence 10 and, independent of hypertension, is associated with elevated maternal cardiovascular risk.11,12 Offspring born to women who have experienced pregnancy complications also display adverse cardiovascular findings. Those born preterm have increased blood pressure in adolescence 13–18 and adult life,19–26 with a 10.5 % prevalence of clinical hypertension and 45.9 % prevalence of prehypertension in 19-year-old preterm born adults.16 They are also relatively more likely to require antihypertensive medication in young adulthood. 27 Preterm born

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women have a doubling of lifetime coronary heart disease risk 28 and offspring born prior to 32 weeks have a twofold increase in cerebrovascular disease. 29 Some evidence is also emerging of increased insulin resistance in those born preterm,19,20,22,23,30 which may be a precursor to later development of metabolic syndrome 31 or type 2 diabetes. 30 In a meta-analysis using data from 45,249 individuals we reported an increase in systolic and diastolic blood pressure in children and adolescents born to preeclamptic pregnancies32 that, if it tracked into adult life, would be associated with an 8 % increased risk of mortality from ischaemic heart disease and a 12 % increased risk of stroke.32 These findings are supported by our analysis of data from a 20-year prospective follow-up birth cohort study of 2,868 young adults, which reported that the clinical incidence of hypertension was increased in those born to mothers who had hypertensive disorders of pregnancy.33 These young adults were 2.5 times more likely to have global lifetime risk (QRISK®) scores above the 75th centile and 30 % of 20-year-olds with hypertensive blood pressures were born following a hypertensive pregnancy. Those whose mother had more severe hypertensive pregnancy disease, such as preeclampsia or preterm birth, had a threefold greater risk of being clinically hypertensive.33 Furthermore, one study showed that offspring of preeclamptic pregnancies were more likely to be prescribed antihypertensive medication by the age of 50 years34 and had double the risk of stroke in adult life35 Figure 1 highlights potential links between pregnancy complications in the mother and future cardiovascular health for them and their child, as well as the risk of pregnancy disease in future generations.

© RADCLIFFE CARDIOLOGY 2017

Cardiac Disease after Pregnancy Potential Pathophysiological Pathways A number of risk factors common to both pregnancy complications and cardiovascular disease might explain these links. Raised blood pressure, high maternal age, diabetes and obesity increase the risk of preeclampsia;1,36–41 whereas smoking,42 lower socioeconomic group43 and maternal age44 are risk factors for preterm delivery. Pregnancy complications might therefore unmask existing subclinical cardiovascular disease in the mother due to the physiological stress she is under.

Alternatively there may be common disease mechanisms between pregnancy and cardiovascular disease. Unfortunately longitudinal studies that track from pre-pregnancy through to later life clinical events do not exist and therefore it remains difficult to unpick these associations.

Cross-sectional observational studies that measure surrogate markers several months and years after affected pregnancy can be informative of potential pathophysiological associations. However, the majority of such studies recruit during or after pregnancy and so the relevance of the cardiovascular system pre-conception in these populations is not yet clear. Nevertheless, what these studies have shown is that women who delivered preterm had higher blood pressure, adverse lipid profiles and higher carotid intima media thickness 4–12 years after delivery compared to women who delivered at term.45 Women with a history of hypertensive pregnancy have an adverse cardiac structure and function, with higher left ventricular mass index and greater diastolic dysfunction.46 They also have evidence of greater blood pressure,47 arterial stiffness,48 reduced capillary density49 and adverse grey and white matter brain differences.50 These studies suggest that there is a range of adverse cardiovascular phenotypic differences in women in the months and years after complicated pregnancy prior to the development of cardiovascular events. The identification of higher risk subgroups within these populations might therefore be possible and risk reduction strategies could be targeted to reduce cardiovascular morbidity and mortality.

Similar phenotypic differences are also evident in the offspring early in life. We have demonstrated cardiovascular modifications in young adults born preterm using cardiovascular magnetic resonance.51,52 Those born preterm had an increased left ventricular mass and a distinct ventricular shape with shorter ventricles, small internal diameters and a displaced apex.52 Similar but proportionately greater differences were evident in the right ventricle51 with associated left and right systolic and diastolic dysfunction.51,52 These distinct cardiovascular phenotypes emerge in the first few months of postnatal life in preterm infants,53 probably because at birth there is a myocardial switch from a foetal hyperplastic cellular phenotype to one of hypertrophy.54 Animal models have demonstrated that this switch also happens at the time of preterm birth.55,56 This switch, in addition to significant flow changes, may result in the cardiac remodelling that has been observed in both animal and human studies.

It has been suggested that preterm birth also has an effect on vascular structure and function, with several studies reporting that large arteries are significantly smaller in children, adolescents14,57–59 and adults born preterm.60 Abnormalities in the microvascular system have also been demonstrated, with a reduction in cutaneous capillary61–63 and retinal vascular64–66 beds in individuals born preterm. Capillary rarefaction is thought to play an important role in the increased peripheral vascular resistance found in patients with hypertension.67–69 It has also been hypothesised that microvascular changes may play a causative role in the disease as it is also observed in normotensive at-risk populations70 and arteriolar narrowing in the retina has been shown

EUROPEAN CARDIOLOGY REVIEW

Figure 1: Potential Links Between Pregnancy Complications and Future Cardiovascular Health in Mother and Child Pregnancy complication Identifies babies with different cardiovascular phenotype

Identifies individuals with increased cardiovascular risk in later life Identifies adults at risk of pregnancy disease

Identifies young adults with different cardiovascular health

to be an accurate predictor of hypertension.71 Several mechanisms for these microvascular differences have been put forward, including that preterm birth causes a shift towards a more anti-angiogenic profile, which may then have an effect on microvascular development.

Young adults born preterm have been shown to exhibit an enhanced anti-angiogenic state, with elevations in soluble endoglin and soluble fms-like tyrosine kinase-1 that are associated with elevations in blood pressure mediated through capillary rarefaction.62 The offspring of hypertensive pregnancies also have a distinct cardiovascular phenotype characterised by impaired flow-mediated endothelial responses25 and an increased intima-media thickness25 suggesting an early atherogenic phenotype consistent with the aortic arterial thickening known to occur in preeclamptic offspring at birth.72 A recent study has also demonstrated cardiac remodelling in adolescents exposed to hypertensive disorders of pregnancy, with a greater relative wall thickness compared to controls and a reduced left ventricular end-diastolic volume.73 The natural history of these cardiovascular modifications linked with pregnancy complications and their relevance to future cardiovascular disease risk is of emerging interest.

Where does this Leave Clinicians and Researchers?

National and international guidelines include a maternal history of hypertensive pregnancy as a risk factor for cardiovascular disease and some also offer recommendations that blood pressure and other cardiovascular risk factors should be assessed postpartum.74–78 Most guidelines do not offer detailed recommendations, however, and leave the specifics on how to follow up this population to the clinician.74 The potential from using a history of pregnancy complication for the early identification of individuals at increased cardiovascular risk, both for mothers and offspring, is highly attractive as it could potentially allow a significant time window for risk attenuation. Future research into which are the most sensitive characteristics of pregnancy

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Cardiovascular Disease in Women complications for identifying individuals at increased cardiovascular risk will be of value.

Understanding why there are links between pregnancy complications and cardiovascular disease remains of importance for two major reasons. First, it will help to identify populations who are at a higher risk of developing cardiovascular disease in later life. This could enable

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DOI: 10.1097/HJH.0b013e328331b8c6; PMID: 19893428 Kajantie E, Eriksson JG, Osmond C, et al. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: The Helsinki birth cohort study. Stroke 2009;40:1176–80.

DOI: 10.1161/STROKEAHA.108.538025; PMID: 19265049 Toshimitsu M, Nagamatsu T, Nagasaka T, et al. Increased risk of pregnancy-induced hypertension and operative delivery after conception induced by in vitro fertilization/ intracytoplasmic sperm injection in women aged 40 years and older. Fertil Steril 2014;102:1065–70 e1061. DOI: 10.1016/ j.fertnstert.2014.07.011; PMID: 25123639 Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: Systematic review of controlled studies.

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Epidemiology 1996;7:306–8 PMID: 8728447 Li DK, Wi S. Changing paternity and the risk of preeclampsia/ eclampsia in the subsequent pregnancy. Am J Epidemiol 2000;151:57–62. DOI: 10.1093/oxfordjournals.aje.a010122; PMID: 10625174 Andres RL, Day MC. Perinatal complications associated with maternal tobacco use. Semin Neonatol 2000;5:231–41.

DOI: 10.1053/siny.2000.0025; PMID: 10956448 Thompson JMD, Irgens LM, Rasmussen S, et al. Secular trends in socio-economic status and the implications for preterm birth. Paediatr Perinat Epidemiol 2006;20:182–7.

DOI: 10.1111/j.1365-3016.2006.00711.x; PMID: 16629692 Astolfi P, Zonta LA. Risks of preterm delivery and association with maternal age, birth order, and fetal gender. Hum Reprod 1999;14:2891–4. PMID: 10548643 Catov JM, Dodge R, Barinas-Mitchell E, et al. Prior preterm birth and maternal subclinical cardiovascular disease 4 to 12 years after pregnancy. J Womens Health (Larchmt) 2013;22:835–43.

DOI: 10.1089/jwh.2013.4248 Scantlebury DC, Kane GC, Wiste HJ, et al. Left ventricular hypertrophy after hypertensive pregnancy disorders. Heart 2015;101:1584–90. DOI: 10.1136/heartjnl-2015-308098; PMID: 26243788 Fraser A, Nelson SM, Macdonald-Wallis C, et al.

Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: The Avon Longitudinal Study of Parents and Children. Circulation 2012;125:1367–80. DOI: 10.1161/ CIRCULATIONAHA.111.044784; PMID: 22344039 Hausvater A, Giannone T, Sandoval YH, et al. The association between preeclampsia and arterial stiffness. J Hypertens 2012;30:17–33. DOI: 10.1097/HJH.0b013e32834e4b0f; PMID: 22134391 Nama V, Manyonda IT, Onwude J, et al. Structural capillary rarefaction and the onset of preeclampsia. Obstet Gynecol 2012;119:967–74. DOI: 10.1097/AOG.0b013e31824ea092; PMID: 22525907 Siepmann T, Boardman H, Bilderbeck A, et al. Longterm cerebral white and gray matter changes after preeclampsia. Neurology 2017;88:1256–64. DOI: 10.1212/ WNL.0000000000003765; PMID: 28235810 Lewandowski AJ, Bradlow WM, Augustine D, et al. Right ventricular systolic dysfunction in young adults born preterm. Circulation 2013;128:713–20. DOI: 10.1161/ CIRCULATIONAHA.113.002583; PMID: 23940387 Lewandowski AJ, Augustine D, Lamata P, et al. Preterm heart in adult life: Cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function. Circulation 2013;127:197–206. DOI: 10.1161/ CIRCULATIONAHA.112.126920; PMID: 23224059 Aye CYL, Lewandowski AJ, Lamata P, et al. Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm. Pediatr Res 2017; DOI: 10.1038/pr.2017.96; PMID: 28399117: epub ahead of press Rudolph AM. Myocardial growth before and after birth: Clinical implications. Acta Paediatr 2000;89:129–33. PMID: 10709876 Bensley JG, Stacy VK, De Matteo R, et al. Cardiac remodelling as a result of pre-term birth: Implications for future cardiovascular disease. Eur Heart J 2010;31:2058–66. DOI: 10.1093/eurheartj/ehq104; PMID: 20453064 Bertagnolli M, Huyard F, Cloutier A, et al. Transient neonatal high oxygen exposure leads to early adult cardiac dysfunction, remodeling, and activation of the reninangiotensin system. Hypertension 2014;63:143–50. DOI: 10.1161/ HYPERTENSIONAHA.113.01760; PMID: 24166752 Edstedt Bonamy AK, Bengtsson J, Nagy Z, et al. Preterm birth and maternal smoking in pregnancy are strong risk factors for aortic narrowing in adolescence. Acta Paediatr 2008;97:1080–5.

DOI: 10.1111/j.1651-2227.2008.00890.x; PMID: 18662347 Singhal A, Kattenhorn M, Cole TJ, et al. Preterm birth, vascular function, and risk factors for atherosclerosis. Lancet 2001;358:1159–60. DOI: 10.1016/S0140-6736(01)06276-6; PMID: 11597675 Hovi P, Turanlahti M, Strang-Karlsson S, et al. Intima-media thickness and flow-mediated dilatation in the Helsinki study of very low birth weight adults. Pediatrics 2011;127:e304–11.

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Cardiac Disease after Pregnancy

60. B oardman H, Birse K, Davis EF, et al. Comprehensive multimodality assessment of regional and global arterial structure and function in adults born preterm. Hypertens Res 2016;39: 39–45. DOI: 10.1038/hr.2015.102; PMID: 26399455 61. Bonamy AK, Martin H, Jörneskog G, et al. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med 2007;262: 635–42. DOI: 10.1111/j.1365-2796.2007.01868.x; PMID: 17986202 62. Lewandowski AJ, Davis EF, Yu G, et al. Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life. Hypertension 2015;65:607–14. DOI: 10.1161/ HYPERTENSIONAHA.114.04662; PMID: 25534704 63. Yu GZ, Aye CY, Lewandowski AJ, et al. Association of maternal antiangiogenic profile at birth with early postnatal loss of microvascular density in offspring of hypertensive pregnancies. Hypertension 2016;68:749–59. DOI: 10.1161/ HYPERTENSIONAHA.116.07586; PMID: 27456522 64. Gishti O, Jaddoe VW, Duijts L, et al. Impact of birth parameters and early life growth patterns on retinal microvascular structure in children: The Generation R Study. J Hypertens 2015;33:1429–37. DOI: 10.1097/HJH.0000000000000561; PMID: 25799210 65. Kistner A, Jacobson L, Jacobson SH, et al. Low gestational age associated with abnormal retinal vascularization and increased blood pressure in adult women. Pediatr Res 2002;51:675–80. DOI: 10.1203/00006450-200206000-00003; PMID: 12032260

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66. H ellstrom A, Hard AL, Niklasson A, et al. Abnormal retinal vascularisation in preterm children as a general vascular phenomenon. Lancet 1998;352:1827. DOI: 10.1016/S01406736(05)79889-5; PMID: 9851388 67. Montagna W, Carlisle K. Structural changes in aging human skin. J Invest Dermatol 1979;73:47–53. PMID: 448177 68. Shore AC, Tooke JE. Microvascular function in human essential hypertension. J Hypertens 1994;12:717–28.

PMID: 7963499 69. Feihl F, Liaudet L, Waeber B, et al. Hypertension: A disease of the microcirculation? Hypertension 2006;48:1012–7. DOI: 10.1161/01.HYP.0000249510.20326.72; PMID: 17060505 70. Antonios TF, Rattray FM, Singer DR, et al. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart 2003;89:175–8. DOI: 10.1136/ heart.89.2.175; PMID: 12527671 71. Mitchell P, Cheung N, de Haseth K, et al. Blood pressure and retinal arteriolar narrowing in children. Hypertension 2007;49:1156–62. DOI: 10.1161/ HYPERTENSIONAHA.106.085910; PMID: 17372033 72. Akcakus M, Altunay L, Yikilmaz A, et al. The relationship between abdominal aortic intima-media thickness and lipid profile in neonates born to mothers with preeclampsia. J Pediatr Endocrinol Metab 2010;23:1143–9. PMID: 21284327 73. Timpka S, Macdonald-Wallis C, Hughes AD, et al. Hypertensive disorders of pregnancy and offspring cardiac structure and function in adolescence. J Am Heart Assoc 2016;5:pii:e003906.

DOI: 10.1161/JAHA.116.003906; PMID: 27799232 74. Staff AC, Redman CW, Williams D, et al. Global Pregnancy

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Aus N Z J Obstet Gynaecol 2009;49:242–6. DOI: 10.1111/j.1479828X.2009.01003.x; PMID: 19566552 European Society of Gynaecololgy; Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM); Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al; ESC Committee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32:3147–97. DOI: 10.1093/eurheartj/ehr218; PMID: 21873418 Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women – 2011 update: A guideline from the American Heart Association. Circulation 2011;123:1243–62. DOI: 10.1161/ CIR.0b013e31820faaf8; PMID: 21325087

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Environment and Cardiovascular Disease

Guest Editorial Noise Pollution and Arterial Hypertension: Can we Remain Mute Anymore?

Juan Carlos Kaski

Sreenivasa Rao Kondapally Seshasai

St George’s, University of London, London, UK

St George’s, University of London, London, UK

Citation: European Cardiology Review 2017;12(1):24–5. DOI: 10.15420/ecr.2017.12.1.GE4 Correspondence: Dr Sreenivasa Rao Kondapally Seshasai, Cardiac and Vascular Sciences Research Centre, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK. E: rkondapa@sgul.ac.uk

A

lthough the gains of the industrial revolution have transformed human life, they have also left an adverse impact on our health and environment.1 Therefore, factors such as environmental pollution (and pollutants) have lately been the subject of intense scientific investigation.

Traffic noise represents a major environmental burden, which has been suggested to lead to serious cardiovascular diseases.1–3 Studies in the field of environmental pollution indicate that only airborne particulate matter affects more people in the industrialized world than environmental noise.2 The WHO has identified a threshold of >55 dB as a level of noise that is associated with health problems3 and very large numbers of individuals across the whole age spectrum are affected by traffic noise in cities in the developed world. Noise pollution above the WHO identified threshold is considered to cause more than 500 additional cases of myocardial infarction2 and approximately 800 cases of stroke.4 Exposure to noise can increase heart rate, blood pressure, concentrations of cortisol and noradrenaline and also promote low grade inflammation, which is likely to be a key pathogenic process in the development of atherosclerosis and other major diseases.5,6 Noise pollution can affect sleep patterns and the latter are known to be associated with increased cardiovascular morbi-mortality.7 Indeed, epidemiological studies have shown that individuals who are exposed to traffic noise at night for long periods of time are more likely to suffer from atherosclerosis than subjects who live in an environment with low levels of traffic noise.8 Some investigators have reported an association between noise pollution (mainly derived from road traffic) and mortality from cardiovascular diseases. A recent study by Halonen et al. involving over 8 million people in London, assessed the effects of long-term exposure to road traffic noise on both all-cause and cardiovascular mortality and

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on hospital admissions for cardiovascular disease.9 The study, which looked at both younger and older subjects, showed that long-term exposure to road traffic noise was associated with an increased risk of all-cause mortality and cardiovascular mortality and morbidity in the general population. Among this increased risk, the prevalence of stroke was particularly high in the elderly.

In this issue of European Cardiology Review, Münzel and Sørensen review the role of noise pollution in enhancing the risk of arterial hypertension in a scholarly and timely fashion.10 The authors showcase a multitude of individual studies and meta-analyses that suggest a positive association between noise pollution and hypertension. The authors further speculate that the association could be mediated by direct and indirect pathways (of relevance being the biological effects on autonomic nervous system, sleep physiology and endothelial function).

However, there are several limitations to available evidence about this association. First, as the authors themselves have acknowledged, the clear majority of studies cited were cross-sectional and therefore limited in their ability to inform whether the association is indeed real. Second, where prospective studies were conducted, the associations were either inconsistent or became non-significant upon adjustments for potential confounding factors. Finally, outdoor (especially traffic-related) noise pollution is intertwined heavily with air pollution and other environmental factors such as temperature and human activity, which have not been adequately and consistently accounted for, even among the largest of the epidemiological studies to date. Hence, it is yet unclear whether the observed associations are real or artefactual.

Should we therefore remain mute, both towards the science as well as the implications of the scientific findings so far? Perhaps

© RADCLIFFE CARDIOLOGY 2017

Noise Pollution and Arterial Hypertension: Can we Remain Mute Anymore? not – in fact, certainly not! While the existing body of evidence on the association between noise pollution and arterial hypertension is not yet strong, it is becoming increasingly obvious through parallel investigation (e.g. by the inverse association between air pollution and HDL cholesterol levels) 11 that adverse environmental factors likely have a major impact on human health and wellbeing.

However, it is unlikely – using simplistic methodological approaches – that debates regarding causality will be resolved successfully, especially in complex exposures such as environmental risk factors.

1.

2.

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Hanninen O, Knol AB, Jantunen M, et al. Environmental burden of disease in Europe: assessing nine risk factors in six countries.

Environ Health Perspect 2014;122:439–46. DOI: 10.1289/ehp.1206154; PMID: 24584099 Gulliver J, Morley D, Vienneau D, et al. Development of an open-source road traffic noise model for exposure assessment.

Environmental Modelling & Software 2015;74:183–93. DOI: 10.1016/j. envsoft.2014.12.022 World Health Organization. Guidelines for Community Noise.

1999. Available at: www.who.int/docstore/peh/noise/guidelines2. html (accessed 16 June 2017) Harding AH, Frost GA, Tan E, et al. The cost of hypertensionrelated ill-health attributable to environmental noise. Noise Health 2013;15:437–45. DOI: 10.4103/1463-1741.121253; PMID: 24231422

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5.

6.

7.

8.

There is an urgent need to establish and undertake large-scale, adequately powered prospective studies having the unabashed ability to borrow cross-cutting methods (e.g. principal components analysis, which is widely used in metabolomic research) to enhance the scientific veracity of findings related to complex environmental exposures. This will not only help address the causality debate, but will also provide a robust scientific framework to support key policy decisions worldwide. To this end, a recent announcement by the British Heart Foundation12 pledging support for environmental research in relation to cardiovascular diseases, is an important step forward. n

asner M, Babisch W, Davis A, et al. Auditory and non-auditory B effects of noise on health. Lancet 2014;383:1325–32.

Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med 2014;76:181– 9. DOI: 10.1097/PSY.0000000000000049; PMID: 24608036 Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009;6:e1000132. DOI: 10.1371/journal.pmed.1000132; PMID: 19688045 Kälsch H, Hennig F, Moebus S, et al. Are air pollution and traffic noise independently associated with atherosclerosis: the Heinz Nixdorf Recall study.

Eur Heart J 2014;35:853–60; DOI: 10.1093/eurheartj/ eht426; PMID: 24194529

9.

alonen JI, Hansell AL, Gulliver J, et al. Road traffic noise H is associated with increased cardiovascular morbidity and mortality and all-cause mortality in London. Eur Heart J 2015; 36(39):2653–61. DOI: 10.1093/eurheartj/ehv216; PMID: 26104392 10. Munzel T, Sorensen M. Noise pollution and arterial hypertension.

European Cardiology Review 2017;12:24–5 11. Bell G, Mora S, Greenland P, et al. Association of air pollution exposures with high-density lipoprotein cholesterol and particle number: the multi-ethnic study of atherosclerosis.

Arterioscler Thromb Vasc Biol 2017 May;37(5):976–82; DOI: 10.1161/ ATVBAHA.116.308193;PMID: 28408373 12. British Heart Foundation. BHF responds to new research that reveals how air pollution causes heart attacks and strokes.

2017. Available at: http://bit.ly/2sKQ93G (accessed 16 June 2017)

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Environment and Cardiovascular Disease

Noise Pollution and Arterial Hypertension T ho m a s M ü n z e l 1 a n d M e t t e S ø r e n s e n 2 1. Center for Cardiology, University Medical Center Mainz, Mainz, Germany; 2. Danish Cancer Society Research Center, Copenhagen, Denmark

Abstract Noise exposure modifies the function of multiple organs and systems. Acute noise exposure – both in laboratory settings where traffic noise is simulated and in real-life working environments – can cause increases in blood pressure, heart rate and cardiac output. This review examines the effects of noise pollution on the cardiovascular system, with a particular focus on non-auditory effects such as noise-induced arterial hypertension.

Keywords Transportation noise, vascular function, hypertension Disclosure: The authors have no conflicts of interest to declare Received: 27 October 2016 Accepted: 28 November 2016 Citation: European Cardiology Review 2017;12(1):26–9 DOI: 10.15420/ecr.2016:31:2 Correspondence: Thomas Münzel MD, University Medical Center Mainz, Center for Cardiology, Cardiology I, Langenbeckstrasse 1, 55131 Mainz, Germany.

E: tmuenzel@uni-mainz.de

The health burden of environmental noise has recently been quantified in a report of the WHO in terms of disability-adjusted life years (DALYs; i.e., the number of years lost because of disability or death – a measure that combines both morbidity and mortality).

The WHO estimates that – in western Europeans – each year 45,000 DALYs are lost because of noise-induced cognitive impairment in children, 903,000 because of noise-induced sleep disturbance, 61,000 because of noise-induced cardiovascular disease, and 22,000 because of tinnitus. Additionally, while not being a disease per se, noise-induced annoyance decreases quality-of-life and thus also causes disability, quantified as 654,000 DALYs lost in the western European population.1

Pathophysiology of Noise-induced Increases in Blood Pressure According to the noise reaction scheme by Babisch, noise may induce damage through a direct pathway – for instance by causing hearing loss – and indirect pathways, reflecting disturbances of sleep, communication and daily activities, with or without noiseinduced annoyance (see Figure 1).2 Chronic annoyance causes stress characterised by increased levels of stress hormones such as cortisol and catecholamines. Chronic stress may in turn cause a number of pathophysiological adaptations, such as increased blood pressure, increases in heart rate and cardiac output, increases in blood lipids (cholesterol, triglycerides, free fatty acids, phosphatides) and carbohydrates (glucose) as well as the activation of blood coagulation.3 This may ultimately manifest as cardiovascular diseases such as arterial hypertension, coronary artery disease and stroke (see Figure 1).

