Value-Based Care Cardiometabolic Health May 2012, Vol 1, No 1 by Value-Based Cancer Care

AMERICAN COLLEGE OF CARDIOLOGY 2012 HIGHLIGHTS* MAY 2012, VOL 1, NO 1

Value-Based Care Cardiometabolic Health

F R O M T H E P U B L I S H E R S O F A M E R I CA N H E A LT H & D R U G B E N E F I T S

Lipid-Lowering Drug Pipeline: ACC Launches Legends of Is Life After Statins Cardiovascular Medicine Series There By Wayne Kuznar Eugene Braunwald on advances in acute myocardial infarction

Photo taken at ACC 2012.

By Mary Mosley

Chicago, IL—“There is life beyond statins, and the next 10 years will be as exciting, and hopefully beneficial, to patients as the statin era has been,” said Evan A. Stein, MD, PhD, Director, Metabolic and Atherosclerosis Research Center, Cincinnati, OH, in review of the current landscape for lipid-modifying drugs at the 2012 Annual Meeting of the American College of Cardiology. He summarized the current data behind 2 new classes of drugs: apolipoprotein (Apo) B antisense drugs and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors. ApoB Antisense Drugs Mipomersen is an injectable ApoB antisense drug that inhibits the release

Chicago, IL—Kicking off the new Legends of Cardiovascular Medicine series during the 2012 American College of Cardiology meeting, Eugene Braunwald, MD, FRCP, Distinguished

Hersey Professor of Medicine at Harvard Medical School, and Chairman of the Thrombolysis In Myocardial Infarction (TIMI) Study Group at Continued on page 23

New Oral Anticoagulants Show Superior Efficacy versus Warfarin, and No Need for Monitoring By Wayne Kuznar Chicago, IL—The new oral anticoagulants—the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis), and the direct thrombin inhibitor dabigatran (Pradaxa)—are superior to war-

farin (Coumadin) in preventing stroke and systemic embolism in patients with atrial fibrillation (AF), according to a review/meta-analysis conducted Continued on page 20

*This publication is not endorsed by nor associated with the American College of Cardiology.

Continued on page 16

Value-Based Purchasing: Cardiologists Urged to Move from Quantity to Quality of Care By Mary Mosley Chicago, IL—Value-based purchasing (VBP), a program created by the Affordable Care Act (ACA) and administered by the Centers for Medicare & Medicaid Services (CMS), uses pay for performance for hospital payment of inpatient acute care services to shift the emphasis to paying for care quality not quantity. Physicians should understand VBP, because it represents an opportunity to work with hospitals to

increase their own compensation, said Gregory D. Timmers, MD, Prairie Cardiovascular Consultants, Springfield, OH, at the 2012 American College of Cardiology meeting. Physician compensation is changing in concert with changes in healthcare delivery. The shift of ancillary services from the physician office to the hospital outpatient setting is one example Continued on page 6

INSIDE HEALTH ECONOMICS . . . . . . . . . . .6 Coronary CTA cost-effective in CAD What parameters determine value in CVD imaging? HYPERTENSION . . . . . . . . . . . . .13 New JNC-8 guidelines expected by year end Consider combination therapy for low- and high-risk hypertension LIPID DISORDERS . . . . . . . . . . .15 Lipid-lowering drug pipeline Monoclonal antibody produces powerful LDL-C reductions

of Apo B-100, an important structural and functional component of lipoproteins, from the liver. Blocking Apo B100 release blocks the production of very-low-density lipoprotein, lowdensity lipoprotein (LDL), and lipoprotein (Lp) (a), said Dr Stein. The drawback to studying ApoB antisense drugs has been the 6 months it takes to achieve maximum effect on ApoB and LDL cholesterol (LDL-C) levels, “making it difficult to do doseranging studies,” he said. Although the primary effect of mipomersen is on ApoB production, it has an equal effect on LDL-C reduction, Dr Stein pointed out. It has dosedependent efficacy; at 400 mg weekly, mipomersen monotherapy reduces

ATRIAL FIBRILLATION . . . . . . . .17 New drug therapies for difficult-tocontrol AF HEART FAILURE . . . . . . . . . . . . .21 Blood test for galectin-3 identifies patients at risk in the community setting Advances in stem-cell therapy for HF CVD MANAGEMENT . . . . . . . . .23 Gene expression a new way to identify obstructive CAD Value of remote disease management of arrhythmia highlighted at ACC 2012 PAYER PERSPECTIVE . . . . . . . .28

FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTA (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. TRADJENTA has not been studied in combination with insulin.

a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. MACROVASCULAR OUTCOMES There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

Important Safety Information

ADVERSE REACTIONS

CONTRAINDICATIONS

Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS USE WITH MEDICATIONS KNOWN TO CAUSE HYPOGLYCEMIA Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

TRADJENTA delivers proven glycemic control Placebo-adjusted mean change in A1C at 24 weeks (%)

Significant A1C reductions from baseline at 24 weeks †

-0.2

-0.4

TRADJENTA monotherapy 1,2* (n=333) P<0.0001

-0.6

-0.8

TRADJENTA + metformin 2,3† (n=513) P<0.0001

-0.6% -0.7%

A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufﬁcient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. Results are adjusted for a 0.15% mean A1C increase for placebo and 0.5% mean decrease for TRADJENTA in add-on combination with metformin. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

*A randomized, multicenter, double-blind, placebo-controlled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Results adjusted for a 0.3% mean A1C increase for placebo and 0.4% mean decrease for TRADJENTA monotherapy. Full analysis population using last observation on study.

TRADJENTA: Experience dosing simplicity No dose adjustment required, regardless of declining renal function or hepatic impairment4 TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

ENTA J D A R T 30 5 MG # O QD Sig: i P ILLS x2 REF

One dose, once daily for adult patients with type 2 diabetes

TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure [1 per 538 person-years]) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efﬁcacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(03/12) TJ184308PROFB

milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI FEB132012 References: 1. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle H-J, Dugi K. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. 4. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28:447-459.

Please see brief summary of full Prescribing Information on the adjacent page.

Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in combination with insulin. CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in *5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in *2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in * 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to Table 1

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and *1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment. OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in *2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

TJ-BS (7-11)

TJ104305PROF

In This Issue Value-BasedCare Cardiometabolic Health

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Executive Vice President Chuck Collins Engaged Managed Markets ccollins@engagehc.com 732-992-1894 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 National Accounts Manager Zach Ceretelle zach@engagehc.com 732-992-1898 Senior Production Manager Lynn Hamilton

HEALTH ECONOMICS Cost-effective imaging: what parameters determine value? Coronary CTA cost-effective in CAD More…..

ATRIAL FIBRILLATION New drug therapies for difficult-to-control AF Comparative effectiveness analysis of antithrombotics in older patients More…..

ACUTE CORONARY SYNDROME Benefits of inexpensive glucose-insulinpotassium solution Value of new oral anticoagulants in ACS still unclear More…..

HEART FAILURE Blood test for galectin-3 identifies patients at risk in the community setting Advances in stem-cell therapy for HF More…..

HYPERTENSION New JNC-8 guidelines expected by year end Combination therapy for low- and high-risk hypertension More…..

CVD MANAGEMENT Levels of gene expression a new, noninvasive way to identify obstructive CAD Value of remote disease management of arrhythmia highlighted at ACC More…..

LIPID DISORDERS Lipid-lowering drug pipeline Monoclonal antibody produces powerful LDL-C reductions More…..

Quality Control Director Barbara Marino Business Manager Blanche Marchitto Mission Statement

Value-Based Care in Cardiometabolic Health provides a forum for payers, providers, and the entire cardiometabolic team to consider the cost-value issues particular to cardiovascular and metabolic treatments. This unique focus is achieved through news coverage from major professional meetings and the literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com.

Value-Based Care in Cardiometabolic Health, ISSN applied, is published 3 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Cardiometabolic Health is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Cardiometabolic Health do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Cardiometabolic Health should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Value-Based Care in Cardiometabolic Health, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VOL 1

NO 1

PAYER PERSPECTIVE By Gary M. Owens, MD

EDITORIAL BOARD EDITOR-IN-CHIEF

GOVERNMENT

PHARMACY BENEFIT DESIGN

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Senior Counselor, Fleishman-Hillard

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

HEALTH INFORMATION TECHNOLOGY

William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

DEPUTY EDITORS

Joseph E. Couto, PharmD, MBA Assistant Professor, Jefferson School of Population Health Director, Health Economics and Outcomes Research Fellowship Program Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York EMPLOYERS

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL HEALTH & VALUE PROMOTION

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

MAY 2012

Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

Health Economics

Value-Based Purchasing: Cardiologists Urged... of decreasing revenue for physician groups. Dr Timmers advised physicians to be proactive and engage with hospitals regarding VBP to reduce costs and improve resource utilization, with savings being a metric for reimbursement to offset lost revenue streams. The majority of the initial clinical process care measures are cardiology related, representing a concrete opportunity for cardiologists to lead. VBP begins in October 2012 (fiscal year 2013). VBP and Care Integration VBP, along with accountable care organizations (ACOs), is part of a new concept established by CMS—a care model that moves from volume to value. Physicians and ACOs will be accountable for quality and efficiency, including lower costs per patient en-

Key Points ➤ VBP is part of a new concept for a care model that moves from volume to value ➤ The VBP program has 2 components: compensation for core measures and for patient satisfaction ➤ A notable change for cardiologists is that CMS is first increasing costs to patients and then directing patients to the provider who can deliver their CV care, rather than patients selecting their provider

counter and per capita (ie, utilization) and improved coordination across the care continuum. CMS has 3 stated aims with VBP—better care for individuals, better health for populations, and lower per-capita costs. Regardless of the disposition of the ACA, a private– public dynamic related to quality and costs will continue, said Dr Timmers. The VBP program has 2 components —compensation for core measures (70% of total score) and compensation for patient satisfaction (30% of total score). The development of the core measures began in 2002 by the Joint Commission and CMS. The VBP core measures are a subset of this list of full core measures. A large proportion of the core measures are based on cardiovascular (CV) components, which Dr Timmers said is not surprising, because CV care comprises approximately 40% of the Medicare dollars spent. Provider-based billing incentivizes the integration of care providers (ie, hospitals and physicians) and better decision-making for healthcare expenditures by patients who will be paying more through deductibles and copays under healthcare reform. The movement of ancillary services to the hospital from the physician office is one motivator for integration. A notable change that is coming for cardiologists, as part of the population-risk management goal, is that CMS is first increasing costs to patients and then directing patients to the provider who can deliver their CV care, rather than patients selecting their provider. This will have a signif-

icant impact on cardiologists, because an estimated 60% to 65% of their current patient population comprises Medicare patients.

VBP represents an opportunity for physicians to work with hospitals to increase their own compensation. VBP, along with ACOs, is part of a care model that moves from volume to value. —Gregory D. Timmers, MD

How VBP Works VBP represents a continuation of the existing inpatient quality reporting. Value-based payments are made to hospitals that meet performance standards. Initially there are 12 core clinical measures and 8 patient satisfaction measures, called HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems). In year 1, there is a 1% reduction in diagnosisrelated group payments to the hospital in fiscal year 2013, increasing 0.25% annually up to 2% at 5 years. VBP is a revenue-neutral program, with Medicare withholding payments and hospitals earning back funds based on the performance measures. HCAHPS represents an effort by Medicare to ensure that patients who are directed to specific hospitals or physician

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groups are receiving fair, equitable, and good care, according to Dr Timmers. How Does VBP Impact Physicians? Care integration strategies and the employment of physician groups represent the greatest impacts on physicians. Physicians excel at coordinating delivery of care and providing high patient satisfaction. One approach is for physicians to work with the hospital to substitute these new VBP measures, which have real dollars attached to them, for the current metrics used for physician compensation. A recent survey by MedAxiom shows that of the hospital-acquired physician groups, 57% have incentives to improve quality and 47% have incentives to improve other metrics. Cardiologists can use the VBP components that have compensation from Medicare for these incentives, Dr Timmers recommended. Medical director agreements and CV comanagement agreements also include bonus options and represent an opportunity to include VBP performancebased measures required of hospitals; physicians increase their compensation, and hospitals meet their mandates. Physician groups that include the VBP revenue component in their agreements with hospitals have the potential to recoup revenue lost when ancillary services were moved to the hospital. The shift to value-based care will continue, and understanding the various programs and incentives will benefit the CV community. ■

Coronary Computed Tomography Angiography Cost-Effective in CAD By Mary Mosley Chicago, IL—Diagnostic accuracy is the primary determinant of cost-effectiveness of medical imaging for patients with chronic coronary artery disease (CAD), stated Matthew J. Budoff, MD, Professor of Medicine at David Geffen School of Medicine at University of California Los Angeles (UCLA), and Director of Cardiac CT at Harbor-UCLA Medical Center, Torrance, CA, at the 2012 American College of Cardiology meeting. Coronary computed tomography angiography (CTA) as currently performed has the highest diagnostic accuracy, with a sensitivity of 95% and specificity of 83%, followed by pharmacology nuclear imaging (89% sensitivity, 75% specificity). Exercise electrocardiogram has the lowest diagnostic accu-

racy (68% sensitivity, 77% specificity). Patient selection for testing is poor, and improvement is needed to achieve cost-effectiveness. A total of 62% of patients sent to the diagnostic catheterization laboratory to rule out CAD do not have it, according to data from the 2005 to 2007 National Cardiovascular Data Registry published in 2010. On average, catheterization laboratory testing costs >$10,000 per patient; this adds hundreds of millions of dollars in healthcare costs, according to Dr Budoff. CTA as a “Gatekeeper” to Invasive Coronary Angiography CTA can prevent the need for invasive coronary angiography (ICA) in a percentage of patients. A recent study

showed a combined 73% rate of falsepositives in 241 patients with abnormal findings on myocardial perfusion imaging (MPI)—23% had normal coronary arteries, 40% had nonsignificant disease, and 10% had mild disease (Patel N, et al. Am J Cardiol. 2012;109: 165-168). This translated to a net savings of $1295 per patient (a 51% savings) and a total savings of $320,000, based on Medicare costs. A larger, 2007 study also provides evidence that “correlates to the idea that dollars can be saved by not having to perform invasive coronary angiography,” commented Dr Budoff. In 421 patients with intermediate risk of CAD and an abnormal MPI result, an 80% reduction in ICA with CTA was demonstrated. Safety of this strategy was confirmed by event-free survival at 15 months. Of the total patients, 6 had a late ICA, 1 patient had revasculariza-

tion, and no myocardial infarctions or deaths occurred. A 2007 study of 206 patients with mildly abnormal or equivocal tests (only 32% had obstructive CAD) showed that selective catheterization saved $1454 per patient. Dr Budoff noted the relation between cost-savings and pretest probability of prevalence of disease, with CTA saving the most money in lower-probability patients and the savings decreasing as the probability increased. “At a prevalence of CAD of about 80%, CTA is cost-effective as a gatekeeper to ICA,” said Dr Budoff.

