Endpoint Selection and Relative (Versus Absolute) Risk Reporting in Published Medication Trials

Original Research

ABSTRACT

BACKGROUND

The use of surrogate and composite endpoints, disease-specific mortality as an endpoint, and relative (rather than absolute) risk reporting in clinical trials may produce results that are misleading or difficult to interpret.

OBJECTIVE

To describe the prevalence of these endpoints and of relative risk reporting in medication trials.

DESIGN AND MAIN MEASURES

We analyzed all randomized medication trials published in the six highest impact general medicine journals between June 1, 2008 and September 30, 2010 and determined the percentage using these endpoints and the percentage reporting results in the abstract exclusively in relative terms.

KEY RESULTS

We identified 316 medication trials, of which 116 (37%) used a surrogate primary endpoint and 106 (34%) used a composite primary endpoint. Among 118 trials in which the primary endpoint involved mortality, 32 (27%) used disease-specific mortality rather than all-cause mortality. Among 157 trials with positive results, 69 (44%) reported these results in the abstract exclusively in relative terms. Trials using surrogate endpoints and disease-specific mortality as an endpoint were more likely to be exclusively commercially funded (45% vs. 29%, difference 15% [95% CI 5%–26%], P = 0.004, and 39% vs. 16%, difference 22% [95% CI 6%-37%], P = 0.007, respectively). Trials using surrogate endpoints were more likely to report positive results (66% vs. 49%, difference 17% [95% CI 5%–28%], P = 0.006) while those using mortality endpoints were less likely to be positive (46% vs. 62%, difference −16% [95% CI −27%–−4%], P = 0.01).

CONCLUSIONS

The use of surrogate and composite endpoints, endpoints involving disease-specific mortality, and relative risk reporting is common. Articles should highlight the limitations of these endpoints and should report results in absolute terms.

KEY WORDS

surrogate endpoints composite endpoints disease-specific mortality relative risk reduction 

Supplementary material

11606_2011_1813_MOESM1_ESM.doc (44 kb)
ESM 1(DOC 44 kb)

References

  1. 1.
    Kraemer HC, Frank E. Evaluation of comparative treatment trials: assessing clinical benefits and risks for patients, rather than statistical effects on measures. JAMA. 2010;304(6):683–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Krumholz HM, Lee TH. Redefining quality–implications of recent clinical trials. N Engl J Med. 2008;358(24):2537–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Bero L, Oostvogel F, Bacchetti P, Lee K. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. 2007;4(6):e184.PubMedCrossRefGoogle Scholar
  4. 4.
    Ridker PM, Torres J. Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005. JAMA. 2006;295(19):2270–4.PubMedCrossRefGoogle Scholar
  5. 5.
    la Cour JL, Brok J, Gøtzsche PC. Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study. BMJ. 2010;341:c3653.PubMedCrossRefGoogle Scholar
  6. 6.
    Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605–13.PubMedGoogle Scholar
  7. 7.
    Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289(19):2554–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Yeh RW, Go AS. Rethinking the epidemiology of acute myocardial infarction: challenges and opportunities. Arch Intern Med. 2010;170(9):759–64.PubMedCrossRefGoogle Scholar
  9. 9.
    Ferreira-González I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, Alonso-Coello P, Alonso J, Worster A, Upadhye S, Jaeschke R, Schünemann HJ, Permanyer-Miralda G, Pacheco-Huergo V, Domingo-Salvany A, Wu P, Mills EJ, Guyatt GH. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334(7597):786.PubMedCrossRefGoogle Scholar
  10. 10.
    Freemantle N, Calvert MJ. Interpreting composite outcomes in trials. BMJ. 2010;341:c3529.PubMedCrossRefGoogle Scholar
  11. 11.
    Cordoba G, Schwartz L, Woloshin S, Bae H, Gøtzsche PC. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ. 2010;341:c3920.PubMedCrossRefGoogle Scholar
  12. 12.
    Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst. 2002;94(3):167–73.PubMedGoogle Scholar
  13. 13.
    Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318:1728–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Nuovo J, Melnikow J, Chang D. Reporting number needed to treat and absolute risk reduction in randomized controlled trials. JAMA. 2002;287(21):2813–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Marshall KG. Prevent: how much harm? How much benefit? 1. Influence of reporting methods on perception of benefits. CMAJ. 1996;154(10):1493–9.PubMedGoogle Scholar
  16. 16.
    Lim E, Brown A, Helmy A, Mussa S, Altman DG. Composite outcomes in cardiovascular research: a survey of randomized trials. Ann Intern Med. 2008;149(9):612–7.PubMedGoogle Scholar
  17. 17.
    Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of major cardiac events and percutaneous coronary intervention. J Am Coll Cardiol. 2008;51(7):701–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Dryver E, Hux JE. Reporting of numerical and statistical differences in abstracts: improving but not optimal. J Gen Intern Med. 2002;17(3):203–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Schwartz LM, Woloshin S, Dvorin EL, Welch HG. Ratio measures in leading medical journals: structured review of accessibility of underlying absolute risks. BMJ. 2006;333(7581):1248.PubMedCrossRefGoogle Scholar
  20. 20.
    Hochman M, McCormick D. Characteristics of published comparative effectiveness studies of medications. JAMA. 2010;303(10):951–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Science journal citation reports ISI: Summer 2008. Thomson Reuters Web site. http://scientific.thomson.com/products/jcr/. Accessed July 5, 2011.
  22. 22.
    Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA. How to use an article measuring the effect of an intervention on surrogate end points. JAMA. 1999;282(8):771–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Temple RJ. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical Measurement in Drug Evaluation. New York: Wiley; 1995.Google Scholar
  24. 24.
    Grady D, Redberg RF. Less is more: how less health care can result in better health. Arch Intern Med. 2010;170(9):749–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Rosen C. Revisiting the rosiglitazone story – lessons learned. NEJM. 2010;363(9):803–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA. 2003;290(7):921–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Kjaergard LL, Als-Nielsen B. Association between competing interests and authors’ conclusions: epidemiological study of randomised clinical studies published in the BMJ. BMJ. 2002;325(7358):249–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289(4):454–65.PubMedCrossRefGoogle Scholar
  29. 29.
    Tomlinson G, Detsky AS. Composite endpoints in randomized trials: there is no free lunch. JAMA. 2010;303(3):267–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Guyatt G, Rennie D, Meade MO, Cook DJ. Can one be confident that the component endpoints share similar relative risk reductions? Users’ guides to the medical literature. Chapter 10.4. Composite Endpoints.Google Scholar
  31. 31.
    Montori VM, Permanyer-Miralda G, Ferreira-González I, Busse JW, Pacheco-Huergo V, Bryant D, Alonso J, Akl EA, Domingo-Salvany A, Mills E, Wu P, Schünemann HJ, Jaeschke R, Guyatt GH. Validity of composite endpoints in clinical trials. BMJ. 2005;330(7491):594–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Guyatt GH, Sackett DL, Cook DJ. Users’ guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA. 1993;270(21):2598–601.PubMedCrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2011

Authors and Affiliations

  1. 1.The Robert Wood Johnson Clinical Scholars® ProgramUniversity of California, Los Angeles, and the U.S. Department of Veterans AffairsLos AngelesUSA
  2. 2.Department of Medicine, Cambridge Health Alliance, and Harvard Medical SchoolCambridgeUSA

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