Journal of General Internal Medicine

, Volume 34, Issue 8, pp 1607–1614 | Cite as

Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials

  • Morten Rix HansenEmail author
  • Asbjørn Hróbjartsson
  • Anton Pottegård
  • Per Damkier
  • Kasper Søltoft Larsen
  • Kenneth Grønkjær Madsen
  • René dePont Christensen
  • Malene Elisa Lopez Kristensen
  • Palle Mark Christensen
  • Jesper Hallas
Review Article



The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons.


To develop a novel approach for modeling outcome postponement achieved within a trial’s duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials.


The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial’s duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan–Meier curves. Statin trials were identified through a systematic review.


The median modeled outcome postponement was 10.0 days (interquartile range, 2.9–19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1–18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0–16.3), 17.4 days (PI, 6.0–28.8), and 8.5 days (PI, 1.9–15.0).


The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial.

Systematic Review Registration

The systematic review was registered in PROSPERO [CRD42016037507].



We thank Jesper Urban Pedersen, Senior Creative, for the technical advice regarding the use of Adobe Photoshop and Manan Pareek, M.D., for reviewing the statin trial classifications.

Authors’ Contribution

All authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. They have all participated in drafting of the paper or revising it critically for important intellectual content. All authors have read and approved the final version of the manuscript.


This study was funded by the University of Southern Denmark. The funder played no role in the design, conduct, or reporting.

Compliance with Ethical Standards

Conflict of Interest

All authors have completed the ICMJE uniform disclosure form at The authors declare that they do not have a conflict of interest.

Supplementary material

11606_2019_5024_Fig4_ESM.png (213 kb)
Supplementary Figure 4

Funnel Plots of hazard ratios for Investigation of Publication Bias (PNG 212 kb)

11606_2019_5024_MOESM1_ESM.tif (160 kb)
High resolution image (TIF 160 kb)
11606_2019_5024_MOESM2_ESM.docx (325 kb)
ESM 1 (DOCX 325 kb)


