Skip to main content
SpringerLink
Log in

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

  • Original Research
  • Published:
Journal of General Internal Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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.

    Article  PubMed  CAS  Google Scholar 

  2. Krumholz HM, Lee TH. Redefining quality–implications of recent clinical trials. N Engl J Med. 2008;358(24):2537–9.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  5. la Cour JL, Brok J, Gøtzsche PC. Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study. BMJ. 2010;341:c3653.

    Article  PubMed  Google Scholar 

  6. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605–13.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Yeh RW, Go AS. Rethinking the epidemiology of acute myocardial infarction: challenges and opportunities. Arch Intern Med. 2010;170(9):759–64.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  10. Freemantle N, Calvert MJ. Interpreting composite outcomes in trials. BMJ. 2010;341:c3529.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  20. Hochman M, McCormick D. Characteristics of published comparative effectiveness studies of medications. JAMA. 2010;303(10):951–8.

    Article  PubMed  CAS  Google Scholar 

  21. Science journal citation reports ISI: Summer 2008. Thomson Reuters Web site. http://scientific.thomson.com/products/jcr/. Accessed July 5, 2011.

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Grady D, Redberg RF. Less is more: how less health care can result in better health. Arch Intern Med. 2010;170(9):749–50.

    Article  PubMed  Google Scholar 

  25. Rosen C. Revisiting the rosiglitazone story – lessons learned. NEJM. 2010;363(9):803–5.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  29. Tomlinson G, Detsky AS. Composite endpoints in randomized trials: there is no free lunch. JAMA. 2010;303(3):267–8.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Contributors

We have listed everyone who made substantial contributions to this analysis as authors of the article.

Funders

This study was unfunded (i.e. it received no internal or external funding).

Prior Presentations

This work was presented as a poster at the 2011 Society of General Internal Medicine National Meeting in Phoenix, Arizona.

Conflict of Interest

None disclosed.

Author information

Authors and Affiliations

  1. The Robert Wood Johnson Clinical Scholars® Program, University of California, Los Angeles, and the U.S. Department of Veterans Affairs, 911 Broxton Ave., 3rd Floor, Los Angeles, CA, 90024, USA

    Michael Hochman MD

  2. Department of Medicine, Cambridge Health Alliance, and Harvard Medical School, Cambridge, MA, USA

    Danny McCormick MD, MPH

Authors
  1. Michael Hochman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danny McCormick MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Hochman MD.

Additional information

The views expressed in this article are solely those of the author and do not necessarily represent those of the Department of Veterans Affairs or of the Robert Wood Johnson Foundation

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 44 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hochman, M., McCormick, D. Endpoint Selection and Relative (Versus Absolute) Risk Reporting in Published Medication Trials. J GEN INTERN MED 26, 1246–1252 (2011). https://doi.org/10.1007/s11606-011-1813-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11606-011-1813-7

KEY WORDS

Search

Navigation