Composite Endpoints for Clinical Trials

Current Perspectives
Current Opinion

Abstract

Composite endpoints are commonly used in randomised controlled clinical trials because they offer potential advantages, such as smaller sample sizes, shorter completion times and the summary measure for a treatment effect if more than one outcome is important. However, they are also associated with risks and pitfalls, particularly if basic clinical and statistical requirements are not adequately respected. This article focuses on time-to-event composite endpoints that combine fatal and nonfatal events and aim to demonstrate efficacy of a treatment in long-term trials.

The most important issues with the selection of individual endpoint components — the trial conduct, data analysis, interpretation and reporting — are discussed. Composite endpoints should be clinically meaningful and the expected effects on each component should be similar, based on biological plausibility. Surrogates as endpoint components must have been validated, i.e. a correlation to a hard clinical outcome must have been confirmed. Patients need to be followed up on assigned treatment (clinical status permitting) until death or end of planned follow-up in the absence of events, and must not be regarded as ‘a trial completer’ after occurrence of the first component event. Difficulties in interpretation arise when the results on single components of the composite endpoint go in opposite directions, and when hard clinical outcomes are combined with soft endpoints, particularly if the latter occur much more frequently but are of inferior relevance. Accordingly, all individual components of the composite need to be analysed separately. In this review, several examples from recently published trials are used to illustrate both the principal needs and the inherent problems of using a composite endpoint.

More specific regulatory guidelines and better reporting standards are needed. The ultimate goals of a trial with a composite endpoint should be to solve a medical problem and to support clinical decision making, rather than just to provide statistical convenience.