  1. 1.
    Hux JE, Naylor CD. Communicating the benefits of chronic preventive therapy does the format of efficacy data determine patients’ acceptance of treatment? Med Decis Mak 1995;15(2):152–157.CrossRefGoogle Scholar
  2. 2.
    Malenka DJ, Baron JA, Johansen S, Wahrenberger JW, Ross JM. The framing effect of relative and absolute risk. J Gen Intern Med 1993;8(10):543–548.CrossRefGoogle Scholar
  3. 3.
    Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318(26):1728–1733. CrossRefPubMedGoogle Scholar
  4. 4.
    Wright JC, Weinstein MC. Gains in life expectancy from medical interventions—standardizing data on outcomes. N Engl J Med 1998;339(6):380–386.CrossRefGoogle Scholar
  5. 5.
    Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open 2015;5(9):e007118. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Christensen PM, Brosen K, Brixen K, Andersen M, Kristiansen IS. A randomized trial of laypersons’ perception of the benefit of osteoporosis therapy: number needed to treat versus postponement of hip fracture. Clin Ther 2003;25(10):2575–2585.CrossRefGoogle Scholar
  7. 7.
    Morris J, Hammitt JK. Using life expectancy to communicate benefits of health care programs in contingent valuation studies. Med Decis Mak 2001;21(6):468–478.CrossRefGoogle Scholar
  8. 8.
    Halvorsen PA, Aasland OG, Kristiansen IS. Decisions on statin therapy by patients’ opinions about survival gains: cross sectional survey of general practitioners. BMC Fam Pract 2015;16(1).
  9. 9.
    Kapur NK, Musunuru K, et al. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag 2008;4(2):341.CrossRefGoogle Scholar
  10. 10.
    Trialists CT, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376(9753):1670–1681.CrossRefGoogle Scholar
  11. 11.
    Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Vol 2008.Google Scholar
  12. 12.
    Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361(9364):1149–1158. CrossRefPubMedGoogle Scholar
  13. 13.
    Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364(9435):685–696. doi: CrossRefPubMedGoogle Scholar
  14. 14.
    Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195.CrossRefGoogle Scholar
  15. 15.
    Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333(20):1301–1308.CrossRefGoogle Scholar
  16. 16.
    Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383–1389.Google Scholar
  17. 17.
    Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231–1239. doi: CrossRefPubMedGoogle Scholar
  18. 18.
    Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339(19):1349–1357. doi:
  19. 19.
    Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357(22):2248–2261.CrossRefGoogle Scholar
  20. 20.
    Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353(3):238–248. doi: CrossRefPubMedGoogle Scholar
  21. 21.
    Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361(9374):2024–2031.CrossRefGoogle Scholar
  22. 22.
    Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360(14):1395–1407. doi: CrossRefPubMedGoogle Scholar
  23. 23.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335(14):1001–1009. doi: CrossRefPubMedGoogle Scholar
  24. 24.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7–22. doi: CrossRefGoogle Scholar
  25. 25.
    Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA J Am Med Assoc 2002;287(24):3215–3222.CrossRefGoogle Scholar
  26. 26.
    Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623–1630.CrossRefGoogle Scholar
  27. 27.
    Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355(6):549–559. doi: CrossRefPubMedGoogle Scholar
  28. 28.
    Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ. 2017:j4530. doi:
  29. 29.
    Halvorsen PA, Selmer R, Kristiansen IS. Different ways to describe the benefits of risk-reducing treatments: a randomized trial. Ann Intern Med 2007;146(12):848–856.CrossRefGoogle Scholar
  30. 30.
    Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement, Web comments. BMJ Open 2015;5(9):e007118.CrossRefGoogle Scholar
  31. 31.
    Stovring H, Harmsen CG, Wisloff T, et al. A competing risk approach for the European Heart SCORE model based on cause-specific and all-cause mortality. Eur J Prev Cardiol 2013;20(5):827–836. doi: CrossRefPubMedGoogle Scholar
  32. 32.
    Franco OH. Effectiveness calculation in economic analysis: the case of statins for cardiovascular disease prevention. J Epidemiol Community Health 2006;60(10):839–845. doi: CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shah ND, Dunlay SM, Ting HH, et al. Long-term medication adherence after myocardial infarction: experience of a community. Am J Med 2009;122(10):961.e7–961.e13. doi: CrossRefGoogle Scholar
  34. 34.
    Chan DC, Shrank WH, Cutler D, et al. Patient, physician, and payment predictors of statin adherence. Med Care 2010;48(3):196–202.CrossRefGoogle Scholar
  35. 35.
    Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation. 2016;133(11):1073–1080.CrossRefGoogle Scholar
  36. 36.
    Lytsy P, Berglund L, Sundström J. A proposal for an additional clinical trial outcome measure assessing preventive effect as delay of events. Eur J Epidemiol 2012;27(12):903–909. doi: CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Dehbi H-M, Royston P, Hackshaw A. Life expectancy difference and life expectancy ratio: two measures of treatment effects in randomised trials with non-proportional hazards. BMJ 2017:j2250. doi:
  38. 38.
    Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol 2013;13(1):152.CrossRefGoogle Scholar
  39. 39.
    Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781–1790.CrossRefGoogle Scholar
  40. 40.
    Johannesson M, Jönsson B, Kjekshus J, Olsson AG, Pedersen TR, Wedel H. Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. N Engl J Med 1997;336(5):332–336.CrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2019

Authors and Affiliations

  • Morten Rix Hansen
    • 1
    • 2
    • 3
    Email author
  • Asbjørn Hróbjartsson
    • 4
    • 5
    • 6
  • Anton Pottegård
    • 1
  • Per Damkier
    • 2
    • 7
  • Kasper Søltoft Larsen
    • 1
  • Kenneth Grønkjær Madsen
    • 1
  • René dePont Christensen
    • 8
  • Malene Elisa Lopez Kristensen
    • 1
  • Palle Mark Christensen
    • 1
  • Jesper Hallas
    • 1
    • 2
  1. 1.Clinical Pharmacology and PharmacyUniversity of Southern DenmarkOdenseDenmark
  2. 2.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdenseDenmark
  3. 3.Department of Clinical PharmacologyAarhus University HospitalAarhusDenmark
  4. 4.Center for Evidence-Based Medicine OdenseUniversity of Southern DenmarkSønderborgDenmark
  5. 5.Department of Clinical ResearchUniversity of Southern DenmarkSønderborgDenmark
  6. 6.Odense Explorative Patient data Network (OPEN)Odense University HospitalOdenseDenmark
  7. 7.Department of Clinical ResearchUniversity of Southern DenmarkSønderborgDenmark
  8. 8.Research Unit for General PracticeOdenseDenmark

Personalised recommendations