Cost per Correct Diagnosis, Quality-Adjusted Life-Year Imaging can save downstream costs, and the savings differ by imaging modality. In a 2008 study of patients at intermediate risk for CAD, the downContinued on page 7

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Health Economics

Cost-Effective Imaging: What Parameters Determine Value? By Mary Mosley Chicago, IL—The rapid growth of medical imaging in cardiovascular (CV) medicine, as well as downward pressure on reimbursement have brought an increased focus on cost and the need to show cost-effectiveness. Imaging is estimated to be growing at a rate of 13% to 22% annually, according to a US Government Accountability Office and Medicare Payment Advisory Commission study, compared with 9% annually for other physician services, stated Rita F. Redberg, MD, MSc, FACC, Professor of Medicine and Director, Women’s Cardiovascular Services, Division of Cardiology, University of California, San Francisco Medical Center, in a session at the 2012 American College of Cardiology (ACC) meeting. Healthcare spending is projected to double to $4.1 trillion by 2016, an estimated 20% of the US gross domestic product, and an increase from 16% in 2012. Yet, how to define value and costeffectiveness for medical imaging is “not straightforward,” said Rory Hachamovitch, MD, MSc, FACC, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Cleveland Clinic, OH. The nature of imaging makes determining its costeffectiveness complex, in part because of its relation to outcomes—the usual denominator in cost-effectiveness equations—that can be indirect, and its unclear metric. Change in subsequent treatment may be the best end point, stated Dr Hachamovitch. Data for costeffectiveness of CV medical imaging are in their infancy. Little prospective data are available, although ongoing studies may soon start to provide the necessary evidence. “Imaging provides an immediate re-

“Imaging provides an immediate result and information that may be used to avoid or implement a treatment strategy.” —Rita F. Redberg, MD, MSc, FACC

sult and information that may be used to avoid or implement a treatment strategy,” said Dr Redberg. She noted that the bar is higher for the cost-effectiveness of diagnostic testing, because it does not translate directly to outcomes. “We must consider how the information will change management, and how change in management will lead to change in outcomes, and whether that same end point could be achieved without doing the test,” Dr Redberg said. Historically, diagnostic end points, such as coronary anatomy or presence or absence of disease, have been used, but this is shifting to prognostic or outcomes-based end points. Net reclassification improvement (NRI), that is, “what is the net gain in reclassifying patient risk status with the addition of data, with the notion that this optimally enhances subsequent patient

management,” is now a popular metric to show the value of an imaging test. One application of the NRI metric was shown by Shaw and colleagues in a study of more than 4500 patients who were prospectively enrolled in a multicenter registry (JACC CV Imaging. 2010;3:1139-1148). A weighted multivariable model of prognostically important information from nuclear studies and treadmill score data showed that NRI was approximately 3 times greater with nuclear studies, but the cost was nearly 40 times greater (both compared with a treadmill exercise test). The cost-effectiveness ratio, calculated as cost per NRI, was approximately $60 per exercise test and more than $600 for nuclear imaging, Dr Hachamovitch said. The challenge is, “what is a clinically meaningful effect in terms of diagnosis?” The results of imaging tests must be used to drive subsequent treatment for it to be cost-effective and clinically relevant. A study by Ling and colleagues (J Am Coll Cardiol. 2012;59:E2143) presented at the 2012 ACC Fellowship Young Investigators Award session illustrated the concept of the “interface between what is seen on the test and what is best for the patient to achieve benefit,” said Dr Hachamovitch. In this single-site study of 661 patients (average 30% ejection fraction, 34% abnormal myocardium) who underwent stress/rest positron emission tomography with fluorodeoxyglucose imaging, complete revascularization compared with medical therapy was associated with improved survival, whereas incomplete revascularization increased risk. Other issues for determining valuebased cost-effectiveness of imaging

Key Points ➤ Imaging is estimated to be growing at a rate of 13% to 22% annually ➤Determining its costeffectiveness is complex ➤ Imaging tests must drive treatment decisions for costeffective management ➤ The cost-effectiveness ratio was approximately $60 per exercise test and more than $600 for nuclear imaging in a recent study

include downstream costs resulting from information obtained from imaging; false-positives that may lead to more tests or unnecessary treatment; direct costs for performing and interpreting a test; indirect costs, such as those incurred as a consequence of medical care (eg, loss of work time); temporal changes (short-term vs longterm); and variations in cost by geography and payer. Cost-effectiveness—a comparison of 2 alternative treatments on outcomes—is a method to obtain better value for healthcare dollars spent. In general, cost-effectiveness studies in the United States use a cut-off of $50,000 per quality-adjusted life-year saved; below that figure a new technology or treatment is considered to be cost-effective. In imaging, this is most often the comparison of one imaging modality against another. Dr Hachamovitch stated that costeffectiveness data need to be defined for CV imaging tests. ■

Coronary Computed Tomography Angiography Cost... Continued from page 6 stream costs in patients without known CAD was $1572 for CTA (N = 1647) and $2531 for single-photon emission computed tomography (N = 6588) at 1 year, based on Medicare data. The average savings was $1075, which increased to $1838 per person when the observation was expanded to include 39,174 patients. CTA was shown in one series to be cost-effective in terms of cost per correct diagnosis in patients with a low prevalence of CAD, whereas ICA performed better in patients with higher probability of disease, which Dr Budoff noted is concordant with other trials. In patients with a 10% disease probability, CTA alone reduces costs, at a cost per correct diagnosis of $81,591

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compared with $349,880 for ICA. The cost for CTA per correct diagnosis was $17,516 with a 30% CAD probability, $9847 with a 40% proba-

“At a prevalence of CAD of about 80%, CTA is cost-effective as a gatekeeper to ICA.” —Matthew J. Budoff, MD bility, and $5281 with a 50% probability; the corresponding costs with ICA were $73,175, $43,008, and $25,315, respectively. The cost per quality-adjusted lifeyear (QALY), the gold standard for

measuring cost-effectiveness, varies by age but not by sex. For example, at a 30% CAD probability, the cost per QALY for CTA alone is $18,862 and $594,264 for ICA at age 60 years; this shifts to $21,636 and $162,229, respectively, at age 80 years. For patients in their 40s and 50s, the cost for CTA alone is $39,574 and $23,440, respectively, but ICA was the dominant strategy in this series. CTA: Cost-Effective Triage for Acute Coronary Syndrome In a 2007 single-center study of 197 patients presenting with chest pain at the emergency department, CTA used immediately to exclude or identify CAD resulted in an approximate 15%

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cost-savings, at a cost of $1586 per patient compared with $1872 in the standard-of-care arm. The time to diagnosis was significantly reduced with CTA compared with standard of care (3.4 hours vs 15.0 hours, respectively), and its diagnostic accuracy was 75%. The 16-center, international Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment (CTSTAT) trial exhibited a significant 38% reduction in cost of care with CTA ($2137 with CTA, $3458 with MPI) in 699 patients presenting to the emergency department and a 54% reduction in time to diagnosis (Goldstein JA, et al. J Am Coll Cardiol. 2011;58:1414-1422). ■

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Health Economics

Novel Oral Anticoagulants Reduce Total Medical Costs in Patients with Nonvalvular Atrial Fibrillation See also Atrial Fibrillation By Mary Mosley Chicago, IL—Atrial fibrillation (AF) is associated with a 5-fold increased risk for ischemic stroke, and its prevalence is rapidly increasing, representing a substantial burden for patients and healthcare consumption. Recent trials of new oral anticoagulants have shown them to be an effective alternative to warfarin (Coumadin) for stroke prevention in patients with nonvalvular AF. Steven Deitelzweig, MD, Associate Professor, Tulane School of Medicine, Vice President of Medical Affairs, Chairman of Department of Medicine, Ochsner Clinic Foundation, New Orleans, LA, presented the results of research on the impact of these emerging agents on medical costs for patients with AF, at the 2012 American College of Cardiology meeting. Dr Deitelzweig and colleagues found that compared with warfarin, the use of dabigatran (Pradaxa), rivaroxaban (Xarelto), and the investigational apixaban (which is approved in Europe but not in the United States) was associated with a reduction in the medical costs related to the management of clinical events in patients with AF. This finding is based on the results related to clinical events reported with dabigatran in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, rivaroxaban in the ROCKET-AF trial, and apixaban in the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial. The total annual medical cost for clin-

ical events with warfarin was $2084 per patient. This was reduced to $1599 with apixaban, $1905 with dabigatran, and $1995 with rivaroxaban. The investigators determined the 1-year incremental costs for each category of clinical event in patients with AF using published data and expert reports. Their analysis

The total annual medical cost for clinical events with warfarin was $2084 per patient. This was reduced to $1599 with apixaban, $1905 with dabigatran, and $1995 with rivaroxaban. —Steven Deitelzweig, MD showed that a hemorrhagic stroke was the costliest event at $51,659 compared with $39,511 for an ischemic stroke, $37,446 for a myocardial infarction (MI), and $34,617 for major bleeding. All costs were inflation-adjusted to 2010 costs using the Consumer Price Index for Medical Care. The clinical events included in this analysis were ischemic or uncertain type of stroke, hemorrhagic stroke, systemic embolism, MI, pulmonary em-

bolism, deep-vein thrombosis, and major bleeding, excluding hemorrhagic stroke, clinically relevant nonmajor bleeding, and other minor bleeding events. The clinical event rate with each of the new oral anticoagulants was derived from weighting of the reported relative risk using the warfarin clinical event rate that was estimated as the averages weighted by the sample size of each of the trials. The new anticoagulants reduced the total medical costs based on their estimated lower absolute risk for a clinical event. The total medical cost for ischemic and hemorrhagic strokes, the primary efficacy end points, was lowest with dabigatran (150 mg). For ischemic stroke, the costs were $373 with dabigatran compared with $461 with rivaroxaban, $451 with apixaban, and $490 with warfarin. For hemorrhagic stroke, the costs were $59, $133, $115, and $225, respectively. For the secondary end point of MI, the costs were $292 with warfarin, $371 with dabigatran, $237 with rivaroxaban, and $257 with apixaban. The costs for major bleeding, a safety end point, were $998 with warfarin, $1030 with dabigatran, $1106 with rivaroxaban, and $715 with apixaban. The study results were consistent even when other scenarios were evaluated, such as using the median rather than the mean, using incremental medical costs for patients with AF, or when the clinical events in each trial were considered separately rather than the

Key Points ➤ AF is associated with a 5-fold increased risk for ischemic stroke, and its prevalence is rapidly increasing, representing a substantial burden for patients and healthcare consumption ➤ The use of dabigatran, rivaroxaban, and apixaban is associated with a reduction in medical costs related to treating clinical events in patients with AF ➤ The total annual medical cost for clinical events with warfarin was $2084 per patient, which was reduced to $1599 with apixaban, $1905 with dabigatran, and $1995 with rivaroxaban ➤ The total medical costs for ischemic and hemorrhagic strokes were lowest with dabigatran and highest with warfarin

weighted average. These scenarios and the sensitivity analyses were performed to reflect the variety of the real-world settings. The study main limitation is that the results cannot be applied in the real-world setting, because the economic analysis did not include factors such as drug costs, local healthcare costs, drug adherence, and variance in population risk, among others. ■

AVERROES: Cost Comparison of Apixaban versus Aspirin Chicago, IL—A cost analysis comparing the use of apixaban (Eliquis) and aspirin in patients with atrial fibrillation (AF) shows a net reduction in total medical costs with apixaban, based on data from the AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes) trial, said Alpesh N. Amin, MD, MBA, FACP, Associate Professor of Medicine, Executive Director, Hospitalist Program, University of California, Irvine School of Medicine, at the 2012 American College of Cardiology meeting. The multicenter, multinational, double-blind AVERROES trial compared the new oral anticoagulant apixaban (which is approved in Europe but not yet in the United States) with aspirin in 5559 patients with AF and at least 1 other stroke risk factor who were unable or unwilling to take warfarin (Coumadin).

In 42% of the patients, the international normalized ratio could not be maintained within the required therapeutic range with warfarin use. This trial was terminated early, because of the superior benefit with apixaban for the primary end point of stroke or systemic embolism event. A total of 51 events occurred with apixaban compared with 113 with aspirin (hazard ratio for apixaban, 0.45). However, major bleeding events were more common with apixaban than with aspirin. Dr Amin and colleagues calculated the costs of apixaban or aspirin based on the rates of primary, secondary, and safety end points in the trial and their associated cost. Compared with aspirin, apixaban was associated with a $655 per patient-year reduction in total medical costs. The largest reduction ($546)

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was for the cost associated with an ischemic stroke. Other reductions were $51 for hemorrhagic stroke, $77 for myocardial infarction, and $55 for systemic embolism. However, the cost for bleed-

“These results serve to start and further the discussion at a hospital system level about which of the new anticoagulants should be included in their formulary.” —Alpesh N. Amin, MD, MBA, FACP ing increased by $75 with apixaban. The estimated total cost reduction with apixaban compared with aspirin were consistent across sensitivity analy-

ses and models with varying clinical event rates and associated costs. “These results serve to start and further the discussion at a hospital system level about which of the new anticoagulants should be included in their formulary, and how AF will be managed overall,” said Dr Amin. “Also, hospitals and physician groups across the United States are working toward the so-called ‘triple aim’ of the Centers for Medicare & Medicaid Services: improved resource utilization, quality, and service. In this regard, the new oral anticoagulants improve resource utilization, as they are more cost-effective across the board, potentially providing better quality, because they have better efficacy outcomes, with a similar safety profile that contributes to patient service.”—MM ■

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o 5, N Vol

CLINICAL

Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted Time Series Analysis

Ame rican Healt h&D rug B enefi ts

R. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD; Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm

271

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

INDUSTRY TRENDS Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape

American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers. Areas of High Interest Include: • Adherence Concerns

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Health Economics

Comparative Effectiveness Analysis: Emergency Department CTA versus Standard ACS Symptom Evaluation By Mary Mosley Chicago, IL—The evaluation of patients presenting to the emergency department with symptoms of an acute coronary syndrome (ACS) with coronary computed tomography angiography (CTA) resulted in faster diagnosis, shorter length of stay, and more direct discharge compared with standard evaluation, according to Udo Hoffmann, MD, MPH, Cardiac Radiologist, Director of Cardiac Imaging, Massachusetts General Hospital, Boston, and lead investigator of the multicenter study Rule Out Myocardial Infarction by Computer-Assisted Tomography (ROMICAT) II. In ROMICAT II, 1000 patients (mean age, 54 years) at 9 centers were randomized to CTA or standard evaluation by a local physician. The length of hospital stay, the primary end point, was significantly shorter with CTA: 23

hours compared with 30 hours with standard evaluation. This difference was driven by the shorter length of stay in the patients who were not diagnosed with ACS (17.2 hours vs 27.2 hours, respectively). In patients diagnosed with ACS, the length of stay was similar. Cost Results Mixed The cost data were mixed. Although costs were reduced for the emergency department with CTA compared with standard evaluation, hospital costs were higher with CTA, and total costs were similar for both strategies (Table). The investigators were pleased to see that total costs were similar, because Medicare data suggested there was a doubling in procedures and costs after CTA compared with function testing in the observational ROMICAT I study. However, CTA examination was lim-

Table Cost Comparison: CTA versus Standard Evaluation

Care setting

CTA cost, $

Standard evaluation cost, $

Emergency departmenta

2053

2532

–19

<.001

Hospital

1950

1297

+50

.17

Total

4004

3828

.72

Difference, %

P value

a The cost for the emergency department includes the observation unit. NOTE: Cost is per person for a subset of 650 patients from 5 study centers. CTA indicates computed tomography angiography.

ited in ROMICAT II to business weekday hours; expansion to 24-hour availability could impact costs. With a 1-second scan, CTA can accurately and noninvasively determine the extent of coronary artery disease (CAD), whereas standard evaluation typically requires 24 to 36 hours and requires additional work-up to rule out CAD. CTA has been shown to have a high predictive value for ruling out

Early CTA led to quick discharge of patients without ACS; 50% were discharged within 8 hours compared with 28 hours with standard evaluation. CAD. ROMICAT I showed that patients presenting with chest pain had a low 8% prevalence of ACS, that most patients did not have CAD or obstructive plaque, and that CTA had a very high negative predictive value to predict events over the next 2 years. Of note, in ROMICAT II, early CTA led to advanced discharge in patients without an ACS diagnosis. Of patients undergoing CTA, 50% were discharged within 8 hours compared with 28 hours with standard evaluation, said Dr Hoffmann. A diagnosis of ACS was made in 8.6% of patients who had CTA and in 6.4% of the standard-evaluation patients.

Care and Discharge Differences Direct discharge rate from the emergency department was 4-fold higher with CTA (46%) than with standard evaluation (12%). Fewer patients in the CTA arm were admitted to the hospital. The time to diagnosis was shorter by approximately 8 hours with CTA for patients with and without ACS (10 hours vs 18.7 hours with standard evaluation). Repeat visits to the emergency department for chest pains were reduced 13% with CTA compared with 19% with standard evaluation. Testing was significantly higher in the clinical trial arm, and was primarily driven by the higher number of patients in the standard-evaluation arm who did not have any tests (22% vs 2%, respectively). More patients who had CTA had 1 test (75%) and >2 tests (23%) compared with 67% and 10.6% of the standard-evaluation arm. There was no missed ACS diagnoses in either arm. Two periprocedural complications occurred in the CTA arm. At 28 days, 2 major adverse events (defined as death, myocardial infarction, unstable angina pectoris, or the need for urgent revascularization) occurred in the CTA group and 5 in the standard-evaluation arm. Invasive coronary angiography was performed in 12% of the CTA patients and 8% of the standard-evaluation patients. There were also more interventions (6.4%) in the CTA arm than with standard evaluation (4.2%). ■

Acute Coronary Syndrome

IMMEDIATE: Early Use of Inexpensive Glucose-InsulinPotassium Solution Can Prevent Cardiac Arrest in ACS By Wayne Kuznar Chicago, IL—Glucose-insulin-potassium (GIK) solution, given by paramedics very early after symptom onset in patients with an acute coronary syndrome (ACS), can reduce the risk for cardiac arrest or death by 50% during the first 30 days after the ACS event, according to results of a new study presented at the 2012 American College of Cardiology meeting. Although the treatment did not prevent myocardial infarction (MI), the GIK solution did reduce infarct size, said co–lead investigator Harry Selker, MD, MSPH, Executive Director of the Institute for Clinical Research and

Health Policy Studies, Tufts Medical Center, Boston. The IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care) clinical trial was funded by the National Heart, Lung, and Blood Institute.