References

  1. 1.
    Neaton JD, Gray G, Zuckerman BD, et al. Key issues in end point selection for heart failure trials: composite end points. J Cardiac Failure 2005; 11: 567–75CrossRefGoogle Scholar
  2. 2.
    International Conference on Harmonisation. ICH harmonized tripartite guideline E9: statistical principals for clinical trials [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA485.pdf [Accessed 2007 Jan 23]
  3. 3.
    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiat 1960; 23: 56–62PubMedCrossRefGoogle Scholar
  4. 4.
    American College of Rheumatology. Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002; 46: 328–46CrossRefGoogle Scholar
  5. 5.
    Lubsen J, Kirwan B-A. Combined endpoints: can we use them? Stat Med 2002; 21: 2959–70PubMedCrossRefGoogle Scholar
  6. 6.
    Rappaport M. The disability rating and coma/near-coma scales in evaluating severe head injury. Neuropsychol Rehabil 2005; 15: 442–53PubMedCrossRefGoogle Scholar
  7. 7.
    Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. Dermatologica 1978; 157: 238–44PubMedCrossRefGoogle Scholar
  8. 8.
    Chi GYH. Some issues with composite endpoints in clinical trials. Fundam Clin Pharmacol 2005; 19: 609–19PubMedCrossRefGoogle Scholar
  9. 9.
    Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003PubMedCrossRefGoogle Scholar
  10. 10.
    Cohn JN, Tognoni G, for the Valsartan Heart Failure Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–75PubMedCrossRefGoogle Scholar
  11. 11.
    Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711–8PubMedCrossRefGoogle Scholar
  12. 12.
    Gerstein HC, Yusuf S, Pogue J, et al. for the DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096–105PubMedCrossRefGoogle Scholar
  13. 13.
    Dormandy JA, Charbonnel B, Eckland DA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–60PubMedCrossRefGoogle Scholar
  15. 15.
    Vitko S, Margreiter R, Weimar W, et al. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 2004; 78: 1532–40PubMedCrossRefGoogle Scholar
  16. 16.
    Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 241–9PubMedGoogle Scholar
  17. 17.
    Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 1999; 17: 846–54PubMedGoogle Scholar
  18. 18.
    Beasley CM, Sutton VK, Hamilton SH, et al. The olanzapine relapse prevention study group: a double-blind, randomized, placebo-controlled trial of olanzapine in the prevention of psychotic relapse. J Clin Psychopharmacol 2003; 23: 582–94PubMedCrossRefGoogle Scholar
  19. 19.
    Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003; 289: 2554–9PubMedCrossRefGoogle Scholar
  20. 20.
    Cannon CP. Clinical perspectives on the use of composite endpoints. Control Clin Trials 1997; 18: 517–29PubMedCrossRefGoogle Scholar
  21. 21.
    Fox KAA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet 2002; 360: 743–51PubMedCrossRefGoogle Scholar
  22. 22.
    The TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet 2001; 358: 951–7CrossRefGoogle Scholar
  23. 23.
    Torp-Pederson C, Moller M, Bloch-Thomsen P, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med 1999; 341: 857–65CrossRefGoogle Scholar
  24. 24.
    Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I, et al. Validity of composite endpoints in clinical trials. BMJ 2005; 330: 594–6PubMedCrossRefGoogle Scholar
  25. 25.
    Lauer MS, Topol AJ. Clinical trials: multiple treatments, multiple end points, and multiple lessons. JAMA 2003; 289: 2575–7PubMedCrossRefGoogle Scholar
  26. 26.
    The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665–73CrossRefGoogle Scholar
  27. 27.
    Cairns JA, Connolly SJ, Roberts R, et al. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet 1997; 349: 675–82PubMedCrossRefGoogle Scholar
  28. 28.
    Gottlieb SS. Dead is dead: artificial definitions are no substitute. Lancet 1997; 349: 662–3PubMedCrossRefGoogle Scholar
  29. 29.
    Committee for Proprietary Medicinal Products (CPMP). Points to consider on multiplicity issues in clinical trials. CPMP/EWP/908/99. London, 19 Dec 2002 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/ewp/090899en.pdf [Accessed 2007 Jan 23]Google Scholar
  30. 30.
    Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340: 1941–7PubMedCrossRefGoogle Scholar
  31. 31.
    Echt DS, Liebson PR, Mitchell IB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the cardiac arrhythmia suppression trial. N Engl J Med 1991; 324: 781–8PubMedCrossRefGoogle Scholar
  32. 32.
    Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo- controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial. Circulation 1996; 94: 2793–9PubMedCrossRefGoogle Scholar
  33. 33.
    Lubsen J. Exercise testing as outcome in congestive heart failure trials: design considerations when interpreting results. Drugs 1994; 47: 25–30PubMedCrossRefGoogle Scholar
  34. 34.
    Pocock SJ. Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation. Control Clin Trials 1997; 18: 530–45PubMedCrossRefGoogle Scholar
  35. 35.
    UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13CrossRefGoogle Scholar
  36. 36.
    McGuire DK, Califf RM. Diabetes and cardiovascular disease: current opinions and future directions. Am Heart J 1999; 138 (5 Pt 1): S327–9PubMedGoogle Scholar
  37. 37.
    FDA, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Draft guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. April 2005 [online]. Available from URL: http://www.fda.gov/cder/Guidance/6592dft.pdf [Accessed 2007 Jan 23]Google Scholar
  38. 38.
    Johnson JR, Williams G, Pazdur R, et al. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003; 21: 1404–11PubMedCrossRefGoogle Scholar
  39. 39.
    Schulz KF, Grimes DA. Multiplicity in randomized trials I: endpoints and treatments. Lancet 2005; 365: 1591–5PubMedCrossRefGoogle Scholar
  40. 40.
    Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, et al. Problems with the use of composite endpoints in cardiovascular trials: systematic review of randomised controlled trials. BMJ 2007; 334: 786–8PubMedCrossRefGoogle Scholar
  41. 41.
    Yudkin JS. The DREAM trial [comment]. Lancet 2006; 368: 2049–50PubMedCrossRefGoogle Scholar
