Limited data are available evaluating how the timing and intensity of
statin therapy following an acute coronary syndrome (ACS) event affect clinical
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.
Among the patients in the placebo plus simvastatin group, the median
low-density 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).
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.
Published online August 30, 2004 (doi:10.1001/jama.292.11.1307).