Noise Affects Vascular Function Two recently published field studies examined the effect of nocturnal aircraft noise exposure played-back with loudspeakers in subjects’ bedrooms. It was shown to dose-dependently affect parameters of vascular (endothelial) function in healthy subjects and in patients with

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established coronary artery disease, including endothelial function as measured by flow-dependent dilation of the brachial artery.4,5 Although these studies were limited to single-night exposures, a priming effect of noise was detected, i.e. the adverse effects of noise on vascular function were clearly more pronounced if the subject had previously been exposed to noise.5 Thus, in response to repeated exposure, the vessel appears to be unable to develop a form of accommodation, and is somewhat sensitised to noise-induced vascular damage.5 As expected, the deterioration in endothelial function was paralleled by increased catecholamine production and impaired sleep quality.5 In subjects with established coronary artery disease, there was also a significant increase in blood pressure.4 Interestingly, in these studies of patients with coronary artery disease, there was no correlation between annoyance reactions and the degree of deterioration of vascular function in response to noise, suggesting that noise per se adversely affects vascular function, whether the person is getting annoyed or not.4 Many epidemiological studies indicate that nocturnal noise exposure may be more relevant for cardiovascular health than daytime noise exposure. For aircraft noise, the Hypertension and Exposure to Noise near Airports (HYENA) study found no significant association for daytime noise, but a significant increase in blood pressure with increases in nighttime noise.6 Furthermore, a recent Swiss study showed an adverse effect of railway noise on blood pressure, which was more strongly associated with nighttime exposure. 7 Compatible with this evidence, it has been demonstrated that road traffic noise exposure has a larger impact in those who sleep with open windows or whose bedroom faces the road.8 A sustained decrease in blood pressure during the night (so-called ‘dipping’) seems to be important for resetting the cardiovascular system and for long-term cardiovascular health.9 Repeated nocturnal autonomic arousals may prevent blood pressure dipping and contribute to the risk for developing hypertension in those exposed to relevant levels

© RADCLIFFE CARDIOLOGY 2017

Noise Pollution and Arterial Hypertension of environmental noise for prolonged periods of time.10,11 In line with this, it has been reported that the risk of developing hypertension is higher in subjects sleeping with open windows during the night, whereas people sleeping in houses with sound insulation or where the bedroom does not face the main road have lower risk.12

Figure 1: Simplified Scheme Showing Progress to Cardiovascular Diseases in Response to Noise-induced Stress Reactions

The Night Noise Guidelines for Europe published by the WHO in 2009 constitute an expert consensus correlating four noise exposure ranges to negative health outcomes ranging from ‘no substantial biological effects’ to ‘increased risk of cardiovascular disease’.13 The WHO considers average nocturnal noise levels of equivalent A-weighted noise outside (LAeq) of 55 dB as the interim goal when the recommended guideline value of 40 dB is not feasible in the short term for the prevention of noise-induced health effects.

In sum, nocturnal noise has been shown to affect both autonomic regulation, with increases in heart rate mediated by sympathetic activation and/or parasympathetic withdrawal10,14,15 and with increases in blood pressure.16 Furthermore, nocturnal noise has been shown to directly affect vascular function through the induction of endothelial dysfunction. Importantly, both endothelial dysfunction and reduced heart rate variability have been demonstrated to have prognostic value in patients with peripheral artery disease, arterial hypertension, and patients with an acute coronary syndrome or chronic stable coronary artery disease.17–19 Taken together, these observations are compatible with the observation of an increased incidence of arterial hypertension and subsequent myocardial infarction and stroke in subjects with long-term exposure to relevant noise levels.

It should also be noted that residential exposure to road traffic noise correlates with exposure to ambient air pollution – another environmental pollutant suspected of increasing the risk for hypertension. The suggested pathophysiological pathway behind an effect of air pollution on cardiovascular disease shares some characteristics with the mechanisms proposed for noise, including effects on the immune system, endothelial dysfunction and changed levels of blood lipids.20 It is possible, therefore, that these two environmental pollutants can act together to increase the risk for hypertension, which needs to be addressed in future studies.

Epidemiological Studies: Noise and Arterial Hypertension Studies on chronic exposure to road traffic and/or railway or aircraft noise have reported a relationship with elevated blood pressure, arterial hypertension or the use of antihypertensive medications.

These studies indicate that environmental noise may carry a considerable health burden with important medical and economic implications. A recent report from the European Environment Agency concluded that in Europe, more than 900,000 cases of hypertension are caused by environmental noise each year.21

Road Traffic Noise, Blood Pressure and Hypertension A 2012 meta-analysis of 24 cross-sectional studies on the relationship between road traffic noise and the prevalence of hypertension among adults reported an OR of 1.07 (95 % CI [1.02–1.12]) per 10 dB increase in the 16-hours daytime average road traffic noise level (LAeq16h) in the range <50 to >75 dB.22 A certain degree of heterogeneity among studies was detected with respect to age, gender, the way the exposure was assessed, the noise reference level used, and the duration of the exposure. For example, in the large HYENA study, road

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Disturbance of activities, sleep, communication

Cognitive and emotional response

Annoyance Stress responses Activation of autonomic and endocrine systems Autonomic nervous system (sympathetic nerve)

Endocrine system (pituitary gland, adrenal gland)

Chronic stress generates risk factors Blood pressure

Blood lipids

Blood viscosity

Cardiac output

Blood glucose

Blood clotting factors

Cardiovascular diseases Arterial hypertension

Ischemic heart disease

Stroke

Source: Münzel, et al.2, © 2014.Reproduced with permission of the author under Creative Commons.

traffic noise was linked to hypertension in men but not women,6 and in a Dutch study road traffic noise was significantly associated with hypertension only among people aged 45–55 years.23 Later studies have confirmed the association between road traffic noise and prevalence of hypertension. A large Danish cohort study found a significantly higher systolic blood pressure per 10 dB increase in road traffic noise in middle-aged subjects, with stronger and significant associations in men and older subjects.24 No associations were found between road traffic noise and diastolic blood pressure. Similarly, a Spanish cohort study also found road traffic noise to be associated with systolic blood pressure as well as prevalent hypertension.25 In this study, exposure to nighttime noise was estimated outdoors as well as indoors, using information about the bedroom’s orientation and indoor insulation.

As expected, indoor nighttime noise levels were more consistently

27

Environment and Cardiovascular Disease associated with systolic blood pressure and hypertension when compared with the outdoor levels. A major concern in studies of road traffic noise is potential confounding from air pollution. In the Spanish study, exposure to especially indoor traffic noise was associated with systolic blood pressure and hypertension independently of estimated exposure to air pollution, probably reflecting that indoor levels of road traffic noise and air pollution are less correlated than outdoor levels.25

to nighttime outdoor aircraft noise of 50 dB(A) were followed over a period of three months. The ‘western group’ were exposed for 75 % of the time, and the ‘eastern group’ for 25 % of the time. The evaluation of ~8,000 blood pressure measurements from 53 individuals showed a statistically significant 10 mmHg higher morning systolic blood pressure and an 8 mmHg higher diastolic blood pressure for the western group compared with the less exposed eastern group.

The association between transportation noise and blood pressure in children has also been investigated. A recent meta-analysis examined 13 studies comprising 8,770 children that addressed the relationship between road traffic noise and blood pressure in kindergarten and school children.26 The authors reported that a 5 dB rise in road traffic noise at kindergarten/school was associated with a 0.48 mmHg higher systolic blood pressure (95 % CI [−0.87–1.83]) and a 0.22 mmHg higher diastolic blood pressure (95 % CI [−0.64–1.07]). However, there was high heterogeneity in the study, and further well-designed studies are needed to further assess this association.

One of the largest and most comprehensive studies on aircraft noise and hypertension is the HYENA study, based on almost 5,000 participants from six European countries.6 In this study, an exposure-response relationship was found, showing that for every 10 dB increase in nighttime aircraft noise (Lnight) the prevalence of hypertension increased by 14 % (95 % CI [1.01–1.29]; p=0.031). In contrast, no effect was found for daytime aircraft noise exposure (LAeq: OR 0.93; 95 % CI [0.83–1.04]; p=0.19). Results from the HYENA study also suggest an effect of aircraft noise on the use of antihypertensive medication, but this effect did not hold for all participating study centers.31

All these studies, both in children and adults, are of cross-sectional design, which prevents conclusions on causality and chronological order of events. Only one study has addressed the association between road traffic and railway noise and hypertension using a longitudinal design.24 This study found no association between longterm exposure to road traffic noise and risk of hypertension, whereas for railway noise the results indicated an association. However, this study was based on self-reported information on hypertension, which probably leads to underestimation of the actual number of subjects with hypertension, and longitudinal studies based on repeated blood pressure measurements are needed.

Data from the European Union-funded Road Traffic and Aircraft Noise Exposure and Children’s Cognition and Health study reported an association between both daytime and nocturnal noise exposure at home and blood pressure values in children aged 9–10 years living near Schiphol (Amsterdam) or Heathrow (London).32 A 2009 metaanalysis of four cross-sectional studies and one cohort study on the relationship between aircraft traffic noise and the prevalence of hypertension reported an OR of 1.13 (95 % CI [1.00–1.28]; p<0.001) per 10 dB increase of the day-night weighted noise level (LDEN) in

The effect of transportation noise on hypertension during pregnancy has also been examined. A recent Danish study found road traffic noise to be associated with hypertension among pregnant women.27 Based on a birth cohort including almost 73,000 pregnant women with singleton pregnancies,27 a 10 dB higher exposure to residential road traffic noise during the first trimester was associated with a higher risk of preeclampsia (OR 1.10; 95 % CI [1.02–1.18]) and pregnancy-induced hypertensive disorders (OR 1.08; 95 % CI [1.02–1.15]). Adjustment for air pollution lowered the estimates slightly (OR 1.08; 95 % CI [0.98–1.17] for preeclampsia and OR 1.06; 95 % CI [0.98–1.14] for all subtypes of hypertensive disorders during pregnancy). The results are comparable with results from a small Lithuanian study of approximately 3,000 women, which reported a non-significant association between road traffic noise and gestational hypertension.28 Although these two studies indicate that transportation noise may be a risk factor for hypertension during pregnancy, more studies addressing this end-point are warranted.

the range <55 to >65 dB.33 This picture has been confirmed in later studies, such as a recent French study that found that 10 dB higher nighttime aircraft noise was associated with a 34 % higher prevalence of hypertension in men (95 % CI [1.00–1.97]).34 Only one study has investigated the association between aircraft noise and hypertension using a longitudinal approach.35 This study is based on a cohort of almost 5,000 participants with repeated blood pressure measurements and living around Stockholm Arlanda airport.

The authors reported that a 5 dB increase in long-term exposure to aircraft noise was associated with an 8 % increased risk for developing hypertension among men. After exclusion of the ~30 % that smoked or used snuff during or directly preceding the blood pressure measurements, this estimate increased to 21 % per 5 dB (95 % CI [1.05–1.39]). In contrast, the study indicated no association between aircraft noise and hypertension among women. The study, however, included only few subjects exposed to high levels of aircraft noise (≥60 dB), and larger prospective studies are needed in this area.

Conclusion Aircraft Noise and Arterial Hypertension An increased prevalence of arterial hypertension in the vicinity of Stockholm airport was reported in 2001.29 With respect to the early stages of hypertension, a time-series study in the area surrounding Frankfurt Airport showed that, even in the physiological blood pressure range, a relationship existed between aircraft noise and early-morning blood pressure.30 In this study, two groups exposed

1.

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World Health Organization. Burden of disease from environmental noise. Available at: http://www.euro.who. int/__data/assets/pdf_file/0008/136466/e94888.pdf (accessed 22 January 2017) Münzel T, Gori T, Babisch W, Basner M. Cardiovascular effects

3.

The existing literature of both mechanistic and epidemiological design strongly points towards a relationship between exposure to transportation noise and elevated blood pressure. The consequence is that noise per se as an environmental stressor should be considered as a novel cardiovascular risk factor. This calls for prevention strategies, as around one third of the European population is exposed to transportation levels exceeding 55 dB; a number that is rising.21 ■

of environmental noise exposure. Eur Heart J 2014;35:829–36.

DOI: 10.1093/eurheartj/ehu030; PMID: 24616334 Lundberg U. Coping with stress: Neuroendocrine reactions and implications for health. Noise Health 1999;1 :67–74.

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Schmidt F, Kolle K, Kreuder K, et al. Nighttime aircraft noise impairs endothelial function and increases blood pressure in patients with or at high risk for coronary artery disease. Clin Res Cardiol 2015;104 :23–30. DOI: 10.1007/s00392-014-0751-x; PMID: 25145323

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Noise Pollution and Arterial Hypertension

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Hypertension and exposure to noise near airports: The HYENA study. Environ Health Perspect 2008;116 :329–33.

DOI: 10.1289/ehp.10775; PMID: 18335099 Dratva J, Phuleria HC, Foraster M, et al. Transportation noise and blood pressure in a population-based sample of adults. Environ Health Perspect 2011;120 :50–5. DOI: 10.1289/ ehp.1103448; PMID: 21885382 Babisch W, Ising H, Gallacher JEJ, et al. Traffic noise and cardiovascular risk: The Caerphilly and Speedwell studies, third phase-10-year follow up. Arch Environ Health 1999;54 :210–6. DOI: 10.1080/00039899909602261; PMID: 10444043 Sayk F, Becker C, Teckentrup C, et al. To dip or not to dip: On the physiology of blood pressure decrease during nocturnal sleep in healthy humans. Hypertension 2007;49 :1070–6. DOI: 10.1161/ HYPERTENSIONAHA.106.084343; PMID: 17353512 Haralabidis AS, Dimakopoulou K, Vigna-Taglianti F, et al.

HYENA Consortium. Acute effects of night-time noise exposure on blood pressure in populations living near airports. Eur Heart J 2008;29 :658–64. DOI: 10.1093/eurheartj/ ehn013; PMID: 18270210 Carrington MJ, Trinder J. Blood pressure and heart rate during continuous experimental sleep fragmentation in healthy adults. Sleep 2008;31 :1701–12. PMID: 19090326 Lercher P, Widmann U, Kofler W. Transportation noise and blood pressure: The importance of modifying factors. Presented at the 29th International Congress and Exhibition on Noise Control Engineering, Nice, France, 27–30 August, 2000.

World Health Organization. Night noise guidelines for Europe. 2009. Available at: http://www.euro.who.int/__data/ assets/pdf_file/0017/43316/E92845.pdf (accessed 7 December 2016), Lusk SL, Gillespie B, Hagerty BM, Ziemba RA. Acute effects of noise on blood pressure and heart rate. Arch Environ Health 2004;59 :392–9. DOI: 10.3200/AEOH.59.8.392-399; PMID: 16268115 Björ B, Burström L, Karlsson M, et al. Acute effects on

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heart rate variability when exposed to hand transmitted vibration and noise. Int Arch Occup Environ Health 2007;81 :193– 9. DOI: 10.1007/s00420-007-0205-0; PMID: 17541625 Chang TY, Lai YA, Hsieh HH, et al. Effects of environmental noise exposure on ambulatory blood pressure in young adults. Environ Res 2009;109 :900–5. DOI: 10.1016/j. envres.2009.05.008; PMID: 19559411 Münzel T, Sinning C, Post F, et al. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med 2008;40 :180–96. DOI: 10.1080/07853890701854702; PMID: 18382884 Muxel S, Fasola F, Radmacher MC, et al. Endothelial functions: Translating theory into clinical application. Clin Hemorheol Microcirc 2010;45 :109–15. DOI: 10.3233/CH-20101288; PMID: 20675890 Buccelletti E, Gilardi E, Scaini E, et al. Heart rate variability and myocardial infarction: Systematic literature review and metanalysis. Eur Rev Med Pharmacol Sci 2009;13 :299–307.

PMID: 19694345 Münzel T, Sørensen M, Gori T, et al. Environmental stressors and cardio-metabolic disease: Part II-mechanistic insights.

Eur Heart J 2016; DOI: 10.1093/eurheartj/ehw294: PMID: 27460891: epub ahead of press European Environment Agency. Noise in Europe 2014. 2014.

Available at: www.eea.europa.eu/publications/noise-ineurope-2014 (accessed 7 December 2016) van Kempen E, Babisch W. The quantitative relationship between road traffic noise and hypertension: A metaanalysis. J Hypertens 2012;30 :1075–86. DOI: 10.1097/ HJH.0b013e328352ac54; PMID: 22473017 de Kluizenaar Y, Gansevoort RT, Miedema HM, de Jong PE. Hypertension and road traffic noise exposure. J Occup Environ Med 2007;49 :484–92. DOI: 10.1097/JOM.0b013e318058a9ff; PMID: 17495691 Sørensen M, Hvidberg M, Hoffmann B, et al. Exposure to road traffic and railway noise and associations with blood pressure and self-reported hypertension: A cohort study.

Environ Health 2011;10 :92. DOI: 10.1186/1476-069X-10-92; PMID: 22034939 Foraster M, Kunzli N, Aguilera I, et al. High blood pressure and long-term exposure to indoor noise and air pollution from road traffic. Environ Health Perspect 2014;122 :1193–200.

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26. Dzhambov AM, Dimitrova DD. Children’s blood pressure and its association with road traffic noise exposure - A systematic review with meta-analysis. Environ Res 2017;152 :244–55. DOI: 10.1016/j.envres.2016.10.024; MID: 27810682 27. Pedersen M, Halldorsson TI, Olsen SF, et al. Impact of road traffic pollution on pre-eclampsia and pregnancyinduced hypertensive disorders. Epidemiology 2017;28 :99– 106. DOI: 10.1097/EDE.0000000000000555; PMID: 27648591 28. Bendokiene I, Grazuleviciene R, Dedele A. Risk of hypertension related to road traffic noise among reproductive-age women. Noise Health 2011;13 :371–7.

DOI: 10.4103/1463-1741.90288; PMID: 22122952 29. Rosenlund M, Berglind N, Pershagen G, et al. Increased prevalence of hypertension in a population exposed to aircraft noise. Occup Environ Med 2001;58 :769–73.

DOI: 10.1136/oem.58.12.769; PMID: 11706142 30. Aydin Y, Kaltenbach M. Noise perception, heart rate and blood pressure in relation to aircraft noise in the vicinity of the Frankfurt airport. Clin Res Cardiol 2007;96 :347–58.

DOI: 10.1007/s00392-007-0507-y; PMID: 17393058 31. Floud S, Vigna-Taglianti F, Hansell A, et al. HYENA Study Team. Medication use in relation to noise from aircraft and road traffic in six European countries: Results of the HYENA study. Occup Environ Med 2011;68 :518–24. DOI: 10.1136/ oem.2010.058586; PMID: 21084328 32. van Kempen E, van Kamp I, Fischer P, et al. Noise exposure and children‘s blood pressure and heart rate: The RANCH project. Occup Environ Med 2006;63 :632–9. DOI: 10.1136/ oem.2006.026831; PMID: 16728500 33. Babisch W, Kamp I. Exposure-response relationship of the association between aircraft noise and the risk of hypertension. Noise Health 2009;11 :161–68. DOI: 10.4103/1463-1741.53363; PMID: 19602770 34. Evrard AS, Lefevre M, Champelovier P, et al. Does aircraft noise exposure increase the risk of hypertension in the population living near airports in France? Occup Environ Med 2016; DOI: 10.1136/oemed-2016-103648; PMID: 27481872: epub ahead of press 35. Eriksson C, Bluhm G, Hilding A, et al. Aircraft noise and incidence of hypertension-gender specific effects. Environ Res 2010;110 :764–72. DOI: 10.1016/j.envres.2010.09.001; PMID: 20880521

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Cardiovascular Pharmacotherapy

ISCP Guest Editorial Key Recent Advances in Atherosclerosis Treatment with Modern Lipid-lowering Drugs: The New Frontier with PCSK9 Inhibitors

Román Freixa Pamias Member of the International Society of Cardiovascular Pharmacotherapy, based at the Department of Cardiology, Moisès Broggi Hospital, Barcelona, Spain

Antoni Martínez-Rubio President of the International Society of Cardiovascular Pharmacotherapy, based at the Department of Cardiology, University Hospital of Sabadell and the Autonomous University of Barcelona, Barcelona, Spain

Citation: European Cardiology Review 2017;12(1):30–2. DOI: 10.15420/ecr.2017.12.1.GE3 Correspondence: Antoni Martínez-Rubio, University Hospital Sabadell, Department of Cardiology, Autonomous University of Barcelona, Parc Taulí 1, E-08208 Sabadell, Barcelona, Spain. E: amartinezrubio@icloud.com

Hypercholesterolemia has been known for several years to be a major risk factor in the development of atherosclerosis and consecutively cardiovascular disease. This epidemiological concept has been widely confirmed using different strategies that have reduced low-density lipoprotein (LDL) levels and cardiovascular events (morbidity and mortality) in primary as well as in secondary prevention, in different groups of patients.

Because statins have broadly demonstrated a significant improvement in prognosis for reducing atherosclerotic heart disease, they are considered the treatment of choice for reducing LDL.1,2 However, some patients present secondary effects (mainly muscular pain or hepatic enzyme elevation), which can lead to non-adherence or even discontinuation of their therapeutic regimen. Statins may also exert diabetogenesis.3 In addition, although statins are effective lipidlowering drugs, there remains a residual cardiovascular risk in many patients. In this context, ezetimibe was developed as an alternative drug for statin-intolerant patients or as an addition to statins.

Ezetimibe may further improve the prognosis of atherosclerotic patients.4 However, even in combined statin and ezetimibe therapy, some patients still present elevated (“non-optimal”) LDL levels, cardiovascular risk and events. Thus, there was a need to identity additional effective and safe lipid-lowering strategies to be used either in combination with statins, ezetimibe or alone.

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on hepatocyte surface. Monoclonal antibodies targeting PCSK9 provoke significant lowering of LDL-C, non-high-density lipoprotein cholesterol and lipoprotein(a) as monotherapy or in combination with other lipid-lowering drugs. In fact, only two PCSK9 inhibitors are

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Access at: www.ECRjournal.com

clinically available: alirocumab and evolocumab. Interestingly, PCSK9 inhibitors demonstrate favourable impact on atherosclerotic plaque progression and lipidic profile of patients with and without familial hypercholesterolemia.5–7 Importantly, the available data suggest that PCSK9 inhibitors do not adversely affect glucose metabolism, do not increase the incidence of new onset diabetes mellitus3 and reduce cardiovascular events in patients with type 2 diabetes mellitus at least as much as in those without. However, although there is a possible association of PCSK9 levels with kidney function, no data are available for the administration of PCSK9 inhibitors in patients with severe chronic kidney disease.8 In addition, the physiological limits of lowering LDL-C are not yet established.9 The most interesting and important analysis end-point of PCSK9 inhibitor treatment is related to the long-term outcomes of broad treatment populations with evolocumab (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk [FOURIER])10 and alirocumab (ODYSSEY).11 Some trials are on-going (ODYSSEY) while others have been completed and their results are available.10 Previous long-term studies using evolocumab, including the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) (78 weeks), Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER-1) (4 years), and pooled analyses of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations (PROFICIO) (~1 year) have shown sustained LDL-C reduction, without evidence of safety concerns, regardless of LDL-C level achieved.6,7,12 Importantly, the recently presented FOURIER trial analyzed the outcome of 27,564 patients with atherosclerotic cardiovascular disease and LDL-C >70 mg/dl who were receiving statin (±ezetimibe) therapy and were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as

© RADCLIFFE CARDIOLOGY 2017

ISCP Guest Editorial Table 1: Primary, Secondary and Other Endpoints in Patients with Cardiovascular Disease Receiving Evolocumab and Patients Receiving Placebo

Outcome

Evolocumab (n=13,784) n (%)

Placebo (n=13,780) n (%)

HR (95% CI)

P-value

Primary endpoint*

1,344 (9.8)

1,563 (11.3)

0.85 (0.79–0.92)

<0.001

Key secondary endpoint**

816 (5.9)

1,013 (7.4)

0.80 (0.73–0.88)

<0.001

Miocardial infarction

468 (3.4)

639 (4.6)

0.73 (0.65–0.82)

<0.001

Coronary revascularization

759 (5.5)

965 (7.0)

0.78 (0.71–0.86)

<0.001

I schaemic stroke or transient ischaemic attack

229 (1.7)

295 (2.1)

0.77 (0.65–0.92)

0.003

Other endpoints

*Time to cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularization, whichever comes first; **Cardiovascular death, myocardial infarction, or stroke. Adapted from Sabatine MS, et al., 2017.10

subcutaneous injections.10 The median pre-randomization LDL-C was 92 mg/dl in both cohorts of patients. With evolocumab, LDL-C was quickly (in approximately 4 weeks) and significantly reduced, and thereafter sustained (median: 30 mg/dl). Furthermore, 42 % of patients treated with evolocumab achieved levels ≤25 mg/dl (versus <0.1 % in the placebo group). The median duration of follow-up was 2.2 years.

The primary endpoint (composite of cardiovascular death, myocardial infarction [MI], stroke, hospitalization for unstable angina or coronary revascularization) was reduced with evolocumab compared to placebo (1,344 patients [9.8 %] versus 1,563 patients [11.3 %]; HR 0.85; 95 % CI [0.79–0.92]; p<0.001). These results were mainly driven by reductions in MI, stroke, and coronary revascularization (see Table 1). Also, the secondary endpoint (composite of cardiovascular death, MI or stroke) was significantly improved by evolocumab (see Table 1) but without safety concerns. Adverse events in the evolocumab (n=13,769) and placebo (n=13,756) groups included injection-site reaction, allergic reaction, muscle-related event, rhabdomyolysis, cataract, adjudicated case of diabetes, and neurocognitive event; however, there were no significant differences in major side-effects or laboratory results (aminotransferase >3 x ULN and creatinine kinase >5 x ULN) between the two groups. Importantly, the incidence of neurocognitive events, cataracts and new-onset diabetes were similar between the two treatment arms. Only injection site reactions were more frequent with evolocumab (82.1 % versus 1.6 %). Post-baseline anti-evolocumab antibodies were detected in 0.3 % patients, with no detected neutralizing antibodies.

The key findings of the FOURIER trial are as follows: • Treatment with evolocumab in patients with established cardiovascular disease, who were receiving high to moderate intensity statin therapy, over a median of 2.2 years compared with placebo resulted in significant and maintained lowering of LDL-C and significant cardiovascular risk reduction.

• Levels of even LDL-C of 22 mg/dl had beneficial effects (reduction of the key secondary endpoint) without major safety concerns.

