A Tale of Two Trials

Abstract

Background-The Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trials compared intensive and moderate statin therapy after acute coronary syndromes, with seemingly disparate results. We analyzed the design, implementation, and results of the two trials in an attempt to clarify the effects of early intensive statin therapy. Methods and Results-Study design, end points, and definitions were compared. In each trial, comparisons were made between intensive and moderate arms for both trials' primary end points and death/myocardial infarction. Analyses were performed over various time points: at the end of the trials, Յ4 months, and Ͼ4 months. Subjects in A to Z had higher-risk demographics. More PROVE IT subjects were enrolled in the United States and underwent prerandomization revascularization. The low-density lipoprotein (LDL) difference was greater in A to Z than in PROVE IT early (Յ4 months) but less late. Significant C-reactive protein reduction was earlier in PROVE IT. With common end points, event rates were higher in A to Z, and early favorable separation of event curves was seen in PROVE IT but not in A to Z. Clinical end point rates and reductions were similar in both trials after 4 months. Conclusions-An early benefit was seen in PROVE IT but not in A to Z. Late-phase results were similar. Factors that may explain this disparity include the intensity of therapy in the early phase, timing, and magnitude of LDL and C-reactive protein lowering, differences in early revascularization, and the play of chance. Taken together, the results of these trials support a strategy of early intensive statin therapy coupled with revascularization when appropriate in patients after acute coronary syndrome.

Effect of Early Use of Low-Dose Pravastatin on Major Adverse Cardiac Events in Patients With Acute Myocardial Infarction

“…Furthermore, a recently published metaanalysis suggests that the clinical benefit of statins vs placebo is proportional to treatment changes in LDL, 28 and it is possible that LDL lowering may be more closely related to long-term than to short-term outcomes. 29 An interesting point is that, despite the smaller dose of pravastatin administered in this trial, there was an equivalent reduction in the risk of coronary events to the value seen in previous studies. 6,7 Possible reasons include chance, synergistic effects of Japanese-style diet therapy, or highsensitivity of Japanese to pravastatin.…”

Probucol Attenuates Inflammation and Increases Stability of Vulnerable Atherosclerotic Plaques in Rabbits

“…All diets were dried of the solvent before use. The doses used were based on previous literature reports (Carew et al 1987) and the ratio of the highest clinical dose of simvastatin in patients to the highest experimental dose of simvastatin in rabbits (Hernández-Presa et al 2003;Wiviott et al 2006). The amount of diet for each animal was restricted to 120 g/ day during the study period.…”

Direct Comparison of the A to Z and PROVE IT Trials

“…In the late phase, LDL-C averaged Ϸ63 mg/dL with intensive therapy in both studies ( Figure 2A in the article by Wiviott et al 3 ), 75 mg/dL with 20 mg simvastatin in A to Z, and 95 mg/dL with 40 mg pravastatin in PROVE IT. On the basis of results from a recent meta-analysis 10 and with the assumption that it can be applied to a 20-month follow-up, the 12-mg/dL LDL-C differential in A to Z would predict a major coronary event reduction, relative to moderate therapy, of 7%; the 32-mg/dL differential in PROVE IT would similarly predict a reduction of 18%.…”