Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy

Abstract Background: Randomized trials evaluating intensive dose statin therapy have found enhanced protection against cardiovascular (CV) events compared with moderate-dose statin therapy in patients with acute coronary syndromes (ACS) or stable coronary artery disease (CAD). However, the potential for an increase in the risk of drug-induced adverse events with such therapy has not been quantified. Objective: This meta-analysis was performed to compare the incremental risks associated with intensive- and moderate-dose statin therapy. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1995 to 2006 using the following terms: acute, coronary syndrome, stable coronary artery disease, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin , and fluvastatin . Prospective, randomized controlled trials evaluating intensive- and moderate-dose statin therapy for the reduction of CV events were included in the review. The safety end points examined were elevations in creatine kinase (CK) ≥ 10 times the upper limit of normal (ULN), elevations in alanine or aspartate aminotransferase ≥3 times the ULN, rhabdornyolysis, drug-induced adverse events requiring discontinuation of therapy, and any drug-induced events. The efficacy end points examined were all-cause mortality, CV death, nonfatal myocardial infarction (MI), and stroke. Each analysis compared the effect of intensive- or moderate-dose statin therapy on statin-induced adverse events and clinical efficacy outcomes. Simple absolute risk, the number needed to treat, and the number needed to harrrn were also calculated to quantify the incremental benefit or harm associated with intensive-dose statin therapy. Results: Four trials were included in the analysis.Together, they included 27,548 patients with ACS or stable CAD followed for a mean of 3.4 years, representing 108,049 patient-years of clinical-trial experience. Intensive-dose therapy with atorvastatin or simvastatin 80 mg was associated with a significant increase in the risk for any adverse event (odds ratio [OR] = 1.44; 95% CI, 1.33–1.55; P < 0.001) and adverse events requiring discontinuation of therapy (OR = 1.28; 95% CI, 1.18–1.39; P < 0.001). Intensive-dose therapy also was associated with an increased risk for abnormalities on liver function testing (OR = 4.48; 95% Cl, 3.27–6.16; P < 0.001) and elevations in CK (OR = 9.97; 95% CI, 1.28–77.92; P = 0.028). The benefits of intensive-dose statin ther