Direct Comparison of the A to Z and PROVE IT Trials

Two similar clinical trials in patients presenting with acute coronary syndromes (ACS), the Aggrastat to Zocor (A to Z)1 and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)–TIMI 222 trials, each compared intensive versus moderate statin therapies for 2 years. PROVE IT demonstrated a significant benefit from intensive therapy (16% reduction, P =0.005 in its primary end point), whereas A to Z found only a favorable trend (11% reduction, P =0.14 in its somewhat different primary end point). Like many clinicians reading these 2 reports, my first impression was that these data demonstrated the superiority of 80 mg of atorvastatin over 80 mg of simvastatin. Market share shifts soon reflected this perception. Wiviott et al3 have compared these studies in detail to ask whether the observed differences were explained by true differences in drug efficacy or, alternatively, by differences in trial design or practice differences among the 2 studies’ clinical sites (factors that, in this analysis, may be linked to different practice patterns inside or outside the United States). Event rates in the “early” 4-month phase and the “late” 20-month phase were examined separately. This is a well-written and well-reasoned post hoc comparison between 2 “similar” trials that nevertheless have certain important hypothesis-generating differences.Article p 1406 First, it should be noted that the between-trial comparisons of the overall benefits of intensive therapy, though tending to favor PROVE IT, were not statistically significant in 2 of the 3 between-trial endpoint comparisons ( P =0.52, 0.03, and 0.55). The PROVE IT trial’s intensive-therapy benefits were significantly greater than those of the A to Z trial ( P =0.03) only for the PROVE IT primary end point, which included revascularization >30 days after enrollment. This weakened my first impression. Second, during the final 20 months of treatment, there were compelling …