Table IMMEDIATE End Points: Intention-to-Treat Analysis

GIK Solution Costs Approximately $50 Previous clinical trials have shown no consistent effect with GIK, likely because it was given to patients in the hospital approximately 6 hours after the onset of ischemia, which was too

End point

GIK, %

Placebo, %

Risk ratio

P value

Progression to MI

0.88

.28

30-day mortality

0.72

.27

Cardiac arrest or hospital mortality

0.48

.01

30-day mortality or hospitalization for HF

0.73

.24

GIK indicates glucose-insulin-potassium; HF, heart failure; MI, myocardial infarction.

late to help. IMMEDIATE was the first trial to test real-world effectiveness of

administering GIK at the very first signs of an ACS in the community. Continued on page 11

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

MAY 2012

VOL 1

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Acute Coronary Syndrome

IMMEDIATE: Early Use of Inexpensive... Continued from page 10 “Because the trial is the first to show GIK as effective when used by paramedics in real-world community settings, it could have important implications for the treatment of heart attacks,” said Dr Selker.

“Because the trial is the first to show GIK as effective when used by paramedics in real-world community settings, it could have important implications for the treatment of heart attacks.”

were 40% less likely to have cardiac arrest, to die, or to be hospitalized because of heart failure. The effect was even more striking for patients with ST-segment elevation MI (STEMI), in whom immediate GIK was associated with a 60% reduction in cardiac arrest or death relative to placebo.

Infarct size as a percentage of leftventricular mass was 10% in the placebo group and only 2% in the GIK group. In the cohort with STEMI, infarct size was reduced from 12% in the placebo group to 3% in the GIK group. “The risks and side effects rates from GIK are very low,” said Dr Selker, “and

GIK is inexpensive, potentially available in all communities, and deserves further evaluation in trials for widespread EMS use.” The research team will follow up with study participants at 6 and 12 months to evaluate the longer-term benefit of the GIK treatment. ■

Tell your patients about NovoTwist®, the first and only single-twist needle attachment on the market.

—Harry Selker, MD, MSPH For the study, paramedics in 36 emergency medical services (EMS) systems in 13 cities across the United States were trained to administer GIK after determining that a patient was likely having an ACS using electrocardiograph-based criteria and thrombolytic predictive instrument decision support that prints patient-specific predictions in addition to an electrocardiogram. The paramedics used the predictive instruments to decide if a patient would likely benefit from treatment. There were 911 patients randomized to receive either GIK or placebo. At 30 days, a similar proportion of patients in each group progressed to MI (49% in the GIK group vs 53% in the placebo group), but cardiac arrest or hospital mortality occurred in only 4% of patients receiving the GIK solution compared with 9% of those in the placebo group, for a 52% reduction in risk (Table, page 10). Patients randomized to receive GIK

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Key Points ➤ IMMEDIATE was the first trial to test real-world effectiveness of administering GIK at the very first signs of an ACS ➤ Although it did not prevent an MI, GIK reduced infarct size; infarct size as a percentage of left-ventricular mass was 10% in the placebo group versus 2% in the GIK group ➤ Patients randomized to receive GIK were 40% less likely to have cardiac arrest, die, or be hospitalized for heart failure ➤ GIK’s risks and side effects are very low; it is inexpensive and is potentially available in all communities, making it a desirable treatment

VOL 1

NO 1

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MAY 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

Acute Coronary Syndrome

Value of New Anticoagulants in Acute Coronary Syndrome Still Unclear

See also Atrial Fibrillation

By Wayne Kuznar Chicago, IL—The new oral anticoagulants rivaroxaban (Xarelto), dabigatran (Pradaxa), and the yet-to-be-approved apixaban (Eliquis) have been shown to be superior to warfarin (Coumadin) in preventing stroke in patients with atrial fibrillation (AF). However, the jury is still out on their value in patients with acute coronary syndrome (ACS), and the safety profiles of these agents have not been fully elucidated, said William Dager, PharmD, Clinical Professor of Pharmacy, University of California School of Pharmacy, San Francisco, and Clinical Professor of Pharmacy, University of California-Davis School of Medicine, at the 2012 American College of Cardiology meeting. Issues remain about reversing the anticoagulant effects of the new drugs in cases of life-threatening bleeding and appropriate monitoring of their activity. Most of the data with rivaroxaban, dabigatran, and apixaban have been collected in the setting of AF. Both rivaroxaban and the 150-mg dosage of dabigatran were shown to reduce the risk for stroke and systemic embolism with lower rates of intracerebral hemorrhage (ICH) compared with warfarin in large, randomized clinical trials of patients with AF. In the ROCKET-AF trial of rivaroxaban, there was an increase in the incidence of stroke in the rivaroxaban arm during the posttrial transition to open-label warfarin. Apixaban has produced favorable outcomes (prevention of stroke or systemic embolism) compared with aspirin and warfarin in separate trials in patients with AF. Consider Renal Function When Dosing Both dabigatran and rivaroxaban require dosing that is sensitive to renal function, said Dr Dager. The standard approved dosage of rivaroxaban for stroke prevention in patients with nonvalvular AF is 20 mg daily, but in patients with renal impairment—creatinine clearance (CrCl) in the range of 30 mL/min to 49 mL/min—the dosage should be reduced to 15 mg once daily. Rivaroxaban’s use should be avoided in patients with CrCl <15 mL/min. “The way renal failure is calculated is one thing you have to consider,” said Dr Dager. “In the trials, we used the Cockcroft-Gault, using ideal total body weight to do renal assessments; that was for both dabigatran and rivaroxaban.”

The ACS Setting In the setting of ACS, dabigatran was associated with an excess of acute myocardial infarction (MI) of approximately 0.2% compared with warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. However, further analysis of the RE-LY data showed a nonsignificant increase in the risk for MI with dabigatran, irrespective of risk factors.

With bleeding issues unresolved, rivaroxaban cannot yet be considered an option in the long-term management of ACS. —William Dager, PharmD

A review of 7 clinical trials conducted with dabigatran in various settings uncovered a consistently significant increased risk for MI or ACS with dabigatran against various controls. There was no significant difference between dabigatran and warfarin in the rates of ACS in clinical trials conducted

in patients with deep-vein thrombosis. With bleeding issues unresolved, rivaroxaban cannot yet be considered an option in the long-term management of ACS, said Dr Dager. In low-risk patients with recent ACS, rivaroxaban added to aspirin, with or without clopidogrel, was associated with a significant reduction in the occurrence of major adverse cardiovascular events compared with placebo, but it increased the rates of major bleeding and ICH, without an increase in fatal bleeding. APPRAISE-2A (Apixaban for Prevention of Acute Ischemic Events 2), a clinical trial of apixaban in patients with ACS, was stopped early because of a significant increase in major bleeding and ICH in the apixaban group. Vorapaxar, a protease-activated receptor 1 antagonist, was not effective in reducing the risk of adverse thrombotic events in addition to standard antiplatelet therapy in patients with non–ST-segment elevation ACS, while increasing bleeding risk. Can They Be Reversed? A potential drawback to the use of the new anticoagulants is the so-far

lack of an effective agent to reverse their anticoagulant effects in the presence of life-threatening bleeding. Prothrombin complex concentrates (PCCs) have been studied in rats and humans with varying success. There are encouraging signs that activated PCC (aPCC) may work in this regard. The effect of dabigatran was successfully reversed with the use of 25 U/kg of aPCC (factor VIII inhibitor bypass activity) in 1 patient with a transseptal perforation who lost 4 L of blood during cardiac ablation, said Dr Dager. Is Monitoring Needed? Although routine monitoring is not recommended for the new anticoagulants, their activity may need to be measured in certain situations. An elevated thrombin time may indicate the presence of dabigatran, and a chromogenic anti–factor Xa can indicate the presence of rivaroxaban, Dr Dager noted. Quantitative tests are not readily available for assessing the intensity of anticoagulation effects with either agent. A chromogenic ecarin clotting time–driven dabigatran level has been developed but requires further study. ■

CALL FOR PAPERS Cardiometabolic Health Theme Issue American Health & Drug Benefits will be publishing a Theme Issue on Cardiometabolic Health later this year. Readers are invited to submit articles on topics relevant to the clinical, business, and policy aspects of cardiometabolic health. Original research studies, white papers, evidence-based comprehensive reviews, and case studies are of particular interest. All healthcare stakeholders are invited to present their data, best practices, innovations, and initiatives to facilitate management strategies and benefit design to improve cardiometabolic outcomes and prevent common risk factors while reducing costs for those at risk for cardiovascular disease, diabetes, or obesity.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as: • Benefit designs to improve cardiometabolic outcomes • Best practices in diabetes management and prevention • Best practices in insulin control, lipid management, or blood pressure control • Comparative effectiveness analyses of best therapies for cardiovascular health • Cost-effectiveness comparisons • Employers’ strategies to enhance cardiometabolic wellness • New and emerging therapies

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

• Health plan initiatives in cardiometabolic health and wellness • Hot topics in diabetes, obesity, or cardiovascular disease • Lifestyle strategies and cardiometabolic health • Lipid management in patients with diabetes • Medication adherence and diabetes progression • New biomarkers for assessing cardiometabolic risk • Prevention strategies for diabetes risk reduction • Prevention programs for cardiometabolic comorbidities

Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) Submit articles to editorial@engagehc.com, or call 732-992-1889

MAY 2012

VOL 1

NO 1

Hypertension

New JNC-8 Hypertension Guidelines to Be Released by Year End See also page 14

Evidence-based guidance for subgroups, including patients with diabetes and kidney disease By Mary Mosley Chicago, IL—The long-awaited update of the hypertension treatment guidelines, the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-8), will be published at the end of 2012. The previous guidelines (JNC-7) were last published in 2003. Suzanne Oparil, MD, Professor, Department of Medicine, Division of Cardiovascular Disease, University of Alabama, Birmingham, and cochair of the expert panel that developed these guidelines, discussed the process that has contributed to the lengthy delay in publishing the JNC-8 guidelines at the 2012 American College of Cardiology (ACC) meeting. The new JNC-8 hypertension guidelines will answer 3 clinical questions: • When to initiate drug treatment? • How low should blood pressure (BP) be lowered? • How do you get there? These questions were defined to answer whether health outcomes in patients with hypertension are improved by initiating antihypertensive pharmacologic therapy at specific BP thresholds, by reaching specific BP goals, and by using different antihypertensive drugs or classes of drugs that differ in comparative benefits and harms. Dr Oparil gave no indication of what the specific recommendations will be. The development of the JNC-8 clinical practice guidelines is part of the current National Heart, Lung, and Blood Institute (NHLBI)-sponsored adult cardiovascular disease (CVD) prevention guidelines program. The Adult Treatment Panel guidelines for the treatment of elevated blood choles-

The long-awaited new JNC-8 guidelines will use evidencebased strategies for their implementation and will provide guidance across prespecified subgroups, including diabetes, chronic kidney disease, CVD, older adults, racial and ethnic groups, and smokers. —Suzanne Oparil, MD terol and the overweight and obesity guidelines are being developed simultaneously. Ultimately, these 3 guidelines will be integrated into 1 CVD risk-reduction guideline. Ensuring that the JNC-8 guidelines are firmly evidence-based is the reason that it has taken so long to write them, said Dr Oparil. This intensified focus is a direct result of an Institute of Medicine (IOM) report published in 2001 about the quality chasm, which noted that clinical decision-making is based on training and experience. The report also advocated patient

Increased Focus on Level of Evidence A process for developing the guidelines was established to “ensure the rigor and to minimize bias,” said Dr Oparil, and it uses methods to meet many of the new IOM standards for systematic reviews. Strict criteria were established for the systematic literature search, rating the study quality with instruments for different studies, and for data abstraction and developing evidence tables. The quality of the evidence is rated as low, moderate, and high. The strength of a recommendation will range from A for strong evidence, B for moderate, C for weak, D for against, E for expert opinion, and N for no recommendation. There is wide representation of expertise on the JNC-8 expert panel, ranging from hypertension, primary care, cardiology, nephrology, research methodology, evidence-based medicine, epidemiology, and guideline development and implementation, among others. The rationale for the clinical questions driving the JNC-8 guidelines is to assess the evidence for BP level of 140/90 mm Hg as a treatment goal; to determine if this treatment threshold should be adjusted for specific disease conditions, comorbidities, characteristics, or age; and to determine whether there is evidence of improved outcomes by lowering BP with a particular drug or drug class. The JNC-8 guidelines will provide practice guidance for patients aged ≥18 years across a number of prespecified subgroups, such as diabetes, chronic kidney disease, CVD, older adults, sex, racial and ethnic groups, and smokers. ■

care based on the best-available scientific knowledge and the elimination of variability in healthcare. Dr Oparil noted that only 3 of the ACC/American Heart Association guidelines have the top level of evidence (level A) for >20% of the recommendations in the guideline; the others range from 15% to 55%. The new NHLBI-sponsored adult cardiovascular guidelines, including JNC-8, will not look like the previous guidelines, Dr Oparil pointed out. They will be strictly evidence-based, have more depth and rigor, be more focused, and use evidence-based strategies for their implementation, she explained. The practice guidelines will include a summary of the evidence for each clinical question, graded evidence statements, graded recommendations, and references.

Key Points ➤ The JNC-8 hypertension guidelines will be published at the end of 2012 and will address when to initiate drug treatment, how low BP should be lowered, and how to achieve these goals ➤ The guidelines will have more depth and rigor, and use evidence-based strategies for their implementation ➤ The clinical questions driving the JNC-8 guidelines will assess the evidence for 140/90 mm Hg as a BP treatment goal and to determine if it should be adjusted for specific diseases, comorbidities, or age

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VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

Hypertension

Consider Combination Therapy for Patients with Low- and High-Risk Hypertension By Wayne Kuznar Chicago, IL—Combination therapy from the start should be considered for all patients in whom pharmacotherapy is chosen for the treatment of hypertension, said Kenneth A. Jamerson, MD, Professor of Medicine, University of Michigan Health System, Ann Arbor, at the 2012 American College of Cardiology meeting. In high-risk patients, combining an angiotensin-converting enzyme (ACE) inhibitor with amlodipine is superior to diuretic-based combinations, he said, and in low-risk patients, combination therapy from the outset achieves faster blood pressure (BP) control. Clinical trials in which monotherapies were compared were, in essence, trials of combination therapy, because patients required multiple drugs to reach prespecified targets, Dr Jamerson noted. In making his case for target BP and the choice of therapy, he drew on his experience as part of the group that wrote the International Society on Hypertension in Blacks (ISHIB) Consensus Statement for the management of hypertension in blacks. In patients without target-organ

damage or overt cardiovascular disease (CVD), ISHIB consensus statement recommended modest lowering of the BP target to <135/85 mm Hg, he said, adding that an attempt to lower BP in these low-risk patients with up to 3 months of lifestyle modification is reasonable. The lower BP goal is based on clinical trial evidence showing better outcomes with the lower goal versus a goal of <140 mm Hg systolic BP. In low-risk patients, combination therapy offers more prompt and efficient control of BP compared with monotherapy. For patients with target-organ damage or preclinical/clinical CVD, ISHIB recommended that BP be lowered and maintained consistently to <130/80 mm Hg. “Combination therapy with an ACE inhibitor and amlodipine is superior to diuretic-based combination therapy in reducing cardiovascular disease morbidity and mortality in high-risk patients,” said Dr Jamerson. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) compared an amlodipine/perindopril combina-

“Combination therapy with an ACE inhibitor and amlodipine is superior to diuretic-based combination therapy in reducing cardiovascular disease morbidity and mortality in high-risk patients.” —Kenneth A. Jamerson, MD

tion with a combination of atenolol/ bendroflumethiazide in patients with

hypertension and at least 3 other cardiovascular (CV) risk factors. All-cause mortality and CV mortality occurred significantly less often in the amlodipine/perindopril arm of the study. Another trial to support the ACE inhibitor/amlodipine combination was Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), in which a combination of benazepril and amlodipine proved superior to benazepril and hydrochlorothiazide as initial therapy on the primary end point of time to first CV morbidity/mortality (20% relative risk reduction; P = .002) in patients with high-risk hypertension. Diuretics should no longer be considered preferred therapy for hypertension; in fact, they should be relegated to add-on therapy, said Dr Jamerson. There is no BP-lowering advantage to diuretics, he said, and they require more laboratory monitoring than other classes of antihypertensives. In addition, the cost advantage to diuretics has disappeared, because most other antihypertensive drug classes now have generic formulations. ■

Patient Web-Based Blood Pressure Reporting May Improve Control Chicago, IL—Patients with uncontrolled hypertension who reported blood pressure (BP) readings to their physicians through a web-based portal received more frequent medication adjustments and more timely treatment decisions compared with a group of patients with hypertension who had only conventional routine office visits, according to a study presented at the 2012 American College of Cardiology meeting. According to the researchers, “Blood pressure control plays an integral role in the prevention of cardiovascular disease. Aside from lifestyle changes, pharmacotherapy is the physician’s most effective method of lowering blood pressure.” According to the Centers for Disease Control and Prevention, as many as 65 million American adults have elevated BP, and roughly 74% take medication for it. In a secondary analysis of this study, patients (average age, 59 ± 13

years) with uncontrolled hypertension (≥150/90 mm Hg) from 2 large medical centers were randomized to usual care (N = 121) or telemedicine with usual care (N = 120). More than