Furthermore, the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) cognitive function trial13 conducted in FOURIER patients showed

EUROPEAN CARDIOLOGY REVIEW

non-inferiority of evolocumab in comparison to placebo (data presented at the American College of Cardiology Congress 2017, not yet published).

For alirocumab, the other clinically available PCSK9 inhibitor, a large Phase III program (ODYSSEY) has been conducted with 12 fulfilled trials designed to demonstrate superiority of alirocumab versus placebo, the superiority of the addition of alirocumab over up-titration of statin and/or ezetimibe.5 In addition, a large Phase III study (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab [ODYSSEY OUTCOMES]) is on-going to evaluate the long-term effect of alirocumab on cardiovascular events in approximately 18,000 patients after an acute coronary syndrome on a background of intensive statin therapy.11 The important differences between the FOURIER and ODYSSEY OUTCOMES trials are:10,11 • ODYSSEY OUTCOMES includes a post-acute coronary syndrome population versus established atherosclerotic coronary disease in FOURIER. • Two different doses of alirocumab, which allows some flexibility in titrating with regard to the LDL-C level, are used in ODYSSEY OUTCOMES versus evolocumab, either 140 mg every 2 weeks or 420 mg every month, according to patient preference in FOURIER. • The primary composite outcome in FOURIER includes cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization, but ODYSSEY OUTCOMES does not include revascularization in its key primary composite outcome.

• FOURIER includes a larger population (n=27,564) than ODYSSEY OUTCOMES (approximately 18,000), but with shorter follow-up (approximately 2 years versus 3 years).

Thus, both trials are complementary and aimed at demonstrating that PCSK9 inhibition reduces cardiovascular risk via potent LDL-C reduction and that this approach is safe in the long term. However, the longest follow-up of these trials is approximately 3 years. Therefore, these trials and future data will provide a sense of the true cardiovascular benefit and a more accurate understanding of very long-term (e.g. >10 years) treatment risks and possible physiological effects of potent (e.g. LDL <40 mg/dl) lowering of LDL-C. n

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3.

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Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic 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;63:2889–934. DOI: 10.1016/j.jacc.2013.11.002; PMID: 24239923.

Catapano AL, Graham I, De Backer G, et al. 2016 ESC/ EAS Guidelines for the Management of Dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).

Eur Heart J 2016;37:2999–3058. DOI: 10.1016/ j.atherosclerosis.2016.08.018; PMID: 27594540.

Athyros VG, Tziomalos K, Doumas M, et al. The effect of proprotein convertase subtilisin-kexin type 9 and its inhibition on glucose metabolism and cardiovascular risk.

We should do better the second time after statins. Curr Pharm Des 2017; DOI: 10.2174/1381612823666170125154257; PMID: 28128061; epub ahead of press.

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes.

N Engl J Med 2015;372:2387–97. DOI: 10.1056/ NEJMoa1410489; PMID: 26039521.

Farnier M. An evaluation of alirocumab for the treatment of hypercholesterolemia. Expert Rev Cardiovasc Ther 2015;13:1307–23. DOI: 10.1586/14779072.2015.1111759; PMID: 26563849; epub ahead of press.

6. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016;316:2373–84. DOI: 10.1001/jama.2016.16951; PMID: 27846344.

7. Toth PP, Descamps O, Genest J, et al. Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies. Circulation 2017;135:1819–31.

DOI: 10.1161/CIRCULATIONAHA.116.025233; PMID: 28249876.

8. Pavlakou P, Liberopoulos E, Dounousi E, Elisaf M. PCSK9 in chronic kidney disease. Int Urol Nephrol 2017: DOI: 10.1007/ s11255-017-1505-2; PMID: 28084558; epub ahead of press.

9. Everett BM. Low-density lipoprotein cholesterol and the on-target effects of therapy: how low is too low? J Am Coll Cardiol 2017;69:483–5. PMID: 28153103; DOI: 10.1016/j. jacc.2016.11.036.

10. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular 5.

disease. N Engl J Med 2017: PMID: 28304224; DOI: 10.1056/ NEJMoa1615664; epub ahead of press.

11. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on longterm cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682–9. PMID: 25440796 DOI: 10.1016/j.ahj.2014.07.028.

12. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol 2017; DOI: 10.1001/jamacardio.2017.0747; PMID: 28291870; epub ahead of press.

13. Giugliano RP, Mach F, Zavitz K, et al. Design and rationale of the EBBINGHAUS trial: a phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial. Clin Cardiol 2017;40:59–65. DOI: 10.1002/clc.22678; PMID: 28207168; epub ahead of press.

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Cardiovascular Pharmacotherapy

Antiplatelet Therapy in Acute Coronary Syndrome Kerry Layne and Albert Ferro Department of Clinical Pharmacology, Cardiovascular Division, King’s College London, London, UK

Abstract Antiplatelet agents have for decades been used to improve outcomes in patients with acute coronary syndromes and have become increasingly valued, not only for their antithrombotic properties but also for their anti-inflammatory effects. The drug class continues to evolve as novel agents with increasingly efficacious antiplatelet actions are identified. This review will discuss antiplatelet agents, including aspirin, the P2Y12 receptor antagonists and the glycoprotein IIb/IIIa inhibitors, that are currently used to treat patients with unstable angina and myocardial infarction, focusing on their pharmacological properties and the clinical evidence supporting their use.

Keywords Antiplatelet agent, acute coronary syndromes, antithrombotic, anti-inflammatory, aspirin, P2Y12 receptor antagonist, glycoprotein IIb/IIIa inhibitors Disclosure: The authors have no conflicts of interest to declare.

Received: 29 November 2016 Accepted: 18 January 2017 Citation: European Cardiology Review 2017;12(1):33–7. DOI: 10.15420/ecr.2016:34:2 Correspondence: Albert Ferro, Department of Clinical Pharmacology, Cardiovascular Division, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. E: albert.ferro@kcl.ac.uk

Acute coronary syndrome (ACS) is a term used to encompass unstable angina (UA) and myocardial infarction (MI) with or without electrocardiographic (ECG) evidence of ST-segment elevation.

Antiplatelet therapy has formed the backbone of ACS management for decades and the drug class continues to evolve as novel agents with increasingly efficacious antiplatelet actions are identified. The main risk associated with all antiplatelet therapies is bleeding, and physicians need to carefully weigh the possible adverse effects against the benefits of prescribing these drugs to patients with ACS. Aspirin, which has been recognised to have antithrombotic effects since the 1960s, continues to be prescribed almost ubiquitously for patients with ACS, and P2Y12 antagonists are now often added in; such dual antiplatelet therapy confers greater antithrombotic efficacy but at the risk of increased bleeding. Over recent years, it has become apparent that these drugs may also exert powerful anti-inflammatory effects that provide additional benefit in the management of ACS. This review will discuss antiplatelet agents that are currently used to treat patients with UA and MI.

Aspirin in Acute Coronary Syndrome Alongside its analgesic and antipyretic effects, aspirin has been recognised as an inhibitor of platelet function for around 50 years1 and, to date, remains the most commonly prescribed drug worldwide.2 Current guidelines for the treatment of ACS recommend that all patients routinely receive a loading dose of aspirin, followed by maintenance therapy unless contraindicated.3,4 There is a wide range of maintenance dosages of aspirin that are prescribed in this context, ranging from 75 to 325 mg daily in different countries.5 In patients who have suffered a MI, recommended secondary prevention therapy typically entails 12 months of dual antiplatelet therapy, followed by lifelong aspirin, whilst patients with angina (stable or unstable) commence aspirin monotherapy.6,7

© RADCLIFFE CARDIOLOGY 2017

The cyclooxygenase (COX) enzyme converts arachidonic acid to prostaglandins. There are two human isoforms: COX-1, which is expressed in most tissues and COX-2, which is typically present in areas of active inflammation but can also (like COX-1) be expressed constitutively in some tissues.8 Prostaglandins are a large subgroup of eicosanoids; of these, two derivatives, prostacyclin and thromboxane A2 (TXA2), are of particular importance in maintaining platelet homeostasis.

Prostacyclin inhibits while TXA2 increases platelet activation. Aspirin irreversibly inhibits both COX enzymes through acetylation of a critical serine residue, although its effect on COX-1 is at least tenfold greater than that on COX-2.8 By predominantly inhibiting COX-1, TXA2induced platelet activation and aggregation are blocked.9 Circulating platelets have a lifespan of 8–10 days, and are typically present at a concentration of 150–400 x 109 per litre of blood (see Figure 1 and Table 1).10 Aspirin achieves maximum platelet inhibition within 2 hours following a loading dose and inhibits aggregation in 50 % of circulating platelets for at least five days.11,12 There has been some debate over the past decade as to whether aspirin resistance is a clinically significant issue, requiring patients deemed to be ‘poor responders’ to switch to an alternative antiplatelet agent.13,14 It has since been shown that whilst platelet function assays may produce variable results, and thus suggest that aspirin resistance is present, platelet COX-1 activity, as reflected by TXA2 levels, is uniformly and persistently suppressed by low-dose aspirin15 and it is now generally accepted that true pharmacological resistance to aspirin is rare.16 Data from one of the first large-scale randomised controlled studies assessing the effectiveness of aspirin as an antithrombotic agent were published in 1983 – 1,266 men with UA received treatment with either aspirin or placebo, with results showing a significant reduction in progression to MI among those taking aspirin.17 Aspirin in the setting of acute MI has subsequently been found to have

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Cardiovascular Pharmacotherapy major beneficial effects on morbidity and mortality,18,19 and multiple meta-analyses have confirmed the pivotal role that aspirin plays in reducing cardiovascular events and mortality in patients with ACS.20,21

Adenosine Diphosphate Receptor Antagonists in Acute Coronary Syndrome Alongside aspirin therapy, patients with UA or non-ST-elevation MI (NSTEMI) who are considered to have a predicted 6-month mortality of >1.5 % (which is the case for the vast majority of such patients), are typically treated with a loading dose of 300 mg clopidogrel.22 Those with acute ST-elevation MIs (STEMIs) will go on to receive coronary reperfusion therapy, usually with percutaneous coronary intervention (PCI) but more rarely these days with fibrinolytic therapy, and also receive a second antiplatelet agent, namely clopidogrel, prasugrel or ticagrelor depending on local guidelines.

Clopidogrel, prasugrel and ticagrelor are all adenosine diphosphate (ADP) antagonists, a class of therapeutic agents that bind selectively to the P2Y12 receptor to inhibit platelet function (see Figure 1 and Table 1).23 The thienopyridine, ticlopidine was the first drug in this class but is seldom prescribed now, following reports of serious adverse reactions, in particular neutropaenia24 and thrombotic thrombocytopaenic purpura.25

Prasugrel Prasugrel is an oral thienopyridine prodrug that is hydrolysed by esterases to the metabolite, R-95913. This inactive metabolite is then activated by cytochrome P450 enzymes, forming the active metabolite R-138727. As with clopidogrel, the active metabolite subsequently binds irreversibly via a covalent bond to the platelet P2Y12 receptor and thus inhibits platelet function.33 A loading dose of 60 mg is given, followed by 5–10 mg daily maintenance dosing.34 Peak plasma concentration is reached within 30 minutes and the drug has a half-life of 7 hours.33 Phase I and II studies have demonstrated that prasugrel has a faster onset of action than clopidogrel, as well as being more efficacious and more predictable in its antiplatelet action.35–37 The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 phase III study found that in patients with ACS undergoing PCI, prasugrel was more effective than clopidogrel in reducing further ischaemic events although it conveyed a higher risk of major bleeding.38 Further analysis of a subgroup of patients with STEMI undergoing PCI found that prasugrel was more effective than clopidogrel in preventing additional cardiovascular events without any increased risk of minor or major bleeding.39 Among patients with ACS without ST-elevation who did not undergo PCI, prasugrel was not found to be superior to clopidogrel in preventing ischaemic events.40

Clopidogrel The second generation thienopyridine prodrug, clopidogrel, is currently the most commonly prescribed ADP receptor antagonist. It is administered orally and up to 85 % of the absorbed drug undergoes hepatic metabolism by carboxylesterases to form an inactive carboxylic acid derivative, clopidogrelic acid, whilst the remaining 15 % is metabolised into the active thiol product by cytochrome P450 isoenzymes.23,26 Although clopidogrel has a relatively short half-life of 6 hours,27 the thiol metabolite covalently binds to the P2Y12 receptor, inducing an irreversible conformational change in the receptor and thus impairing thrombotic function for the remaining lifespan of the affected platelet. Genetic polymorphisms in cytochrome P450 enzymes, particularly CYP2C19 and CYP2C9, may result in impaired generation of the active thiol metabolite in patients taking clopidogrel, resulting in lack of efficacy.28 Variable responses to clopidogrel may additionally result from mutations in the ABCB1 gene that encodes the P-glycoprotein involved in clopidogrel absorption.28 The standard dosing regime is a 300 mg loading dose and 75 mg daily maintenance dose. Following this, steady state ADP inhibition is typically achieved within 3–7 days, with a 40–60 % reduction in ADPinduced platelet aggregation from baseline.27 Randomised controlled trials have demonstrated that clopidogrel is more effective than aspirin in preventing cardiovascular events in patients with vascular disease,29 reduces mortality further in patients with MI when used alongside aspirin,30 and improves outcomes in patients undergoing PCI again when used in combination with aspirin.31,32 The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study showed that clopidogrel administration was associated with similar adverse effects to those observed with aspirin, including gastrointestinal discomfort and increased bleeding, but the overall safety profile of clopidogrel 75 mg daily was considered to be at least as good as that of aspirin 325 mg daily.29 However, the inter-patient unpredictability in clopidogrel responsiveness (with some patients not responding at all) due to the above factors led to the development of newer P2Y12 antagonists.

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Ticagrelor Unlike clopidogrel and prasugrel, ticagrelor is a cyclopentyl-triazolopyrimidine ADP antagonist and has distinct pharmacokinetic and pharmacodynamic properties. Ticagrelor binds directly to the P2Y12 receptor and alters its conformation, resulting in reversible inhibition.

The drug does not require metabolic activation and thus exhibits a comparatively rapid onset and offset of effect, necessitating comparatively frequent dosing to achieve steady state ADP inhibition.41 Plasma levels of ticagrelor peak at 1.5–3.0 hours post-ingestion and reach steady state after 2–3 days.42 Although metabolic activation is not required for initiation of its antiplatelet effects, the drug does have an active metabolite, AR-C124910XX, which is produced following the interaction of the parent drug with cytochrome P450.41,42 Ticagrelor is administered as a loading dose of 180 mg, followed by maintenance dosing of either 60 or 90 mg twice daily. The Platelet Inhibition and Patient Outcomes (PLATO) study showed that ticagrelor was superior to clopidogrel in reducing mortality and further cardiovascular events in patients presenting with ACS, regardless of the presence or absence of CYP2C19 and CYP2C9 polymorphisms.43 The Dose Confirmation Study Assessing Anti-platelet Effects of AZD6140 versus Clopidogrel in Non–ST-Segment Elevation Myocardial Infarction-2 (DISPERSE-2) showed that there was no increase in major bleeding events in patients with non-ST segment ACS taking ticagrelor compared to clopidogrel; however, there were significantly more minor bleeding events.44 Ticagrelor achieves higher levels of platelet inhibition than clopidogrel,45 likely due to a combination of factors, including the aforementioned genetic variations in absorption and metabolism of clopidogrel.

In view of the greater platelet inhibition and consequent improved outcomes that are observed with prasugrel and ticagrelor compared with clopidogrel, many cardiology centres now recommend that the latter is not used as a first-line P2Y12 inhibitor in the management of acute STEMI.46

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Antiplatelet Therapy in Acute Coronary Syndrome Figure 1: Sites of Action for Antiplatelet Agents

Platelet R

ADP

III a

Cangrelor is a novel P2Y12 inhibitor that, like ticagrelor, binds directly to the receptor and induces reversible blockade. The drug is a nonthienopyridine adenosine triphosphate analogue that is administered intravenously and has shown promising results in clinical trials to date.47 The drug has a rapid onset and offset of action, reaches steady state within a few minutes and achieves greater than 90 % inhibition of platelet activation resulting from the P2Y12 pathway.48

GP IIb /

Cangrelor

2 Fibrinogen

Glycoprotein IIb/IIIa Inhibitors in Acute Coronary Syndrome The platelet integrin complex glycoprotein (GP) IIb/IIIa represents the final common pathway of platelet activation.54,55 This molecule mediates platelet adhesion via binding to fibrinogen thereby forming bridges between platelets. A haemostatic platelet plug subsequently develops, which increases in size as further platelet activation is propagated.54 GP IIb/IIIa receptor inhibitors block this pathway and thus reduce thrombogenesis. Of the drugs in this class, abciximab (a monoclonal antibody fragment), tirofiban (a small, non-peptide molecule) and eptifibatide (a cyclic heptapeptide derived from rattlesnake venom) are used in clinical practice.55,56 Abciximab additionally binds to integrin receptors on leucocytes and endothelial cells, thus reducing the adhesion of platelets to these cells.56 GP IIb/IIIa inhibitors have played varying roles as antiplatelet agents over the past 20 years.55 Data from several large-scale meta-analyses looking at GP IIb/IIIa inhibitor clinical trials in the medical management of non-ST-elevation ACS indicate a significant reduction in further MI and overall mortality in patients treated with these agents,57,58 and although they were formerly used as key therapies in the management of acute MI for several years, GP IIb/IIIa inhibitors have been gradually phased out in favour of the P2Y12 inhibitors.

A similar trend has followed with regard to the use of GP IIb/IIIa inhibitors as prophylactic antithrombotic agents in patients undergoing PCI, where their use has been declining in favour of novel antithrombotic/ anticoagulant drugs. The TRITON-TIMI 38 study found that prasugrel significantly reduced the risk of cardiovascular events in patients with ACS after PCI regardless of whether or not a GP IIb/IIIa inhibitor was used concurrently.59 The Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR–REACT) trial enrolled 2,159 patients with coronary artery disease who underwent elective PCI following pre-treatment with clopidogrel 600 mg and either abciximab or placebo; there was no observable clinical benefit in those receiving abciximab over the 30 days post-procedure.60 The ISAR–REACT 2 study subsequently assessed 2,022 patients with UA or NSTEMI undergoing PCI who were pre-treated with 600 mg clopidogrel and either abciximab or placebo, and found that abciximab significantly

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3 P2Y12R

R IIb /II Ia GP

In a series of randomised controlled studies, when compared with current standard therapy, no significant differences in mortality or further MI were observed when patients were treated with either clopidogrel or cangrelor before49 or during PCI.50 A double-blind placebo-controlled trial involving 11,145 patients subsequently found that cangrelor significantly reduced the rate of ischaemic events during PCI, with no increase in severe bleeding, compared with clopidogrel.51 At present, cangrelor has been approved by US and European regulatory agencies for use in patients undergoing PCI, although it has not yet been recommended by the National Institute for Health and Care Excellence (NICE) for use in the UK due to a relative lack of clear data.52,53

ADP

Platelet Intracellular activation pathways

AA

COX

TXA2

1 This figure shows the pathways that are interrupted by antiplatelet drugs to impair platelet activation and aggregation. 1: Aspirin acts to inhibit the activity of the cyclooxygenase enzyme and thus attenuates the production of prostaglandins and thromboxane. 2: The ADP receptor antagonists bind to the P2Y12 receptor to prevent ADP-induced platelet activation.

3: Glycoprotein IIb/IIIa inhibitors impair platelet adhesion by preventing the formation of fibrinogen bridges between platelets. AA = arachidonic acid; ADP = adenosine diphosphate; COX = cyclooxygenase; GP = glycoprotein; TXA2 = thromboxane A2.

reduced the incidence of adverse events, although only in those patients with elevated troponin levels at presentation.61 In the UK, current NICE guidance recommends GP IIb/IIIa inhibitors as an adjunct to PCI for all patients with diabetes undergoing elective PCI, and for those patients undergoing complex procedures, but not for the routine management of ACS or PCI.62

Anti-inflammatory Effects of Antiplatelet Drugs: Possible Relevance to Acute Coronary Syndrome In addition to their antiplatelet effects, it has become increasingly recognised that aspirin and the ADP receptor antagonists also exhibit beneficial anti-inflammatory effects in the context of ACS. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) identified that elevated levels of high-sensitivity C-reactive protein (hsCRP), a hepatically synthesised biomarker of inflammation produced in response to macrophagederived interleukin-6, were associated with cardiovascular events including MI and stroke in patients with no known cardiac disease.63,64 HsCRP was found to be a stronger predictor of events than the traditionally used low-density lipoprotein levels, demonstrating the importance of underlying inflammation in the development of atherosclerosis.

Pro-inflammatory biomarkers have been shown to have significant prognostic value in STEMI,65 and a recent clinical trial has also identified a potential benefit of an anti-inflammatory therapy (colchicine) in the management of STEMI.66 Furthermore, levels of pro-inflammatory CD14highCD16+ monocytes are also associated with ACS, and a multitude of clinical studies have highlighted the association between raised levels of CD16+ monocytes and coronary disease. CD16+ monocyte counts are elevated in patients with UA compared with matched control subjects with stable coronary artery disease and, among the UA patients, those with intermediate–high risk of MI had significantly higher counts of the

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Cardiovascular Pharmacotherapy Table 1: Pharmacological Properties of the Antiplatelet Drugs Discussed in this Review Drug

Site of Action

Aspirin

Inhibition of COX 1–2 hours 15–20 min enzyme

Time to Peak Action

Half-life

Typical Dose Administered

Route/Dosing Interval

In Europe loading dose 300 mg, maintenance dose 75 mg

Oral Once daily

Clopidogrel Thienopyridine 45 min 6 hours

prodrug irreversibly

binds to the P2Y12 receptor

Loading dose 300 – 600 mg, maintenance dose 75 mg

Oral Once daily

Prasugrel Thienopyridine 30 min 7 hours

prodrug, irreversibly

binds to the P2Y12 receptor

Loading dose 60 mg, maintenance dose 10 mg

Oral Once daily

Ticagrelor Cyclopentyl-triazolo- 1.5 hours 7 hours

pyrimidine drug,

reversibly binds to P2Y12 receptor

Loading dose 180 mg, maintenance dose 90 mg

Oral Twice daily

Cangrelor

Bolus 30 mcg/kg injection then 4 mcg/kg/min infusion

Intravenous One-off treatment

Adenosine triphosphate 2 min 3–6 min analogue, reversibly binds to P2Y12 receptor

Abciximab Glycoprotein IIb/IIIa 30 min 30 min Bolus 0.25 mg/kg injection

receptor inhibitor then 0.125 mcg/kg/min infusion

Intravenous One-off treatment

COX = cyclooxygenase.

CD14highCD16 monocyte subset.67 Tapp et al. found a correlation between CD14highCD16+ counts and peak troponin-T levels post-STEMI, as well as a correlation between CD14highCD16+ counts and left ventricular ejection fraction post STEMI.68 A study of 951 patients referred for elective coronary angiography showed that a higher CD14highCD16+ count was predictive of cardiovascular events including MI, ischaemic stroke and death from cardiovascular causes.69 It has been demonstrated that both aspirin and clopidogrel exert immunomodulatory effects and are capable of counteracting the CD14highCD16+ monocyte increase that occurs in vivo under pro-inflammatory conditions,70 suggesting a potential role for these drugs in reducing monocytic biomarkers of inflammation in patients with cardiovascular disease and possibly thereby improving outcomes further in ACS.

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Conclusion Coronary artery disease and its related pathologies remain the leading cause of death worldwide. Antiplatelet agents have been used for decades to improve outcomes in patients with ACS and may do so not only through their antithrombotic properties but also through their anti-inflammatory effects, although their relative contribution in this context remains a subject of debate. What is clear, however, is that increased antithrombotic efficacy improves outcomes post-ACS, but carries the price of increased bleeding risk, so that at some point diminishing returns accrue from ever more efficacious antiplatelet therapy. The challenge for the future is to better predict the benefit:risk ratio in individual patients, so that the intensity of antiplatelet therapy can be optimised on a personalised basis. n

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Engl J Med 2009;361:1045–57. DOI:10.1056/NEJMoa0904327; PMID:19717846 44. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50:1844–51. DOI:10.1016/j.jacc.2007.07.053; PMID:17980250 45. Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010;56:1456–62. DOI:10.1016/j.jacc.2010.03.100; PMID:20832963 46. Kloppenborg RP, Richard E, Sprengers MES, et al. Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of evidence for immunosuppressive treatment. J Neuroinflammation 2010;7:18. DOI: 10.1186/17422094-7-18; PMCID: PMC2846904 47. Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 2006;151:689. e1–689 e10. DOI:10.1016/j.ahj.2005.11.014; PMID:16504633 48. Marcano AL, Ferreiro JL. Role of New Antiplatelet Drugs on Cardiovascular Disease: Update on Cangrelor. Curr Atheroscler Rep 2016;18:66. DOI:10.1007/s11883-016-0617-y; PMID:27714642 49. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361:2318–29. DOI:10.1056/NEJMoa0908628; PMID:19915221 50. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330–41. DOI:10.1056/NEJMoa0908629; PMID:19915222 51. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303–13. DOI:10.1056/NEJMoa1300815; PMID:23473369 52. Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost 2004;30:579–89.

DOI:10.1055/s-2004-835678; PMID:15497100 53. De Luca L, Capranzano P, Patti G, Parodi G. Switching of platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Review of the literature and practical considerations. Am Heart J 2016;176:44–52. DOI:10.1016/j. ahj.2016.03.006; PMID:27264219 54. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006;99:1293–304.