  42. 42.
    Nissen SE. The DREAM trial [comment]. Lancet 2006; 368: 2049PubMedCrossRefGoogle Scholar
  43. 43.
    Hallstrom AP, Litwin PE, Weaver WD. A method of assigning scores to the components of a composite outcome: an example from the MITI trial. Control Clin Trials 1992; 13: 148–55PubMedCrossRefGoogle Scholar
  44. 44.
    Neaton JD, Wentworth DN, Rhame F, et al. Considerations in choice of a clinical endpoint for AIDS clinical trials. Stat Med 1994; 13: 2107–25PubMedCrossRefGoogle Scholar
  45. 45.
    Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Gen Psychiatry 2000; 57: 481–9CrossRefGoogle Scholar
  46. 46.
    Bristow MR, Saxon LA, Boehmer J, et al. for the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140–50PubMedCrossRefGoogle Scholar
  47. 47.
    Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–72PubMedCrossRefGoogle Scholar
  48. 48.
    Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359–65PubMedCrossRefGoogle Scholar
  49. 49.
    Committee for Medicinal Products for Human Use (CHMP). Guideline on data monitoring committees: EMEA/CHMP/EWP/5872/03. London, 27 Jul 2005 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/ewp/587203en.pdf [Accessed 2007 Jan 23]Google Scholar
  50. 50.
    FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH). Draft guidance for clinical trial sponsors. On the establishment and operation of clinical trial data monitoring committees. 2001 Nov [online]. Available from URL: http://www.fda.gov/cber/gdlns/clindatmon.pdf [Accessed 2007 Jan 23]Google Scholar
  51. 51.
    The Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients: a double-blind, randomized, dose-finding study. Eur Heart J 1997; 18: 1416–25CrossRefGoogle Scholar
  52. 52.
    Näslund U, Grip L, Fischer-Hansen J, et al. The impact of an end-point committee in large multicentre, randomized, placebo-controlled clinical trial. Eur Heart J 1999; 20: 771–7PubMedCrossRefGoogle Scholar
  53. 53.
    Mahaffey KW, Roe MT, Dyke CK, et al. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial: misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Am Heart J 2002; 143: 242–8PubMedCrossRefGoogle Scholar
  54. 54.
    Mahaffey KW, Harrington RA, Akkerhuis M, et al. Systematic adjudication of myocardial infarction end-points in an international clinical trial. Curr Control Trials Cardiovasc Med 2001; 2: 180–6PubMedCrossRefGoogle Scholar
  55. 55.
    Skyler JS. PROactive results overstated and misleading. DOC News 2005; 2: 4Google Scholar
  56. 56.
    Charbonnel B, Dormandy J, Erdmann E, et al. The prospective pioglitazone clinical trial in macrovascular events (PROactive). Can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients. Diabetes Care 2004; 27: 1647–53PubMedCrossRefGoogle Scholar
  57. 57.
    The PROactive Study Executive Committee and Data and Safety Monitoring Committee. PROactive study. Lancet 2006; 367: 982Google Scholar
  58. 58.
    The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. 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: 782–8CrossRefGoogle Scholar
  59. 59.
    Montori VM, Guyatt GH. Intention-to-treat principle. CMAJ 2001; 165: 1339–41PubMedGoogle Scholar
  60. 60.
    Skali H, Pfeffer MA, Lubsen J. Variable impact of combining fatal and nonfatal endpoints in heart failure trials. Circulation 2006; 114: 2298–303PubMedCrossRefGoogle Scholar
  61. 61.
    Lubsen J, Poole-Wilson PA. The DREAM trial [comment]. Lancet 2006; 368: 2050PubMedCrossRefGoogle Scholar
  62. 62.
    Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102PubMedCrossRefGoogle Scholar
  63. 63.
    Lagakos SW. Time-to-event analyses for long-term treatments: the APPROVe Trial. N Engl J Med 2006; 355: 113–7PubMedCrossRefGoogle Scholar
  64. 64.
    Poole-Wilson PA, Lubsen J, Kirwan BA, 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: 849–57PubMedCrossRefGoogle Scholar
  65. 65.
    Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004; 351: 2481–8PubMedCrossRefGoogle Scholar
  66. 66.
    Chen YHJ, DeMets DL, Lan KKG. Monitoring mortality at interim analyses while testing a composite endpoint at the final analysis. Control Clin Trials 2003; 24: 16–27PubMedCrossRefGoogle Scholar
  67. 67.
    Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55PubMedCrossRefGoogle Scholar
  68. 68.
    Fisher LD, Moye LA. Carvedilol and the Food and Drug Administration (FDA) approval process: an introduction. Control Clin Trials 1999; 20: 1–15PubMedCrossRefGoogle Scholar
  69. 69.
    Fisher LD. Carvedilol and the Food and Drug Administration (FDA) approval process: the FDA paradigm and reflections on hypothesis testing. Control Clin Trials 1999; 20: 16–39PubMedCrossRefGoogle Scholar
  70. 70.
    Kleist P. Stopping a trial early for treatment benefit: pros and cons. Appl Clin Trials 2007; Jan: 34–7Google Scholar
  71. 71.
    Montori VM, Devereaux PJ, Adhikari NKJ, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294: 2203–9PubMedCrossRefGoogle Scholar
  72. 72.
    The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001; 357: 1385–90CrossRefGoogle Scholar
  73. 73.
    Brown DL, Fann CSJ, Chang CJ. Effect of glycoprotein IIb/IIIa inhibitors on the individual components of composite endpoints used in clinical trials of unstable angina and non-Q-wave myocardial infarction. Cardiovasc Drugs Ther 2000; 14: 253–8PubMedCrossRefGoogle Scholar
  74. 74.
    Freemantle N, Calvert M. Composite and surrogate outcomes in randomised controlled trials. BMJ 2007; 334: 756–7PubMedCrossRefGoogle Scholar
  75. 75.
    Le May MR, Labinaz M, Davies RF, et al. Stenting versus thrombolysis in acute myocardial infarction trial (STAT). J Am Coll Cardiol 2001; 37: 985–91PubMedCrossRefGoogle Scholar
  76. 76.
    Temple R. Multiple endpoints: statistical framework for clinical decision making. Drug Information Association 39th Annual Meeting; 2003 Jun 15–19; San Antonio (TX).Google Scholar
  77. 77.
    Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663–94PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.PFC Pharma Focus AGVolketswilSwitzerland

Personalised recommendations