Hiatt, William R.

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.

The Society for Vascular Medicine was founded in 1989. During the subsequent 25 years, the Society has grown to approximately 500 members and has achieved international recognition while making important contributions to vascular disease education, clinical vascular medicine and biology research, and patient care. In celebration of the Society’s 25th anniversary, its past and current presidents reflect on the Society’s history, challenges, and achievements, and emphasize the vital role of the SVM in the discipline of vascular medicine.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 μg/kg for 6 sequential weeks (total dose 12 μg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.