DOI:10.1161/01.RES.0000251742.71301.16; PMID:17158345 55. Subban V, Sarat Chandra K. Glycoprotein IIb-IIIa inhibitors - do we still need them? Indian Heart J 2013;65:260–3. DOI: 10.1016/ j.ihj.2013.04.032; PMCID: PMC3861204 56. Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–94. DOI:10.1056/NEJM200106213442502; PMID:11419425 57. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of

benefit related to the revascularization strategy. Eur Heart J 2002;23:1441–8. PMID:12208224 58. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–98. DOI:10.1016/S0140-6736(02)07442-1; PMID:11812552 59. O’Donoghue M, Antman EM, Braunwald E, et al. The efficacy and safety of prasugrel with and without a glycoprotein IIb/ IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes

by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) analysis. J Am Coll Cardiol 2009;54:​ 678–85. DOI:10.1016/j.jacc.2009.05.025; PMID:19679245 60. Kastrati A, Mehilli J, Schühlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:​ 232–8. DOI:10.1056/NEJMoa031859; PMID:14724302 61. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295:1531–8. DOI:10.1001/jama.295.13.joc60034; PMID:16533938 62. Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 1990;33:1114–21.

PMID:2202310 63. Ridker PM. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol 2003;92:17K–22K. PMID:12948872 64. Ridker PM; JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292–7. DOI:10.1161/01.

CIR.0000100688.17280.E6; PMID:14609996 65. van Diepen S, Newby LK, Lopes RD, et al. Prognostic relevance of baseline pro- and anti-inflammatory markers in STEMI: an APEX AMI substudy. Int J Cardiol 2013;168:2127–33.

DOI:10.1016/j.ijcard.2013.01.004; PMID:23394896 66. Deftereos S, Giannopoulos G, Angelidis C, et al. AntiInflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation 2015;132:1395–403.

DOI:10.1161/CIRCULATIONAHA.115.017611; PMID:26265659 67. Zeng S, Zhou X, Ge L, et al. Monocyte subsets and monocyteplatelet aggregates in patients with unstable angina. J Thromb Thrombolysis 2014;38:439–46. DOI:10.1007/s11239-014-1083-4; PMID:24844803 68. Tapp LD, Shantsila E, Wrigley BJ, et al. The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. J Thromb Haemost 2012;10:1231–41. DOI:10.1111/j.15387836.2011.04603.x; PMID:22212813 69. Rogacev KS, Cremers B, Zawada AM, et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012;60:1512–20. DOI:10.1016/ j.jacc.2012.07.019; PMID:22999728 70. Layne K, Di Giosia P, Ferro A, Passacquale G. Anti-platelet drugs attenuate the expansion of circulating CD14highCD16+ monocytes under pro-inflammatory conditions. Cardiovasc Res 2016;111:26–33. DOI:10.1093/cvr/cvw089; PMID:27118470; PMCID:PMC4909161

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Contemporary Management of Stroke Prevention in Atrial Fibrillation Following the European Society of Cardiology Guidelines Manav Sohal Cardiology Clinical Academic Group, St George’s University Hospitals, London, UK

Abstract The recent publication of the European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation provides a timely update at a time when the rapid uptake of non-vitamin K antagonist oral anticoagulants has changed the landscape of clinical practice. Several key changes have been highlighted, including better identification of those deemed to be low risk for thromboembolic complications and a more standardised approach to patients with atrial fibrillation who require concomitant antiplatelet therapy following either percutaneous coronary intervention or an acute coronary syndrome. This article distils the key messages from the ESC guidelines and draws the reader’s attention to both gaps and advances in our knowledge.

Keywords Atrial fibrillation, stroke prevention, non-vitamin K antagonist oral anticoagulants, risk-stratification, bleeding risk Disclosure: The author has no conflicts of interest to declare.

Received: 25 May 2017 Accepted: 28 June 2017 Citation: European Cardiology Review 2017;12(1):38–9. DOI: 10.15420/ecr.2017:10:2 Correspondence: Manav Sohal, Cardiology Clinical Academic Group, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK. E: manav.sohal@stgeorges.nhs.uk

Prevention of ischaemic stroke has long been central to the management of patients with atrial fibrillation (AF), historically relying on the use of vitamin K antagonists (VKAs) or antiplatelet agents depending on the risk of thromboembolism. Difficulties associated with maintaining VKAs in therapeutic range and the perceived risk of bleeding have been highlighted as reasons to withhold oral anticoagulation (OAC) and these issues have partly been addressed by the introduction of non-vitamin K antagonist oral anticoagulants (NOACs). These agents require less intensive monitoring and are generally better tolerated by patients. The 2016 iteration of the European Society of Cardiology (ESC) guidelines for the management of AF provide a contemporary update on stroke prevention in the era of NOAC therapy and present important new recommendations with respect to those deemed to be at low risk of thromboembolic events and also those who require antiplatelet therapy following percutaneous coronary intervention (PCI).1 At the same time it is important to acknowledge that there are some gaps in our knowledge that are not covered by the guidelines. This brief review presents an assessment of the main recommendations and also highlights areas where further work is needed.

Identifying Those at Risk of Stroke The guidelines continue to recommend use of the CHA 2 DS 2 -VASc score as the main risk stratification tool, but the blanket recommendation to initiate OAC in all patients with a score of 2 or more is no longer advocated. Equally, those deemed to be low risk (no clinical risk factors for stroke) should not receive antithrombotic therapy. This therefore recognises that antiplatelet therapy has no role in the prevention of stroke and its use as monotherapy should be actively discouraged.

Female gender alone is not deemed to be a risk factor for stroke in the absence of another risk factor. The guidelines acknowledge the relative over-representation of patients at high risk of stroke in the major trials of OAC and stroke prevention. Accordingly, guidance on how to manage patients with one clinical risk factor (i.e. men with a

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score of 1 and women with a score of 2) is given more nuance. The ESC commissioned an analysis of stroke risk in this group to inform their recommendations and identified the importance of age as a risk factor. Age (≥65 years) conveys a relatively high and continuously increasing stroke risk that also potentiates other risk factors (such as heart failure and sex). It is therefore recommended that risk in this group should entail an individualised weighing of risk as well as patient preference. Looking to the future, newer risk scoring systems may provide better identification of the truly low-risk group (who do not require anticoagulation). Data from nearly 40,000 patients enrolled in the Global Anticoagulant Registry In The Field-Atrial Fibrillation (GARFIELD-AF) registry has been used to develop risk models and the resulting GARFIELD-AF score appears to offer better discrimination in predicting all-cause mortality, ischaemic stroke/ systemic embolism, or haemorrhagic stroke/major bleed in low-risk patients and may provide more detailed risk estimation pending external validation.2

Addressing Bleeding Risk Another important aspect of clinical care described in the guidelines is bleeding risk. Several bleeding risk scores have been proposed, including the HAS-BLED (hypertension, abnormal renal/liver function [1 point each] stroke, bleeding history or predisposition, labile international normalised ratio, elderly [>65 years], drugs/alcohol concomitantly [1 point each]), ORBIT (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), or the more recent ABC (age, biomarkers, clinical history) bleeding scores. No single scoring system is favoured over the others, but the emphasis is now to generally refrain from withholding OAC, rather bleeding risk factors should be identified and treatable factors corrected. This is an important point, as the perceived risk of bleeding can often be erroneously elevated and is in fact often outweighed by the risk of ischaemic stroke in most cases.

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Stroke prevention in AF VKA or NOAC? VKAs are effective but efficacy depends on adequate time in therapeutic range. Clearly, VKAs are the only option for AF patients with mechanical valve prostheses or rheumatic mitral stenosis that is more than mild in severity. Outside this specific group, the need for intensive monitoring makes them slightly cumbersome for patients and clinicians alike. Data from the GARFIELD-AF registry indicate that there has been an increase in newly diagnosed patients with AF receiving guideline-recommended therapy since NOACs were introduced.3 This is predominantly driven by the increased use of NOACs and reduced use of VKAs. This is not a universal phenomenon, and the second phase of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation (GLORIA-AF) demonstrates that a large proportion of patients remain undertreated, particularly in Asia and north America.4 There is also a safety argument for the use of NOACs over VKAs as there appears to be less haemorrhagic stroke with NOACs and this is reflected in the guideline recommendation that NOACs should be the first-choice agent in most patients. At the current time, there is not enough evidence to recommend one particular NOAC over the others and the decision on which agent to use is best taken after accounting for individual patient characteristics. Specific attention should be paid to patients with chronic kidney disease (CKD). Both VKAs and NOACs are effective in patients with mild–moderate CKD (creatinine clearance >30 mL/min) but none of the major NOAC trails included patients with severe CKD. If used, NOACs should be subject to dose adjustment (reduction) when administered to patients with mild–moderate CKD and dabigatran should not be used in patients with creatinine clearance <30 mL/min. The benefit of OAC in dialysisdependent patients is debatable, with conflicting evidence from large observational studies. The association of AF with higher mortality in these patients is important and randomised trials of OACs versus placebo are urgently required.

OACs in Combination with Antiplatelet Agents It is estimated that 5–15 % of AF patients will require PCI at some point in their lives. The accompanying need to administer antiplatelet therapy and the recognition that so-called triple therapy (VKA plus dual anti-platelet therapy) is associated with high rates of bleeding complications has led to widespread variation of practice. This most often manifests as eligible AF patients being less likely to receive OACs following PCI. The introduction of NOACs has further complicated the issue. A meta-analysis involving more than 30,000 patients with recent acute coronary syndrome (ACS) evaluated the effects of adding NOAC therapy to single or dual antiplatelet therapy. Bleeding risk increased

1.

2.

irchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines K for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962.

DOI: 10.1093/eurheartj/ehw210; PMID: 27567408 Fox KAA. Identifying patients with atrial fibrillation and “truly low” thromboembolic risk who are poorly characterized by CHA2DS2-VASc: Superior performance of a novel machine learning tool in GARFIELD-AF. Abstract 2950. Eur Heart J 2016; 37 (Abstract Supplement)

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3.

4.

by 79–134 % with only a marginal decrease in ischaemic events in patients without AF.5 The guidelines adopt a pragmatic approach and place the emphasis on limiting the duration of triple therapy (OAC, aspirin, clopidogrel). In general, a short period of triple therapy is recommended, followed by a period of dual therapy (OAC plus single antiplatelet). A key recommendation is that most AF patients with stable coronary artery disease who are >1 year post PCI or ACS should continue OAC as monotherapy (without any antiplatelet agent). The guidelines expressly advise against using dual antiplatelets (aspirin and clopidogrel) with a low dose of the NOAC rivaroxaban (2.5 mg twice daily) as there are concerns that this does not offer sufficient stroke prevention. Recent publication of the Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose Adjusted Oral Vitamin K Antagonist Treatment Strategy in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) has demonstrated that triple therapy with VKA, aspirin and clopidogrel is associated with significantly higher rates of bleeding when compared with reduced-dose rivaroxaban (15 mg once daily) with a single antiplatelet agent or low-dose rivaroxaban (2.5 mg twice daily) with aspirin and clopidogrel. Crucially, there was no difference in ischaemic or thromboembolic events between the three arms.6 The study was powered for safety (bleeding risk) and not efficacy but it represents the best data available given the fact that an appropriately powered efficacy study would require an unfeasible 30,000 patients to be recruited. There is a move towards adopting the low-dose rivaroxaban plus a dual antiplatelet regimen for a limited period (3–6 months) before stepping down to an OAC and single antiplatelet and then finally OAC monotherapy at 1 year. Similar studies involving the other NOACs are on-going and will provide further information in this area.

Conclusion The updated ESC guidelines for AF management provide contemporary guidance in the NOAC era. There are still gaps in our knowledge, particularly when trying to identify the truly low-risk groups who do not require anticoagulation. Large-scale ‘real-world’ initiatives such as the GARFIELD-AF registry will provide more detailed scoring systems that are likely to supersede the widely recommended CHA2DS2-VASc risk stratification tool and these should help better identify these patients. Similarly, determining the optimal stroke prevention strategy in patients with severe kidney disease should be a priority as there is a compelling association between AF and morbidity in these patients.

Finally, the evidence base has begun to overtake the recommendations (as we have seen with the PIONEER AF-PCI study) and it is important that clinicians acknowledge the fluid nature of clinical medicine and do not treat the guidelines as dogma. n

amm AJ, Accetta G, Ambrosio G, et al; GARFIELD-AF C Investigators. Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation. Heart 2017;103: 307–14. DOI: 10.1136/heartjnl-2016-309832; PMID: 27647168 Huisman MV, Rothman KJ, Paquette M, et al; GLORIA-AF Investigators. The changing landscape for stroke prevention in AF. Findings from the GLORIA-AF Registry phase 2. J Am Coll Cardiol 2017;69:777–85. DOI: 10.1016/j.jacc.2016.11.061; PMID: 28209218

5.

6.

ldgren J, Wallentin L, Alexander JH, et al. New oral O anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013;34:1670–80.

DOI: 10.1093/eurheartj/eht049; PMID: 23470494 Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423–34. DOI: 10.1056/NEJMoa1611594; PMID: 27959713

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Direct Oral Anticoagulants: A Quick Guide Julia Sikorska and James Uprichard The Centre for Haemostasis and Thrombosis, Department of Haematology, St George’s Hospital, London, UK

Abstract Vitamin K antagonists, such as warfarin, have been the anticoagulants of choice for many years for patients with AF and other thrombotic conditions. The introduction of direct oral anticoagulants (DOACs) as alternatives represents a major advance in anticoagulation. DOACs have been found to be at least as safe and effective as vitamin K antagonists in randomised, controlled trials for stroke prevention in AF and the management of venous thromboembolism, with real-world data showing similar outcomes. With the availability of several agents, selecting the most appropriate DOAC can be challenging. The aim of the present article is to provide useful guidance on the implementation of DOAC treatment in clinical practice.

Keywords AF, direct oral anticoagulant, vitamin K antagonist, venous thromboembolic event Disclosure: JS has no conflicts of interest to declare. JU has sat on scientific advisory boards for Bayer and Leo Pharma; speaker bureaus for Bayer, Pfizer, Bristol-Myers Squibb, Octapharma, Shire and Portola; clinical trials for Portola, Bayer, Boehringer-Ingelheim and Baxalta; and received travel support from Bayer, Baxter and Pfizer.

Received: 20 May 2017 Accepted: 23 June 2017 Citation: European Cardiology Review 2017;12(1):40–5. DOI: 10.15420/ecr.2017:11:2 Correspondence: James Uprichard, The Centre for Haemostasis and Thrombosis, Department of Haematology, St George’s Hospital, Blackshaw Road, SW17 0QT London, UK. E: j.uprichard@nhs.net

For more than 50 years, oral vitamin K antagonists (VKAs) were the choice of anticoagulant for the long-term treatment and prevention of arterial and venous thromboembolic events (VTE). VKA treatment is safe and effective, if a high time in therapeutic range is achieved. However, achieving a stable, therapeutic international normalised ratio can prove challenging in the context of drug and food interactions and liver disease, resulting in either an increased risk of thromboembolism due to undertreatment or bleeding due to overtreatment. In recent years, four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban, have been compared with warfarin for stroke prevention in AF, in large, phase 3, randomised, controlled trials (RCTs).

Various terms have been used to describe these drugs, including new/ novel oral anticoagulants or non-vitamin K oral anticoagulants. The International Society on Thrombosis and Haemostasis recommends using the term ‘DOAC’.1 These anticoagulants directly inhibit specific proteins within the coagulation cascade; in contrast, VKAs inhibit the synthesis of vitamin K-dependent clotting factors.

Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect; they have been shown to be at least as safe and effective as warfarin in stroke prevention in AF. As the availability of DOACs has expanded anticoagulant treatment options, it is important that clinicians familiarise themselves with these novel agents. They are licensed for use in stroke prevention in non-valvular AF, the treatment of VTE and as thromboprophylaxis following major orthopaedic surgery. Rivaroxaban has also been approved in Europe for the prevention of atherothrombotic events following acute coronary syndrome (ACS). The purpose of the present article was to summarise the available trial data and

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provide useful clinical guidance on the different DOACs for stroke prevention in non-valvular AF.

Efficacy and Safety Non-Valvular AF DOACs have been studied extensively, and results have shown that they are at least as effective and safe as treatment with warfarin in stroke prevention in non-valvular AF. DOACs are not licensed for use in patients with mechanical heart valves. The Randomised, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN) was terminated early due to increased rates of thromboembolic and bleeding complications in patients with mechanical heart valves taking dabigatran compared with warfarin patients.2 In the phase 3 clinical trials, many patient subgroups were excluded or underrepresented. In contrast to the RCTs, patients in the real world demonstrate heterogeneity with a greater variation in stroke risk, renal impairment, liver disease and other conditions associated with an increased risk of bleeding. Real-world data are therefore needed to assess whether the efficacy and safety of DOACs achieved in patients with non-valvular AF in RCTs translate into routine clinical practice.

In the Randomized Evaluation of Long Term Anticoagulant Therapy With Dabigatran (RE-LY) study, both doses of dabigatran (110 mg twice daily and 150 mg twice daily) were shown to be non-inferior to warfarin in preventing stroke and systemic embolism (p<0.001 in both arms), with the higher dose also being superior to warfarin (p<0.001).3 Interestingly, the rates of haemorrhagic stroke were significantly lower in both dabigatran arms (p<0.001), as well as rates of life-threatening bleeding (low dose: p<0.001, high dose: p=0.04) and intracranial bleeding (ICH) (p<0.001 in both arms). However, the rate of gastrointestinal (GI)

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A Guide to DOACs bleeding was significantly higher in the higher-dose dabigatran arm (p<0.001). The results of a systematic review and meta-analysis of 348,750 patients on dabigatran in real-world clinical practice were similar, with higher GI bleeding rates compared to warfarin (p=0.041), but a lower rate of ICH (p<0.001).4 In the RE-LY study, there was a non-significant increase in myocardial infarction (MI) with dabigatran compared with warfarin. This has not been reproduced in the realworld data, with a US Food and Drug Administration study of 134,000 Medicare patients5 and a multicentre registry of 555 patients6 showing no difference in the rates of MI.

no-HF patients. Those with HF had reduced rates of total bleeding (p<0.01) and ICH (p<0.01), but a higher rate of all-cause death (p<0.01) and cardiovascular death (p<0.01) compared to no-HF patients treated with DOACs (this finding did not appear to be affected by the choice of oral anticoagulant). The rates of stroke and systemic embolism, major bleeding and ICH were significantly reduced in those treated with DOACs compared with warfarin, regardless of the presence or absence of HF (p>0.05 for each interaction). These findings suggest that DOACs are safe and efficacious in patients with AF, regardless of whether they have HF or not.

In an efficacy and safety study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation (ROCKETAF) trial, rivaroxaban was shown to be non-inferior to warfarin in preventing stroke and systemic embolism (p<0.001);7 the rates of ICH and fatal bleeding were significantly lower in those treated with rivaroxaban (p=0.02 and p=0.003, respectively). However, there was a significant increase in major GI bleeding in the rivaroxaban arm (p<0.001), although there was no difference in all-cause mortality.

In the real-world observational Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation (XANTUS) study, both lower thrombotic and bleeding rates were reported compared with the ROCKET-AF trial, including a lower rate of GI bleeding (0.9 versus two events/100 patient years, respectively).8 In the XANTUS study, patients had a mean CHADS2 score of 2 compared to 3.5 in the ROCKET-AF study, which could explain the discrepancy in the rates of thrombotic complications.

Acute Coronary Syndrome

Apixaban was shown to be non-inferior (p<0.001) and superior to warfarin (p<0.01) for the prevention stroke and systemic embolism in the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Rates of haemorrhagic stroke and ICH were also significantly lower (p<0.001 for both).9 There was no significant difference in ischaemic stroke, but all-cause mortality was significantly lower (p<0.001). These results were corroborated by a retrospective analysis, which showed a significant reduction in the risk of stroke and systemic embolism (p=0.04) and a reduced risk of major bleeding, including GI bleeding and ICH (p<0.001).10 Both doses of edoxaban (30 mg once daily and 60 mg once daily) were shown to be non-inferior to warfarin (p=0.005 and p<0.001) and superior in the case of the higher dose (p=0.02) in preventing stroke and systemic embolism in the Effective Anticoagulation with Factor XA Next Generation in Atrial Fibrillation – Thrombolysis In Myocardial Infarction 48 (ENGAGE AF-TIMI) 48 trial.11 However, edoxaban at the lower dose of 30 mg has been shown to be inferior to warfarin in preventing ischaemic stroke (p<0.001). There was an increase in the rate of stroke in edoxaban patients with a creatinine clearance of >95 ml/min, although this was not statistically significant (p=0.08).12 Both doses were associated with lower rates of bleeding, including ICH and major and life-threatening bleeding (p<0.001 for all). The only exception was the higher dose, which was associated with a higher rate of GI bleeding (p=0.03).

A meta-analysis of the four phase 3 clinical trials was performed to assess the safety and efficacy of DOACs in patients with AF and heart failure (HF).13 A total of 26,384 (48 %) of the 55,011 patients enrolled in the four trials had a diagnosis of HF (defined according to individual trial definitions). There were similar rates of stroke and systemic embolism (p=0.68) and major bleeding (p=0.21) in HF and

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At present, rivaroxaban is the only DOAC licensed for use in ACS. Data from the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2–Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial showed that rivaroxaban at either 2.5 mg twice daily or 5 mg twice daily, in addition to either aspirin or dual antiplatelet therapy (DAPT), significantly reduced the rate of death from cardiovascular causes, compared to the placebo (p=0.008).14 Although there was a higher rate of major bleeding with rivaroxaban (p<0.001), there was no statistically-significant difference in fatal bleeding between rivaroxaban and placebo. Subgroup analysis revealed that major or minor bleeding and fatal bleeding rates were lower in the rivaroxaban 2.5 mg twice daily arm compared to the 5 mg twice daily arm (p=0.021 and p=0.044), but with no significant difference in death from cardiovascular causes. An additional subgroup analysis, evaluating patients who had undergone percutaenous coronary intervention (PCI) as part of the index event or previous stent insertion, demonstrated a reduction in stent thrombosis (p=0.023) and mortality (p=0.039) with the use of rivaroxaban 2.5 mg twice daily, in addition to DAPT, compared to placebo and DAPT. In the Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With AF Who Undergo PCI (PIONEER AF-PCI) trial, patients with non-valvular AF undergoing PCI and stent placement were randomised to receive either low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months, very low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6 or 12 months or standard therapy with a VKA and DAPT for 1, 6 or 12 months.15 Death rates from cardiovascular causes, MI and stroke were similar in the three groups (although the similar efficacies should be interpreted with caution, due to broad confidence intervals), but clinically-significant bleeding rates were lower in both rivaroxaban groups (p<0.001 for both doses). These data suggest that rivaroxaban, in addition to either a P2Y12 inhibitor or DAPT, is safer in terms of bleeding risk in patients with AF undergoing PCI than warfarin. The other DOACs are currently being evaluated for their role in PCI. The results of the Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (RE-DUAL-PCI),16 Apixaban Versus Warfarin in Patients with AF and acute coronary syndrome or PCI (AUGUSTUS) (apixaban)17 and Edoxaban Treatment Versus Vitamin K Antagonist in Patients With AF an Undergoing PCI (ENTRUST AF-PCI; edoxaban) trials18 are awaited.

Selecting a Direct Oral Anticoagulant In comparison to conventional treatment with VKAs, DOACs offer many treatment advantages, including fixed dosing, fewer drug and dietary interactions, rapid onset and short half-lives, which can preclude the

41

Cardiovascular Pharmacotherapy need for peri-procedural bridging, as well as no monitoring requirement.

It is also important to be aware of potential disadvantages: there is no specific reversal agent (with the exception of idarucizumab for dabigatran), there is a need for avoidance or dose reduction in renal impairment and the short half-lives necessitate strict adherence. It is therefore important to take into account patient-specific factors in order to tailor anticoagulant treatment to the individual.

High CHA 2DS 2-VASc Score For patients with a high risk of thromboembolic disease and acceptable bleeding risk, consider using dabigatran 150 mg twice daily, as this is the only DOAC with superior efficacy in the reduction of ischaemic stroke, compared to warfarin.3

activity, and therefore, 1 day without the drug will render the patient unanticoagulated. Patients should therefore be counselled about the risk of missing a dose of a DOAC. If there are concerns regarding non-adherence, warfarin, due to its long half-life, should be considered.

Pregnancy Dabigatran has been shown to cross the placenta.23 Animal studies have demonstrated pregnancy loss and foetal harm with both dabigatran and rivaroxaban.24,25 It is unknown whether they are secreted in breast milk. Data regarding edoxaban and apixaban are limited. DOACs should therefore be avoided in pregnancy and breastfeeding.

Cancer Bleeding Risk Most of the available data evaluating DOACs and bleeding risk have been taken from AF trials. In patients with a high risk of GI bleeding, consider avoiding 150 mg dabigatran, rivaroxaban and 60 mg edoxaban, as these are associated with higher GI bleeding rates compared to warfarin.3,7,11 Rates of GI bleeding associated with 110 mg dabigatran and apixaban were similar to those in the warfarin arms of their trials. Dabigatran should also be avoided in patients with dyspepsia or peptic ulcer disease, as symptoms can worsen. All DOACs are associated with a lower risk of ICH compared with warfarin.3,7,9,11

Renal Impairment Creatinine clearance should be calculated using the Cockcroft– Gault equation prior to commencing a DOAC. Renal clearance of dabigatran accounts for 85 % of total clearance, and it is therefore contraindicated in those with a creatinine clearance of <30 ml/min.

A study by Chan et al. showed that the risk of hospitalisation or death from bleeding was higher in dialysis patients taking dabigatran and rivaroxaban compared with warfarin (p=0.0001 and p=0.04).19 Dose reductions of rivaroxaban, apixaban and edoxaban could be required, depending on the creatinine clearance, but these drugs are not contraindicated unless creatinine clearance is <15 ml/min.

A systematic review and meta-analysis of nine RCTs including 54,667 patients with renal impairment showed a significantly reduced risk of major bleeding in those taking DOACs, with a creatinine clearance of 50–80 ml/min (risk ratio: 0.87 [95 % confidence interval: 0.81–0.93]), and a non-significant decrease in those with a creatinine clearance of <50 ml/min (risk ratio: 0.83 [95 % confidence interval: 0.68–1.02]), compared to warfarin.20 Apixaban was associated with a decreased rate of major bleeding compared with other DOACs in patients with a creatinine clearance of <50 ml/min. A retrospective matchedcohort study assessed the safety and efficacy of apixaban versus warfarin in patients with a creatinine clearance of <25 ml/min, serum creatinine concentration of >2.5 mg/dl or on dialysis.21 There was a non-significant decrease in major bleeding in those who received apixaban compared with warfarin (9.6 % versus 17.8 %, p=0.149), and a similar occurrence of stroke between the two groups (7.5 % in both).

