Journal of Cardiac Failure
Volume 15, Issue 3 , Pages 199-205 , April 2009

Unconventional End Points in Cardiovascular Clinical Trials: Should We Be Moving Away From Morbidity and Mortality?

  • Jay Cohn, MD, FACC

      Affiliations

    • University of Minnesota, Minneapolis, Minnesota
    • Corresponding Author InformationReprint requests: Jay Cohn, MD, FACC, Cardiovascular Division, MMC 508, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. Tel: 612-625-5646.
  • ,
  • John G.F. Cleland, MD, FACC

      Affiliations

    • Department of Cardiology, University of Hull, Kingston-upon-Hull, United Kingdom
  • ,
  • Jacobus Lubsen, MD, PhD

      Affiliations

    • SOCAR Research, Switzerland and Erasmust Medical Centre, Rotterdam, the Netherlands
  • ,
  • Jeffrey S. Borer, MD, FACC

      Affiliations

    • Weill Medical College of Cornell University, New York, New York
  • ,
  • Philippe Gabriel Steg, MD, FACC

      Affiliations

    • INSERM U-698, Paris, France
  • ,
  • Michael Perelman, MD

      Affiliations

    • Schering Plough, Kenilworth, New Jersey
  • ,
  • Faiez Zannad, MD

      Affiliations

    • Hypertension and Preventive Cardiology Division, Department of Cardiovascular Disease, Centre d'Investigations Cliniques INSERM-CHU, Nancy, France

Received 5 August 2008 ,Revised 22 October 2008 ,Accepted 23 October 2008.

References 

  1. Neaton JD, Gray G, Zuckerman BD, Konstam MA. Key issues in end point selection for heart failure trials: composite end points. J Card Fail. 2005;11:567–575
  2. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049–2057
  3. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–788
  4. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet. 2004;364:849–857
  5. Lubsen J, Kirwan BA. Combined end points: can we use them?. Stat Med. 2002;21:2959–2970
  6. Ziesche S, Rector TS, Cohn JN. Interobserver discordance in the classification of mechanisms of death in studies of heart failure. J Cardiac Fail. 1995;1:127–132
  7. Cohn JN. Efficacy and safety in clinical trials in cardiovascular disease. J Am Coll Cardiol. 2006;48:430–433
  8. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJ, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2004;110:2180–2183
  9. Poole-Wilson PA, Swedberg K, Cleland JG, Di LA, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7–13
  10. Dickstein K, Kjekshus J. OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752–760
  11. Investigators CIBIS. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13
  12. Carson P, Tognoni G, Cohn JN. Effect of valsartan on hospitalization: results from Val-HeFT. J Card Fail. 2003;9:164–171
  13. Cleland JG, Atkin SL. Thiazolidinediones, deadly sins, surrogates, and elephants. Lancet. 2007;370:1103–1104
  14. Lewis EF, Johnson PA, Johnson W, Collins C, Griffin L, Stevenson LW. Preferences for quality of life or survival expressed by patients with heart failure. J Heart Lung Transplant. 2001;20:1016–1024
  15. Braunwald E, Cannon CP, McCabe CH. Use of composite end points in thrombolysis trials of acute myocardial infarction. Am J Cardiol. 1993;72:3G–12G
  16. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001;7:176–182
  17. Cleland JG. How to assess new treatments for the management of heart failure: composite scoring systems to assess the patients' clinical journey. Eur J Heart Fail. 2002;4:243–247
  18. Cleland JG, Charlesworth A, Lubsen J, Swedberg K, Remme WJ, Erhardt L, et al. A comparison of the effects of carvedilol and metoprolol on well-being, morbidity, and mortality (the “patient journey”) in patients with heart failure: a report from the Carvedilol Or Metoprolol European Trial (COMET). J Am Coll Cardiol. 2006;47:1603–1611
  19. Olsson G, Lubsen J, van Es GA, Rehnqvist N. Quality of life after myocardial infarction: effect of long term metoprolol on mortality and morbidity. Br Med J(Clin Res Ed). 1986;292:1491–1493
  20. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569–582
  21. Cohn JN. Remodeling as an end-point in heart failure therapy. Cardiovasc Drugs Ther. 2004;18:7–8
  22. Cohn JN, Hoke L, Whitwam W, Sommers PA, Taylor AL, Duprez D, et al. Screening for early detection of cardiovascular disease in asymptomatic individuals. Am Heart J. 2003;146:679–685
  23. Duprez DA, Florea ND, Jones K, Cohn JN. Beneficial effects of valsartan in asymptomatic individuals with vascular or cardiac abnormalities: the DETECTIV Pilot Study. J Am Coll Cardiol. 2007;50:835–839
  24. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled?. Ann Intern Med. 1996;125:605–613
  25. Goode KM, Clark AL, Bristow JA, Sykes KB, Cleland JG. Screening for left ventricular systolic dysfunction in high-risk patients in primary-care: a cost-benefit analysis. Eur J Heart Fail. 2007;9:1186–1195
  26. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003;5:659–667
  27. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators . Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–412
  28. Psaty BM, Lumley T. Surrogate end points and FDA approval: a tale of 2 lipid-altering drugs. JAMA. 2008;299:1474–1476
  29. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122
  30. Greenland P, Lloyd-Jones D. Critical lessons from the ENHANCE trial. JAMA. 2008;299:953–955
  31. Kastrati A, Mehilli J, Pache J. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356:1030–1039
  32. Barnett DB. Flosequinan. Lancet. 1993;341:733–736
  33. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786

 Pfizer Inc. provided an unrestricted educational grant to CIC INSERM-CHU of Nancy, France, to support the workshop from which this manuscript was generated (coordinator: Faiez Zannad).

 Conflict of interest: None.

PII: S1071-9164(08)01053-1

doi: 10.1016/j.cardfail.2008.10.029

Journal of Cardiac Failure
Volume 15, Issue 3 , Pages 199-205 , April 2009