“The ongoing monitoring and reporting of blood pressure levels seems to bring about important changes in physician prescribing habits, which we think will ultimately benefit patients.” —Val Rakita, MD

half of the patients (56.8%) were taking 1 or 2 BP-lowering medications at the start of the study. Most patients were women; 80% of participants were black. Patients in the telemedicine group

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

MAY 2012

were provided digital sphygmomanometers and were trained on how to use them. They were instructed to report their BP, heart rate, weight, daily steps, and tobacco use twice weekly for 6 months. All patients had baseline and 6month follow-up visits. Monthly reports on BP and treatment guidelines were provided to both the patient and the physician in the telemedicine group. At the end of the study, the patients’ antihypertensive medications were compared with their baseline therapy. At 6 months, the medications prescribed to those in the usual-care group were virtually unchanged, but there was a small increase in the number of medications ordered for patients in the telemedicine group. There were no differences in results with respect to age, ethnicity, education, or income. Val Rakita, MD, Internal Medicine Resident at Temple University Hospital,

Philadelphia, PA, and the study’s coinvestigator, said that prescribing more medication in the telemedicine group did not signify overtreatment but was a reflection of more timely decisions to increase and/or adjust medications. There was no significant difference in the decrease in BP between the groups overall, but the group of nondiabetic patients using telemedicine was found to have lower BP compared with all of the other groups. According to Dr Rakita, the findings suggest that an Internet-based intervention results in more appropriate and effective drug therapy for patients with uncontrolled hypertension, as well as better BP control and an overall reduction in cardiovascular risk. “The ongoing monitoring and reporting of blood pressure levels seems to bring about important changes in physician prescribing habits, which we think will ultimately benefit patients,” Dr Rakita pointed out.—WK ■

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NO 1

Lipid Disorders

Monoclonal Antibody Produces Powerful Reductions in LDL Cholesterol By Wayne Kuznar Chicago, IL—A fully human monoclonal antibody lowered low-density lipoprotein cholesterol (LDL-C) levels an additional 40%, to 72% in hypercholesterolemic patients already being treated with atorvastatin (Lipitor). The antibody binds to PCSK9 to prevent degradation of LDL receptors, facilitating LDL-C transport from the blood to the liver, thereby decreasing circulating levels of LDL-C, reported lead investigator James McKenney, PharmD, President and Chief Executive Officer, National Clinical Research, Inc, and lead investigator of this multicenter, randomized clinical trial of the monoclonal antibody. A 150-mg injection of SAR236553/ REGN727 every 2 weeks lowered LDL-C by 72.4%, from baseline to 12 weeks, said Dr McKenney. “This new mechanism may be the next big step, if it pans out. The data say that [the antibody] is quite powerful, at least as if not more powerful than the statin. It

takes us to another level,” he said. The trial included 183 patients with LDL-C levels of ≥100 mg/dL who

“This new mechanism may be the next big step, if it pans out. The data say that [the antibody] is quite powerful, at least as if not more powerful than the statin. It takes us to another level.” —James McKenney, PharmD

were already receiving treatment with atorvastatin, 10 mg to 40 mg daily

Table Changes in LDL Cholesterol, by Treatment Group Baseline LDL, mg/dL

Change at week 12, %

Placebo

130.2

–5.1

SAR236553 50 mg every 2 wk

123.2

–39.6

SAR236553 100 every 2 wk

127.0

–64.2

SAR236553 150 mg every 2 wk

123.9

–72.4

SAR236553 200 mg every 4 wk

128.2

–43.2

SAR236553 300 mg every 4 wk

131.6

–47.7

LDL indicates low-density lipoprotein.

for at least 6 weeks. They were randomized to placebo or injections of SAR236553/REGN727 every 2 weeks (50, 100, or 150 mg) or every 4 weeks (200 or 300 mg; Table). “Two weeks after administration, we saw an immediate reduction in LDL cholesterol reaching 31% to 63%,” said Dr McKenney. The reductions in LDL-C from baseline to week 12 ranged from 39.6% with 50 mg of SAR236553/REGN727 every 2 weeks to 72.4% with 150 mg every 2 weeks. By comparison, the reduction in LDL-C in the placebo group was 5.1%. There were favorable changes in apolipoprotein B, triglycerides, highdensity lipoprotein cholesterol (HDLC), non–HDL-C, lipoprotein (a), and apolipoprotein A1 in the groups randomized to SAR236553/REGN727. All patients assigned to 150 mg twice weekly of SAR236553/REGN727 achieved a final LDL-C <70 mg/dL; their mean baseline LDL-C while receiving atorvastatin was 123.9 mg/dL. The frequency of treatment-emergent adverse events was similar across all groups—placebo and treatment groups—said Dr McKenney. Six patients randomized to SAR236553/ REGN727 discontinued treatment as a result of treatment-emergent adverse events. One of these patients developed leukocytoclastic vasculitis that resolved after treatment with prednisone. The results support further evaluation of SAR236553/REGN727 in larger, more diverse patient populations, with different background ther-

apies to fully assess efficacy and safety, said Dr McKenney. “Maybe we have another era in the treatment of lipid disorders, and more important, in the reduction of heart disease in this country,” he said.

“For all kinds of reasons, having another major class of LDLlowering drugs that is as powerful as the statins—or more powerful—is a big plus for patients.” —Steven Nissen, MD “This is one of the few drug classes for which most people who have looked at the data would bet on making it to approval. For all kinds of reasons, having another major class of LDL-lowering drugs that is as powerful as the statins—or more powerful— is a big plus for patients,” commented Steven Nissen, MD, Chair, Department of Cardiovascular Medicine, Cleveland Clinic, OH. Further studies of SAR236553/ REGN727 may reveal an incremental benefit to driving LDL-C levels lower than those currently obtainable, perhaps as low as 50 mg/dL, Dr Nissen noted. ■

Boosting HDL Provides No Additional Benefit in Patients Already Taking a Statin Chicago, IL—A meta-regression analysis found that adding a therapy that raises high-density lipoprotein cholesterol (HDL-C) to a statin is unlikely to produce a substantial clinical benefit, said Brian A. Ference, MD, MPhil, MSc, FACC, Associate Chief of Translational Research and Clinical Epidemiology, Director of the Cardiovascular Genomic Research Center and Assistant Professor of Medicine at Wayne State University School of Medicine, Detroit, MI, at the 2012 American College of Cardiology meeting. Dr Ference and colleagues analyzed

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26 statin trials, which included 169,138 participants. The investigators estimated the effect of raising HDL-C on major adverse cardiovascular events, controlling for the effect of reducing the level of low-density lipoprotein cholesterol (LDL-C) with the statin. The risk of major adverse cardiac events (MACE) was reduced by 19% per each mmol/L reduction in LDL-C independent of any change in HDLC. No reduction in the risk of MACE was found per mmol/L increase in HDL-C after controlling for the effect of lowering HDL-C.

“Raising HDL is not associated with any clinical benefit in the presence of statin therapy to lower HDL. Increasing HDL may be deleterious if raised too high.” —Brian A. Ference, MD, MPhil, MSc, FACC In a meta-analysis of 5 clinical trials that included almost 27,000 participants, adding either fenofibrate (Trior,

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Trilipix), niacin (Niacor, Niaspan), torcetrapib, or anacetrapib to a statin to increase the level of HDL-C did not reduce the risk of MACE, despite a weighted mean increase in HDL-C of 24.5 mg/dL (0.63 mmol/L) and a weighted mean additional reduction in LDL-C of 16.0 mg/dL (0.41 mmol/L). “Raising HDL is not associated with any clinical benefit in the presence of statin therapy to lower HDL,” concluded Dr Ference. “Increasing HDL may be deleterious if raised too high. Large ongoing randomized trials may give more information.”—WK ■

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Lipid-Lowering Drug Pipeline... both ApoB and LDL-C levels by a median of 70%. The 200-mg weekly subcutaneous dose was selected for all phase 3 trials of mipomersen in patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia (HeFH) plus coronary artery disease (CAD), severe hypercholesterolemia in HeFH, and hypercholesterolemia plus a high risk of CAD. When used in addition to maximally tolerated lipid-lowering therapies, mipomersen reduced levels of LDL-C by 25% to 37% and ApoB by 26% to 38% in the above patient groups (Table). It also had a “fairly robust” effect in reducing levels of Lp(a) by 21% to 34%, Dr Stein stated. Because mipomersen is not metabolized through the CYP450 enzyme, it has no clinically significant drug–drug interactions with statins or ezetimibe (Zetia), he said. PCSK9 Inhibitors The other class of agents with impressive potential targets PCSK9, a newly discovered hepatic regulator of the LDL receptor. PCSK9 in the plasma binds to LDL receptors and reduces recycling, effectively downregulating LDL receptor activity and resulting in increased plasma LDL-C. Injectable human PCSK9 mono-

clonal antibodies bind to PCSK9 to block its effect and prevent the degradation of LDL receptors. SAR236553/REGN727. Dr Stein was the lead investigator of 3 recently published placebo-controlled studies (Stein EA, et al. N Engl J Med. 2012; 366:1108-1118) in which the PCSK9 monoclonal antibody SAR236553/ REGN727 was administered subcuta-

“It appears as if 2-week, possibly 4[-week], dosing is needed to keep values stable; there may be differences between different monoclonal antibodies.” —Evan A. Stein, MD, PhD neously every 2 weeks in doses of 50, 100, or 150 mg in 51 patients with HeFH or non-HeFH who were being treated with atorvastatin 10 to 40 mg/day. An additional 150-mg arm (n = 7) was enrolled with no background atorvastatin therapy and baseline LDL-C ≥130 mg/dL. Dose-dependent reductions in LDLC of 35% to 61% (150 mg twice weekly) from baseline were observed with SAR236553; a reduction in ApoB levels of >40% with the highest dose was also observed. Dose-dependent increases in

Continued from page 1

Effect of Mipomersen on Selected Lipids in HeFH: Results from a Table Dose-Ranging Study Mipomersen groups (dosages in mg/wk) 300 (6 wk), 300 (13 wk), % %

Lipids

Placebo, %

50, %

100, %

200, %

ApoB

–6

–9

–20a

–33b

–43a

LDL

–5

–12

–11

–20a

–36b

–46a

Lp(a)

–3

–19

–17

–25

–37

P <.02 vs placebo. P <.01 vs placebo. ApoB indicates apolipoprotein B; HeFH, heterozygous familial hypercholesterolemia; LDL, low-density lipoprotein; Lp(a), lipoprotein (a). Source: Adkim F, et al. Am J Cardiol. 2010;105:1413-1419. b

high-density lipoprotein cholesterol also occurred. SAR23655. In a larger placebo-controlled multicenter randomized clinical trial in patients with primary hypercholesterolemia (see article, page 21), a subcutaneous injection of SAR23655 every 2 weeks at a dose of 150 mg reduced LDL-C by 72% in patients who were already being treated with atorvastatin (Lipitor). “The effects [of SAR236553] are additive rather than synergistic,” said Dr Stein. The reductions in LDL-C with the PCSK9 monoclonal antibody occur within days, peaking at 2 weeks. AMG145. Another human monoclonal antibody against PCSK9 is AMG145. Phase 1 data of this agent in

58 patients being treated with rosuvastatin (Crestor), atorvastatin, and simvastatin (Zocor) were reported. In the group receiving low-dose to moderate-dose statins (N = 40), AMG145 given every 2 weeks or every 4 weeks lowered LDL-C by an additional 80%. Further, levels of Lp(a) declined by ≥30% in the patients receiving low-tomoderate doses of statins who were treated with AMG145 every 2 weeks and every 4 weeks; the group receiving high-dose statins (N = 7) had a reduction in Lp(a) that approached 45%. “It appears as if 2-week, possibly 4[-week], dosing is needed to keep values stable; there may be differences between different monoclonal antibodies,” Dr Stein concluded. ■

Low-Potency Statins Initiated in High-Risk Patients in a Managed Care Setting By Wayne Kuznar Chicago, IL—A retrospective analysis of high-risk patients in a managed care setting shows that those who were newly prescribed statin therapy were usually started at low-to-moderate doses, and approximately 50% of them had discontinued therapy within 12 months, reported Terry A. Jacobson, MD, Professor of Medicine and Director of the Office of Health Promotion and Disease Prevention, Emory University, Atlanta, GA. Dr Jacobson and colleagues conducted a retrospective analysis of 11,473 high-risk patients who were not at their low-density lipoprotein cholesterol (LDL-C) goal at baseline and were prescribed statin therapy. The patients were identified from a longitudinal database of claims information from a large, commercially insured population in the United States. All patients had at least 1 medical claim for coronary heart disease (CHD), atherosclerotic vascular disease, or diabetes before initiating

High-risk patients newly initiated on statin therapy in a managed care setting were usually started at lowto-moderate doses, and approximately 50% of the patients had discontinued therapy within 12 months. —Terry A. Jacobson, MD statin monotherapy and were not at the optional LDL-C goal of <70 mg/dL for high-risk patients. Of the 11,473 patients who were included, 7028 had diabetes as their only high-risk feature, 3052 had CHD or atherosclerotic disease, and 1393 had

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diabetes and either CHD or atherosclerotic disease. Some 44.7% of the patients were treated with simvastatin (Zocor) and 31.5% were treated with atorvastatin (Lipitor). Most were receiving statins, which were expected to produce LDL-C lowering of 31% to 50%. The mean LDL-C level was 138 mg/dL before statin initiation, which fell by 24% to 101 mg/dL at the first eligible postindex date (≥4 weeks after treatment initiation). Almost two thirds (64.9%) of patients experienced a first treatment change, with a mean time to change of 93.8 days, including 46.9% who discontinued statin treatment altogether. Of the total patients, 18% were switched to a different statin. Of the patients who had a first treatment change, 13.6% (8.8% of the total cohort) had a second treatment change, with a mean time to change of 178.3 days.

Of the 451 patients who switched statins at the first treatment change, 139 were switched to a statin at the same potency, 187 were switched to a statin with a higher potency, and 125 were switched to a lower potency statin regimen. Of the 123 patients who switched statins at a second treatment change, 24 patients were switched to one with the same potency, 75 were switched to a higher potency regimen, and 24 were switched to a lower potency statin regimen. The majority of patients who had a treatment change continued to take the same statin but had the dosage increased by 1 level; only 3% who had an increase in dosage had it increased by 2 levels. According to the study authors, the treatment patterns demonstrate the need for systemwide improvements to increase medication adherence, in addition to more patient and provider education. ■

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New Drug Therapies for Difficult-to-Control Atrial Fibrillation By Wayne Kuznar Chicago, IL—“Difficult” atrial fibrillation (AF), for which standard ratecontrol therapy or standard rhythmcontrol therapy has not been effective, or AF in the setting of sinus node or other conduction disease, has been shown to sometimes benefit from nonstandard or combination-drug treatment, according to James A. Reiffel, MD, Professor of Clinical Medicine, Columbia University Medical Center, New York City. For patients in whom ventricular rate control cannot be attained with beta-blockers, calcium channel blockers, and/or digitalis, nonhepatically metabolized beta-blockers may be an option. Serum concentrations of metoprolol (Lopressor, Toprol) or propranolol (Inderal, Inderal LA, Innopran XL), for example, can vary up to 10fold for the same dose, partially the result of high first-pass effects. “I would avoid them,” Dr Reiffel cautioned. “I would use a renally cleared beta-blocker.”

This reversal of drug effects can be prevented by concomitant administration of beta-blockers and a drug such as verapamil (Calan, Covera, Isoptin, Verelan).

Evidence for the efficacy of combination treatment comes from several studies. In one trial of patients with persistent AF randomized to either amiodarone (Cordarone, Pacerone)

alone or with verapamil and to flecainide (Tambocor) alone or with verapamil, at the 3-month follow-up, the verapamil groups had lower first-recurrence rates (20% vs 35%) and lower Continued on page 18

For patients in whom ventricular rate control cannot be attained with betablockers, calcium channel blockers, and/or digitalis, “I would avoid [metoprolol and propranolol]. I would use a renally cleared beta-blocker.” —James A. Reiffel, MD

For bradycardia-tachycardia syndrome, he suggests pindolol (Visken), which increases slow heart rates but blocks exercise rates. Digitalis is effective at slowing resting rates but not with exercise rates. In patients with vagally induced AF, anticholinergic agents alone or in combination with traditional antiarrhythmic drugs may improve rhythm control. Occasionally, AF is associated with stress, exercise, or stimulant intake. In these patients, beta-blockers alone or in combination with traditional antiarrhythmic drugs may improve rhythm control. “It has long been known that the electrophysiologic effects of antiarrhythmic drugs can be reversed by catecholamines,” Dr Reiffel noted.