Further studies are needed to establish whether apixaban is safe and effective in those with a creatinine clearance of <15 ml/min.

In patients with cancer-associated VTE, low molecular weight heparin (LMWH) is currently the treatment of choice, due to its superiority in preventing recurrent thrombosis and a reduction in bleeding, compared to warfarin.26–29 DOACs are being evaluated for their role in cancer-associated VTE in a number of ongoing trials, including Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D; rivaroxaban),30 Apixaban for the Treatment of Venous Thromboembolism in Patients With Cancer (CARAVAGGIO trial; apixaban),31 Hokusai VTE–cancer (edoxaban)32 and DOACs versus LMWH ± Warfarin for VTE in Cancer: A Randomized Effectiveness Trial (CANVAS; all four DOACs).33 The management of AF in patients with cancer can be challenging due to a number of factors, including increased bleeding risk, drug interactions and frequent invasive procedures. Not only is there a lack of evidence regarding the use of LMWH in AF but it is also not licensed for this indication. In patients taking chemotherapy, dabigatran might be preferable to other DOACs due to fewer drug interactions in view of its non-CYP-mediated metabolism.34 Patients with cancer were excluded from the AF trials, and so there are limited data regarding the use of DOACs in cancer patients with AF. Therefore, further studies are needed to establish their role in this situation. However, in the VTE trials, preliminary evidence suggests that DOACs were safe and efficacious in cancer patients who subsequently developed AF. Furthermore, an observational study on cancer patients with AF showed that bleeding rates were similar or lower in those taking DOACs compared to warfarin.35 Although there was no difference in the risk of ischaemic stroke, DOACs were superior to warfarin in lowering the risk of incident VTE.

Drug Interactions Although drug interactions are less frequent than with warfarin, it is important to be aware of which drugs interfere with DOAC metabolism.

The hepatic enzyme CYP3A4 is important in the metabolism of rivaroxaban and apixaban, and all DOACs are substrates of the P-glycoprotein transporter system. Enzyme inducers can cause a reduction in DOAC plasma concentration, and could therefore increase the risk of thromboembolic events, while inhibitors potentiate the DOAC concentration, which could result in bleeding. The important drug interactions are highlighted in Table 1.

Adherence Obamiro et al. assessed patients’ anticoagulation knowledge, and showed that patients taking DOACs were less likely to view missing a dose as a problem, compared to those taking warfarin (p<0.05).22 Unlike warfarin, DOACs have a rapid onset and offset of anticoagulant

42

Measurement of Direct Oral Anticoagulant Activity Because DOACs have a predictable anticoagulant effect and are administered at a fixed dose, they do not require routine monitoring.

EUROPEAN CARDIOLOGY REVIEW

A Guide to DOACs Table 1: Drug Interactions with Direct Oral Anticoagulants Dabigatran

Rivaroxaban Apixaban

Edoxaban

Increased concentration

Strong p-gp inhibitors: Strong CYP3A4 and p-gp Strong CYP3A4 and p-gp ketoconazole, ciclosporin, inhibitors: ketoconazole, inhibitors: ketoconazole, tacrolimus, ritonavir, dronedarone ritonavir, dronedarone ritonavir, dronedarone Caution with: amiodarone, Caution with: ciclosporin, verapamil, clarithromycin, tacrolimus quinidine, ticagrelor

Strong p-gp inhibitors: reduce dose with ketoconazole, ciclosporin, dronedarone Caution with: ritonavir

Reduced concentration

Strong p-gp inducers: rifampicin, St John’s wort, carbamazepine, phenytoin, barbiturates, dexamethasone

Strong p-gp inducers: rifampicin, St John’s wort, carbamazepine, phenytoin, barbiturates, dexamethasone

Strong CYP3A4 and p-gp inducers: rifampicin, St John’s wort, carbamazepine, phenytoin, barbiturates

Strong CYP3A4 and p-gp inducers: rifampicin, St John’s wort, carbamazepine, phenytoin, barbiturates

p-gp = P-glycoprotein.

Table 2: Effect of Direct Oral Anticoagulants on Haemostasis Tests and Drug Concentration Quantification 36,37 NOAC Quantification

PT aPTT

TT

Dabigatran

Variable depending on reagent

If normal, excludes supratherapeutic concentration

If normal, excludes clinicallyrelevant concentration

Rivaroxaban Anti-Xa concentration

(calibrated for rivaroxaban)

If normal, excludes supratherapeutic concentration; can be used for crude estimation

Less sensitive than PT

Insensitive

Apixaban Anti-Xa concentration

(calibrated for apixaban)

Insensitive; might have normal PT, despite therapeutic concentration

Insensitive; might have normal aPTT, despite therapeutic concentration

Insensitive

Edoxaban

If normal, excludes clinically- relevant concentration

If normal, excludes clinically- relevant concentration

Insensitive

Dilute TT (DTI assay), ECT, chromogenic anti-IIa assay

Anti-Xa concentration (calibrated for edoxaban)

aPTT = activated partial thromboplastin time; DTI = direct thrombin inhibitor; ECT = ecarin clotting time; NOAC = new/novel oral anticoagulant; PT = prothrombin time; TT = thrombin time.

However, there could be circumstances in which the measurement of DOAC activity would be useful, for example, in bleeding patients or those requiring emergency surgery, patients with recurrent thrombosis on treatment or if there are concerns regarding adherence.

Table 2 outlines how each DOAC affects conventional tests of haemostasis, and which tests should be performed to quantify drug concentration. To enable interpretation of the coagulation screen, each laboratory should be aware of the sensitivity of their reagents to the different DOACs.

Perioperative Management The timing of stopping a DOAC prior to an invasive procedure or operation depends on the half-life of the drug, creatinine clearance and the risk of bleeding (Table 3). Invasive procedures associated with a very low risk of bleeding, such as dentistry, joint injections, cataract surgery and pacemaker insertion, might not require interruption of anticoagulation, whereas high-risk procedures, such as spinal anaesthesia, coronary artery bypass, heart valve surgery and neurosurgery, will require discontinuation of the DOAC at least 48 hours before. Anticoagulation can be recommenced at 6–12 hours following low-risk procedures if haemostasis has been achieved, and at 48 hours following high-risk procedures.

Management of Bleeding With the exception of dabigatran, there is currently no licensed reversal agent for DOACs. Andexanet alfa has been shown to rapidly reverse the antifactor Xa activity in those with acute major bleeding associated with rivaroxaban or apixaban, 39 but is not yet available in clinical practice. It is a recombinant modified human factor Xa decoy protein that is catalytically inactive due to the substitution of the active-site serine with alanine. It lacks the gamma-carboxyglutamic

EUROPEAN CARDIOLOGY REVIEW

Table 3: Recommended Timing of Discontinuation of Direct Oral Anticoagulants Pre-procedure 38 CrCl Half-life (h)

Risk of bleeding (h)

(ml/min)

Low

High

Dabigatran

≥80 13 ≥50 to <80 ≥30 to <50

24 24–48 48–72

48 48–72 96

Rivaroxaban

≥30 9 <30

24 48

48 72

Apixaban

≥30 8 <30

24 48

48 72

Edoxaban

≥30 10–14 24 <30 48

48 72

CrCl = creatinine clearance using Cockroft–Gault method.

acid domain, preventing it from binding to phospholipid membranes, but retains the ability to bind to factor Xa inhibitors with a high affinity. Ciraparantag (aripazine) is a broad-spectrum reversal agent that binds to the oral factor Xa and direct thombin inhibitors, unfractionated heparin and LMWH, and is currently being evaluated in phase 2 clinical trials. If the patient is taking an oral factor Xa inhibitor and is unresponsive to general haemostatic measures, prothrombin complex concentrate (PCC) at a dose of 25–50 units/kg should be considered. Idarucizumab, a monoclonal antibody, binds free and thrombin-bound dabigatran, thereby preventing it from exerting its anticoagulant effect, and is now licensed for use. The recommended dose is 5 g, given intravenously when rapid reversal is required in those who need emergency surgery or those with uncontrolled bleeding. A second dose might be considered if bleeding recurs or if there is a potential for life-threatening rebleeding in association with prolonged clotting times.

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Cardiovascular Pharmacotherapy Local protocols should be developed to ensure that patients on DOACs with serious or life-threatening bleeding are managed appropriately. The general approach to a bleeding patient on any form of anticoagulation should be as follows:40

• c onsider intravenous tranexamic acid and seek advice from a haematologist regarding the administration of PCC, or idarucizumab if the patient has taken dabigatran.

Conclusion • stop the anticoagulant; • request an urgent coagulation screen (activated partial thromboplastin time, prothrombin time, thrombin time [TT]), full blood count and group and save; • haemodynamic monitoring and resuscitation with fluid and blood products, if indicated; • mechanical compression or surgical or radiological intervention to identify and treat the source of bleeding.

If the patient is taking a DOAC: • e stablish the timing of the last dose; if ingestion was within the past 2 hours, consider oral activated charcoal; • renal function should be assessed urgently; this allows estimation of the remaining duration of drug exposure; • if the patient is taking dabigatran, a normal TT excludes a clinicallyrelevant dabigatran concentration; if the TT is prolonged, a dabigatran effect might be present; • a normal coagulation screen excludes supratherapeutic concentrations of rivaroxaban and edoxaban, but might not exclude clinically-relevant drug concentrations; • t he coagulation screen might be normal in patients taking apixaban;

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Large, phase 3 clinical trials have shown that DOACs are at least as safe and effective as VKAs in the prevention of stroke in non-valvular AF. Real-world data have allowed us to determine the efficacy and safety of these drugs in everyday clinical practice, outside the confines of RCTs, and thus far, have shown similar outcomes, with reduced rates of major bleeding, including ICH and increased or similar rates of GI bleeding.

Betrixaban, an oral factor Xa inhibitor, has shown promise in extended VTE prophylaxis41 and stroke prevention42 in those hospitalised with an acute medical illness. Due to its distinct pharmacokinetic profile with minimal renal clearance and a long half-life, this might overcome some of the limitations of the other DOACs in clinical practice. The availability of andexanet alfa and ciraparantag will address the unmet need for reversal agents in the management of DOAC-associated major and life-threatening bleeding.

DOACs have many advantages over VKAs, including a rapid onset and offset of anticoagulant effect, fixed dosing, fewer drug and dietary interactions and no monitoring requirement; these make attractive options for anticoagulation. As there are several agents available, it is important that clinicians are familiar with the efficacy and safety profiles of DOACs, based on both the trial and real-world data, to counsel and tailor treatment to the individual patient. n

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23. B apat P, Kedar R, Lubetsky A, et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2013;123(6):1256–61. DOI: 10.1097/AOG.0000000000000277; PMID: 24807346.

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Ischaemic Heart Disease

Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions Andrew Mc Neic e, A n d r e w L a d w i n i e c , S i m o n Wa l s h a n d Co l m H a n r a t t y Department of Cardiology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK

Abstract The hybrid approach is a systematic algorithm-led percutaneous coronary intervention strategy based on the identification of key anatomical features on coronary angiography to treat chronic total occlusions. The aims of this approach are to provide a standardised tool for physician training and programme development, avoiding futile strategies to improve safety, procedural success and reduce the contrast and radiation required to complete the case.

Keywords percutaneous coronary intervention, chronic total occlusions, hybrid approach Disclosure: The authors have no conflicts of interest to declare.

Received: 11 October 2016 Accepted: 30 November 2016 Citation: European Cardiology Review, 2017;12(1):46–51 DOI: 10.15420/ecr.2016:25:2 Correspondence: Colm Hanratty, Department of Cardiology, Belfast Health and Social Care Trust, c/o Level 9, Belfast City Hospital, Lisburn Road, Belfast, Northern Ireland, BT9 7AB, UK. E: Colm.Hanratty@belfasttrust.hscni.net

The treatment of patients with clinically significant chronic total occlusions (CTOs) will become more frequent with an ageing population, an increasing number of patients undergoing transcatheter aortic valve implantation (TAVI) (20 % have co-existing coronary disease) and patients presenting following coronary artery bypass graft (CABG) failure where redo CABG is not attractive or not possible.

The evolution of percutaneous coronary intervention (PCI) understanding and techniques has meant that these lesions can be treated percutaneously with a 90 % success rate in expert hands.

Therefore, having access to a CTO programme with dedicated operators seems sensible.

Background In clinical practice, coronary CTOs are defined as angiographic evidence of a total occlusion with thrombolysis in myocardial infarction (TIMI) grade 0 flow and an estimated or proven occlusion duration of more than 3 months.1 Contemporary practice in specialist CTO centres should expect success rates of 90 % for CTO PCI, which approaches success rates for non-occluded vessels. Despite this, the overall attempt rate for CTO lesions remains low, representing approximately 10–15 % of all PCIs that are performed for stable disease and only 5 % as a proportion of all PCIs across different healthcare systems.2,3 The hybrid approach to CTO PCI is a systematic algorithm-led PCI strategy based on the identification of key anatomical features on coronary angiography (see Figure 1).4 The main aim of this approach is to provide a standardised tool for training and programme development, avoiding futile strategies to improve safety, procedural success and reduce the contrast and radiation required to complete the case.

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The hybrid algorithm utilises four techniques of crossing a CTO lesion: • Antegrade wire escalation (AWE).

• Retrograde wire escalation (RWE).

• Antegrade dissection re-entry (ADR) often using dedicated re-entry equipment (CrossBoss/Stingray; Boston Scientific).

• Retrograde dissection re-entry (RDR).

Each of these techniques has a success rate of around 80 % in isolation;5–7 however, when the techniques are used in combination higher overall success rates are obtained.8 Utilising only one or two of the strategies will limit overall success.

The anatomical features that dictate which technique is recommended include: proximal cap appearance, lesion length, distal landing zone and collateral channels (CCs).

Proximal Cap Is the proximal cap clear or ambiguous? An unambiguous proximal cap will favour an initial antegrade strategy whereas an ambiguous cap will often require retrograde techniques (see Figure 2). Intravascular ultrasound (IVUS) can be used to overcome ambiguity of the proximal cap (see Figure 3).

Lesion Length Lesions that are <20 mm are generally of lower complexity and are commonly suitable for AWE as the primary strategy with high success rates.9

Distal Landing Zone If the distal vessel is well-defined and remote from major side branches it may favour an ADR strategy. Whereas a distal cap at a heavily diseased landing zone or close to a bifurcation will not

© RADCLIFFE CARDIOLOGY 2017

Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions Figure 1: Hybrid Algorithm for Chronic Total Occlusion Percutaneous Coronary Intervention

Figure 4: Features of Distal Landing Zone that Determine Strategy

Dual catheter injection ± IVUS

1. Ambiguous proximal cap 2. Poor distal target 3. Good Interventional collaterals 4. Major side branch at distal cap No

Yes

Retrograde

Antegrade <20 mm Wire Escalation (AWE)

<20 mm

>20 mm Fail

Dissection Re-entry (ADR)

Wire Escalation (RWE)

>20 mm Fail

Dissection Re-entry (RDR)

A

Fail

Fail

ADR

RDR

The initial approach is based on anatomical features, with a switch from a failing strategy advised at an early stage. ADR = antegrade dissection re-entry; AWE = antegrade wire escalation; IVUS = intravascular ultrasound; RDR = retrograde dissection re-entry; RWE = retrograde wire escalation.

Figure 2: Features of the Proximal Cap that Determine Strategy

B Image A shows a right coronary artery (RCA) occlusion with no proximal cap ambiguity and a clear landing zone before the bifurcation (white arrows). In addition, the lesion is long and is therefore more suitable for an initial antegrade dissection re-entry (ADR) approach. Image B shows a poor distal landing zone; it is heavily diseased with the distal cap at the bifurcation (white arrows). A primary retrograde dissection re-entry (RDR) approach is preferable.

and RDR may be the initial strategy especially in the setting of interventional collaterals (see Figure 4).

Collateral Channels A

B

Image A shows a clear proximal cap (black arrow). This tapered cap is suitable for wire escalation strategies. The lesion length is short (<20 mm), which is also favourable. Image B shows an ambiguous proximal cap. It originates somewhere between the left anterior descending (LAD) (top white arrow) and the diagonal branch (black arrow). The distal vessel is seen (black dashed line and bottom white arrow) but the ambiguity of the proximal cap suggests a retrograde approach unless intravascular ultrasound (IVUS) can identify the proximal cap.

Figure 3: Use of Intravascular Ultrasound to Resolve Proximal Cap Ambiguity

Interventional CCs are ones that can be safely navigated with a wire and a microcatheter to access the distal vessel. This definition will vary according to operator experience and ability.

Assessing Complexity The Japanese CTO score (J-CTO) is a simple and effective method of assessing anatomical complexity. A point is given for each of the five following variables: • • • • •

a blunt (versus tapered) proximal cap; lesion length >20 mm; calcification anywhere within the CTO segment; tortuosity defined as a >45° bend within the CTO segment; and if a prior attempt had been made.

When the J-CTO score was low, the CTO would be crossed in under 30 minutes, 90 % of the time. Whereas AWE was only successful at 30 minutes in 10 % of cases when the J-CTO score was high.9

Proximal cap marked with a white arrow.

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The J-CTO score is a marker of complexity with high J-CTO score cases requiring more time, radiation and contrast, but does not strongly predict procedural success when dissection techniques (ADR/RDR) are available to experienced operators.10

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Ischaemic Heart Disease We have demonstrated that educating and proctoring physicians on the hybrid algorithm and techniques leads to improved success rates.

Physicians were more likely to undertake more complex lesions with higher success rates in both the low and higher complexity groups after dedicated training.11 This was mainly driven by an increase in success for patients with JCTO scores ≥2 (70.7 versus 49.5 %; p=0.0003).

Technical Approaches

the same aims as historical parallel wiring and have succeeded this technique for many operators. Ongoing manipulation of equipment within the CTO segment is likely to expand subintimal spaces and extend intramural haematoma. This will not only continually decrease the likelihood of wiring the distal lumen but will also vastly reduce the reliability of ADR as a bail-out. We have found contemporary ADR to be a much more reliable strategy for successful revascularisation and will default to this for failed AWE after redirection manoeuvres have failed.

Diagnostic Coronary Angiogram The diagnostic angiogram should be taken with dual catheters unless the collateral filling is purely ipsilateral. A wide camera field of view is required with no panning and a long acquisition run to obtain complete information on collateral filling patterns, occlusion length and vessel course. Often collateral filling of the CTO can be compromised as a case progresses, therefore obtaining all the information at the start is important. Ideally the angiogram should be analysed prior to the procedure to completely understand the anatomy.

Retrograde Wire Escalation There are anatomical situations when approaching a CTO from a retrograde approach may be advantageous. When the CTO is ostial and/or the proximal cap is ambiguous, a retrograde approach will help overcome proximal cap ambiguity safely. When the distal cap involves a major bifurcation, a retrograde approach will more likely preserve both distal branches whereas antegrade strategies, especially ADR, may compromise a branch. Finally, if an antegrade CTO attempt is unsuccessful, a bail-out retrograde approach may still be successful.

Antegrade Wire Escalation The initial strategy of AWE is suitable when the proximal cap is unambiguous, the lesion length is short and the CTO segment is without significant tortuosity (see Figure 2A). The initial setup for simple anatomy should be the same as for more complex anatomy with dual catheter angiography with guides in both vessels, using a larger calibre catheter in the target vessel (we recommend 8F) to facilitate a change in strategy. Use of a microcatheter is recommended in all cases to facilitate guidewire exchange or tip re-shaping without losing position within the CTO segment. The initial wire for AWE should ideally be a tapered, polymer wire with a low tip load (see Table 1).

These wires are designed for loose tissue tracking and are ideal for functional occlusions or short duration CTOs.12 If the initial wire does not cross, then escalating to a wire with more penetration force but good torque control and trackability is indicated (Gaia family; Asahi Intecc) (Pilot 200; Abbott Vascular).

The proximal cap is often calcified.12,13 If the initial wire fails to penetrate the proximal cap, operators should consider a wire designed to puncture through the proximal cap of high penetration force (see Table 1). However, as soon as the cap is punctured and the microcatheter passed beyond this barrier we recommend de-escalation to a second line wire (e.g. Gaia family or Pilot 200). Jacketed wires may be preferred if there is tortuosity within the CTO segment.

With wire escalation techniques, care should be taken to ensure that the wire is advancing in the correct path. When passing through the CTO body and especially approaching the distal cap, it is worth confirming in multiple angiographic views that the wire is within the correct vascular structure. The distal cap may be resistant just like the proximal cap, and a more penetrative wire may be required to puncture through. To confirm that the wire is within the true lumen distally, two orthogonal views should be taken with donor vessel (vessel supplying CCs) angiography and/or IVUS. A common safety step is to exchange out the specialist CTO wire for a workhorse wire using a microcatheter, to avoid the risk of distal vessel perforation.

In contemporary practice, most expert operators will use a microcatheter to cross a CTO. If the guidewire is noted to be in the incorrect position in the vessel, it can be removed and reshaped before re-use or else swapped for a different wire that has different properties and/or tip shapes. These ’redirection’ manoeuvres have

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There are also differences in pathological composition between the proximal and distal cap. More frequently, the distal cap is tapered rather than blunt.12 This favours wire-based strategies and RWE is often successful for shorter lesions when retrograde access is achieved.

Retrograde procedures are technically more challenging, with several additional features requiring specific attention, which include safe crossing of CCs, careful monitoring of anticoagulation, appropriate guide catheter selection (both in terms of diameter and the support offered) as well as familiarity with a range of microcatheters and their manipulation.

Once a microcatheter is positioned at the distal cap a similar wire escalation approach is used for RWE as described for AWE. Initially a Fielder XT-A (Asahi Intecc) can be considered but if this fails to progress or buckles then escalation to a stronger lesion crossing wire should be considered to penetrate the distal cap (see Table 1).

CCs will be discussed in a later section.

Antegrade Dissection and Re-entry There are two common scenarios where this strategy is utilised.

If AWE has been attempted but has failed due to subintimal wire passage beyond the distal cap and failure to re-enter the distal lumen, and where lesions are long and complex meaning that AWE has a high possibility of failure and that ADR will potentially lead to a safer and more efficacious procedure for the patient, particularly in the absence of retrograde options.

This second scenario led to the evolution ADR strategies. As many as 50 % of all cases may have no retrograde option due to the type, size, course or lack of an interventional CC.14 Even when a case is selected for an initial retrograde approach, experienced operators fail to get a wire across the CCs 20 % of the time.5 Early antegrade dissection techniques (subintimal tracking and re-entry (STAR), mini-STAR) were associated with high rates of target vessel revascularisation and re-occlusion due to unselected re-entry often at point of bifurcation with compromise of some distal branches.15–17 Nevertheless, the concepts of these early techniques have led us to contemporary ADR.

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Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions Table 1: Table of Chronic Total Occlusion Wires Wire Purpose Within

Typical Properties

Example

Manufacturer

Vessel access, collateral access

Workhorse Usually not jacketed High torque control and trackability desirable

• BMW family, VersaTurn • Sion/Sion Blue • Marvel/Samurai • Prowater/Runthrough

• Abbott Vascular • Asahi Intecc • Boston Scientific • Terumo

Collateral crossing

Not pre-shaped Excellent torque control and trackability necessary Flexible body helpful

• Sion/Sion Black/Fielder XTR • Samurai RC

• Asahi Intecc • Boston Scientific

Loose tissue tracking

± Jacketed Often tapered tip Low tip load Low penetration force

• Pilot 50 • Fielder XT family • Fighter/Hornet

• Abbott Vascular • Asahi Intecc • Boston Scientific

Lesion crossing

Vary by manufacturer Usually low–medium tip load (1–6 g) Low–medium penetration force

• • • •

Pilot 200 Gaia family/Ultimate Bros ProVia 3 and 6 Crosswire NT

• Abbott Vascular • Asahi Intecc • Medtronic • Terumo

Proximal/distal cap and resistant segment crossing

High tip load Tapered tip Potential for perforation High penetration force

• • • •

Progress 140T/200T Confianza Pro 9/12 Hornet 10/14 ProVia 9/12/15

• Abbott Vascular • Asahi Intecc • Boston Scientific • Medtronic

Knuckling

Usually jacketed wire Folds easily at tip NB: any guidewire can be knuckled

• Pilot 200 • Fielder family/Gaia family • Fighter

• Abbott Vascular • Asahi Intecc • Boston Scientific

Externalisation

>300 cm length

• RG3 • ViperWire Advance • R350

• Asahi Intecc • CSI • Vascular Solutions

Re-entry

High penetration force Barbed tip to catch tissue

• Stingray wire

• Boston Scientific

CTO Case

CTO = chronic total occlusion; NB = to be noted.

The CrossBoss and Stingray system (Boston Scientific; see Figure 5) have been developed as a combination of devices that can create a controlled antegrade dissection plane to facilitate targeted distal vessel re-entry. The CrossBoss catheter is a blunt dissection tool with a 1-mm rounded tip. The CrossBoss will either track through intimal plaque and re-enter the distal true lumen itself or create a controlled dissection plane in the subintima that allows the Stingray balloon to be delivered just beyond the distal cap of the occlusion. The Stingray balloon is then inflated to wrap itself around the artery lumen. This allows a purpose-built wire to re-enter in a predictable and controlled position of the distal artery. When the vessel is reconstructed with stents, outflow is therefore guaranteed to multiple branches.18 The ideal lesion for ADR as a primary strategy would be one with a defined proximal cap, where there is a long CTO segment with a good target vessel that is clear of major bifurcations (see Figure 4A). There are several principles that should be applied to these procedures. The proximal cap anatomy must be safely defined (angiographically or with a supplementary IVUS). The CrossBoss can struggle with proximal cap penetration and it may be necessary to penetrate the proximal cap and then modify the proximal cap with a microcatheter or focused balloon inflation. Once the proximal cap has been crossed with any equipment, antegrade contrast injections must be avoided to prevent hydraulic dissection distally into the vessel and subsequent loss of the landing zone.

