JAMA. 2004;292:1307-1316 Early Intensive vs a Delayed Conservative Simvastatin Strategy in Patients With Acute Coronary Syndromes: Phase Z of the A to Z Trial the A to Z Investigators Cardiology Division， University of Texas Southwestern Medical Center， 5323 Harry Hines Blvd， Dallas， TX 75390-9047
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 patients 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 Measure: The primary end point was a composite of cardiovascular death， nonfatal myocardial 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 simvastatin group， the median lowdensity lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group， the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR]， 0.89; 95% confidence interval [CI] 0.76-1.04; P=.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR， 0.75; 95% CI， 0.57-1.00; P = .05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR， 1.01; 95% CI， 0.83- 1.25; P=.89)， but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR， 0.75; 95% CI， 0.60-0.95; P = .02). Myopathy (creatine kinase 10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d， in no patients receiving lower doses of simvastatin， and in 1 patient receiving placebo (P=.02).
Conclusions: The trial did not achieve the prespecified end point. However， among patients with ACS， the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.