STATIN BENEFIT-RISK PROFILES IN INDIVIDUALS AT INTERMEDIATE RISK FOR CARDIOVASCULAR DISEASE

Purpose: To assess the benefit-risk (BR) profiles of six statins currently on market (atorvastatin 10-40 mg/d, fluvastatin 40-80 mg/d, lovastatin 40-80 mg/d, pravastatin 40-80 mg/d, rosuvastatin 10-20 mg/d and simvastatin 20-40 mg/d), in individuals at intermediate risk for cardiovascular disease (CVD).

Method(s): Using a database of published clinical trials, we conducted a quantitative benefit-risk (BR) assessment of six statins in subjects with a baseline low density lipoprotein cholesterol (LDL-C) level of 125 mg/dl (3.23 mmol/L). Treatment benefit was quantified in terms of achieved LDL-C reduction at trial completion. Risks were quantified in terms of probability of experiencing common statin side effects (myalgia (MA), transaminase (TA) elevation, and creatine kinase (CK) elevation). Using a Bayesian network meta-regression analysis, we estimated the effect of each statin on LDL-C relative to control, adjusting for LDL-C level at baseline. In a separate model, we estimated the absolute change in LDL-C achieved by control alone. We derived distributions for the achieved LDL-C levels by adding together baseline level of LDL-C, control effect, and relative effect of each statin adjusted for baseline LDL-C. Separate network meta-analyses were performed to estimate relative effects for the three side effects. Baseline estimates for the side effects were obtained by pooling placebo arms, and subsequently used to obtain absolute effect estimates. Expert opinion was elicited to develop ordinal constraints for the BR model.

Result(s): The meta-regression analysis adjusting for baseline LDL-C showed a good fit to the data, and significantly decreased heterogeneity compared to an unadjusted analysis. At a baseline LDL-C of 125 mg/dl, the scale ranges for achieved LDL-C were set at 55-125 mg/dl. Side-effect scale ranges were 0.0-0.13 for MA, 0.00-0.19 for TA and 0.00-0.06 for CK. Expert opinion indicated LDL reduction to be more important than decrease in side effect risks. With 4 forms of LDL partial value functions the best treatment was rosuvastatin (first rank probability 0.91-0.99). Uncertainty coefficients showed that further preference data was unlikely to alter first rank probabilities significantly.

Conclusion(s): When treatment benefits are quantified solely in terms of LDL-C reduction, rosuvastatin seems to have the best BR balance among the six statins in an intermediate CVD risk population. Results may be sensitive to possible confounders in the meta-regression analysis and should be examined further.