The CrossBoss should be advanced ahead of a guidewire into the distal vessel using a fast spin technique until it passes just beyond the

EUROPEAN CARDIOLOGY REVIEW

distal cap. At this point, re-entry should be attempted. The CrossBoss should be removed, with a guidewire left in position and the Stingray balloon introduced into the vessel and passed to the same position. It is imperative that re-entry occurs at a site proximal to any bifurcation to preserve all distal branches.

The Stingray balloon must be meticulously prepared to ensure that it is visible radiographically and that it can be orientated correctly to facilitate safe and controlled re-entry. Once introduced into the correct position in the vessel, the Stingray should be inflated to 4–6 atmospheres and then orientated to understand if the target vessel is above or below the balloon by using contralateral contrast injection.

At this point, re-entry is performed by advancing the dedicated Stingray wire back into the true lumen of the vessel. This is a penetrative wire with a barb at its tip designed to catch and penetrate tissue (see Figure 5). The distal vessel can be wired directly with the Stingray wire or more commonly changed for a more controllable wire (e.g. Pilot 200).

Once the distal vessel is secured, the Stingray balloon should be deflated and removed. As a safety step, we would suggest using a microcatheter to exchange the stingray wire for a workhorse guidewire. The vessel can then be predilated and stented. Care should be taken with stent sizing, recognising that stents may be deployed in the subintimal space. A balance must be struck between obtaining a luminal area that will provide a good long-term outcome versus oversizing stents and risking a perforation.

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Ischaemic Heart Disease Figure 5: Images of the CrossBoss and Stingray Devices

Collateral Channels There are three types of retrograde channels to access the distal vessel: bypass graft, septal and epicardial collaterals. It is important to consider the CC size, take-off, course and exit.

Image provided courtesy of Boston Scientific. © 2016 Boston Scientific Corporation or its affiliates. All rights reserved.

Retrograde Dissection and Re-entry A RDR approach is recommended when there is an ostial occlusion, proximal cap ambiguity that cannot be resolved safely, when the distal cap involves a bifurcation (to preserve all branches) or when an antegrade approach has been unsuccessful (see Figure 4B) and when there are ’interventional collaterals’ that in the experience of the operator can be used to obtain retrograde access to the distal target vessel. The rationale for adopting a RDR approach is procedural safety and efficacy.

With long, tortuous occlusions the risk of wire-based perforations with stiff tapered guidewires is higher. When blunt force is applied to the artery using a knuckled (or folded) polymer jacketed wire the risk of exiting from the vessel architecture is low. This theory is analogous to cardiac device implanters using their hands to bluntly dissect and therefore safely separate tissues when forming a pacemaker pocket, rather than using a scalpel or scissors.

The main limitation of retrograde approaches is often the inability to cross an interventional CC. Additional modes of failure (equipment not crossing, failure to complete) means that the overall failure with an initial retrograde approach is approximately 25 % of pre-selected cases.5 The original use of a retrograde approach with dissection was described in Japan as the controlled antegrade and retrograde tracking (CART) technique, when a balloon was brought retrogradely to facilitate antegrade wire passage. CART has now been largely superseded by the reverse CART (rCART) technique. The advent of modern microcatheters has meant that these are passed into the target vessel retrogradely in preference. Antegrade equipment is introduced into the vessel and wires are passed into the CTO segment from both directions. A balloon is introduced on the antegrade wire and inflated within this common subintimal space, thus allowing the retrograde wire to be directed via this segment into the proximal true lumen.

Frequently, guide catheter extensions are used in the antegrade system and brought as close to the retrograde equipment in the dissection as possible. This minimises the distance the retrograde wire has to travel to complete the case and increases efficiency and reduces complications.19

The initial Rentrop system20 has been modified21 and is used to describe CCs: CC grade 0; no continuous connection, CC1; threadlike continuous connection and CC2; side branch-like connection.

While the classification is descriptive it does not correlate well with crossing success and sometimes CC0 collaterals are crossable especially with modern wires.

Septal CCs are preferred mainly for patient safety and should be used preferentially, especially early in the learning curve. The septum is more forgiving in terms of equipment-induced vessel injury; this usually results in localised haematoma rather than perforation and tamponade. It is also possible to dilate septal CCs whereas it is not advisable to dilate the epicardial vessels due to risk of perforation. Septals are, however, often tortuous and complex connections and it is possible to spend prolonged periods of time failing to cross a septal CC. Epicardial connections are usually more predictable in terms of understanding whether crossing is feasible. However, small calibre, friable epicardial CCs should be avoided until the operator is very experienced.

To enter a CC, a workhorse wire with a significant primary bend is initially used through the microcatheter. Once the CC has been engaged the microcatheter is introduced and the wire is exchanged for a specialist collateral crossing wire (see Table 1) with a short (1 mm) and subtle primary bend (<40°). Septal CCs can be crossed by ’surfing’. This is a blind, repetitive wiring technique, where the wire is passed forwards until resistance is felt. It is then withdrawn slightly and re-directed until it passes into the distal vessel. The other technique is to perform ’tip injections’ with neat contrast through the microcatheter to understand the CC course in detail, ensuring there is no air in the catheter and that blood can be withdrawn. Tip injections are often needed in epicardial CC crossing as the microcatheter frequently obstructs contrast passage. It is important to ensure microcatheters are not advanced over the wire until the operator is certain that they are safely within the CC or distal target vessel.

Occasionally the microcatheter fails to advance due to tortuosity or size of the CC. If it is a septal CC the microcatheter should be removed using a trapping technique. Trapping will prevent the need for prolonged fluoroscopy for equipment exchanges. Where trapping is not possible, wire extensions or 300 cm wires are required. A small diameter balloon can be used to dilate the septal track (usually 1.2–1.5 mm with longer balloon lengths preferred) and nominal pressure balloon inflation is sufficient. This must not be performed in epicardial CCs. If septal dilation fails or epicardial CCs are not crossed with a Corsair or Turnpike, a lower profile microcatheter (Turnpike LP, Vascular Solutions Inc; Caravel, Asahi Intecc; Finecross, Terumo, etc.) may facilitate passage.

Conclusion RDR procedures are complex and involve multiple steps. They are associated with increased complication rates compared with AWE procedures. We would suggest that operators undertake dedicated education and training before embarking on this type of intervention.

Nevertheless, these techniques can be learnt and effectively taught with good outcomes produced from training programmes.11

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Based on historical data the number of CTO procedures performed are much lower than would be reasonably expected. The treatment of patients with clinically significant CTOs will become more frequent with an ageing population, an increasing number of patients undergoing TAVI (20 % have co-existing coronary disease) and patients presenting following CABG failure where redo CABG is not

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Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions attractive or not possible. Meanwhile understanding and techniques have developed such that 90 % success can be expected in expert

1.

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Di Mario C, Werner GS, Sianos G, et al. European perspective in the recanalisation of Chronic Total Occlusions (CTO): consensus document from the EuroCTO Club. EuroIntervention 2007;3 :30–43. PMID: 19737682 Ludman PF. British Cardiovascular Intervention Society Audit Returns Adult Interventional Procedures. January 2013–December 2013. Available at: www.bcis.org.uk/ documents/E15_BCIS_Audit_2013_for_web_no_track_ Version_03-11-2014.pdf (Accessed 7 December 2016).

Grantham JA, Marso SP, Spertus J, et al. Chronic Total Occlusion Angioplasty in the United States. JACC Cardiovasc Interv 2009;2:479–86. DOI: 10.1016/j.jcin.2009.02.008; PMID: 19539249 Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5 :367–79. DOI: 10.1016/j.jcin.2012.02.006; PMID: 22516392 Tsuchikane E, Yamane M, Mutoh M, et al. Japanese multicenter registry evaluating the retrograde approach for chronic coronary total occlusion. Catheter Cardiovasc Interv 2013;82 (5):E654–61. DOI: 10.1002/ccd.24823; PMID: 23404874 Sianos G, Werner GS, Galassi AR, et al. Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club. EuroIntervention 2012;15 ;8(1):139–45.

DOI: 10.4244/EIJV8I1A21; PMID: 22580257 Wilson WM, Walsh SJ, Yan AT, et al. Hybrid approach improves success of chronic total occlusion angioplasty. Heart 2016;102 (18):1486–93. DOI: 10.1136/ heartjnl-2015-308891 Wilson W, Walsh S, Hanratty C, et al. TCT-201 Outcomes From The UK Hybrid CTO Registry. J Am Coll Cardiol 2014;64 (11_S). DOI: 10.1016/j.jacc.2014.07.242

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hands. Therefore, having access to a CTO programme with dedicated operators seems sensible. ■

Morino Y, Abe M, Morimoto, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4 :213–21. DOI: 10.1016/j.jcin.2010.09.024; PMID: 21349461 Wilson W, Walsh S, Hanratty C, et al. Outcomes From The UK Hybrid CTO Registry. J Am Coll Cardiol 2014;64 :suppl B59. DOI: 10.1016/j.jacc.2014.07.242 Sharma V, Jadhav ST, Harcombe AA, et al. Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions. Open Heart 2015;2 :e000228. DOI: 10.1136/openhrt-2014-000228; PMID: 25852949; PMCID: PMC4379886 Sakakura K, Nakano M, Otsuka F, et al. Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft. Eur Heart J 2014;35:1683–93. DOI: 10.1093/ eurheartj/eht422; PMID: 24126875; PMCID: PMC4076662 Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29 :955–63. PMID: 9120181 McEntegart MB, Badar AA, Ahmad FA, et al. The collateral circulation of coronary chronic total occlusions.

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Interv 2012;79 :20–7. DOI: 10.1002/ccd.23058; PMID: 21805559 16. Valenti R, Vegara R, Migliorini A, et al. Predictors of Reocclusion After Successful Drug-Eluting Stent–Supported Percutaneous Coronary Intervention of Chronic Total Occlusion. J Am Coll Cardiol 2013;61 :545–50. DOI: 10.1016/j. jacc.2012.10.036; PMID: 23273395 17. Galassi AR, Boukhris M, Tomasello SD, et al. Long-term clinical and angiographic outcomes of the mini-STAR technique as a bailout strategy for percutaneous coronary intervention of chronic total occlusion. Can J Cardiol 2014;30 :1400–6. DOI: 10.1016/j.cjca.2014.07.016; PMID: 25442438 18. Rinfret S, Ribeiro HB, Nguyen CM, et al. Dissection and re-entry techniques and longer-term outcomes following successful percutaneous coronary intervention of chronic total occlusion. Am J Cardiol 2014;114 :1354–60. DOI: 10.1016/j. amjcard.2014.07.067; PMID: 25242364 19. Mozid AM, Davies JR, Spratt JC. The utility of a guideliner catheter in retrograde percutaneous coronary intervention of a chronic total occlusion with reverse cart-the “capture” technique. Catheter Cardiovasc Interv 2014;83 (6):929–32. DOI: 10.1002/ccd.25205; PMID: 24089343 20. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects.

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Health Literacy

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, 1 Brittany Edgar, 2 Wendy Lin, 3 Maria Auxiliadora Parreiras Martins, 4 Michael K Paasche-Orlow 5 and Jared W Magnani 6 1. Department of Medicine, Johns Hopkins University, Baltimore, MD, USA; 2. Columbia University School of Nursing, Columbia University, New York, NY, USA; 3. Boston University School of Medicine, Boston University, Boston, MA, USA; 4. School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil; 5. Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 6. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia with significant clinical outcomes, and is associated with high medical and social costs. AF is complicated for patients because of its specialised terminology, long-term adherence, symptom monitoring, referral to specialty care, array of potential interventions and potential for adversity. Health literacy is a frequently under-recognised, yet fundamental, component towards successful care in AF. Health literacy is defined as the capacity to obtain, process and understand health information, and has had markedly limited study in AF. However, health literacy could contribute to how patients interpret symptoms, navigate care, and participate in treatment evaluation and decision-making. This review aims to summarise the clinical importance and essential relevance of health literacy in AF. We focus here on central aspects of AF care that are most related to self-care, including understanding the symptoms of AF, shared decision-making, adherence and anticoagulation for stroke prevention. We discuss opportunities to enhance AF care based on findings from the literature on health literacy, and identify important gaps. Our overall objective is to articulate the importance and relevance of integrating health literacy in the care of individuals with AF.

Keywords Atrial fibrillation, health literacy, prevention, patients, risk factors, patient-centred care Disclosure: The authors have no conflict of interest to declare.

Received: 30 March 2017 Accepted: 5 May 2017 Citation: European Cardiology Review 2017;12(1):52–7. DOI: 10.15420/ecr.2017:2:2 Correspondence: Jared W Magnani, UPMC Presbyterian Hospital, Suite 5-B, 200 Lothrop Street, Pittsburgh, PA 15213, USA. E: magnanij@pitt.edu

Atrial fibrillation (AF) requires complex management to prevent adverse outcomes. To succeed with AF, patients need to learn specialised medical terminology and the self-care skills and activation to interpret and report symptoms. AF care involves long-term adherence to medications with deleterious side-effects, such as antiarrhythmics and anticoagulants.

The patient experience of AF is further complicated by the range of debilitating symptoms, complications and navigation of specialty care.

Health literacy is essential for patients to navigate AF management and self-care successfully. This review of health literacy and AF aims to: (a) identify the importance of health literacy for patients with AF; and (b) describe how healthcare providers’ attention to health literacy can improve the clinical management of AF. Health literacy has had limited investigation in AF. Indeed, none of the large community-based studies or clinical trials in AF have included the measurement of health literacy. Multiple knowledge gaps remain in understanding the role of health literacy in AF; aspects of AF where health literacy is particularly relevant include: (a) assessment and monitoring of symptoms and quality of life (QOL); (b) patient engagement and activation for meaningful participation in shared decision-making; and (c) anticoagulation for prevention of ischaemic stroke. Within each of these domains, we identified pertinent studies to summarise present knowledge and identify critical gaps. We describe strategies at the patient, provider and system level for improving the experience of people with limited health literacy and AF.

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Access at: www.ECRjournal.com

The Clinical Significance of Health Literacy Health literacy is the “capacity to obtain, process, and understand basic health information and services needed to make appropriate medical decisions”.1 Reading, writing and numeracy along with the ability to interact with health professionals, as well as seek and comprehend medical information, are fundamental to health literacy. Further dimensions include the ability to act on health-related information, evaluate treatment courses and the ability to navigate the healthcare system.2 National surveys have demonstrated that 36 % of US adults have limited health literacy.3 Limited health literacy is associated with limited knowledge of health conditions,4,5 poorer medication adherence,6 worse disease status, early hospital readmission and mortality.7 In multivariable analyses, including sociodemographic and health status, older adults with inadequate health literacy have a 1.5-fold increased risk of both cardiovascular and all-cause mortality, relative to those with adequate literacy.6 In patients with heart failure, limited health literacy has been associated with increased hospitalisation8 and a two-fold increase in mortality,9 relative to those with adequate literacy.

There are multiple gaps in our understanding of the clinical and epidemiological relations of health literacy and AF. Social determinants of health, such as health literacy, have been largely absent from investigations of AF epidemiology, risk factors and adverse outcomes.

© RADCLIFFE CARDIOLOGY 2017

Health Literacy and Atrial Fibrillation Table 1: Future Directions for Incorporating Health Literacy in Atrial Fibrillation (AF) Clinical Investigation and Epidemiology Domain

Specific direction

Clinical significance of health literacy

• Utilise health literacy as an ancillary measure in AF clinical trials • Describe the epidemiology of limited health literacy and its associations in patients with AF • Assess the impact of health literacy on clinical outcomes in patients with AF • Incorporate health literacy assessments and examine their associations with knowledge, communication, quality of life and health-related outcomes in AF • Account for health literacy when examining the effects of educational interventions

Management of AF Symptoms and quality of life

Knowledge and shared decision-making

• Examine the relations between health literacy and symptoms • Assess the effect of health literacy on the ability of patients to express symptoms and describe their quality of life and health status • Validate methods and instruments assessing patient health status across levels of health literacy.

• Develop and validate assessments in diverse racial/ethnic and socioeconomic settings with a high prevalence of limited health literacy

• Evaluate the associations between health literacy, knowledge of AF and participation in shared decisionmaking in AF • Develop and validate tools assessing AF knowledge that account for health literacy • Build educational interventions for AF appropriate for all levels of health literacy (<sixth-grade reading level) • Assess the effect of educational interventions to improve AF knowledge on patient-related health status, patient participation in shared decision-making and health-related outcomes in clinical trials and real-life clinical practice

Anticoagulation and thromboprophylaxis

• Assess the associations between health literacy and risk of stroke in AF • Assess the associations between health literacy and risk of bleeding in AF • Relate health literacy with adherence to anticoagulation, monitoring and dose adjustments • Integrate health literacy assessments and educational interventions in trials of anticoagulation in AF

Table 2: AHRQ Health Literacy Universal Precautions Toolkit Components and Modification for Atrial Fibrillation (AF) Clinical Care and Practice 10 Tool

Title

1

Form a team Develop a team of multidisciplinary stakeholders (e.g. anticoagulation, primary care, cardiology and electrophysiology representatives) to promote HL in AF

Potential application in AF

2

Create a health literacy improvement plan

Improve AF education, anticoagulation adherence or symptom assessment

3

Raise awareness

Educate staff about HL and challenges of HL relevant to AF

4

Communicate clearly Use plain language, avoiding jargon, adopt the patient’s words, show pictures to teach about heart rhythm irregularity and stroke risk

5

Use the teach-back method

Use written materials, such as medication and INR logs, enhance teaching

6

Follow up with patients

Involve patient in monitoring (e.g. INR values, heart rates, symptom tracking)

7

Improve telephone access

Implement universal precautions to facilitate patient-centred communications

8

Conduct brown-bag medicine reviews Review all medications as a standard for quality patient care, review anticoagulation logs and adherence routinely with patients.

9

Address language differences

10

Consider culture, customs and beliefs Receive training in cultural competence; remember the patient’s expertise in the intersection of culture and beliefs with AF and other medical care

11

Assess, select and create easy-to-understand materials

Evaluate forms, informed consent, procedural brochures for readability

12

Use health-education material effectively

Create information order sets or collected materials on AF treatment options

13

Welcome patients: helpful attitude, signs and more

Use the environment to promote questions about AF and medication review

14

Encourage questions

Invite questions routinely on causes of AF; what patients experience, treatments

15

Make action plans Have patients choose realisable goals on AF (e.g. adherence or addressing risk factors for AF, such as smoking, physical activity, blood pressure control)

16

Help patients remember how and when to take their medicine Facilitate tools to support medication use; educate patients on systems for tracking medication; anticipate errors; provide tools, such as pill boxes

Provide AF education and adherence counselling with a trained interpreter

17

Get patient feedback Utilise patient expertise on being a patient with AF through surveys and suggestions

18

Link patients to non-medical support Appreciate the impact of social determinants on health, utilise community-based resources

19

Direct patients to medicine resources Review insurance coverage and verify eligibility for anticoagulants, antiarrhythmics and other medications

20

Connect patients with literacy and math resources Discern how literacy impacts patients’ lives and experience with a chronic condition, such as AF; identify community resources

21

Make referrals easy Make sure the patient understands the rationale for a referral (e.g. explain electrophysiology and guide patient in utilising the visit)

Full details regarding the tools are available at the indicated reference and not explicated here. AHRQ = Agency for Healthcare Research and Quality; INR = international normalised ratio; HL = health literacy.

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Health Literacy Figure 1: Addressing Atrial Fibrillation (AF) and Health Literacy

Health literacy “The capacity to obtain, process, understand” Reading literacy Interaction Comprehension Numeracy Application, function Decision-making Evaluation Responsibility Confidence Navigation

AF patient behaviours Adherence Activation Engagement AF patient outcomes Heart failure stroke Hospitalisation Mortality AF patient experience Symptoms Quality of life

Clinician opportunities Patient-centred care Enhanced teaching Decision-aide tools Avoid jargon Teach-back method Enfranchise patients in care Brown-bag med review Evaluate printed materials Encourage questions Connect to Resources/ support

Health literacy has been associated with patient interaction with the healthcare system, increased risk for adverse outcomes and a poor experience of disease. Clinician opportunities for addressing health literacy are summarised and described in the AHRQ Universal Precautions Toolkit.10

How health literacy and socioeconomic factors might influence AF merits examination to determine opportunities to improve patients’ QOL and outcomes. An important first step would be to incorporate validated measures of health literacy in AF clinical trials and registries.

Table 1 summarises the future directions for examining the relations of health literacy and AF in such contexts.

The Agency for Healthcare Research and Quality (AHRQ) has developed the Health Literacy Universal Precautions Toolkit.10 A fundamental premise is the professional and institutional mandate to make healthcare accessible for individuals across the spectrum of health literacy. The toolkit promotes a “universal precautions” approach – to confirm patient comprehension – as a mechanism to improve accessibility, communication and utilisation, regardless of a person’s level of health literacy. In Table 2, we adapted the 21 tools of the AHRQ Universal Precautions Toolkit to illustrate their application for individuals with AF. Figure 1 summarises the definition of health literacy, its potential impact in AF and multiple clinician opportunities, selected from the Toolkit. A common thread relates to opportunities that health systems and providers can take to simplify the experience of being a patient, and empower patients to succeed in their care.

Health Literacy in Symptoms and QOL in AF Symptom severity and QOL guide AF treatment. Yet there are large differences in how patients experience and report AF symptoms.11 Socioeconomic status and education, both strongly related to health literacy, have been related to severity of AF symptoms.12 Health literacy affects how patients recognise and communicate their symptoms. 5 In addition, health literacy is implicated in the burden and experience of symptoms. In a cross-sectional study of over 400 individuals with heart failure, for example, limited literacy was associated with worse QOL and a higher level of symptoms.13 A similar assessment in AF is lacking. Further, limited health literacy could influence symptom reporting in AF, particularly given the complexity of its associated symptoms.

Standardised instruments have been developed to quantify symptom burden in AF; we selected instruments commonly used for the assessment of symptoms and QOL in AF (see Table 3), and measured their reading level with validated measures. Specifically, we employed

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the Flesch–Kincaid Grade Level,14 Simple Measure of Gobbledygook score,15 Dale–Chall Readability16 and the Lexile Framework17 to quantify reading levels of the AF-specific instruments. While some are rated at a middle-school reading level, other tools are more complex and require college- or even graduate-level reading capacity. In contrast, the recommended reading level for health information is at a sixthgrade level.18 We identified no study testing the validity of any AF-related QOL measure for use with patients who have limited health literacy. Accordingly, the quality of the data gleaned from such instruments might be limited, especially for older adults, racial and ethnic minorities and individuals with lower income or educational attainment, populations with higher rates of limited health literacy.3 Assessments of symptoms and QOL are now routine in clinical studies, trials and registries of individuals with AF. The concurrent assessment of health literacy in such studies would enhance understanding of the real-world challenges experienced by individuals with AF. It is imperative that physicians treating individuals with AF incorporate strategies for identifying patient symptoms and optimising therapy, regardless of the level of health literacy. Adapting a patient’s treatment plan for AF in relation to their symptoms is paramount and complex, as this work needs to incorporate details of patients’ biopsychosocial circumstances, as well as their language skills, educational needs and health literacy.

Health Literacy, Patient Education, and Shared Decision-Making There has been consistent recognition of adverse consequences associated with patients’ knowledge of AF. An international survey revealed that one in four patients was unable to explain AF.19 In a cohort of patients undergoing pulmonary vein isolation for AF, less than half were able to correctly answer questions regarding the condition. Knowledge deficits in AF were increased in individuals with less education.20 AF knowledge scales have been developed and validated for assessing and evaluating patient knowledge of AF.20,21 However, such measures have not been promulgated or used to trigger educational or empowerment interventions. To our knowledge, measurement of AF knowledge has not been implemented in settings with limited health literacy.

Single, one-time educational interventions have been shown to have marginal improvement of AF knowledge 2–8 weeks following the intervention.22,23 We identified patient education materials for AF from websites from medical professional societies, major academic medical centres and Internet-based medical references by conducting an Internet-based search, using widely-accessible search engines. Table 4 summarises a sample of the identified websites with information related to AF management. On average, these materials require a 10-grade reading level (range seventh grade to graduate level).

Educational material written in simpler language or describing AF with images, cartoons, photo-novellas or descriptive narratives were not identified.

There has been increased attention on shared-decision making in AF.24 Shared decision-making requires a specific orientation of patients and their healthcare providers. Patients must have sufficient knowledge of the arrhythmia and the rationale for treatment strategies and options to participate. It also requires that patients have sufficient knowledge and initiative, i.e., activation, to participate in decision-making.25 Patient knowledge about the disease, available therapeutic options,

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Health Literacy and Atrial Fibrillation Table 3: Readability and Grade Level of Selected Instruments for Patient-Reported Health Status Flesch–Kincaid grade level14

Simple Measure of Gobbledygook15

Dale–Chall Readability16

SF-3643

6.1

6.8

6.1 1250

SF-1244

6.1

6.7

5.9 1100

EQ-5D-5L45

16.1

12.8

8.0 1920

Instrument

Estimated Lexile Measure

Generic

Selected Instruments, specific to AF AF Quality of Life Instrument46,47

4.3

5.4

7.2 1750

AF Effect on Quality of Life48

12.9

11.6

8.0 1770

AF Symptom and Burden49

10.5

9.6

7.4

1510

Items presented are not comprehensive. Flesch-Kincaid and Simple Measure of Gobbledygook provide grade-level estimates. Dale–Chall Readability is a scaled measure for evaluating the expected reading grade level for text comprehension; for example, a score of 7.0–7.9 indicates reading grade level 9–10, and 8.0–8.9 indicates grade level 11–12. Estimated Lexile Measure is an internationally-employed measure for gauging reading level, with higher scores corresponding to greater text complexity. AF = atrial fibrillation.

