Published Online
on March 13, 2006

A more recent version of this article appeared on March 21, 2006

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Submitted on August 31, 2005
Revised on December 23, 2005
Accepted on January 3, 2006

A Tale of Two Trials. A Comparison of the Post-Acute Coronary Syndrome Lipid-Lowering Trials A to Z and PROVE IT-TIMI 22

Stephen D. Wiviott MD^*, James A. de Lemos MD, Christopher P. Cannon MD, Michael Blazing MD, Sabina A. Murphy MPH, Carolyn H. McCabe BS, Robert Califf MD, and Eugene Braunwald MD

From the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, The Department of Medicine, Harvard Medical School, Boston, Mass (S.D.W., C.P.C., S.A.M., C.M.C., E.B.); The Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical School, Dallas (J.A.d.L.); and the Duke Clinical Research Institute, Durham, NC (M.B., R.C.).

^* To whom correspondence should be addressed. E-mail: swiviott{at}partners.org.

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, 4 months, and >4 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 (4 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.

Key words: acute coronary syndrome • cholesterol • clinical trial • lipid lowering • statins

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