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New Drug Therapies for Difficult-to-Control... Continued from page 17 second-recurrence rates (68% vs 88%). For rhythm control, novel antiarrhythmic drugs such as ranolazine (Ranexa) can be considered. Trials of ranolazine in patients with previous antiarrhythmic drug therapy for persistent AF showed good tolerance and a success rate of ≥75% in reducing the

frequency or duration of persistent AF, said Dr Reiffel. Combination Therapy: The Future? Dr Reiffel is enthusiastic about the future of antiarrhythmic drug combinations in improving efficacy. In a retrospective chart review in his own

practice from 1990 to 2010, Dr Reiffel found that he used antiarrhythmic drug combinations in highly symptomatic AF patients who were refractory to multiple antiarrhythmic drugs, including amiodarone. Combinations that provided clinically significant improvement included:

• Amiodarone plus propafenone (Rhythmol) • Amiodarone plus disopyramide (Norpace) • Amiodarone plus ranolazine • Dronedarone (Mutlaq) plus ranolazine. No proarrhythmia occurred in these patients, Dr Reiffel noted.

Associated bradycardia should be treated and/or ablated and then the previous antiarrhythmic drugs retried. Consider having the patient enroll in a clinical trial of an investigational agent. In reviewing charts from 1980 to 1995, he encountered 9 patients who had effective AF control with quinidine or disopyramide, with each dosed to efficacy. Gastrointestinal intolerance was ameliorated with a combination of these agents, each at half the previously effective dose. A study of ibutilide (Corvert) and propafenone in combination had a success rate of 71.4%, and a study of amiodarone plus wenxin granules showed that at 6 months, normal sinus rhythm had been restored in 65.1% of patients. For chronic maintenance of sinus rhythm, the combination of quinidine plus verapamil was studied. Patients randomized to digoxin or to verapamil were dosed until rate control had been achieved (<100 beats per minute). Conversion within 6 hours occurred in 84% of patients assigned to quinidine plus verapamil versus 45% of those assigned to quinidine plus digoxin, with no serious morbidity or mortality in either group. As adjunctive therapy, Dr Reiffel says to consider improvement of concomitant disorders/underlying pathophysiologic alterations (“upstream therapies”), such as with angiotensinconverting enzyme inhibitors, angiotensin 2 receptor blockers, or their combination. Associated bradycardia should be treated and/or ablated and then the previous antiarrhythmic drugs retried. Consider having the patient enroll in a clinical trial of an investigational agent. Dr Reiffel concluded by saying that the efficacy rate of an antiarrhythmic drug is lower when tried after a prior antiarrhythmic drug failure. “Nonetheless, drug therapy can be effective. Not all patients need to go to ablation. But just remember, as is true elsewhere, therapy is not perfect in all cases.” ■

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Comparative Effectiveness Analysis of Antithrombotics in Older Patients with Post-ACS Atrial Fibrillation By Mary Mosley Chicago, IL—Similar outcomes were found with 2 different antithrombotic strategies in a comparative effectiveness study in patients with atrial fibrillation (AF) after a non–ST-segment elevation myocardial infarction (NSTEMI). But a trend toward more bleeding with intensified treatment was found. Emil L. Fosbøl, MD, PhD, Fellow, Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark, explained there are no robust data to support the recommendation of the American College of Cardiology (ACC)/American Heart Association guidelines to add warfarin (Coumadin) to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. The study was presented at the 2012 ACC meeting. The evidence from ongoing clinical trials with rivaroxaban (Xarelto), dabigatran (Pradaxa), and apixaban (Eliquis) is awaited to provide clearer answers about the best treatment strategy. The prevalence of coexisting AF and NSTEMI is 25% in this patient population, yet “we do not know how to treat these patients, and whether dual antiplatelet therapy is sufficient to prevent future events,” said Dr Fosbøl. The investigators linked observa-

tional data from the CRUSADE Registry with Medicare data to look at longitudinal outcomes. The CRUSADE Registry—a national quality improvement initiative to promote evidencebased treatment of hospitalized patients with NSTEMI acute coronary syndromes (ACS)—included data from 200,000 patients from 500 hospitals across the United States from 2001 to 2006.

The prevalence of coexisting AF and NSTEMI is 25% in this patient population, yet “we do not know how to treat these patients, and whether dual antiplatelet therapy is sufficient to prevent future events.” —Emil L. Fosbøl, MD, PhD In this comparative effectiveness analysis, the registry of patients with AF who received coronary stenting and were discharged on either DAPT (N = 1200) or DAPT plus warfarin (N = 448) were included. The in-hospital major bleeding rate was 16.3% in

the DAPT group and 13.5% in the DAPT plus warfarin group, and the inhospital stroke rate was similar at 0.4% and 0.5%, respectively. The median age was 78 and 77 years, respectively. Although this analysis included patients aged ≥65 years only, based on Medicare data, it reflects the typical population with AF. “This is the patient most commonly seen,” said Dr Fosbøl, “but physicians are hesitant about antithrombotic treatment, because of their age and frailty.” At 1 year after discharge, there was a similarly high rate of the composite end point of myocardial infarction (MI), ischemic stroke, and death, at 20.6% in the DAPT group and 19.4% in the DAPT plus warfarin group. These rates remained similar after adjusting for confounders and clinical characteristics. The incidences of bleeding requiring hospitalization at 1 year were 11.9% and 14.4%, respectively. The difference between the groups did not reach significance, but there was a trend toward more bleeding with DAPT plus warfarin. “Their predictive risk for ischemic events and bleeding was similar, and we feel fairly confident that the 2 groups are similar,” in this analysis,

said Dr Fosbøl. The median scores for CHADS2 (approximately 2.0) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA; nearly 6) were similar in the DAPT and DAPT plus warfarin patients. CHADS2 predicts the risk of a thromboembolic event, and ATRIA, a fairly new score, assesses longitudinal bleeding. The ATRIA score includes previous hospitalization for bleeding, sex, and age, among other factors, and ranges from 0 to 10. The strongest predictor for long-term bleeding is a previous bleeding incident. The use of drug-eluting stents (DES) was similar in both groups at 80%. The type of stent did not influence the bleeding risk in the 2 groups, but more MIs, strokes, and deaths were reported in the patients with a DES compared with a bare-metal stent. Although efficacy was similar with the 2 treatment strategies, the trend toward higher rates of bleeding with DAPT plus warfarin is a concern. However, Dr Fosbøl noted that clinical trial data are needed to determine the best treatment strategies for these patients. For now, physicians must individualize the treatment to the patient and include the patient in the discussion to select the treatment strategy. ■

Cardiac Resynchronization Therapy Still Challenging in Patients with Atrial Fibrillation and Heart Failure Chicago, IL—Cardiac resynchronization therapy (CRT) in the setting of atrial fibrillation (AF) and heart failure (HF) has clear challenges, and the evidence is mixed about its benefit. Randomized clinical trial evidence is needed, including the use of atrioventricular junction (AVJ) ablation, according to Jonathan S. Steinberg, MD, FACC, Cardiologist and Professor of Medicine at Columbia University, College of Physicians and Surgeons of New York, and Director of the Arrhythmia Institute at Valley Health System in New York and New Jersey, at the 2012 American College of Cardiology meeting. The prevalence of AF ranges from approximately 10% in patients with mild HF to 50% in patients with New York Heart Association (NYHA) class IV HF. AF markedly worsens the prognosis of HF and the clinical course in those with left ventricle dysfunction

and those with an implantable cardioverter-defibrillator. AF also affects ventricular arrhythmias, increases the likelihood of ventricular tachycardia fibrillation, and causes hemodynamic deterioration. The benefit of CRT may depend on ventricular rate control in patients with AF, independent of resynchronization, making it more complicated to assess the alternate effects of CRT in the population with AF. Dr Steinberg noted that US Food and Drug Administration approval of CRT was based on clinical trials of patients with sinus rhythm, and the benefit of CRT may be mediated in part by optimizing atrioventricular timing in patients with sinus rhythm; however, this timing is not relevant if the patient is experiencing AF. CRT is more challenging in patients with permanent AF than in those with sinus rhythm.

Approximately 66% of patients with AF ultimately have AVJ ablation, which is a stepwise process based on clinical response and capture rates. —Jonathan S. Steinberg, MD, FACC

Biventricular Pacing Needed Biventricular pacing is needed virtually all the time in patients with CRT to accrue the most benefit. Yet, this can be challenging in patients with AF and competing asynchronous rhythm. Pacing options are designed to try to maintain biventricular pacing when CRT is used in patients with AF, but no benefit has been proved. Medical therapy to slow the ventricular rate and block atrioventricular nodal conduction is often unsuccessful. A challenge to achieving consistent biventricular capture is the need for a higher programmed pacing rate for a higher intrinsic heart rate. Frequent fusion and pseudofusion beats can occur and represent ineffective biventricular capture, “in which only a small amount of left-ventricular myocardium is captured by the leftventricular pacing, negating the intended effects of CRT,” Dr Steinberg Continued on page 20

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New Oral Anticoagulants Show Superior Efficacy... by Mark J. Eisenberg, MD, MPH, Associate Professor of Medicine, Director of McGill Cardiology Fellowship Programs at McGill University, Montreal, Quebec, Canada, and colleagues at the 2012 American College of Cardiology meeting. These newer agents have been shown to be superior to warfarin on efficacy end points and to reduce the risk for a major bleeding event compared with warfarin, although they do appear to increase the risk for gastrointestinal (GI) bleeding. Superior Efficacy in Stroke Prevention This review encompassed the 3 large, randomized controlled trials Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY); Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE); and 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 (ROCKET-AF). Dr Eisenberg’s group used a random effects model to pool the efficacy and safety data across the 3 trials, in which more than 40,000 patients were randomized to one of these new oral anticoagulants or to warfarin. Patients randomized to one of the new oral anticoagulants had a 22% decreased risk for a composite end point of all stroke and systemic embolism compared with patients randomized to warfarin. In this analysis, compared with warfarin, the new oral anticoagulants

“These new oral anticoagulants are easily administered and do not require monitoring, making them promising alternatives for prevention of stroke and systemic embolism in patients with AF.” —Mark J. Eisenberg, MD, MPH were associated with a: • 23% reduction in the relative risk for ischemic and unidentified stroke • 55% risk reduction of hemorrhagic stroke • 12% risk reduction of all-cause mortality • 13% risk reduction of vascular mortality. The risk for myocardial infarction was similar between warfarin and the new anticoagulants. Reduced Risk for Major Bleeding, but Increase for GI Bleeding In addition, the relative risk for

major bleeding was 12% lower with the new anticoagulants compared with warfarin, but the relative risk for GI bleeding was increased by >25% with the newer agents. “These new oral anticoagulants are easily administered and do not require monitoring, making them promising alternatives for prevention of stroke and systemic embolism in patients with AF,” Dr Eisenberg stated. Corey Miller, a medical student at McGill University and a coinvestigator in this analysis, said that the results suggest notable trends with the new anticoagulants. More research will be required to confirm the suggestion for decreased risk for major bleeding and increased GI bleeding with the new agents. Although cost was not included in this meta-analysis, he noted that the extra cost for the new medications may be offset by the significant cost associated with monitoring patients receiving warfarin. These same 3 trials, along with the PETRO (Stroke Prevention in Patients with AF by Treatment with Dabigatran, with and without Aspirin, Compared to Warfarin) trial, were used to indirectly compare the newer anticoagulants regarding efficacy and safety end points using a random effects model, which was performed by William L. Baker, PharmD, Assistant Professor of Pharmacy, University of Connecticut Schools of Pharmacy and Medicine, Farmington, and colleagues. When compared with dabigatran, apixaban was associated with 26% lower odds for major bleeding and 42% lower odds for GI bleeding. In comparing dabigatran and riv-

Continued from page 1

Key Points ➤ The newer oral anticoagulants apixaban, dabigatran, and rivaroxaban are superior to warfarin in preventing stroke and systemic embolism in AF ➤ These newer agents also reduce the risk for major bleeding, although they increase the GI bleeding risk compared with warfarin ➤ The new anticoagulants showed a 23% risk reduction of ischemic and unidentified stroke, 55% risk reduction of hemorrhagic stroke, 12% risk reduction of all-cause mortality, and 13% risk reduction of vascular mortality ➤ These oral agents are easily administered and do not require monitoring of patients as with warfarin

aroxaban, the odds of the composite outcome of stroke or systemic embolism was 25% lower with dabigatran, as were the odds for ischemic stroke (33% lower) and hemorrhagic stroke (55% lower). Compared with rivaroxaban, apixaban was associated with 32% lower odds for a major bleeding event, but rivaroxaban was superior in preventing systemic emboli by nearly 400%. The researchers concluded head-tohead clinical trials are needed to confirm these findings. ■

Cardiac Resynchronization... Continued from page 19 said. Inaccurate assessment of biventricular capture on device counters— the gold standard to assess proper delivery of CRT—can occur.

rate of inaccurate recording of the absolute percentage of biventricular pacing, as much as 40% of the >90% documented pacing.

Benefit of CRT In terms of left-ventricular ejection fraction (LVEF) and NYHA class, CRT showed benefit in some studies and equivalence in others in a meta-analysis. Dr Steinberg presented a prospective study in patients with permanent AF receiving CRT that showed that effective pacing improved NYHA class, reverse remodeling, and LVEF; however, effective pacing occurred in only 44% of the patients in that study. This study also identified a high

The prevalence of AF ranges from approximately 10% in patients with mild HF to 50% in patients with NYHA class IV HF.

AVJ ablation improved survival as was shown in a large observational study of CRT in patients with AF and sinus rhythm. Dr Steinberg noted that this is strong evidence for the need for

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AVJ ablation, which is the ultimate atrioventricular nodal blockade and forces completely effective ventricular capture, although this is an observational study. Similar results were shown in 2 subsequent observational studies. Who Should Receive CRT? Dr Steinberg said that appropriate patients for CRT are those with permanent AF meeting the clinical criteria for CRT, those who have mild HF and left bundle branch block only, and patients with advanced HF and left bundle branch blockage. Approximately 66% of patients with AF ultimately have AVJ ablation, which is a stepwise process based on clinical response and capture

rates, according to Dr Steinberg. Candidates for AVJ ablation are patients with moderately rapid ventricular rates that cannot be slowed and will not have pacing capture (performed with CRT implantation); those with pacing counters that do not reach ≥90% (subsequent AVJ ablation); and nonresponders whose electrocardiogram and Holter recordings show high percentages of ineffective capture. Patients with relatively slow rates who are pharmacologically controlled at the time of CRT implantation are followed. Careful attention to rate control is required, and physicians should not rely solely on pacing counters to ensure effective CRT capture.—MM ■

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Dabigatran Safe and Effective Anticoagulant Postablation in Patients with Atrial Fibrillation By Mary Mosley Chicago, IL—In patients with atrial fibrillation (AF) who underwent catheter ablation, the new anticoagulant dabigatran (Pradaxa), an oral direct thrombin inhibitor, was found to effectively prevent thromboembolic events in a small prospective study presented by Charlotte Eitel, MD, Department of Electrophysiology, Heart Center Leipzig, Germany, at the 2012 American College of Cardiology meeting. Patients with AF are known to be at increased risk for thromboembolic events. Dr Eitel and colleagues conducted this study from July 2010 to September 2011 to determine the longer-term safety and efficacy of dabigatran in this setting, because existing evidence with postablation dabigatran was limited to a small, 30-day study. A total of 89 patients with AF (average age, 63 years) were prospectively started therapy with dabigatran the evening of their catheter ablation, if permitted by the status of the femoral puncture site, or with low-molecularweight heparin until dabigatran could be started. Renal insufficiency was a study exclusion criterion. The results of the serial 7-day Holter electrocardiograms and CHA2DS2-

VASc score drove the decision about whether to continue anticoagulation. The average follow-up was 274 days (interquartile range, 59, 497).