Table 4: Selected online materials available for AF education, and their readability levels, as assessed by the FKGL and SMOG measures Provider

URL

FKGL

SMOG

Dale–Chall Readability

Estimated Lexile Measure

Mayo Clinic

http://www.mayoclinic.org/diseases- conditions/atrial-fibrillation/basics/ definition/con-20027014

10.7

10.6

9.7

1230

Wikipedia

http://en.wikipedia.org/wiki/Atrial_fibrillation 11.5 10.8

8.3

2950

American Heart Association

http://www.heart.org/HEARTORG/ Conditions/Arrhythmia/AboutArrhythmia/ Atrial-Fibrillation-AF-or-AFib_UCM_ 302027_Article.jsp

7.9

1150

Web MD

http://www.webmd.com/heart-disease/ 6.5 7.1 7.6 atrial-fibrillation/

760

Atrial Fibrillation Association

http://www.atrialfibrillation-us.org/ patient-information

9.4

9.2

7.5

1130

Cleveland Clinic

http://my.clevelandclinic.org/services/ heart/disorders/arrhythmia/afib

8.8

7.3

8.1

1070

Heart Rhythm Society

http://www.hrsonline.org/Patient- Resources/Heart-Diseases-Disorders/ Atrial-Fibrillation-AFib

7.6

7.7

7.6

910

C-Health

http://chealth.canoe.ca/atrial_fibrillation_ 9.3 9.1 details.asp?channel_id=2126&relation_ id=101925

7.6

1190

National Institute of Health

http://www.nhlbi.nih.gov/health/health- topics/topics/af

7.6

7.9

7.1

950

Medicine Net

http://www.medicinenet.com/atrial_ fibrillation/article.htm

12.7

12.3

8.2

1220

Up To Date

http://www.uptodate.com/contents/atrial- fibrillation-beyond-the-basics?source= search_result&search=atrial+fibrillation& selectedTitle=1~15

11.1

10.6

9.6

1190

Access Medicine

http://accessmedicine.mhmedical.com/ patientEdHandouts.aspx

8.1

8.6

7.7

910

9.9

9.6

Websites of selected medical professional societies, major academic medical centres and Internet-based medical references were identified through an Internet-based search using widelyaccessible search engines. FKGL and SMOG provide grade-level estimates. Dale–Chall Readability is a scaled measure for evaluating the expected reading grade level for text comprehension; for example, a score of 7.0–7.9 indicates reading grade level 9–10, and 8.0–8.9 indicates grade level 11–12. Estimated Lexile Measure is an internationally-employed measure for gauging reading level, with higher scores corresponding to greater text complexity. FKGL = Flesch-Kincaid Grade Level; (for consistency) SMOG = Simple Measure of Gobbledygook score.

and personal values and preferences are essential for successful participation in shared decision-making.26 Thus, by necessity, shared decision-making in AF requires that the patient have sufficient health literacy. Barriers to patient-centred, shared-decision making include lower educational level, inability to understand medical information and lack of sufficient information.26 For the clinician, successfully establishing shared decision-making requires an adaptive approach,

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one that accommodates patients’ health literacy in addition to other social determinants of health and patient characteristics. We did not identify studies examining the effects of health literacy on patient participation in shared decision-making in AF. In a randomised, clinical trial, patients receiving nurse-directed care in AF clinics had decreased hospitalisation and better adherence to

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Health Literacy treatment guidelines compared to those receiving standard care. The intervention cohort received extended visits that included education and symptom recognition.27 This single-centre experience shows the promise of more extended visits, with a patient-centred focus. Other examples of educational intervention in chronic diseases could provide paradigms for improving AF care. Educational interventions in heart failure are associated with improved QOL28 and reduced hospitalisation and mortality rates.29 Interventions that have been studied include education on self-management, picture-based educational materials, scheduled telephone follow ups, telephone reinforcement of learning goals and self-management, and high-intensity, multidisciplinary education. In these trials, approximately 40 % of participants had limited health literacy.28 Interventions that have been studied in patients with diabetes include intensive educational sessions by pharmacists, frequent telephone or in person follow-up visits to ensure adherence and structured group educational programmes.30,31 In randomised trials, these interventions have been associated with improved diabetes knowledge, blood pressure and glycaemic control, weight loss, smoking cessation and patient satisfaction.

Educational interventions that improve AF knowledge and empowerment are essential. The European Heart Rhythm Association (EHRA) emphasised the central relevance of patient education as part of AF treatment and management in a consensus statement on patient values and preferences for addressing arrhythmias.32 Improvement of patients’ understanding of their symptoms and capacity to use their knowledge to advance their care is fundamental to guide and enhance meaningful shared decision-making. The EHRA consensus statement emphasises: (a) patients’ “expertise” in the experience of living with a chronic, highly-morbid condition; and (b) the essential role of developing educational interventions that are appropriately tailored for patients, based on their values, preferences, cognition and educational level.

Available studies evaluating educational interventions in AF have been limited by having short follow-up periods and lack of standardisation in the methods to quantify knowledge. Studies with longer followup periods, standardised instruments and appropriate across levels of health literacy are required. In this work, patients cannot be the only intervention target; improving clinicians’ communication skills, receptivity to shared decision-making and systems to support the collection of quality of life data to use in adapting treatment plans are all also part of the health literacy agenda. In addition, patients with AF are cared for in diverse settings, yet most data on educational interventions are derived from specialised arrhythmia or anticoagulation settings. Future studies are required to assess the utility and results of educational interventions across settings. Easy-touse, plainly-written educational materials in all languages are essential.

However, patient education materials are not likely to succeed in a vacuum. Implementation research is needed to determine how education and empowerment for patients, as well as clinicians and their staff, can become a routine element of the care for patients with AF. Whether educational materials written for a lower reading level improve communication, satisfaction, AF or anticoagulation knowledge and increase patient participation in shared decision-making, also merit investigation.

associated with increased risk for bleeding, and requires adherence with frequent monitoring. Studies have demonstrated that individuals receiving oral anticoagulation have significant knowledge deficits about the purpose of anticoagulation.33–35 In cross-sectional studies utilising anticoagulation-specific knowledge scales and questionnaires, patients answered correctly only 48–62 % of questions about anticoagulation.34,35 In a limited-sized (n=183), ethnically-diverse cohort, as few as 9 % of patients knew the indication for being prescribed warfarin, many reporting the indication as hypertension, high cholesterol or “thick blood”.33 Only 40–52 % of patients on anticoagulation therapy had even a basic understanding about the action of anticoagulants23 or the consequences of over- or under-dosing.36 In addition, patients with AF answered correctly <20 % of questions on drug, herbal and vitamin interactions with warfarin.35 Evidence regarding the associations between health literacy and anticoagulation knowledge remains limited. One study demonstrated a strong association between health literacy and anticoagulation knowledge.33 Other studies have used educational level, rather than assessments of health literacy. There is evidence, however, suggesting that improved knowledge is related to better metrics of anticoagulation.

A higher knowledge level of both anticoagulation and AF has been associated with greater warfarin time in therapeutic range.37 Similarly, educational interventions have been shown to improve time in therapeutic range. Interventions that have been studied include oneon-one counselling sessions;38 a 20-minute, nurse-led class;39 a 2-hour, interactive, physician-led small-group session;40 educational videos36,37 and visual aids.41 Limitations include small-sized samples and short follow-up duration.

Overall, these interventions demonstrated modest improvement in patient knowledge over 12 months of follow up. Visual aids improved patients’ ability to describe their warfarin regimen. 41 Informational videos focused on patient narrative were more effective than presenting statistical information. 36 A systematic review of educational interventions for anticoagulation therapy in AF42 concluded that the effect on patient outcomes is inconclusive. The data remain limited by small sample sizes, inadequate follow up, absence of standardisation for educational or assessment methods and lack of health literacy assessments.

Multiple gaps remain in the investigation of health literacy and anticoagulation for stroke prevention in AF. The contribution of health literacy towards stroke risk and prevention has not been examined. Patient-centred AF care requires assessments of health literacy alongside adherence to anticoagulation, monitoring and dose adjustment. In addition, we identified no studies examining health literacy in the context of novel oral anticoagulants. In contrast, the EHRA consensus statement on patient values and preferences advocates for assessing health literacy as a starting point in evaluating patients with AF.32 Expectations of sustained adherence to anticoagulation is unrealistic without appropriate education, patient knowledge and expectations and commitment to treatment.

Health literacy resides at the centre of such a model of patientcentred care.

Conclusion Health Literacy in AF and Anticoagulation Oral anticoagulation is a mainstay for stroke prevention in AF. However, oral anticoagulation with warfarin is challenging, as warfarin is

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Incorporation of health literacy has been identified by the Institute of Medicine as an essential priority to bolster healthcare quality and disease prevention. Health literacy has a fundamental contribution

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Health Literacy and Atrial Fibrillation to patient safety, patient-centred care and AF treatment and has additionally emerged as a major barrier to the meaningful participation of patients in shared decision-making. Given the increasingly complicated therapeutic options and treatment decisions that characterise the

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37. Clarkesmith DE, Pattison HM, Lip GY, Lane DA. Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial. PLoS One 2013;8(9):e74037. DOI: 10.1371/journal.pone.0074037; PMID: 24040156.

38. Pernod G, Labarere J, Yver J, et al. EDUC’AVK: Reduction of oral anticoagulant-related adverse events after patient education: a prospective multicenter open randomized study.

J Gen Intern Med 2008;23(9):1441–6. DOI: 10.1007/s11606-0080690-1; PMID: 18566863.

39. Eickhoff JS, Wangen TM, Notch KB, et al. Creating an anticoagulant patient education class. J Vasc Nurs 2010;28(4):132–5. DOI: 10.1016/j.jvn.2010.08.002; PMID: 21074115.

40. Khan TI, Kamali F, Kesteven P, et al. The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation.

Br J Haematol 2004;126(4):557–64. DOI: 10.1111/j.13652141.2004.05074.x; PMID: 15287950.

41. Schillinger D, Machtinger EL, Wang F, et al. Language, literacy, and communication regarding medication in an anticoagulation clinic: are pictures better than words? In: Henriksen K, Battles JB, Marks ES, Lewin DI (eds). Advances in Patient Safety: From Research to Implementation (Volume 2: Concepts and Methodology). Rockville, MD: Agency for Healthcare Research and Quality, 2005. Available at: https://www.ncbi. nlm.nih.gov/books/NBK20494/?report=reader#_NBK20494_ pubdet_ (Accessed on 3 March 2017).

42. Clarkesmith DE, Pattison HM, Lane DA. Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation. Cochrane Database Syst Rev 2013;6:CD008600. DOI: 10.1002/14651858.CD008600.pub2; PMID: 23736948.

43. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30(6):473–83. PMID: 1593914.

44. Ware J Jr, Kosinski M, Keller SD. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34(3):220–33. PMID: 8628042.

45. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20(10):1727–36. DOI: 10.1007/ s11136-011-9903-x; PMID: 21479777.

46. Badia X, Arribas F, Ormaetxe JM, et al. Development of a questionnaire to measure health-related quality of life (HRQol) in patients with atrial fibrillation (AF-Qol). Health Qual Life Outcomes 2007;5:37. DOI: 10.1186/1477-7525-5-37; PMID: 17610734.

47. Arribas F, Ormaetxe JM, Peinado R, et al. Validation of the AF-Qol, a disease-specific quality of life questionnaire for patients with atrial fibrillation. Europace 2010;12(3):364–70.

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48. Spertus J, Dorian P, Bubien R, et al. Development and validation of the atrial fibrillation effect on quality-of-life (AFEQT) questionnaire in patients with atrial fibrillation.

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49. Koci F, Forbes P, Mansour MC, et al. New classification scheme for atrial fibrillation symptom severity and burden. Am J Cardiol 2014;114(2):260–5. DOI: 10.1016/ j.amjcard.2014.04.032; PMID: 24878121.

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Cardiac Magnetic Resonance in Takotsubo Syndrome Konstantinos Bratis Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, London, UK

Abstract Takotsubo syndrome is an acute, profound but reversible heart failure syndrome of unknown aetiology, usually but not always triggered by physical or emotional stress. Cardiac magnetic resonance has become an important tool for the non-invasive assessment of the syndrome, allowing for a comprehensive, safe and reproducible assessment of functional and anatomical myocardial properties, including perfusion, oedema and necrosis. This review focuses on the emerging role of cardiac magnetic resonance for the characterisation, differential diagnosis as well as risk stratification of patients with Takotsubo syndrome.

Keywords Takotsubo syndrome, cardiac magnetic resonance, tissue characterisation, functional assessment, differential diagnosis, prognosis Disclosure: The author has no conflicts of interest to declare.

Received: 17 May 2016 Accepted: 21 June 2017 Citation: European Cardiology Review 2017;12(1):58–62. DOI: 10.15420/ecr.2017:7:2 Correspondence: Konstantinos Bratis, St George’s NHS Hospital, Blackshaw Road, Tooting, London, SW17 0QT, UK. E: c_bratis@hotmail.com

Takotsubo syndrome (TTS) is an acute, profound, but reversible heart failure syndrome, usually but not always triggered by physical or emotional stress. To date, the exact pathogenic mechanism of this syndrome remains unclear; however, several hypotheses involving vascular mechanisms (i.e. abnormal coronary epicardial or microvascular vasoreactivity),1-3 endocrine and gender-related mechanisms (i.e. oestrogen deficiency),4 and both autonomic and central nervous system abnormalities involving catecholamine surges,5,6 have been proposed, suggesting a multifactorial pathogenic background (see Table 1).

Although practically indistinguishable from an acute coronary syndrome at clinical presentation, some characteristics of TTS, such as the involvement of a myocardial area that extends beyond a single coronary vessel territory, the complete recovery of ventricular function in days or weeks, and the absence of significant epicardial coronary artery disease, make TTS a unique form of acute heart failure syndrome. The diagnosis of TTS has been traditionally based on the proposed Mayo Clinic criteria.7 A more recent report by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology has suggested newer diagnostic criteria that include: (a) transient regional wall motion abnormalities of LV or RV myocardium, which are frequently, but not always, preceded by a stressful trigger (emotional or physical); (b) regional wall motion abnormalities usually extend beyond a single epicardial vascular distribution, and often result in circumferential dysfunction of the ventricular segments involved; (c) absence of culprit atherosclerotic coronary artery disease including acute plaque rupture, thrombus formation, and coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g. hypertrophic cardiomyopathy, viral myocarditis); (d) new and reversible electrocardiography (ECG) abnormalities (ST-segment elevation, ST depression, left bundle branch block (LBBB), T-wave inversion, and/or QTc prolongation) during the acute phase (3 months); (e) significantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase; (f) positive but relatively small elevation in cardiac troponin measured with a conventional assay (i.e. disparity between troponin level and amount

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of dysfunctional myocardium present); and (g) recovery of ventricular systolic function on cardiac imaging at follow-up (3–6 months).8 Advanced imaging modalities are becoming increasingly important in the management of TTS, providing essential information for the diagnosis and prognosis of these patients. Cardiac magnetic resonance, in particular, has become a first-line modality for non-invasive assessment of patients with TTS. In addition to a comprehensive assessment of the myocardial functional and anatomical properties, cardiac magnetic resonance (CMR) is uniquely suited to differentiating TTS from other forms of acute ventricular dysfunction associated with patent coronary arteries. In this setting CMR may have a major impact on both clinical and management and risk stratification. This review focuses on the emerging role of CMR in the diagnosis, clinical evaluation and risk stratification of TTS patients.

Cardiac Magnetic Resonance in Takotsubo Syndrome Cardiac magnetic resonance imaging has emerged as a first-line diagnostic tool for the assessment of TTS. In addition to visualizing the hallmark regional wall motion abnormalities that characterize the syndrome, CMR can identify the presence of reversible and irreversible myocardial damage (i.e. myocardial oedema and scarring, respectively).

CMR can also identify potential complications of TTS, such as LV outflow tract (LVOT) obstruction, valve disease, pericardial effusion and LV thrombus.

Steady state-free precession cine, phase contrast sequences, blackblood T2-weighted triple inversion recovery, first-pass perfusion, early gadolinium enhancement (EGE) and late gadolinium enhancement (LGE) sequences are the most widely used sequences in TTS. Other CMR techniques, such as T1 and T2 mapping techniques and feature/ tissue tracking, could be potentially contributive, though at present are used only for research purposes. Table 2 summarizes the CMR tools and information acquired in the setting of suspected TTS.

© RADCLIFFE CARDIOLOGY 2017

CMR in Takotsubo Syndrome Left Ventricular Function and Wall Motion Abnormalities One of the hallmarks of TTS is the presence of a reversible systolic impairment of LV function affecting mainly the LV apex. This regional wall motion abnormality extends beyond a single epicardial vascular distribution. Typically, a mid-cavity to apical ballooning with sparing of the LV basal segments occurs. However, other contraction patterns during the acute phase of TTS including mid-ventricular, basal and focal forms may be identified in up to 18 % of the cases.9 Complete recovery in 96 % of patients occurs within 7−37 days. It has been observed that typical and mid-ventricular TTS forms have more severe heart failure symptoms.10

Table 1: Proposed Pathophysiological Mechanisms of Takotsubo Cardiomyopathy Catecholamine-induced LV myocardial dysfunction Neurogenic stunning of the myocardium; impaired adrenergic neurotransmission Diffuse coronary endothelial function Multivessel epicardial coronary artery spasm Coronary microvascular dysfunction LV outflow tract obstruction and abnormal LV-arterial coupling Acute atherosclerotic plaque rupture in the left anterior descending coronary artery; aborted myocardial infarction with spontaneous coronary artery recanalization.

Overstimulation of the myocardial beta2-adrenoreceptor G1 pathway

With its high spatial resolution, CMR is the modality of choice for the assessment of ventricular function as well as regional wall motion.11 For structural abnormalities, free precession breath-hold cines in short and long axis and outflow tract are useful. The typical form presents with contraction abnormalities in the ventricular wall, equally affecting the anterior, inferior, and lateral walls, that extend beyond a single epicardial vascular territory. Another finding suggestive of TTS is the presence of basal segments hyperkinesia, contributing to the characteristic morphology.

Cardiac magnetic resonance may efficiently demonstrate biventricular involvement and correlate the functional pattern to the tissue properties of the myocardium. In a population of 31 TTS patients presenting predominantly with ST-elevation electrocardiogram, RV functional involvement was identified in half, with associated myocardial oedema in both functioning and malfunctioning segments, persisting for up to 4 months following the acute presentation, as measured by repeatedly abnormal native T1 mapping and increased extracellular volume measurements.12 With the use of left atrial (LA) functional indexes, CMR allows additionally for the assessment of the atrial function. Compared to anterior STEMI patients, TTC patients demonstrated a significantly decreased LA function as assessed by CMR volumetric indexes derived from fractional volume changes during the acute phase of the disease.

However, impairment of LA performance seems to be transient in TTS with full recovery during follow-up.13

LV = left ventricular.

emerging and more robust technique that provides a quantitative means to detect myocardial edema.21 Each tissue type exhibits a characteristic range of normal T1 and T2 relaxation times at a particular magnetic field strength.

Typically, T2-weighted sequences in TTS patients identify the presence of circumferential, transmural oedema of the apical to mid-cavity myocardium matching with the regional wall motion abnormalities.16 Myocardial oedema is a transient dynamic phenomenon, normally progressively resolving between 3 and 6 months. CMR has an excellent diagnostic accuracy in detecting myocardial inflammation in TTS. In a multicentre study by Eitel et al.,22 myocardial oedema was seen in 81 % of patients, whereas patchy delayed gadolinium enhancement was seen in 9 % of TC patients. Neil et al. found increased T2-weighted signal intensity, particularly at the apical cavity in all TTS patients, which persisted after 3 months and was inversely related to myocardial strain.23 Nakamori et al. monitored 23 TTS patients.24 Upon presentation, myocardial oedema on T2-weighted MRI was observed in 96 %, and LGE was observed in 22 %. All instances of LGE were observed in an area that exhibited both wall motion abnormalities and oedema in a transmural distribution.

In accordance with the above-mentioned data, myocardial oedema on CMR is a constant feature in TTS, reflecting acute inflammation.

Myocardial Necrosis Myocardial Inflammation Myocardial inflammation is a key tissue property in the acute phase of TTS, which was been shown to be reversible at follow-up.14 Hallmark changes in inflammation include myocardial hyperaemia, oedema and fibrosis, all of which can be non-invasively visualized using CMR imaging.15 The area of oedema corresponds to the area of wall motion abnormalities.16 The pathophysiological substrate explaining myocardial oedema in these patients has not been elucidated, even though the presence of inflammatory phenomena and transient ischaemia appear to play a pivotal role.

T2-weighted CMR is the standard imaging technique for detecting acute myocardial oedema in vivo.17,18 It is used extensively in the study of myocardial inflammation in acute and chronic myocarditis,15 as well as in the setting of ischaemic heart disease, for the differentiation of acute from chronic MI19 and for assessment of the area at risk.20 When global myocardial involvement is suspected, a quantitative approach is preferred, classically by calculating the SI ratio between myocardium and skeletal muscle. Parametric imaging (T1- and T2-mapping) is an

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In principle, myocardial oedema resolves without any myocardial scarring and with complete functional recovery (see Figure 1). The importance of detecting LGE, which reflects myocardial damage, in TTS patients relies on the observed association between the presence of LGE and poorer prognosis in both ischaemic and nonischaemic cardiomyopathies.25 Early CMR suggested that lack of LGE was a necessary condition to diagnose TTS,26 and would thus help differentiate it from MI, where LGE is always present to some degree, and myocarditis, where 88 % of patients show a patchy type of LGE.27 To assess for the presence/absence of scarring tissue, 10 min after contrast injection, short and long axis acquisitions identical to the ones done in cine mode, are performed using an inversionrecovery gradient echo sequence.28 In general, LGE indicates the relative changes of the extracellular and intracellular volumes. In contrast, T1 mapping sequences provide a different approach to tissue characterization, allowing for the measurement of intrinsic relaxation times of myocardium pre- and post-gadolinium infusion, not dependent on relative signal intensities.29

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Imaging Table 2: Clinical Usefulness of Cardiac Magnetic Resonance in Patients with Suspected Takotsubo Syndrome Properties

Technique

Sequence

Global and regional functional analysis

Cine imaging

Balanced steady-state free precession gradient echo

Myocardial inflammation

Oedema imaging

Black blood T2-weighted fast spin echo triple-inversion recovery

Myocardial necrosis

Late gadolinium enhancement

2D inversion-recovery gradient echo 5â&#x2C6;&#x2019;10 min after contrast administration

Myocardial perfusion

First-pass perfusion imaging After adenosine infusion (140mcg/kg/min) and contrast administration, single-shot turbo fast echo/turbo balanced echo

Complications Pericardial effusion

Black blood T1-weighted spin echo

Ventricular thrombus

Early gadolinium enhancement

2D inversion-recovery gradient echo <2 min after contrast administration

LVOT obstruction

Blood flow imaging

Phase contrast velocity encoding

LVOT = left ventricular outflow tract.

Figure 1: Cardiac Magnetic Resonance Exam of a 70-yearold Female Patient with Takotsubo Cardiomyopathy

studies (using thrombolysis in myocardial infarction frame counts, myocardial perfusion grading, intracoronary Doppler evaluation of vasomotor function, coronary flow reserve and thermodilution) and non-invasive studies (using Doppler echocardiography, myocardial contrast echocardiography and SPECT/PET metabolism/perfusion) have all demonstrated coronary microvascular dysfunction.3,37-40 The above data suggest abnormal perfusion properties within dysfunctional myocardial area in the acute phase, recovered at follow-up. According to the most accepted mechanism of TTS, which proposes a vigorous neurohumoral discharge precipitated by emotional stress, severe microvascular dysfunction could be expected, leading to secondary myocardial stunning. However, whether MVD is the causative factor or a consequence of this disorder remains elusive.

Although perfusion MRI is a well-established exam for the assessment of epicardial41 and microvascular42 ischaemia, there is practically no evidence of the use of perfusion CMR in TTS. Perfusion CMR, in particular with the use of quantitative techniques, may offer significant knowledge on the pattern of MVD in the acute and chronic phase of the disease.

Typical mid-to-apical ballooning in end-diastolic (A) and end-systolic (B) images (upper row).

Associated transmural increased signal on T2-weighted two-chamber (C) and basal (D), mid-ventricular (E) and apical (F) images, representing myocardial oedema (middle row).

Absence of myocardial necrosis is noted in the matched late gadolinium enhancement images (G, H, I and J, respectively).

Some isolated reports30,31 and, more recently, more significant studies,22,32,33 showed that LGE can happen in the context of TTS. However, experimental data show that delayed washout of gadolinium may be caused by increased interstitial water content associated with transient myocardial oedema, rather than irreversible myocardial necrosis/fibrosis.24 Rolf et al. performed multiple endomyocardial biopsies in sites with and without LGE in the acute phase and after recovery.34 All patients with TTS showed a significant increase of collagen-1 compared with control tissue. Moreover, the amount of collagen-1 was significantly higher in LGE-positive patients. There were no differences in the extent of oedema on T2-weighted measurements between groups. Sacha et al.35 and MarĂŠchaux et al.36 have previously reported cases of contractionband necrosis detected at autopsy, a possible explanation for LGE in patients with TTS. Broad evidence on the long-term (reversible or irreversible) presence of LGE and its prognostic value is lacking.

Complications Possible complications in TC include left heart failure with or without pulmonary oedema, acute pericarditis, mitral valve regurgitation, ventricular arrhythmias, intramural thrombus, stroke, LV free wall rupture35 and death.9 In addition to the accurate assessment of the cardiac function with cine imaging as well as the anatomical study of the myocardium, pericardium and valves, CMR offers accurate assessment of any intracavitary thrombus.43 With the use of EGE sequence, performed within 2 minutes after contrast agent infusion, a thrombus appears as a low signal intensity (no gadolinium uptake), nearly black, which makes contrast with the intermediate signal of myocardium and blood pool.

