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CLINICAL RESEARCH: PREVENTIVE CARDIOLOGY

Primary Prevention of Cardiovascular Mortality and Events With Statin Treatments

A Network Meta-Analysis Involving More Than 65,000 Patients

Edward J. Mills, MSc, PhD, LLM^_*,_*, Beth Rachlis, MSc, Ping Wu, MBBS, MSc^||, Philip J. Devereaux, MD, PhD^_*,, Paul Arora, MSc^¶ and Dan Perri, BScPharm, MD, FRCP(C)^,

^_* Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Centre for Evaluation of Medicines, McMaster University, Hamilton, Ontario, Canada
Department of Healthcare and Epidemiology, University of British Columbia, Vancouver, British Columbia, Canada
^|| Department of Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
^¶ Centre for Global Health, University of Toronto, Toronto, Ontario, Canada

Manuscript received July 1, 2008; revised manuscript received August 20, 2008, accepted August 25, 2008.

^_* Reprint requests and correspondence: Dr. Edward J. Mills, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada (Email: millsej{at}mcmaster.ca).

Objectives: This study aimed to evaluate the effectiveness of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) in primary prevention of cardiovascular events.

Background: The role of statins is well established for secondary prevention of cardiovascular disease (CVD) clinical events and mortality. Little is known of their role in primary cardiovascular event prevention.

Methods: We conducted comprehensive searches of 10 electronic databases from inception to May 2008. We contacted study investigators and maintained a comprehensive bibliography of statin studies. We included randomized trials of at least 12-month duration in predominantly primary prevention populations. Two reviewers independently extracted data in duplicate. We performed random-effects meta-analysis and meta-regression, calculated optimal information size, and conducted a mixed-treatment comparison analysis.

Results: We included 20 randomized clinical trials. We pooled 19 trials (n = 63,899) for all-cause mortality and found a relative risk (RR) of 0.93 (95% confidence interval [CI]: 0.87 to 0.99, p = 0.03 [I² = 5%, 95% CI: 0% to 51%]). Eighteen trials (n = 59,469) assessed cardiovascular deaths (RR: 0.89, 95% CI: 0.81 to 0.98, p = 0.01 [I² = 0%, 95% CI: 0% to 41%]). Seventeen trials (n = 53,371) found an RR of 0.85 (95% CI: 0.77 to 0.95, p = 0.004 [I² = 61%, 95% CI: 38% to 77%]) for major cardiovascular events, and 17 trials (n = 52,976) assessed myocardial infarctions (RR: 0.77, 95% CI: 0.63 to 0.95, p = 0.01 [I² = 59%, 95% CI: 24% to 74%]). Incidence of cancer was not elevated in 10 trials (n = 45,469) (RR: 1.02, 95% CI: 0.94 to 1.11, p = 0.59 [I² = 0%, 95% CI: 0% to 46%]), nor was rhabdomyolysis (RR: 0.97, 95% CI: 0.25 to 3.83, p = 0.96 [I² = 0%, 95% CI: 0% to 40%]). Our analysis included a sufficient sample to reliably answer our primary outcome of CVD mortality.

Conclusions: Statins have a clear role in primary prevention of CVD mortality and major events.

Key Words: statins • meta-analysis • primary prevention

Abbreviations and Acronyms   CHD = coronary heart disease   CI = confidence interval   CrI = credibility interval   CVD = cardiovascular disease   HDL = high-density lipoprotein   IQR = interquartile range   LDL = low-density lipoprotein   MI = myocardial infarction   OIS = optimal information size   RR = relative risk

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