Money, Sam

Cilostazol, a phosphodiesterase III inhibitor, is indicated to treat the symptoms of claudication in patients with peripheral arterial disease (PAD). At the time of approval the FDA required an additional long-term safety study to evaluate cilostazol’s effect on mortality. Subjects (n=1899) with a clinical diagnosis of PAD and symptoms of claudication were screened for a randomized, double blinded, placebo-controlled safety study of cilostazol. The modified intent-to-treat (mITT) population (n=1435) included all randomized patients who received at least one dose of study medication and includes follow up of more than 30 days after discontinuation of study drug. A total of 717 patients received cilostazol and 718 received placebo. Cilostazol was administered at a primary dose of 100 mg twice daily. Long-term adherence to study medication was poor with over 60% of participants discontinuing therapy by 36 months. Therefore the mortality analysis focused on deaths during the period on-treatment defined as the period during which study drug was taken plus a 30-day post-dosing follow up period. Total patient-years exposure on-treatment for cilostazol was 1046 and on placebo was 1090. On-treatment there were 18 deaths on cilostazol and 19 deaths on placebo for a hazard ratio of 0.99 (95% confidence interval 0.52 to 1.88). Cardiovascular deaths on-treatment occurred in 14 patients on cilostazol and 14 on placebo. In the full mITT population at 36 months, there were 101 deaths, 49 on cilostazol and 52 on placebo with hazard ratio of 0.94 (0.64 –1.39). Thus most deaths occurred more than 30 days after study drug discontinuation. Serious bleeding events affected 18 patients on cilostazol and 22 on placebo in the on-treatment population. Bleeding events were similar in patients also taking aspirin, aspirin plus clopidogrel or anticoagulants over the course of the study. This long-term study demonstrated no safety signal for cilostazol on all cause or cardiovascular mortality. However the study was under-powered to detect a small adverse impact of cilostazol on mortality (hazard ratio upper bound of the 95% confidence interval 1.88 in the on-treatment population). Serious bleeding events appeared not to be increased by cilostazol.