We appreciate the comments of Drs. Isley and Bittar. Both are correct in pointing out an error in our citation of the work of Stein and colleagues [1], which, in fact, compared simvastatin with cholestyramine and did not study the combination of the two drugs. We regret the misunderstanding.

With regard to Dr. Isley's other comments, we recognize that simvastatin is, in general, more potent than the statins that we had available at the time our study began. However, at the 40-mg pravastatin dose, the incremental effect of 40 mg of simvastatin on LDL cholesterol levels would be only about 4% to 6%. We agree that if a more potent statin had been available at the start of our study, fewer patients would have needed combination therapy to meet the National Cholesterol Education Program goal. Nevertheless, combination therapy would have been necessary to increase HDL cholesterol levels (affecting our LDL/HDL ratio goal) and to decrease triglyceride levels. We also reasoned that, in attempting to both minimize the cost and side effects of lipid therapy, information about combination therapy (such as the strategy we tested) will be useful to the practicing physician.

We certainly did not intend to "ignore the well-known dose-response curves of this agents." In clinical practice, we begin with a low dose; in this trial, however, our prespecified goal was lowering total cholesterol to 160 mg/dL, and we chose to begin with the maximum recommended dose of pravastatin (40 mg). All statins have nonlinear effects on LDL cholesterol, but it has not been our goal to test dose responses; this is why we chose the maximum dose. We were interested in long-term efficacy and side effects. The studies that Dr. Isley refers to are short-term studies. Finally, we agree that the important end point (clinical events) was not testable in this study of 91 patients. The much larger CARE (Cholesterol and Recurrent Events) study [2] did show a significant reduction in coronary events with pravastatin monotherapy in patients who had had myocardial infarction. We agree with the need for further studies to address the question of possible additional clinical benefit from combination therapy used to produce a larger increase in HDL cholesterol levels with even greater decreases in LDL cholesterol levels.