Anticoagulation with dabigatran in patients with AF who underwent catheter ablation was an “attractive alternative to the conventional approach with warfarin,” because of its predictable dose–response relationship. Twice-daily dabigatran was given at 110-mg doses to 78% and at 150-mg doses to 22% of study patients, respectively. Paroxysmal AF was found in 57% of the study patients (78% men). The left atrial parasternal long axis diameter was 42 mm. The study patients had an intermediate risk of thromboembolic events with an average CHA2DS2-VASc score of 2 (interquartile range, 0, 5) and low

risk of bleeding with a HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly [> 65 years], drugs/alcohol concomitantly) score of 1 (interquartile range, 0, 3). In terms of AF-related findings, recurrences of arrhythmia were found in 34%, 25%, and 21% of patients at their 3-month, 6-month, and 12-month clinical follow-ups, respectively. Because of arrhythmia recurrence, 9 patients required electrical cardioversion. Transesophageal echocardiography was required in only 1 patient, because of the discontinuation of dabigatran. The investigators reported that the effectiveness of this anticoagulation strategy was shown by the lack of any prespecified clinical events of stroke and systemic embolism at the mid-term follow-up. Safety was identified by no occurrence of minor or major hemorrhage. Patient acceptance of anticoagulation with dabigatran was high. The investigators stated that anticoagulation with dabigatran in patients with AF who underwent catheter ablation was an “attractive alternative to the conventional approach with war-

Key Points ➤ In patients with AF who underwent catheter ablation, dabigatran, an oral direct thrombin inhibitor, was found to effectively prevent thromboembolic events ➤ The effectiveness of this anticoagulation strategy was shown by the lack of any prespecified clinical events of stroke and systemic embolism at the mid-term follow-up ➤ Anticoagulation with dabigatran in this patient population is an attractive alternative to warfarin, because of its predictable dose–response relationship ➤ Unlike warfarin, dabigatran does not require laboratory monitoring farin” because of its predictable dose– response relationship. In addition, this strategy does not require laboratory monitoring, whereas warfarin use does. ■

Heart Failure

Blood Assay for Galectin-3 Identifies Heart Failure Risk of Patients in the Community Setting Test may also predict response to therapy By Wayne Kuznar Chicago, IL—A blood test for galectin-3, a unique protein that binds to carbohydrates known as “beta-galactosides,” appears to be a reliable predictor of incident heart failure (HF) and of the response to treatment for HF, reported Jennifer E. Ho, MD, a practicing cardiologist in San Francisco, CA, using data from the National Heart, Lung, and Blood Institute’s Framingham Heart Study, at the 2012 American College of Cardiology meeting. Galectin-3 has been implicated in biologic processes important to the development and progression of HF, and is believed to be a primary mediator of progressive cardiac fibrosis. Data have demonstrated that higher levels of galectin-3 are associated with a more aggressive form of HF, and that ≥33% of patients with mild-to-

moderate HF have elevated levels of galectin-3. In a study presented at the meeting, higher levels of galectin-3 were associated with an increased risk of newonset HF and all-cause mortality in the community. The study included 3353 participants (mean age, 59 years) of the Framingham Offspring Cohort whose galectin3 levels were measured and who were followed for development of HF over 10 years. Of this population, 10% to 25% had an elevated level of galectin-3. Incident HF was more common as galectin-3 levels increased. In multivariate analyses, each standard deviation (SD) increase in galectin-3 levels was associated with a 23% increase in the hazard ratio (HR) for incident HF, and on sex- and age-adjusted analyses,

each SD increase was associated with a 28% increase in HR.

Galectin-3 was also associated with all-cause mortality, with a multivariable-adjusted HR of 1.15.

The study provides further confirmation that elevated levels of galectin-3 in the general population are associated with a markedly increased risk of HF development over the subsequent 10 years, said Dr Ho. The findings suggest “that cardiovascular injury due to fibrosis may be evident long before the clinical onset of heart failure,” Dr Ho said. A second analysis found a differential effect of treatment on HF based on patients’ galectin-3 levels. Investigators led by Inder S. Anand, MD, FRCP, FACC, Professor of Medicine at the University of Minnesota, and Director of the Heart Failure Program at the Minneapolis VA Medical Center, looked at treatment response in the Valsartan Heart Failure Trial (ValHeFT), in which patients with HF Continued on page 22

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Advances in Stem-Cell Therapy for Heart Failure Despite negative primary end points, positive clues are promising By Mary Mosley Chicago, IL—A phase 2 study of autologous bone marrow–cell therapy in patients with chronic ischemic heart disease and left-ventricular dysfunction showed no significant differences for the primary end points, but there were hints of benefit from the prespecified exploratory analyses that point to refinements for future studies that will build on these results, according to the study’s lead investigator, Emerson C. Perin, MD, PhD, Director of Clinical Research for Cardiovascular Medicine, Texas Heart Institute, Houston. The results were presented at the 2012 American College of Cardiology meeting. The First Mononuclear Cells Injected in the US (FOCUS) Cardiovascular Cell Therapy Research Network (CCTRN) study is the largest trial to use a patient’s own stem cells in a patient population. A key element of the CCTRN is a biorepository of samples from all study patients, which Dr Perin explained is a treasure trove for researchers to tease out cell functions from and try to correlate them with other end points in this study and additional clinical outcomes. “Developing a cell biorepository is a huge step forward for the future of autologous therapy, because the composition and function of cells in the bone marrow may play a significant role in outcome,” Dr Perin noted. This double-blind randomized multicenter study of 61 treated patients and 31 controls (median age, 62 years) used first-generation cell product— one of the most studied clinically. The patients’ qualifying left-ventricular ejection fraction (LVEF) was approximately 30%.

In this ongoing study, the patients are chronically ill and are out of treatment options; these patients belong to a population for whom we need to find treatment solutions, said Dr Perin. Medical therapy is insufficient, not enough hearts are available for transplants, and left-ventricular assist devices are expensive and have complications. “I believe cell therapy will be one of the solutions for these patients,” he maintained.

“Developing a cell biorepository is a huge step forward for the future of autologous therapy, because the composition and function of cells in the bone marrow may play a significant role in outcome.” —Emerson C. Perin, MD, PhD

The 6-month data showed that LVEF, an exploratory end point, was significantly improved by 2.7% in the treated patients—an increase of 1.7% versus a decline of 1.3% in the control patients. No differences between the treated and control patients were seen in the primary end points of change from baseline in maximal oxygen consumption, change in left-ventricular end systolic volume on echocardiography, and change in ischemic defect size

Blood Assay for Galectin-3 Identifies... Continued from page 21

were randomized to valsartan (Diovan) or placebo in addition to other therapies for HF. Plasma samples were available for approximately 30% of the Val-HeFT participants. Compared with placebo, valsartan caused a significant 44% reduction in hospitalizations for HF in a subgroup of patients with galectin3 below the median. No effect of valsartan was observed in the subgroup with galectin-3 above the median. Another subanalysis of a major study, the landmark Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), suggests that

galectin-3 may be used to prioritize patients with early-stage HF for cardiac resynchronization therapy (CRT), said Kenneth Stein, MD, Senior Vice President and Chief Medical Officer, Cardiac Rhythm Management at Boston Scientific, Minneapolis. The data revealed that CRT conveyed an important benefit in patients with low and high galectin-3 levels. However, because of the markedly higher incidence of events in patients with high levels of galectin-3, the absolute benefit of CRT was approximately double that of the benefit in patients with low galectin-3 levels. ■

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as assessed by single-photon emission tomography imaging. Stem-Cell Variation in Individual Patients There is a large variation within individuals’ own cells, noted Dr Perin, and the potency of the cells depends on the individual—which is much different from giving a fixed dose of a drug in a tablet. Younger patients responded significantly, which may reflect effects of aging, comorbidities, genetics, and possible unknown factors. In this trial, patients aged ≤62 years had a significant 4.7% change in LVEF from baseline compared with only a 0.6% change in patients aged >62 years. The researchers also found that certain cell types provided clinical benefit. There was a relationship between CD34+ and CD133+, endothelial progenitor cells, and improvement in LVEF, as shown by a multiple variable model that included age and treatment. For each 3% higher level of CD34+ cells, there was an associated average 3.0% absolute unit increase in LVEF. Each 3% higher level of CD133+ cells was associated with an average 5.9% absolute unit increase in LVEF. The investigators found that younger patients had distinctly better bone marrow–cell function, which was also seen in the prior pilot and small phase 1 FOCUS-HF studies. Change in maximal oxygen consumption, a good evaluation of the patient’s ability to perform, was significantly positively affected in the younger patients in the prior studies and in FOCUS CCTRN. Dr Perin noted that maximal oxygen consumption status is used to move patients on and off the transplant list; although the results of this study cannot be used in that regard, it does show that the small changes achieved with this therapy have a significant impact. For example, maximal oxygen consumption changed from 14.6 to 15.3 in the treated patients and from 15.2 to

13.4 in the control patients. Despite the small difference between the 2 groups, the change is sufficient to move the treated patients off the transplant list, whereas the control patients would be added to the list.

“The subanalyses from FOCUS give us some very tantalizing hints that we may be able to select out patients in whom bone marrow transplantation is therapeutically beneficial.” —Roberto Bolli, MD, FAHA “These are meaningful things that we are seeing, and perhaps we can use this information prospectively to select those patients and those cells that can fine-tune the therapy for the next generation of studies,” said Dr Perin, who noted that new related studies were beginning soon. Roberto Bolli, MD, FAHA, Professor of Medicine and Executive Vice President, Department of Medicine and Chief, Division of Cardiovascular Medicine, University of Louisville, KY, commented in a press conference that there is a huge potential for the bone marrow to become useful therapeutically, but there is much that is unknown about bone marrow and what it does and how it works. “The subanalyses from FOCUS give us some very tantalizing hints that we may be able to select out patients in whom bone marrow transplantation is therapeutically beneficial. If we can select the patients in whom the bone marrow is still functional, we will see a beneficial effect,” Dr Bolli pointed out. ■

Cardiometabolic Risk Initiative Resource Center The American Diabetes Association provides new resources for providers and for patients regarding cardiometabolic risk factors and assessment, including a patient education toolkit and a detailed discussion of the cardiometabolic risk factors. Key cardiometabolic risk factors

discussed include obesity, hypertension, smoking, and abnormal lipid metabolism. To download the patient education toolkit, or for more information, visit http://professional.diabetes. org/ResourcesForProfessionals.aspx? cid=60379.

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ACC Launches Legends of Cardiovascular... Brigham and Women’s Hospital in Boston, discussed the advances made in treating acute myocardial infarction (AMI) over the past century, and presented an intriguing view of research areas anticipated to bring even greater success. Dr Braunwald is associated with many of the groundbreaking advances in cardiovascular (CV) medicine. Illustrating the magnitude of the problem of AMI, Dr Braunwald said that every 34 seconds an American suffers an infarction. He pointed out that during his 25-minute lecture, 44 Americans will have had an AMI, and 6 of them would have died. “We cannot rest on our laurels,” he warned. Ongoing research is focused on postinfarction treatment, building on knowledge gained from research, including the benefits of myocardial reperfusion. Three promising areas are: • Prevention of lethal myocardial reperfusion injury • Inhibition of thrombin generation • Cell therapy. Prevention of Lethal Myocardial Reperfusion Injury Post-AMI Remote ischemic preconditioning, performed with cyclic ischemia and reperfusion in tissue remote from the coronary occlusion, reduces infarct size. More myocardium was saved at 30 days when remote ischemic preconditioning was performed in the ambulance in patients who subsequently underwent percutaneous coronary intervention (PCI) compared with those who did not have preconditioning, as proved in a recent study. A pharmacologic approach to ischemic preconditioning also limited lethal myocardial injury. An injection of cyclosporine A immediately before PCI significantly reduced infarct size. Pilot studies of these 2 approaches are

under way and are expected to move into phase 3 trials, said Dr Braunwald. Inhibition of Thrombin Generation Post-AMI Recurrent occlusion post-AMI remains a problem, despite treatment with coronary stents and dual antiplatelet therapy (DAPT), and can be fatal. The inhibition of excess thrombin generation, which occurs for months post-AMI, by blocking factor Xa appears to be a promising approach. Vi-

Cell Therapy Post-AMI Reduced infarct size and improved left-ventricular ejection fraction (LVEF) were achieved in the REPAIR (Renal Protection Against Ischaemia Reperfusion in Transplantation) trial, one of the most promising first-generation trials of bone marrow–derived (BMD) progenitor cells. The cells were injected directly into the infarct-related artery, and patients were followed for 2 years. Event-free survival was also superior in the treated patients compared with

“Reperfusion therapy of an infarction is a major success story, with early mortality falling by 75% over a 25-year period in clinical trials.” —Eugene Braunwald, MD, FRCP

tamin K antagonists cannot be used safely, because excessive bleeding can occur in patients receiving DAPT. Rivaroxaban (Xarelto), one of the new factor Xa anticoagulants that blocks thrombin formation, was associated with significant reductions in CV death and all-cause mortality in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin with/without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome 2 (ATLAS ACS2)-TIMI 51 trial. Dr Braunwald, a lead investigator of this study, said that this reduction was achieved with the lowest dose of rivaroxaban studied—2.5 mg twice daily—given for 2 years in addition to guidelines-based treatment, including DAPT. Despite an increase in bleeding, no increase in fatal bleeding or intracranial hemorrhage occurred.

patients in the control group. Following on these findings, the recently announced BAMI (Effect of Intracoronary Reinfusion of Bone Marrow–Derived Mononuclear Cells on All-Cause Mortality in Acute Myocardial Infarction) trial will study the effect of intracoronary infusion of BMD mononuclear cells compared with standard care in approximately 3000 patients with a low LVEF (<45%). The cells will be injected within 3 to 6 days after successful reperfusion, and the goal is to reduce 3-year mortality by 25%. This multinational trial will begin enrollment in the second quarter of 2012. Two proof-of-principle trials, SCIPIO (Stem Cell Infusion in Patients with Ischemic Cardiomyopathy) and CADUCEUS (Cardiosphere-Derived

Key Points

Photo taken at ACC 2012.

➤ Advances in post-AMI treatment include prevention of lethal myocardial reperfusion injury, inhibition of thrombin generation, and cell therapy ➤ The inhibition of excess thrombin generation by blocking factor Xa appears to be a promising treatment for recurrent occlusion post-AMI ➤ Rivaroxaban, a new factor Xa anticoagulant, is associated with significant reductions in CV death and all-cause mortality

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➤ Reperfusion therapy of an infarction has reduced early mortality by 75% over a 25-year period

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Continued from page 1

Autologous Stem Cells to Reverse Ventricular Dysfunction), suggest that cardiac-derived stem cells from a patient can lead to scar resorption and tissue regeneration, and can improve myocardial function. The discovery that stem cells reside in the heart by Piero Anversa, MD, Professor of Medicine and Anesthesia, and Director of the Center of Regenerative Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, provided the foundation for the approach studied in SCIPIO, which was led by Roberto Bolli, MD, FAHA, Professor of Medicine, Physiology and Biophysics, and Executive Vice Chair, Department of Medicine, University of Louisville, KY. Coronary arterial infusion of autologous BMD progenitor cells reduced the size of the infarct from baseline at 4 months and 12 months and improved ejection fraction by approximately 30%, as shown by cardiac magnetic resonance. Dr Braunwald noted that these results are not yet published and are provided courtesy of Dr Bolli. The cells were obtained during bypass surgery from the right atrial appendage by Dr Bolli’s group, and the cells were isolated and expanded by Dr Anversa’s group. The recently published results of the CADUCEUS trial demonstrated a reduction in infarct size, an increase in viable myocardium, and greater thickening of infarct segments—all reflecting better systolic performance, Dr Braunwald stated. The investigators performed subendocardial biopsies in post-AMI patients with left-ventricular dysfunction to obtain the cardiac stem cells that grew into clusters called “cardiospheres.” The cardiospheres were injected into reperfused infarct-related arteries. “Reperfusion therapy of an infarction is a major success story,” said Dr Braunwald, “with early mortality falling by 75% over a 25-year period in clinical trials.” This therapy stands on the work of Dr Braunwald and others to understand myocardial reperfusion and led to the “open-artery hypothesis,” with the 90-minute window established to improve outcomes. The approaches used, with newer ones replacing earlier approaches, include intracoronary thrombolysis, intravenous thrombolysis, intravenous streptokinase, aspirin, tissue plasminogen activator, primary PCI, stenting, and thrombectomy. “I am honored that these and other therapeutic and preventive options will bring this important condition under more control early in the second century,” said Dr Braunwald. ■

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Value of Remote Disease Management of Arrhythmia Highlighted at ACC 2012 Reduced hospitalization, improved arrhythmia management By Mary Mosley Chicago, IL—Remote disease management is effective and more efficient for patients, their caregivers, and for physicians. Although there are few data on its cost-effectiveness, the value for the patient and for guiding treatment is high, by reducing hospitalizations and improving management of arrhythmias. The value and benefits of remote disease management and its effect on improving clinical outcomes were the focus of a clinical session at the 2012 American College of Cardiology (ACC) meeting. Remote Monitoring for Arrhythmias Remote monitoring of arrhythmias is defined as daily and continuous surveillance through a device that allows assessment of arrhythmia burden, patient status, and device integrity. Remote follow-up refers to contact with a patient that replaces a clinic visit. “Remote device monitoring can identify arrhythmia and atrial fibrillation earlier,” said George H. Crossley, III, MD, President of Mid-State Cardiology, St. Thomas Heart, Nashville, TN. A 45% reduction in office visits over a 15-month follow-up period was shown in the 2010 Lumos-T Safely Reduces Routine Office Device Follow-Up (TRUST) study of automatic remote monitoring of implantable cardioverterdefibrillators (ICDs). Dr Crossley said this shows a “huge amount of the efficiency value” of monitoring. Event detection was faster in the TRUST study, “showing the effectiveness of monitoring,” Dr Crossley noted. Clinically relevant asymptomatic events were detected 41 days sooner with wireless remote monitoring compared with traditional in-office follow-up. All arrhythmia events were detected 35 days sooner. Adherence to the follow-up schedule was significantly improved with remote monitoring compared with traditional monitoring (94% vs 88%, respectively). An informal study in Dr Crossley’s office showed that remote follow-up saves time and requires approximately 7 minutes, including the call to the patient, compared with approximately 20 minutes for an in-office visit. Remote follow-up can also be used for taking a patient’s history, which can contribute to shorter office visits, and for the nurse to report data to the patient. The Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision (CONNECT) study showed a

significant reduction in the time to create a treatment plan (approximately 4 days vs 22 days in the control group) after a clinically actionable event was identified in patients with an ICD (Crossley GH, et al. J Am Coll Cardiol. 2011;57:1181-1189).

