A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial

Objective: At hoigher doses, simvastatin has been shown to produce signific antly greater increases in high-density lipoprotein (HDL) cholesterol and a polipoprotein (apo) A-I than atorvastatin. Tb extend and confirm these find ings, a 36-week, randomized, double-blind, dose-titration study was perform ed in 826 hypercholesterolemic patients to compare the effects of simvastat in and atorvastatin on HDL cholesterol, apo A-I, and clinical and laborator y safety. Primary hypothesis: Simvastatin, across a range of doses, will be more effe ctive than atorvastatin at raising HDL cholesterol and apo A-I levels. Methods: A total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patien ts randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 m g/day for the next 6 weeks, and remained on 80 mg/day for the final 24 week s. Patients randomized to atorvastatin received 20 mg/day for the first 6 w eeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 we eks. Results:During the first 12 weeks of the study, simvastatin increased HDL c holesterol and apo A-I more than the comparative doses of atorvastatin, whi le producing slightly lower reductions in low-density lipoprotein (LDL) cho lesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favo ring simvastatin were larger than at the lower doses. In addition, at the m aximal dose comparison, the incidence of drug-related clinical adverse expe riences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a great er incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferas e elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.59/0, p < 0.010), especially in women (6.0 versus 0.6%) . Conclusions:At the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal sym ptoms and clinically significant aminotransferase elevations with simvastat in.