Statin-related adverse events: a meta-analysis.

BACKGROUND The absolute frequencies of adverse events (AEs) between statins and placebo are very low in clinical trials, making clinical interpretation and application difficult. OBJECTIVES This meta-analysis was intended to synthesize the collective AE data observed in prospective randomized clinical trials to facilitate clinical interpretation. METHODS Using the search terms atorvastatin, simvastatin,pravastatin, rosuvastatin, fluvastatin, lovastatin, prospective trial, and randomized trial, the MEDLINE/EMBASE and the Cochrane Collaboration databases were reviewed for prospective randomized primary and secondary prevention trials of statin monotherapy. Nonrandomized uncontrolled studies and those missing AE data were excluded. The Mantel-Haenszel test for fixed and random effects was used to calculate odds ratios (ORs) and log ORs. RESULTS Eighteen trials including 71,108 persons, and 301,374 person-years of follow-up were represented in this analysis. There were 36,062 persons receiving a statin and 35,046 receiving a placebo. Statin therapy increased the risk of any AE by 39% (OR = 1.4; 95% CI, 1.09-1.80; P = 0.008; NNH [number needed to harm] = 197) compared with placebo. Statins were associated with a 26% reduction in the risk of a clinical cardiovascular event (OR = 0.74; 95% CI, 0.69-0.80; P < 0.001; number needed to treat = 27). Treating 1000 patients with a statin would prevent 37 cardiovascular events, and 5 AEs would be observed. Serious events (creatine phosphokinase >10 times the upper limit of normal or rhabdomyolysis) are infrequent (NNH = 3400) and rhabdomyolysis, although serious, is rare (NNH = 7428). Atorvastatin was associated with the greatest risk of AEs and fluvastatin with the least risk. Simvastatin, pravastatin, and lovastatin had similar odds of AEs. Nonurgent AEs such as myalgia and liver function elevations were responsible for approximately two thirds of AEs reported in trials. CONCLUSIONS Statin therapy was associated with greater odds of AEs compared with placebo but with substantial clinical benefit. Similar rates of serious AEs were observed between statin and placebo.

[1]  G J Boerma,et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). , 1995, Circulation.

[2]  P. Sager,et al.  Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia: A Prospective, Randomized, Double-Blind Trial , 2003, Circulation.

[3]  Alexander J Sutton,et al.  What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. , 2004, Statistics in medicine.

[4]  S. Yusuf.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Commentary , 2002 .

[5]  A. Peterson,et al.  Statins and Liver Toxicity: A Meta‐Analysis , 2004, Pharmacotherapy.

[6]  P. Serruys,et al.  Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. , 2002, JAMA.

[7]  P. Macfarlane,et al.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial , 2002, The Lancet.

[8]  A. Olsson,et al.  Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia. , 2001, The American journal of cardiology.

[9]  P. Macfarlane,et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia , 1995 .

[10]  Philip J. Barter,et al.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease. , 2005, The New England journal of medicine.

[11]  M. Pfeffer,et al.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. , 2004, JAMA.

[12]  J. Widimský,et al.  The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. , 1999, Atherosclerosis.

[13]  P. Thompson,et al.  Statin-associated myopathy. , 2003, JAMA.

[14]  P. Serruys,et al.  A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial. , 1999, European heart journal.

[15]  B. Davis,et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. , 1996, The New England journal of medicine.

[16]  J. Shepherd,et al.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial , 2003 .

[17]  S. Ellis,et al.  Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. , 1995, Journal of the American College of Cardiology.

[18]  R. Collins,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 , 2003, The Lancet.

[19]  R. Collins,et al.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. , 1998, The New England journal of medicine.

[20]  Michael F. Oliver,et al.  Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study. , 2001, Indian heart journal.

[21]  A. Gotto,et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. , 1998, JAMA.

[22]  J. Slattery,et al.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. , 1994, Atherosclerosis. Supplements.

[23]  A. Gotto,et al.  Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. , 2002, The American journal of cardiology.

[24]  John H Fuller,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 , 2004, The Lancet.

[25]  Neil J Stone,et al.  Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines , 2004, Circulation.

[26]  AndrewJ. S. Coats.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial , 2002, The Lancet.