“Remote device monitoring can identify arrhythmia and atrial fibrillation earlier.” —George H. Crossley, III, MD

Healthcare utilization was also reduced with remote monitoring in the CONNECT study, including hospitalization and emergency department visits. Length of hospitalization was significantly reduced in patients with an ICD and with a cardiac resynchronization therapy defibrillator; the costsavings in the remote monitoring arm was $1793 per patient. In patients with a pacemaker, the 2009 PREFER study showed that remote pacemaker follow-up was more effective in identifying clinically actionable events over 12 months than transtelephonic monitoring (TTM). In the CareLink arm, 45% of patients had an event, of which 66% were detected remotely. In the TTM arm, 38% had an event, of which only 2% was detected via TTM. TTM requires the patient to manually send the data via the telephone, whereas remote monitoring using the CareLink device automatically sent the data. Remote Monitoring of Atrial Fibrillation More devices are capable of storing electrograms and event counter diagnostics, which can be retrieved remotely through a modem connected to the internet. These diagnostics are reviewed by a remote monitoring center and can be directly retrieved by the physician’s office. The availability of newer devices with this capability makes it more feasible to conduct prospective studies to evaluate their benefits and costs in patients with atrial fibrillation, said Paul A. Levine, MD, Professor of Medicine, Loma Linda University School of Medicine, University of California, Los Angeles. “A wealth of information is obtained from continuous rhythm monitoring,” said Dr Levine. This includes details

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about the onset of sustained arrhythmias, arrhythmia burden, correlation of symptoms with arrhythmias, improved understanding of the rhythms, and timely intervention and the response to the intervention. Yet, there are a number of limitations and cautions that clinicians must consider, Dr Levine pointed out. As the devices and their uses mature, many of these will be addressed. The large volume of data obtained requires sorting out what is a clinically actionable event in a timely fashion. There is marked variation in the recordings, and the clinician must determine when intervention is warranted. Device diagnostics presume that the diagnosis is correct, but independent validation is needed. For example, was a recorded episode truly brief, or was it a result of signal dropout during transmission? What is the role of the cumulative burden or the duration of individual episodes recorded in evaluating the data and

“A wealth of information is obtained from continuous rhythm monitoring.” —Paul A. Levine, MD

determining treatment? In terms of physicians using the data accumulated from remote device monitoring, how does it impact the work flow in the office or clinic? Is there a legal liability if the physician doesn’t use the data? There are currently no data regarding the impact of continuous monitoring and early notification on long-term outcomes. What Is the Cost-Benefit Ratio and for Whom? “There is a paucity of cost data,” said Mark H. Schoenfeld, MD, Clinical Professor of Medicine, Yale University School of Medicine, and Director of the Cardiac Electrophysiology and Pacemaker Laboratory, Hospital of Saint Raphael, New Haven, CT. Although remote monitoring has been reimbursed in the United States since 2006, this was done without demonstrating a cost-savings, and most studies so far relate to transportation costs. For example, one study showed patients saved approximately $1377 to $4113 over 5 years

through avoiding transportation costs for office visits. An informal analysis by Dr Schoenfeld found a $100 annual cost-savings per patient by using remote monitoring to reduce the annual clinic visits from 2 to 1. The calculation did not include other costs, such as transportation or cost to payers, and it was limited to Medicare data for Connecticut. For monitoring of a dual-chamber pacemaker with device interrogations every 3 months with 1 annual clinic visit, the cost was $354.11 using TTM and $378.80 with remote monitoring in that analysis. This cost was increased to $486.28 for device interrogations every 6 months and 2 annual clinic visits. For remote monitoring of a dual-chamber ICD with device interrogations every 3 months plus 1 annual office visit, the cost was $504.85. The cost was $606.62 for device interrogations every 6 months plus 2 annual office visits. Yet, the cost-benefit ratio depends on the perspective, said Dr Schoenfeld. This differs for the individual patient, the provider, society and taxpayers, payers, the government, and industry. For each of these parties, the cost and benefit regarding access to care, quality, efficiency, costs, and financial incentives differ. For the clinician, remote monitoring provides more patient data and can help to provide better care, with faster follow-up and without any increased costs. For the hospital, there are more networked data, perhaps some influence on a better reputation, greater efficiency, and savings from shorter hospital stays that can offset the costs of transmitters, data analysis, and patient education. For the government and insurers, this approach provides more healthcare data, which can contribute to better care, increased efficiency, and cost control. Whether the cost-benefit ratio is viewed from the perspective of the patient or of another party is an ongoing issue, said Dr Schoenfeld. Also, office visits are not eliminated completely, because devices cannot be reprogrammed remotely, and some patients prefer to see the doctor and opt out of remote monitoring. Remote device monitoring via mobile phones is more challenging, and many patients no longer have landline phones. Advances in technology and economic changes may limit the ability to make satisfactory financial projections, Dr Schoenfeld said. ■

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Faster, Safer Discharge from Emergency Department with Coronary CT Angiography Similar outcomes in patients at low to intermediate risk By Mary Mosley Chicago, IL—In patients at low to intermediate risk of coronary artery disease (CAD) presenting with chest pain, a rule-out strategy using primary coronary computed tomographic angiography (CTA) versus traditional care was found to be safe and effective to determine patients who could be discharged directly from the emergency department, according to lead investigator Harold I. Litt, MD, PhD, Chief of Cardiovascular Imaging, Department of Radiology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr Litt presented the results of the multicenter randomized controlled ACRIN (American College of Radiology Imaging Network) PA 4005 study in a late-breaking session at the 2012 American College of Cardiology meeting. No myocardial infarctions (MIs) or cardiac deaths had occurred at 30 days in 89% of patients who had a negative CTA examination (<50% stenosis), which was the primary end point. ACRIN PA 4005 was sufficiently powered to demonstrate an acceptable primary safety end point of <1% for 30-day major adverse cardiovascular events. These results supported the findings from previous studies, indicating that CTA may be beneficial, in observational or randomized studies, which were too small to conclusively prove safety. Coronary Computed Tomography for Systematic Triage of Acute Chest Pain Patients to Treatment (CT-STAT), a multicenter, randomized study showed that CTA compared with single-photon emis-

sion computed tomography myocardial perfusion imaging (SPECT MPI) reduced time to diagnosis and costs, but its numerical reduction in events was not significant. Chest Pain This study addressed a large public health issue. Chest pain is the second most common reason for an emergency department visit, leading to 6 million to 10 million annual visits. Although up to 85% of patients ultimately do not have a cardiac cause for their chest pain, most are admitted to the hospital for an evaluation, at a cost of several billions of dollars annually. “This represents a tremendous cost to society and an inefficient use of resources,” said Dr Litt, as well as contributing to overcrowding of emergency departments. “A technique that can efficiently triage these patients into those who can be discharged quickly and the ones who need further evaluation is very important,” to reduce the currently substantial miss rate of 2% to 3% of patients who are discharged with an unrecognized heart attack. In the CTA arm, 50% of patients were discharged directly from the emergency department compared with 26% of patients receiving traditional care. Length of stay was reduced by 50% in the overall CTA group and by 50% in the patients who had a negative CTA. ACRIN PA 4005 randomized patients (aged ≥30 years) who had signs and symptoms of acute coronary syndromes and a thrombolysis in MI risk

score of 0 to 2 in a 2:1 fashion to either CTA (N = 908) or to traditional care (N = 462). Approximately 60% of the patients were black, and approximately

“A technique that can efficiently triage these patients into those who can be discharged quickly and the ones who need further evaluation is very important.” —Harold I. Litt, MD, PhD 54% were women. Traditional care was the usual protocol for each of the 5 study sites, and providers were free to make all decisions for tests and treatments for this group. In the clinical trial arm, 76% of the cardiac catheterizations were positive compared with 44% in the traditionalcare arm. “Clinical trials were identifying patients who needed the cardiac catheterizations more than traditional care,” explained Dr Litt. Revascularization occurred in 2.7% of the clinical trial group and 1.3% of the traditionalcare group, but the difference was not significant. Resource Utilization Direct discharge from the emergency department was higher (50% vs

23% for traditional care) and the length of stay was shorter in the overall CTA group (18 hours vs 25 hours), which impacted potential cost-savings. Hospitalization was even shorter, at 12 hours in the negative CTA patients compared with 25 hours with traditional care. Resource utilization at 30 days was not significantly different between the 2 strategies. A nonsignificant greater number of patients having CTA had a cardiologist visit (7.1% vs 3.8% traditional care). In-hospital and 30-day cost data are expected within 6 months, with 1-year resource utilization and cost-effectiveness data expected later, including future events, to determine if the CTA strategy remains safe and cost-effective. Other considerations in terms of cost will be what happens to the patients in whom CAD was identified, which was 3 times higher with CTA than traditional care (9.0% vs 3.5%). The influence on subsequent care is an important question. Will it result in more testing, risk reduction because of changes in lifestyle and medications, or prevention of future events? Dr Litt noted that radiation exposure with CTA is lower than with SPECT MPI—currently what most patients undergo—and that, as CTA technology improves, its radiation will be reduced. “We are replacing a higher-dose technique with a lower-dose technique,” he pointed out. The study has been simultaneously published online (N Engl J Med. 2012 Mar 26). ■

Levels of Gene Expression a New Noninvasive Way to Identify Obstructive CAD By Wayne Kuznar Chicago, IL—A noninvasive whole blood test developed from the expression levels of 23 genes can identify patients unlikely to have coronary artery disease (CAD) events or require revascularization procedures over the next 12 months, reported Robert S. Schwartz, MD, FACC, Professor of Medicine at the University of Minnesota Medical School, Medical Director at Minnesota Cardiovascular Research Institute, and a cardiologist at the Minneapolis Heart Institute, at

the 2012 American College of Cardiology meeting. Use of a score based on the blood test (the peripheral blood gene-expression score) may eventually represent a personalized risk evaluation for the noninvasive diagnosis of atherosclerotic CAD, which is precipitated by an interaction of genetic and environmental factors. “Better diagnostic methods are needed to stratify patients for elective invasive angiography,” said Dr

“Better diagnostic methods are needed to stratify patients for elective invasive angiography. Changes in gene expression have been observed in diseased arterial wall samples.” —Robert S. Schwartz, MD, FACC Schwartz. Most patients undergoing first-time angiography do not have ob-

structive CAD: more than 60% of patients with risk factors or symptoms of CAD who are referred for elective cardiac catheterization for evaluation do not have significant CAD, and 40% have minimal to no CAD. Unlike genetic tests, gene-expression testing assesses a dynamic process, integrating both genetic predisposition and behavioral and environmental influences on the current disease state, according to the test’s developer, CardioDx. “Changes in gene expression have been observed in diseased arterial wall Continued on page 26

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Vorapaxar, a Novel Antithrombotic Agent, Reduces Events but Increases Bleeding By Mary Mosley Chicago, IL—When added to traditional antiplatelet therapy, vorapaxar, an investigational thrombin receptor antagonist, reduced the risk of myocardial infarction (MI), stroke, or cardiovascular (CV) death in patients with established ischemic heart disease or atherothrombotic vascular disease. The results of the secondary prevention Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50) trial were presented by lead investigator David A. Morrow, MD, MPH Associate Professor of Medicine at Harvard Medical School, and Director of the Samuel A. Levine Cardiac Unit in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, at the 2012 American College of Cardiology meeting. The patients who took vorapaxar had significantly more bleeding events at 3 years (Table 1). Notably, vorapaxar was stopped after 2 years in patients with a history of stroke, because a higher risk of intracranial hemorrhaging (ICH) was found in patients with a history of stroke in the Thrombin Receptor Antagonist for

Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. The primary end points of CV death, MI, stroke, hospitalization for ischemia, and urgent revascularization in TRACER were not significantly reduced, but its secondary end point was significantly reduced, and it became the primary end point of TRA 2°P, a maneuver the US Food and Drug Administration calls reactive revision to a protocol.

“This is the first study to show definitively that blocking pathways reduces the risk of suffering another cardiovascular event.” —David A. Morrow, MD, MPH

TRA 2°P TIMI-50, a randomized, double-blind, placebo-controlled, multinational study, followed 26,449 patients for a mean of 2.5 years. Enrollees had previous MI (67%), stroke (19%), or to peripheral arterial disease

Levels of Gene Expression... Continued from page 25 samples,” said Dr Schwartz. The study followed more than 1100 nondiabetic patients for 1 year who were clinically indicated for invasive angiography and who had their peripheral blood gene-expression score calculated. The gene-expression score considers age and sex in addition to the expression of the 23 genes. Of the 1166 patients, 850 were eligible for subsequent analysis. Over the 12 months of follow-up, 14 patients had a revascularization procedure (percutaneous coronary intervention or coronary artery bypass graft), and 11 had a major adverse cardiac event (MACE), including myocardial infarction, stroke/transient ischemic attack, or all-cause mortality; 825 of the 850 had no events or procedures. The likelihood of procedures and events was higher with increasing gene-expression score. At a threshold gene-expression score of ≤15, the negative predictive value of the gene-expression score was 91% for procedures within 30 days and 91% at 12 months. The negative predictive value was 99% for MACE within 30 days and at 12 months. Patients with low gene-expression

scores (approximately 35% of the study population) were at very low risk for subsequent MACE and revascularization, Dr Schwartz noted. Only 3 of 1160 patients with a geneexpression score <15 had events at 12 months.

At a threshold geneexpression score of ≤15, the negative predictive value of the gene-expression score was 91% for procedures within 30 days and 91% at 12 months. The negative predictive value was 99% for MACE within 30 days and at 12 months. Of the 8 patients who underwent late revascularization, 7 had a gene- expression score >15. Of those with high geneexpression scores (28-40), 39% had procedures or MACE; 28% of those with medium scores (16-27) had MACE or revascularization procedures. ■

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Table 1 Bleeding Rates at 3 Years in the Total Population of the TRA 2°P TIMI-50 Trial Vorapaxar, %

Placebo, %

P value

GUSTO moderate/severe

4.2

2.5

<.001

Intracranial hemorrhage

1.0

<.001

No prior stroke

.049

Fatal

.19

GUSTO indicates Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; TRA 2°P TIMI-50, Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events.

Table 2 GUSTO Moderate or Severe Bleeding at 3 Years in Subgroups Vorapaxar, %

Placebo, %

Hazard ratio, %

Age ≥75 yrs

8.4

5.5

1.69

<75 yrs

3.7

2.2

1.65

Weight <60 kg

7.7

3.7

1.95

≥60 kg

4.0

2.4

1.64

Stroke

4.2

2.4

1.93

PAD

7.4

4.5

1.62

3.4

2.1

1.61

GUSTO indicates Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; MI, myocardial infarction; PAD, peripheral arterial disease.

(PAD; 14%). The patients were randomized to vorapaxar (2.5 mg once daily) or to placebo in addition to standard antiplatelet therapy of aspirin and a thienopyridine in a large proportion of patients. The primary end point of MI, stroke, or CV death occurred in 9.3% of the vorapaxar group and 10.5% of the placebo group—a significant 13% reduction. A 12% reduction was achieved with vorapaxar for the composite of CV death, MI, stroke, or urgent coronary revascularization (11.2% with vorapaxar vs 12.4% with placebo) and a 14% reduction for CV death or MI (7.3% with vorapaxar vs 8.2% with placebo). The risk of bleeding with vorapaxar was greater in patients with a history of stroke or transischemic attack or those who weighed <60 kg. Patients with a prior MI had a significant 20% reduction in CV death, MI, or stroke. In patients with PAD, there was a small trend for a benefit, with a 6% reduction. A Closer Look at Bleeding, by Subgroups In the 5746 patients with a history of stroke, the absolute increase in the Thrombolysis In Myocardial Infarction

non–coronary artery bypass graft major bleeding rate was 2%, ICH was 1.5%, and fatal bleeding was 0.2%. In the 20,699 patients without a history of stroke, bleeding rates were 0.7%, 0.2%, and 0.1%, respectively. The moderate or severe bleeding rates in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial at 3 years were higher with vorapaxar compared with placebo in patients >75 years, in those with lower weight, and in those with stroke or PAD at baseline (Table 2). Vorapaxar is the first in a new class of investigational protease-activated receptor-1 antagonists. “This is the first study to show definitively that blocking pathways reduces the risk of suffering another cardiovascular event,” said Dr Morrow. The decrease in MI, stroke, or CV death was offset by the increase in moderate and severe bleeding, including ICH. Careful patient selection will be necessary to balance the antithrombotic benefit of reduced events against this increased bleeding risk. The optimal patient cohort appears to be patients who were aged <75 years, those who weighed >60 kg, and those who have not had a prior stroke. ■

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CVD Management

Triple-Antiplatelet Therapy Equal to Double-Dose Dual Therapy After Percutaneous Coronary Intervention By Wayne Kuznar Chicago, IL—A triple-antiplatelet regimen that is popular in Asia was as effective as a high-dose clopidogrel dual regimen used commonly in the United States for preventing events in the first 30 days after percutaneous coronary intervention (PCI). The study was presented at the 2012 American College of Cardiology meeting by lead investigator Hyo-Soo Kim, MD, PhD, Director of Cardiac Catheterization and Coronary Intervention, Seoul National University Hospital, Republic of Korea. The 3-drug regimen consists of cilostazol (Pletal), clopidogrel (Plavix), and aspirin. The dual regimen doubles the dose of clopidogrel in combination with aspirin. The finding came from a large randomized trial, Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis—Safety & Effectiveness of Drug-Eluting Stents & Antiplatelet Regimen (HOST-ASSURE), which included patients undergoing PCI at 40 hospitals in the Republic of Korea.

therapy, the maintenance regimen of clopidogrel was 150 mg daily. The primary end point—a composite of cardiac death, nonfatal myocardial infarction (MI), stroke, definite or probable stent thrombosis, and major bleed-

ing—occurred in 23 patients (1.22%) receiving triple-antiplatelet therapy and 27 patients (1.44%) assigned to doubledose dual-antiplatelet therapy. The absolute risk difference of –0.22% met the criterion specified for noninferiority.

