Meta-Analysis of Results From Eight Randomized, Placebo-Controlled Trials of the Effect of Cilostazol on Patients With Intermittent Claudication - Meta-Analysis of Results From Eight Randomized, Placebo-Controlled Trials of the Effect of Cilostazol on Patients With Intermittent Claudication
The goal of this study was to assess the safety and efficacy of cilostazol or Pletal, a type III phosphodiesterase inhibitor, arterial vasodilator, and platelet antagonist among patients limited by leg claudication.
Patients Enrolled: 2,702
Buerger's disease, ischemic rest pain, ulcers or gangrene, DVT, arterial revascularization within three months, coronary syndromes within six months, anticoagulants, greater than 1200 mg of ibuprofen/day, or greater than 81 mg aspirin/day
A meta-analysis of eight randomized, double-blind, placebo-controlled trials in 2,702 patients was performed. Trial duration ranged from 12 to 24 weeks. Trials were performed in 98 sites in the United States (seven trials) and one site in the United Kingdom.
Eligible pretreatment requirements were limiting claudication, defined as leg pain or fatigue, an ankle brachial index ≤0.9 in seven trials and ≤0.8 in one trial or a 20 mm Hg decrease in leg pressure postexercise, and <20% variability in maximal walk distance (MWD) on two or three consecutive treadmill tests.
Patients were excluded with Buerger’s disease, ischemic rest pain, ulcers or gangrene, deep vein thrombosis (DVT), arterial revascularization within three months, coronary syndromes within six months, anticoagulants, >1200 mg of ibuprofen/day, or >81 mg aspirin/day. Patients received cilostazol in doses of 50, 100, or 150 mg twice a day (BID); pentoxifylline 400 mg three times a day in three studies; or placebo. The trial with the 150 mg BID dose was excluded from efficacy analysis.
The mean age was 65 years, 88% of patients were white, 25% were diabetic, and duration of claudication was at least five years in 40%. Cilostazol improved MWD in six of the eight trials. MWD increased 21.4% over baseline in the placebo group, and cilostazol 50 and 100 mg BID by 44% and 50%, respectively (p<0.05 vs. placebo for both).
Change in pain-free walking distance increased by 40% on placebo, and about 65% with cilostazol. The magnitude of improvement did not vary by age >65 years, gender, and diabetes.
Cilostazol 100 mg BID increased the high-density lipoprotein cholesterol by 13% and decreased triglycerides by 16% (p=0.0001) compared to placebo and pentoxifylline. The physical quality of life indicators were significantly improved with the active drug. About 14% of patients had an adverse experience on the active drug versus 9% on placebo. The following were more common with cilostazol than placebo: headache, palpitations, edema, rhinitis, and diarrhea.
Among patients with claudication without major adverse events, cilostazol significantly increases walking distance and quality of life measures. It should be noted that a "training effect" was observed, with less significant benefits observed in the placebo arm also.
The trial results with cilostazol may underestimate the value since it increases over time. The meta-analysis did not consider active smoking, which may have influenced the results. How cilostazol fares compared to a rigorous exercise program and whether it should be routinely combined with exercise is less clear.
Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials of the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002;90:1314-9.
Keywords: Platelet Aggregation Inhibitors, Ibuprofen, Edema, Fibrinolytic Agents, Headache, Vasodilator Agents, Bronchodilator Agents, Neuroprotective Agents, Cholesterol, HDL, Rhinitis, Exercise Test, Phosphodiesterase 3 Inhibitors, Intermittent Claudication, Gangrene, Ankle Brachial Index, Diarrhea, Pentoxifylline, Tetrazoles, Smoking, Thromboangiitis Obliterans, Walking, Ulcer, Quality of Life, Venous Thrombosis, Triglycerides, Lipoproteins, HDL, Diabetes Mellitus
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