Risk Stratification Although TTS is widely considered as a benign reversible condition, its associated risk for major cardiac events in the acute and chronic phase is increasingly recognized.44 In fact, TTS represents an acute heart failure syndrome with substantial morbidity and mortality, comparable to patients with acute coronary syndromes. Physical triggers, acute neurologic or psychiatric diseases, high troponin levels and a low ejection fraction on admission are recognized as independent predictors for in-hospital and long-term adverse major cardiac events.

Myocardial Perfusion There is a growing body of evidence strongly implying a major role of microvascular dysfunction (MVD) in the pathogenesis of TTS. Invasive

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The clinical spectrum of TTS is considerably broad and a prospective study evaluating a precise CMR pattern related to outcome is lacking.

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CMR in Takotsubo Syndrome In the largest multicentre study in this field enrolling 239 consecutive patients with CMR at initial presentation, 1- and 6-month follow-up, a moderate-to-severe LV function reduction in all patients in the acute phase with associated myocardial oedema in 81 % and focal or patchy LGE in 9 % was identified. During follow-up, four patients died. In the remaining patients, there was full resolution of the above abnormalities. There was no relation between the occurrence of LGE and clinical presentation, mortality, age, sex, ECG pattern, or type of stress trigger.22 Naruse et al. reported, in a cohort of 20 patients with TTS, no significant differences in age, sex, congestive heart failure, peak creatine kinase, noradrenaline elevation, ECG abnormalities, ejection fraction, type of TTS and time from onset of symptoms to CMR in the LGE positive group.32 However, there was a greater prevalence of cardiogenic shock and longer time to normalize ECG and echocardiographic changes.

The incremental prognostic value of LGE in TTC is yet to be elucidated.

Although LGE is widely considered to be a marker associated with an increased frequency of cardiogenic shock, longer duration to resolution of wall motion abnormalities there are no large-scale studies so far to address this hypothesis. In a small CMR study including twenty TTS patients with a mean 11±9 months follow-up, the presence of LGE, reflecting irreversible myocardial damage, was not associated with adverse long-term outcomes as compared to patients with intact myocardium. 45

Differential Diagnosis As patients with TTS commonly present with symptoms similar to those among patients with an acute coronary syndrome, initial diagnosis and treatment of patients in the emergency setting remains challenging.

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In one study, troponin levels and electrocardiographic changes on admission were not sufficient to differentiate between these two disorders, as more than 80 % of patients with TTS had elevated troponin levels and nearly 80 % had signs of myocardial ischemia on initial electrocardiography.46 Notably, in another study examining the angiographic results in TTS patients, 15.3 % of patients had evidence of coexisting coronary artery disease on angiography, thus demonstrating that the presence of coronary artery disease does not preclude the diagnosis of the syndrome.47 The combination of typical regional wall motion abnormalities with matching reversible myocardial oedema and no or subtle delayed enhancement may serve as a very useful set of diagnostic criteria in cases with myocardial infarction with non-obstructive coronary artery disease (MINOCA), 48 helping in particular to distinguish TTS from embolism and myocarditis. Preliminary data demonstrate that in 125 patients with a presumed diagnosis of TTS examined with CMR cine and LGE imaging, 29 % were ultimately diagnosed with apical infarction. 49

Conclusion CMR is a first-line modality for the assessment of TTS, offering a comprehensive, safe and reproducible assessment of the myocardial functional and anatomical properties, as well as of the potential complications of the syndrome. This information allows determination of diagnosis and differentiation from other acute entities with similar clinical presentation. Further large-scale studies are required to elucidate the exact clinical and prognostic value of CMR parameters in the management of the disease. n

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Sacha J, Maselko J, Wester A, et al. Left ventricular apical rupture caused by Takotsubo cardiomyopathy – comprehensive pathological heart investigation. Circulation 2007;71:982–5. DOI: 10.1253/circj.71.982.

Marechaux S, Fornes P, Petit S, et al. Pathology of inverted Takotsubo cardiomyopathy. Cardiovas Pathol 2008;17:241–3. DOI: 10.1016/j.carpath.2007.08.002; PMID: 18402803.

Jain M, Upadaya S, Zarich SW. Serial evaluation of microcirculatory dysfunction in patients with Takotsubo cardiomyopathy by myocardial contrast echocardiography.

Clin Cardiol 2013;36:531–4. DOI: 10.1002/clc.22154; PMID: 23797947.

Afonso L, Bachour K, Awad K, Sandidge G. Takotsubo cardiomyopathy: pathogenetic insights and myocardial

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Feola M, Chauvie S, Rosso GL, et al. Reversible impairment of coronary flow reserve in Takotsubo cardiomyopathy: a myocardial PET study. J Nucl Cardiol 2008;15:811–7. DOI: 10.1007/BF03007363; PMID: 18984457.

Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 2013;6:660–7.

DOI: 10.1016/j.jcmg.2012.12.011; PMID: 23643286.

Hamirani YS, Kramer CM. Cardiac MRI assessment of myocardial perfusion. Future Cardiol 2014;10:349–58. DOI: 10.2217/fca.14.18; PMID: 24976472.

Ismail TF, Hsu LY, Greve AM, et al. Coronary microvascular ischemia in hypertrophic cardiomyopathy – a pixel-wise quantitative cardiovascular magnetic resonance perfusion study. J Cardiovasc Mag Res 2014;16:49. DOI: 10.1186/s12968014-0049-1; PMID: 25160568.

Weinsaft JW, Kim HW, Crowley AL, et al. LV thrombus detection by routine echocardiography: insights into performance characteristics using delayed enhancement CMR. JACC Cardiovasc Imag 2011;4:702–12. DOI: 10.1016/j. jcmg.2011.03.017; PMID: 21757159.

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score (InterTAK Diagnostic Score) to differentiate Takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry. Eur J Heart Fail 2016. DOI: 10.1002/ejhf.683; PMID: 27928880.

Bellera MN, Ortiz JT, Caralt MT, et al. Magnetic resonance reveals long-term sequelae of apical ballooning syndrome.

Int J Cardiol 2010;139:25–31. DOI: 10.1016/j.ijcard.2008.08.023; PMID: 18804880.

Sharkey SW, Windenburg DC, Lesser JR, et al. Natural history and expansive clinical profile of stress (Tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010;55:333–41. DOI: 10.1016/j.jacc.2009.08.057; PMID: 2011743.

Parodi G, Citro R, Bellandi B, et al. Tako-tsubo cardiomyopathy and coronary artery disease: a possible association. Coron Artery Dis 2013;24:527–33. DOI: 10.1097/ MCA.0b013e3283645c4e; PMID: 23863780.

Syed IS, Prasad A, Oh JK, et al. Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging. Int J Cardiovasc Imag 2008;24:875–82. DOI: 10.1007/s10554-008-9320-6; PMID: 18504646.

Ghandi H RJ, Reynolds H. Takotsubo cardiomyopathy vs apical infarction in patients with myocardial infarction and non-obstructive coronary artery disease (MINOCA).

66th Scientific Session & Expo of the American College of Cardiology 2017.

EUROPEAN CARDIOLOGY REVIEW

Cardiology Masters

In the Cardiology Masters section of European Cardiology Review we bring you an insight into the career of a key contributor to the field of cardiology.

In this edition, we feature Professor Carlo Patrono, Adjunct Professor of Pharmacology at the Catholic University School of Medicine in Rome, Italy, and at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

Prof Patronoâ&#x20AC;&#x2122;s main research interest is in the study of platelet activation and inhibition in atherothrombosis and colorectal cancer.

His research has characterised the human pharmacology of aspirin as an inhibitor of platelet cyclooxygenase (COX)-1, and provided the basis for the development of low-dose aspirin as an antithrombotic agent. During the past decade, Prof Patrono has contributed to characterising the human pharmacology of COX-2 inhibitors and evaluating their cardiovascular effects in different clinical settings.

His international experience includes working for 4 years in academic institutions in the USA (Mount Sinai School of Medicine, New York, and University of Pennsylvania School of Medicine, Philadelphia), and in the UK (Royal Postgraduate Medical School, London).

His current international collaborations include the Clinical Trials Unit of the UK Medical Research Council in London (Prof Ruth Langley), the Clinical Trials Service Unit of the University of Oxford (Prof Colin Baigent) and the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania (Prof Garret FitzGerald).

He is an elected member of the Association of American Physicians, Royal College of Physicians, European Society of Cardiology, Academia Europaea and Accademia dei Lincei.

He has received the Alexander B Gutman award from the Mount Sinai School of Medicine, the Distinguished Award in Neuroscience from the Louisiana State University, the 1998 International Aspirin Award from Bayer AG, the 2007 John Vane Award from the William Harvey Research Institute of the University of London, the 2011 Outstanding Achievement Award of the Eicosanoid Research Foundation (shared with Garret FitzGerald), the 2013 Grand Prix Scientifique awarded by the Institut de France (shared with Garret FitzGerald) and the 2013 Lifetime Achievement Award of the European Association for Clinical Pharmacology and Therapeutics (shared with Sir Michael Rawlins).

He is a Section Editor of the Journal of the American College of Cardiology, and a member of the scientific advisory boards of the Dutch Heart Foundation, William Harvey Research Institute and International Aspirin Foundation.

Prof Patrono has published over 220 research articles with over 49,000 citations and an H-index of 95.

I

was 17 when I decided I wanted to study medicine, but there was a time when I thought I wanted to pursue a diplomatic career.

Born and raised in Rome, my parents had a very close friend who worked for an American organisation based in Geneva, so as a teenager, I would often visit Switzerland and be exposed to an international environment, which seemed to trigger an interest in a diplomatic career, but the prevailing influence was my father, who was a physician and endocrinologist, who talked to me about medicine, research and science. By the time I was 17, I was single minded about medicine.

I also liked the idea of doing research that was immediately applicable to human beings, and was more interested in studying man rather than rats or rabbits, so I chose pharmacology straight after getting my medical degree; I felt that it was close enough to clinical medicine among the basic sciences to be a good starting point. Eventually, I contributed to developing clinical pharmacology in my own country.

Š RADCLIFFE CARDIOLOGY 2016

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Cardiology Masters New York A few months later, I was fortunate enough to go New York to train as a Postdoctoral Fellow at the Bronx Veterans Administration Hospital with two outstanding scientists, Rosalyn Yalow and Solomon Berson, to learn what was a new technique at the time: radioimmunoassay.

Based on what I had read, it looked like this new methodology could be a key step towards investigating various kinds of mediators in humans, by being able to measure very low concentrations of autacoids and hormones in blood or urine. Yalow received a Nobel Prize for her joint work with Berson on the discovery of radioimmunoassay in 1977, although sadly, Berson had died prematurely a few years earlier. It was a privilege working with them.

I spent 2 years in New York (between 1969 and 1971) and during the first year, because Yalow and Berson were studying various peptide hormones related to diabetes. They asked me to start working on a peptide hormone called ‘glucagon’, and it was here that I became interested in prostaglandins.

My team of young students and post-docs and I were conducting pioneering studies at the Catholic University School of Medicine in Rome on the human pharmacology of platelet thromboxane inhibition by aspirin. We published the first paper in 1980 on the methodology of serum TXB2 measurement, and a second in 1982 describing the cumulative nature and biochemical selectivity of platelet TXB2 inhibition by low-dose aspirin. These papers were really the foundations of work establishing low-dose aspirin as a potential therapeutic strategy to prevent and treat CVD. During this time, a widely-held view was that aspirin acted as a potential antithrombotic agent at high doses taken three to four times daily (i.e. 1,000–1,500 mg daily), and this was based on a variety of platelet function tests, as well as on the idea that there were dose-dependent antithrombotic effects of aspirin unrelated to COX-1 inhibition. So when we proposed that what aspirin was doing was essentially related to the inhibition of thromboxane production requiring a single daily administration of a very low dose, as low as 30–50 mg, this was initially taken with a high dose of scepticism.

Radioimmunoassay It was an incredible time in a very international lab, and after a brief interlude, when I went back to Rome to marry the love of my life, I returned with Angela for my second year there. At this stage, the focus was to apply the radioimmunoassay methodology that had been developed for measuring peptide hormones to a small molecule of lipid nature, that is, a prostaglandin. I did this by coupling this small molecule to human albumin to make it antigenic and recognisable by the immune system of guinea pigs that were injected with this conjugate to raise antibodies that would specifically recognise the small molecule attached to the large protein.

By the end of 1971, when I went back to Rome, I had developed the very first antibody against a prostaglandin. It felt like I had a unique instrument in my hand. It was a lucky time for me as a pharmacologist, because that year, three papers were published in the same issue of Nature describing the inhibition of prostaglandin synthesis as the mechanism of action of aspirin and aspirin-like drugs.

None of the known prostaglandins at the time had any influence on platelet function, so we had to wait a few years until a Swedish group, led by Prof Bengt Samuelsson, discovered thromboxane (TX) A2 as the main prostanoid produced by activated platelets that was inhibited by aspirin and had a potent pro-aggregatory action.

Samuelsson subsequently shared the Nobel Prize with the British pharmacologist Sir John Vane, who had made the initial observation of inhibition of prostaglandin synthesis as the mechanism of action of aspirin.

I was convinced that the inhibition of prostanoid formation was the key mechanism of action necessary and sufficient to explain all of the major pharmacological activities of aspirin: analgesia, reduction in inflammation, the antipyretic and antiplatelet effects, as well as its gastrointestinal toxicity.

There was another rationale for favouring low-dose aspirin: in 1976, Sir Salvador Moncada and his colleagues had discovered that vascular endothelial cells produce another prostanoid called prostacyclin (PGI2), which has opposite effects to those of TXA2; it prevents platelet aggregation and relaxes blood vessels. Therefore, it seemed logical to try to find out how to separate these two potential effects of aspirin, by selectively inhibiting platelet TXA2 production, while sparing vascular PGI2 biosynthesis.

Aspirin Myocardial Infarction Study Our studies of low-dose aspirin took place at a time when a big trial, called the ‘Aspirin Myocardial Infarction Study’ (AMIS), was published.

It was a multicenter, randomised, double-blind, placebo-controlled trial of 1,000 mg of aspirin daily in over 4,500 men and women who had had a documented MI. It was a total fiasco; total mortality, which was the primary endpoint of the study, was numerically higher in the aspirin-treated patients compared to the placebo-treated group, and routine use of aspirin after MI was not recommended as a result.

So that closed the loop; human platelets produce a prostanoid that makes them aggregate, and aspirin blocks the production of this prostanoid, TXA 2. This was mid-1970s, the starting point of my research on the clinical pharmacology of platelet inhibition by aspirin, and of my interest in how this could influence cardiovascular disease (CVD).

Our 1982 Journal of Clinical Investigation (JCI) paper, entitled ‘Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects’, demonstrated that if you substantially lower the daily dose of aspirin, you can completely inhibit platelet thromboxane production and not interfere with the production of prostacyclin. Dose-dependent inhibition of prostacyclin biosynthesis, as characterized by Garret FitzGerald in a 1983 JCI paper, could hamper the antithrombotic effect of aspirin and be responsible, at least in part, for the negative findings of the AMIS trial.

Cyclooxygenase and Low-Dose Aspirin Research

Collaboration

We then started developing antibodies against TXB2, a stable derivative of TXA2, and by the end of the 1970s, we had developed an original method to investigate inhibition of platelet cyclooxygenase (COX) activity, based on TXB2 production during whole blood clotting.

This was an amazing time, and it was around then that I met my colleague and friend Garret FitzGerald, an Irish-born clinical pharmacologist doing similar aspirin studies at Vanderbilt University in Nashville, based on measurements of urinary prostanoid metabolites.

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Cardiology Masters: Prof Carlo Patrono There was also another group led by haematologist Philip Majerus at the Washington University in St Louis that had discovered the molecular mechanism of platelet COX-1 inactivation by aspirin, and was looking at the human pharmacology of platelet inhibition with a different methodology, based on indirect measurements of the extent of acetylation of the platelet enzyme. So by the mid-1980s, three independent groups using different methodologies concluded the same thing: that a single, daily, low dose of aspirin could completely block this important pathway of platelet aggregation.

I met Garret FitzGerald at an international pharmacology meeting in Japan in 1981, and we realised that we were competing with each other, but after a few discussions and mutual visits decided that it would be interesting to collaborate in studying thromboxane biosynthesis and metabolism in man. This was the start of a very long friendship that is lively and vivid today. It was our independent work on the development of low-dose aspirin as an antithrombotic drug that was the reason we were jointly awarded the 2013 Grand Prix Scientifique by the Institut de France, perhaps the most prestigious award in the field of cardiovascular research.

Receiving the Grand Prix Scientifique in the beautiful setting of the Institut de France in Paris was probably one of the most gratifying moments in my scientific career.

The Turning Point: International Study of Infarct Survival-2 Going back to the mid-1980s, probably one of the most important trials in cardiovascular research was set up in Oxford by a multidisciplinary team led by Sir Rory Collins, Sir Richard Peto and Prof Peter Sleight: The International Study of Infarct Survival-2 (ISIS-2), a randomised, placebo-controlled trial of streptokinase, aspirin (one-sixth of the dose used in AMIS), both or neither in over 17,000 patients with a suspected acute MI. For the first time, it was shown that lowdose aspirin once daily was effective and safe in reducing vascular mortality at 5 weeks by approximately one-quarter, which was quite an impressive (and perhaps unexpected) finding. It also demonstrated an additive effect of using both aspirin and streptokinase, reducing vascular mortality by approximately 40 %. ISIS-2, published in The Lancet in 1988, established a new treatment paradigm in acute MI. It also made three important points: (i) coronary atherothrombosis is a dynamic process; (ii) platelet TXA2 production plays an important role in this process; and (iii) low-dose aspirin is a life-saving drug.

There has since been a flow of other randomised studies testing the efficacy and safety of low-dose aspirin for the acute treatment and long-term prevention of both coronary and cerebrovascular atherothrombosis. Given the largely independent nature of these clinical trials, mostly funded by research grants, it became important to promote dissemination of their knowledge and implementation of their results. I played an active role in this endeavour, by participating in the Antithrombotic Trialists’ Collaboration that performed several collaborative meta-analyses of randomised trials of antiplatelet therapy for the prevention of death, MI and stroke in high-risk patients, under the leadership of Prof Colin Baigent; by acting as the Antiplatelet Chapter Chair of the American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy, which periodically summarised the evidence for the efficacy and safety of low-dose aspirin (and other antiplatelet agents) in different clinical settings, translating the evidence into treatment guidelines,

EUROPEAN CARDIOLOGY REVIEW

under the leadership of Prof Jack Hirsh; and chaired or co-chaired various task forces of the European Society of Cardiology, with a similar scope.

Aspirin Resistance?

During the past 10 years, together with Prof Bianca Rocca, we have revisited the clinical pharmacology of low-dose aspirin in different patient populations at high cardiovascular risk to verify the actual occurrence of ‘resistance’ to its antiplatelet effect, as described by an impressive number of studies published in respected cardiology journals. In contrast to the highly-variable results of platelet aggregation measurements, true pharmacological resistance to the COX-1 inhibitory effect of low-dose aspirin is a very rare phenomenon in patients who actually take aspirin and do not concomitantly take other non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen or naproxen) that might interfere with aspirin pharmacodynamics.

However, our studies have characterized substantial interindividual variability in the rate of recovery of platelet TXA2 production during the 24-hour dosing interval in clinical settings characterised by accelerated renewal of platelet COX-1, such as type-2 diabetes mellitus and essential thrombocythemia. This abnormal biochemical phenotype could be reversed by twice daily dosing of aspirin 100 mg, but not by doubling the once daily dose. These findings have led to new clinical trials being initiated to test the clinical efficacy and safety of this novel dosing strategy.

COX-2 Soon after the withdrawal of rofecoxib (Vioxx), announced on 30 September 2004 because of clear evidence of a cardiovascular hazard associated with selective COX-2 inhibition in a colorectal adenoma prevention trial (APPROVe), together with Colin Baigent, with whom I shared common research interests, complementary expertise and a long-standing friendship, we initiated the Coxib and Traditional NSAID Trialists’ (CNT) Collaboration to gather individual patient data from all randomised trials that recorded the gastrointestinal and cardiovascular complications caused by COX-2 inhibitors. This was meant to address a series of open questions concerning the benefit/risk profile of individual inhibitors, both the newer coxibs and traditional NSAIDs, such as naproxen, ibuprofen and diclofenac. The results of the CNT meta-analyses represent the most comprehensive source of information for evidence-based regulatory action and treatment guidelines.

The main paper we have published in The Lancet (2013) demonstrates that the increased risk of atherothrombotic complications (mainly coronary events) is not just a problem of the newer COX-2 inhibitors, but is shared by some traditional NSAIDs, in particular diclofenac and ibuprofen, that do not adequately inhibit platelet TXA2 production while suppressing vascular PGI2 biosynthesis. This ultimately led to some regulatory revisions and restrictions of these drugs for people with high cardiovascular risk by the US Food and Drug Administration and European Medicines Agency. Mechanistically, these findings are consistent with an important role of COX-2-dependent PGI2 biosynthesis in endothelial thromboresistance, as characterised by the pioneering studies of Garret FitzGerald in the late 1990s.

Aspirin and Colorectal Cancer I became interested in the evidence for an association between NSAID use and the reduced risk of colorectal cancer (CRC) by listening to and collaborating with expert epidemiologists, such as Michael Thun

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Cardiology Masters and Luis Garcia Rodriguez, and gastroenterologists, such as Angel Lanas. When Thun and I reviewed the mechanistic, pharmacologic and clinical issues related to NSAIDs and cancer for the Journal of the National Cancer Institute in 2002, we emphasised the apparent lack of a dose-response relationship in many studies that investigated the chemopreventive effect of aspirin.

It came to my mind that perhaps aspirin was working in cancer prevention through a mechanism analogous to coronary disease prevention, that is, by inhibiting platelet activation and downregulating the participation of platelets in tissue repair, angiogenesis and immune response. So I started developing the idea that the inhibition of platelet activation at sites of mucosal injury throughout the gastrointestinal tract might be a relevant mechanism of action of lowdose aspirin in the initial stage of colorectal carcinogenesis, and that by interfering with this early event, it could prevent the development of CRC. This idea was first articulated in a 2001 JCI review article written with Paola Patrignani and Luis Garcia Rodriguez.

Then came at least four placebo-controlled, randomised studies, published between 2003 and 2008, that to some extent confirmed this hypothesis by showing that low-dose aspirin (as low as 81 mg, the lowest dose on the US market) could prevent the recurrence of colorectal adenoma in people who had their sporadic colorectal adenoma removed at screening colonoscopy.

Subsequent studies by Prof Peter Rothwell in Oxford addressed the question of what happened in people randomised to receive aspirin or placebo for cardiovascular prevention in terms of long-term cancer incidence and mortality. Rothwell et al. published several papers in The Lancet from 2007 up to 2012, which showed that over long-term follow-up, there was a lower incidence and mortality from CRC and other cancers in people who had received aspirin for 3â&#x20AC;&#x201C;5 years compared to people who had received placebo for the same duration. Interestingly enough, this apparent chemopreventive effect was detectable in aspirin trials using as low as 75 mg daily, and there was no convincing evidence that higher doses (<1,200 mg daily) were more effective.

These interesting observations provided further stimulus to collaborative mechanistic studies performed by Prof Paola Patrignani at the University of Chieti-Pescara (Chieti, Italy) and Prof Angel Lanas

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at the University of Zaragoza (Zaragoza, Spain). Understanding the mechanism of action of low-dose aspirin in CRC prevention is currently attracting a renewed research interest of many scientists, and both animal and human studies are addressing this puzzling question through international multidisciplinary collaboration. Eventually, this could lead to characterising common mechanisms of disease in coronary atherothrombosis and CRC, and perhaps opening a new dimension to antiplatelet drug therapy.

Collaboration and Running I have enjoyed pursuing these different lines of research through international collaboration, which has always been important in my scientific career. In fact, some of my best discussions have taken place while running with colleagues at conferences. I have been running long distances, including taking part in marathons, and found that not only has it been instrumental in seeing new places but also a great way to exchange ideas under the influence of increased endorphins, which seem to help the unrestrained flow of novel ideas.

Garret FitzGerald and I have run together in many parts of the world and shared some interesting scientific and political discussions.

Advice for the Young If I could offer advice for young people entering the field of medicine/ pharmacology, I would say try to be persistent in what you do, and try to pursue your ideas through multidisciplinary collaboration. Also be aware that it is essential to develop scientific independence from your mentor and to get funded for what you want to do, so spend enough time learning how to write a proper grant application. And finally, while competition is inevitable in biomedical research, collaboration is an important key to success.

Research is a wonderful and rewarding career, because it allows you to pursue your own scientific curiosity, and potentially have an impact on the health of many people worldwide.

Teamwork I have had the privilege of working in Rome and Chieti with a team of talented scientists and clinical investigators, including Giovanni Ciabattoni, Paola Patrignani, Giovanni DavĂŹ, Bianca Rocca, Francesca Santilli, Dario Pitocco and Alfredo Dragani. Their generous dedication and resilience should be credited for our contributions to the field of aspirin research. n

EUROPEAN CARDIOLOGY REVIEW

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

European Cardiology Review Volume 12 • Issue 1 • Summer 2017

Radcliffe Cardiology

Volume 12 • Issue 1 • Summer 2017

www.ECRjournal.com

Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Marie Mide Michelsen, Naja Dam Mygind, Daria Frestad and Eva Prescott

Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, Brittany Edgar, Wendy Lin, Maria Auxiliadora Parreiras Martins, Michael K Paasche-Orlow and Jared W Magnani

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Supporting life-long learning for cardiovascular professionals Guided by Editor-in-Chief Juan Carlos Kaski and an Editorial Board comprising of world-renowned physicians, European Cardiology Review is a peer-reviewed journal that publishes reviews, case reports and original research. Available in print and online, European Cardiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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