The group assigned to triple-antiplatelet therapy had 1 spontaneous MI after discharge compared with 5 spontaneous MIs in the group assigned to double-dose dual-antiplatelet therapy (nonsignificant). ■

Inhibiting platelet reactivity in the first month after PCI is critical to prevent thrombotic events. Cilostazol is used widely in Korea and Japan to prevent embolization after PCI, because it is thought to have vascular biologic benefit in addition to its antiplatelet activity, explained Dr Kim. Cilostazol may have vasodilatory and renoprotective properties in addition to preventing stent restenosis, he said. In HOST-ASSURE, the triple-drug approach was compared with the 2-drug regimen in 3755 patients with >50% occlusion of any coronary artery or venous or arterial bypass graft. The study was designed to demonstrate noninferiority of the triple-drug regimen. Inhibiting platelet reactivity in the first month after PCI is critical to prevent thrombotic events, said Dr Kim. In previous trials of patients with acute coronary syndromes undergoing PCI, 1 week of double-dose clopidogrel improved outcomes at 1 month compared with conventional-dose clopidogrel. Patients enrolled in HOST-ASSURE received 300 to 600 mg of clopidogrel plus 300 mg of aspirin before PCI, with or without a loading dose of 200 mg of cilostazol. In the group assigned to triple-antiplatelet therapy, 100 mg of cilostazol twice daily was added to dual-antiplatelet therapy for 1 month after the procedure; in the group assigned to double-dose dual-antiplatelet

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VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

Payer Perspective

Value-Based Care in Cardiometabolic Health: A Medical Director’s Perspective on the Inaugural Edition By Gary M. Owens, MD President, Gary Owens Associates

No area of medicine has more impact on patients, creates more use of medical resources, and drives cost more than cardiometabolic disease.

desktop. For instance, in this issue we read about the use of a gene-expression test to assist in the evaluation of chest pain (page 25) and about the use of galectin-3 to assess heart failure risk (page 21). As we know, the evaluation of chest pain can be complex and costly. Current evaluative modalities can lead to invasive procedures in a significant number of patients, with up to 60% of those who undergo elective cardiac catheterization having minimal or no disease. This is an area that is ripe for a better way to stratify patients with disease from those who have minimal risk for a cardiac-related event. Reporting on work presented by Robert S. Schwartz, MD, FACC, we gain insight about a gene-expression test for use in symptomatic, nondiabetic patients. This “noninvasive whole blood test from the expression levels of 23 genes can identify patients unlikely to have coronary artery disease events or require revascularization procedures over the next 12 months.” It is most impressive that “at a threshold geneexpression score of ≤15, the negative predictive value of the gene-expression score was 91% for procedures within 30 days and 91% at 12 months.” Doctors now have access to a simple, noninvasive way to risk-stratify patients with nonacute chest pain more effectively,

150

100

References

Projected Direct Spending on Diabetes and Its Complications among Figure Different Diagnosis Cohorts, 2009-2033 Diagnosed 2029-2033 Diagnosed 2019-2028 Diagnosed 2009-2018 Currently have diabetes

350 300

250 200

50 0

New Technologies For instance, diagnostic testing modalities are areas of near-explosive growth. Health plans must assess these new technologies in a timely manner so

potentially avoiding costly and risky invasive procedures in patients who are unlikely to have significant disease. Regarding heart failure, we learn that “a blood test for galectin-3, a unique protein that binds to carbohydrates known as ‘beta-galactosides,’ appears to be a reliable predictor of incident heart failure (HF) and of the response to treatment for HF.” Again, clinicians will have the potential to better risk-stratify those who are at risk for severe complications or even death from heart failure. These are just 2 examples of timely information on possible “game-changing” technology that should prove invaluable to busy medical and pharmacy directors. Cost Considerations In this issue we also learn about a simple, low-cost, glucose-insulinpotassium solution has the potential to save lives from those experiencing an acute coronary event when used in the field. On the cost side, there is a call to determine the cost-effectiveness of cardiac imaging procedures—one of the fastest growing areas of medical technology today. Finally, I read with interest the article that reviews the physicians’ evolving role in value-based purchasing (page 1). Understanding this approach is essential for those of us who lead change in medical reimbursement as we try to move the system from a volume-based purchasing system to a quality-based system. Keeping up with the technology, policy changes, and clinical advances in cardiology or diabetes care can be a daunting task. Yet we are called on to do this not only in these fields, but in all areas of medicine. After reviewing the content of this first issue of ValueBased Care in Cardiometabolic Health, I am optimistic that this journal will become a trusted resource for providers and payers who must keep abreast of new information in this most prominent area of chronic illness. ■

as not to withhold coverage of promising technologies from their members, while at the same time balancing the fiscal responsibility of not wasting resources on ineffective or marginally effective new technology. To help with this task, Value-Based Care in Cardiometabolic Health brings a wealth of information to my (virtual)

Billions of 2007 dollars

have eagerly awaited the opportunity to preview the first edition of Value-Based Care in Cardiometabolic Health. No area of medicine has more impact on patients, creates more use of medical resources, and drives cost more than cardiometabolic disease. From a health plan perspective, cardiovascular disease (CVD) and diabetes are 2 of the most prevalent chronic conditions in the US population. Although we have made great strides in the diagnosis, prevention, and treatment of heart disease, it still remains the number one killer of Americans today. Similarly, diabetes is growing at epidemic proportions, following the wave of obesity in the United States. For most health plans, medical spending on CVD is the largest category of spending among the major chronic illnesses. And CVD drugs, including drugs for hyperlipidemia and hypertension, as well as diabetes drugs, account for a major portion of the resources spent under the pharmacy benefit. According to the latest Express Scripts’ Drug Trend Report, drugs for diabetes, hyperlipidemia, and hypertension account for approximately 30% of the traditional pharmacy spending.1 A recent report from the Centers for Disease Control and Prevention estimates that 45% of adults in the United States have one of the conditions treated by medications in these top 3 therapy classes when diagnosed and undiagnosed prevalence is considered.2 And things may only get worse. We only have to look at the data (Figure) published in an article by Huang and colleagues3 to get a sense of the impact diabetes will continue to have on the already financially challenged healthcare system. It is imperative that health plans keep up with the latest developments in the field of cardiometabolic diseases, because of the major impact that these illnesses have on the plan’s resources. In addition to keeping abreast of the new developments in cardiometabolic health, we must also be able to understand the economic impact of changes in technology, and how changing technology could potentially add value to the plan’s members, both clinically and economically.

2010

2015

2020

2025

2030

Copyrighted and published by Project HOPE/Health Affairs as Huang ES, et al. Using clinical information to project federal health care spending. Health Aff (Millwood). 2009;28(5):w978-w990. The published article is archived and available online at www.healthaffairs.org.

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

MAY 2012

1. Express Scripts. 2011 Drug Trend Report. April 2012. www.express-scripts.com/research/research/dtr. Accessed May 10, 2012. 2. Fryar CD, Hirsch R, Eberhardt MS, et al. Centers for Disease Control and Prevention. Hypertension, high serum total cholesterol, and diabetes: racial and ethnic prevalence differences in US adults, 1999-2006. NCHS data brief. No 36. April 2010. www.cdc.gov/nchs/ data/databriefs/db36.htm. Accessed May 7, 2012. 3. Huang ES, Basu A, O’Grady MJ, Capretta JC. Using clinical information to project federal health care spending. Health Aff (Millwood). 2009;28:w978-w990. Epub 2009 Sept 1.

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CVD Management

Single-Agent Oral Regimen as Effective as Current Standard for Pulmonary Embolism, Less Bleeding By Wayne Kuznar Chicago, IL—A study presented at the 2012 American College of Cardiology meeting potentially opens the door to all-oral therapy for the treatment of pulmonary embolism (PE), which would permit most of the treatment to take place outside of the hospital. The current standard regimen for treating PE involves injections of enoxaparin (Lovenox) for 5 to 10 days followed by oral warfarin (Coumadin), a vitamin K antagonist, for 3 to 12 months. In the EINSTEIN-PE study, a novel oral rivaroxaban (Xarelto) regimen proved noninferior to standard therapy in preventing recurrence of venous thromboembolism (VTE) in patients with primary PE, while causing less major bleeding, said lead investigator Harry R. Büller, MD, Professor of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. “This study was undertaken so there is increased awareness that VTE or PE could be treated outside the hospital,” Dr Büller said. “Maybe the patient

“VTE or PE could be treated outside the hospital. Maybe the patient needs to be in the hospital for 1 day to be observed, but it is not necessary to have patients in the hospital for 5 to 10 days.” —Harry R. Büller, MD needs to be in the hospital for 1 day to be observed, but it is not necessary to have patients in the hospital for 5 to 10 days, as has been the practice. Therefore, we wanted to make this regimen very simple.” In the United States, the average hospital stay for patients with symptomatic

PE is 6 or 7 days, according to Dr Büller. EINSTEIN-PE tested a regimen of oral rivaroxaban, 15 mg twice daily for 21 days followed by 20 mg once daily, versus standard therapy of enoxaparin twice daily for at least 5 days plus a vitamin K antagonist (warfarin or acenocoumarol [Sintrom, Sinthrome]) titrated to achieve an international normalized ratio (INR) of 2.0 to 3.0 in 4833 patients with objectively confirmed PE with or without deep vein thrombosis (DVT). Enoxaparin was discontinued when the INR was >2.0 for 2 consecutive days, and the patient had received enoxaparin for at least 5 days. A previous study with rivaroxaban for patients with DVT (EINSTEINDVT) used rivaroxaban at 20 mg daily, which proved noninferior to standard medical therapy in reducing the risk of symptomatic recurrent VTE. The new, more intense regimen in EINSTEIN-PE was developed from dose-ranging studies that found superior clot dissolution, said Dr Büller. All patients were treated for 3, 6, or

12 months as determined by the clinician before entering the study. The primary end point was first recurrence of symptomatic VTE, which was 2.1% in the rivaroxaban group and 1.8% in the enoxaparin/vitamin K antagonist group, which met the criterion for noninferiority of efficacy. The principal safety outcome of major or nonmajor clinically relevant bleeding was similar in the 2 arms— 10.3% with rivaroxaban and 11.4% with enoxaparin/vitamin K antagonist. The frequency of major bleeding events, however, was reduced by 50% in the rivaroxaban group compared with the enoxaparin/vitamin K antagonist group. Older patients (aged >75 years) had the greatest reduction in risk of bleeding with rivaroxaban: 23 major bleeding events with the enoxaparin vitamin K antagonist regimen versus 5 patients with rivaroxaban, Dr Büller said. The intensified regimen of rivaroxaban during the first 3 weeks did not result in an increased rate of hemorrhage. ■

Comparative Effectiveness Analysis of Coronary Bypass Surgery and Percutaneous Revascularization By Mary Mosley Chicago, IL—In the American College of Cardiology Foundation-the Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategies (ASCERT), a large nationwide study of health outcomes in nearly 190,000 patients aged ≥65 years with coronary artery disease, long-term survival appears to be better with coronary artery bypass grafting (CABG) surgery than with percutaneous coronary intervention (PCI). At 4 years, adjusted mortality was 16.41% with bypass surgery and 20.8% with PCI. Lead investigator William S. Weintraub, MD, FACC, Chair of Cardiology, Christiana Care Health System, Newark, DE, presented the results at the 2012 American College of Cardiology (ACC) meeting. “This study should help inform decision-making concerning the choice of revascularization in patients with stable ischemic heart disease,” said Dr Weintraub, who cautioned that the results do not indicate that bypass surgery is right for every patient. The results, however, reinforce the need to

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include the patient in the decisionmaking, he said, and this study provides evidence for the physician and the patient to support this process. Furthermore, it should open communication between the interventionalist, the surgeon, and the patient to determine the best approach for the individual patient. The results of this comparative effectiveness research (CER) are largely consistent with previously published clinical trials and observational studies. The researchers combined patient data from the ACC Foundation CathPCI database, the Society of Thoracic Surgeons (STS) CABG database, and the Medicare claims database to compare survival rates among 86,000 bypass surgery patients and 103,000 PCI patients who underwent treatment from 2004 to 2007 at 644 sites. David R. Holmes, Jr, MD, Professor of Medicine at Mayo Clinic College of Medicine, Consultant in the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, and immediate past

president of the ACC, said that this collaboration of ACC and STS initiated during his presidency is a landmark movement for interventionalists

“This study should help inform decision-making concerning the choice of revascularization in patients with stable ischemic heart disease.” —William S. Weintraub, MD, FACC and surgeons to work together, and that such collaborations to obtain health outcomes data are needed in today’s medicine. Adjusted mortality at 1 year was similar with both strategies. All patients had 2- or 3-vessel disease, and none had a previous myocardial infarction. At baseline, more patients in the PCI group had 2-vessel disease; in the bypass surgery group, more had 3-ves-

MAY 2012

sel disease and were older and sicker. A surprise finding was the consistency of the data overall and across all subgroups, regardless of the statistical method used. “Survival was better with coronary surgery for all patient subgroups,” said Dr Weintraub. Even the patients whose propensity scores were consistent with being selected for a PCI had a better survival rate with surgery. According to Dr Weintraub, another important contribution of the ASCERT study is that it provides critical experience in CER using observational data. Acknowledging that randomized clinical trials are the gold standard, he said, observational studies complement the clinical trials, and that both have critical roles for CER to meet its potential. Furthermore, he said, the generalizability of clinical trials is a common complaint, and the totality of evidence, including from analyses like these, is needed for best decision-making. Additional analyses on composite end points, angiographic outcomes, and economics are under way. ■

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

Jentadueto™ (linagliptin and metformin hydrochloride) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:

s Renal impairment (e.g., serum creatinine 1.5 mg/dL for men, 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions] s Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions] s A history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning]. Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment. Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Linagliptin/ Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in 5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in 5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1

Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study Placebo Linagliptin Metformin Combination of n=72 Monotherapy Monotherapy Linagliptin with n=142 n=291 Metformin n=286 n (%) n (%) n (%) n (%)

Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis. Linagliptin Monotherapy: Nasopharyngitis was reported in 5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglycemia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin. DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations. Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Metformin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of JENTADUETO in pediatric patients have not been established. Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions]. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED January 2012

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what matters Improving glycemic control for adult patients with type 2 diabetes *A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study. † Superiority of both free combination therapies, consisting of the twice daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24. Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001). ‡ JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

Indication and Important Limitations of Use JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

Important Safety Information WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately. CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS LACTIC ACIDOSIS Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. MONITORING OF RENAL FUNCTION Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. IMPAIRED HEPATIC FUNCTION Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. HYPOGLYCEMIA Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with

Significant A1C reductions (placebo-adjusted) at 24 weeks*†

Placebo-adjusted mean change in A1C at 24 weeks (%)

D LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET W E FOR ADULT PATIENTS WITH TYPE 2 DIABETES NO ROV P Focusing on AP

Linagliptin 5 mg QD

Metformin 500 mg BID

8.7%

Metformin 1000 mg BID

JENTADUETO Linagliptin 2.5 mg/ Metformin 1000 mg BID‡

Baseline A1C: 8.7%

8.5%

8.7%

-1.3%

(n=138)

JENTADUETO Linagliptin 2.5 mg/ Metformin 500 mg BID‡

-0.2 -0.4 -0.6 -0.8

-0.6% (n=135)

-0.8% (n=141)

-1.0 -1.2 -1.4

-1.2%

(n=137) -1.6

-1.7%

-1.8

(n=140)

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects. an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. VITAMIN B12 LEVELS Vitamin B12 deﬁciency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually. ALCOHOL INTAKE Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. HYPOXIC STATES Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued. MACROVASCULAR OUTCOMES There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug. ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea. In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%). Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator). DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. The efﬁcacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended. The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase. USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established. JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function. JD PROF ISI FEB272012

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

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JD184306PROFB