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Phase Z of the A to Z Trial

James A. de Lemos, MD; Michael A. Blazing, MD; Stephen D. Wiviott, MD; Eldrin F. Lewis, MD; Keith A. A. Fox, MB, ChB; Harvey D. White, DSc; Jean-Lucien Rouleau, MD; Terje R. Pedersen, MD; Laura H. Gardner, BSPH; Robin Mukherjee, PhD; Karen E. Ramsey, BS, RPh; Joanne Palmisano, MD; David W. Bilheimer, MD; Marc A. Pfeffer, MD, PhD; Robert M. Califf, MD; Eugene Braunwald, MD; for the A to Z Investigators

JAMA. 2004;292:1307-1316. Published online August 30, 2004 (doi:10.1001/jama.292.11.1307).

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 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).

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.

Author Affiliations: Donald W. Reynolds Cardiovascular Clinical Research Center, the University of Texas Southwestern Medical Center, Dallas (Dr de Lemos); Duke Clinical Research Institute, Durham, NC (Drs Blazing and Califf and Ms Gardner); Department of Medicine, Brigham and Women's Hospital, Boston, Mass (Drs Wiviott, Lewis, Pfeffer, and Braunwald); Department of Cardiology Research, University of Edinburgh, Edinburgh, Scotland (Dr Fox); Department of Cardiology, Green Lane Hospital, Auckland, New Zealand (Dr White); Department of Medicine, University of Montreal, Montreal, Quebec (Dr Rouleau); Centre for Preventive Medicine, Ullevål University Hospital, Oslo, Norway (Dr Pedersen); and Merck & Company, Whitehouse Station, NJ (Drs Mukherjee, Palmisano, and Bilheimer and Ms Ramsey).

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