Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. Design , Setting, and Participants: International, randomized, double blind trial of p atients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/ d thereafter (n=2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n=2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. Main Outcome Measu re: The primary end point was a composite of cardiovascular death, nonfatal myoc ardial infarction, readmission for ACS, and stroke. Follow up was for at least 6 months and up to 24 months. Results Among the patients in the placebo plus sim vastatin group, the median low density lipoprotein (LDL) cholesterol level achi eved while taking placebo was 122mg/dL (3.16 mmol/L) at 1 month and was 77mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patient s in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68mg/dL (1.76 mmol/L) and was 63 m g/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 3 43 patients (16.7%) in the placebo plus simvastatin group experienced the prima ry end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95%confidence interval [Cl] 0.76-1.04; P=.14 ). C ardiovascular death occurred in 109 (5.4%) and 83 (4.1 %) patients in the 2 gr oups (HR, 0.75; 95%Cl, 0.57-1.00; P=.05) but no differences were observed in other individual components of the primary end po int. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95%Cl, 0.83-1.25; P=.89), but from 4 months t hrough the end of the study the primary end point was significantly reduced in t he simvastatin only group (HR, 0.75; 95%Cl, 0.60-0.95; P=.02). Myopathy (creat ine kinase>10 times the upper limit of normal associated with muscle symptoms) o ccurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients rece iving lower doses of simvastatin, and in 1 patient receiving placebo (P=.02). Co nclusions: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen res ulted in a favorable trend toward reduction of major cardiovascular events.
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