We appreciate the interest of Gazi and Mikhailidis (1) in the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) and their proposed reasons for the nonsignificant results (2).
We mention in our article the high rates of treatment “drop in” and “drop out” and the potential impact on the primary end point (mostly due to changing guidelines and study design changes). While Gazi and Mikhailidis correctly state that there was a high incidence of dropouts, we should clarify that all subjects (including those who withdrew) were included in the final analysis. The authors ask if the substantial differential LDL cholesterol decrease of 29% between active and placebo groups could reflect active subjects taking a second statin. Of the 15% of atorvastatin-treated subjects taking concomitant lipid-lowering medications, the vast majority took an additional statin. However, considered on its own, this would not explain the 29% reduction in LDL cholesterol compared with placebo. Of the 26.9% of subjects in the placebo group who were taking concomitant lipid-lowering medications (mostly statins), 19.7% took them for ≥30 days. It is likely more important that 42% of subjects with cardiovascular events in the atorvastatin group had stopped their randomized medication >1 year before their event.
We agree that lower blood pressure, as well as lower baseline LDL cholesterol, younger age, lower smoking rates, and a smaller proportion of men combined to place primary prevention subjects in the ASPEN at lower CVD risk than those in the Collaborative Atorvastatin Diabetes Study (3). Despite this apparent lower risk, a greater incidence of cardiovascular events was observed in placebo-treated primary prevention subjects in ASPEN (10.8%) than in CARDS (9.0%), indicating inclusion of “softer” end points, such as hospitalization for angina pectoris and interventions. Nonetheless, trends in CVD event reduction with atorvastatin were at the expected rates for the fatal and nonfatal myocardial infarction end point and in the secondary prevention cohort (2).
The subjects in the secondary prevention group entered the study before the primary prevention group. Secondary prevention subjects would have remained in the study longer were it not for the Safety and Data Monitoring Board recommendation late in the study to stop the study drug in the secondary prevention cohort and begin active treatment. As a result, the durations of follow-up were similar: 4.50 and 4.38 years for secondary versus primary prevention subjects taking atorvastatin and 4.38 and 4.46 years, respectively, for those taking placebo.
The nonsignificance of the ASPEN results has many possible explanations. Nonetheless, the ASPEN study reminds us that the many risk factors for heart disease in diabetes require individualized management for a complete treatment approach.
R.H.K. has served on an advisory board for, has received honoraria from, and has received grant/research support from Pfizer.