Cilostazol Reduces Restenosis and Repeat Procedures after Peripheral Arterial Interventions

Abstract & commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.

Source: Soga Y, et al. Efficacy of cilostazol after endovascular therapy for femoropopliteal artery disease in patients with intermittent claudication. J Am Coll Cardiol. 2009;53: 48-53.

Percutaneous intervention for peripheral arterial disease (PAD) results in improvement in claudication symptoms but is complicated by a high rate of restenosis. Cilostazol is an anti-platelet agent that also has anti-restenosis effects, and has been shown to reduce restenosis from bare-metal stents in coronary arteries. Whether cilostazol can reduce restenosis following endovascular therapy (EVT) in peripheral arterial disease is not known.

Accordingly, Soga et al performed a randomized, multi-center, open-label clinical trial of cilostazol 200 mg/day vs placebo for two years following EVT of symptomatic de novo femoral artery lesions. The study was performed in Japan, and 78 patients, ages 18-80 years, with claudication due to a > 50% femoropopliteal lesion, without any inflow lesion, and with a patent outflow artery, were included. Ankle-brachial pressure indices were < 0.9. Exclusion criteria included prior lower extremity bypass surgery, prior EVT in the femoropopliteal region, acute limb ischemia, or severe symptoms. All patients were taking low-dose aspirin and ticlopidine prior to the procedure, with aspirin continued long-term and ticlopidine continued for four weeks post-EVT. Balloon angioplasty was performed for 60 seconds, followed by implantation of self-expanding stents for residual stenoses of > 30%, or flow-limiting dissections. Patients were followed clinically, as well as with Duplex ultrasonography. The primary endpoint was freedom from target vessel revascularization (TVR) after two years, with secondary endpoints of binary restenosis rate, freedom from target lesion revascularization (TLR), and major adverse cardiac events (MACE — death, nonfatal MI, stroke, percutaneous or surgical repeat revascularization, and leg amputation).

Patients receiving cilostazol (n = 39) or placebo (n = 39) were well-matched in terms of baseline clinical and procedural characteristics. Approximately 80% were male, 35% diabetic, 40% current smokers, and the average age was 70 years. The average lesion lengths were approximately 125 mm, and the pre-procedure stenosis severity was 78%; post stenosis 26%. The percentage of patients receiving stents was 41% in the cilostazol group and 51% in the control group. There was no difference in the incidence of occluded vessels or stent fracture. Cilostazol therapy resulted in a significant reduction in the primary outcome of repeat revascularization. After 24 months, the freedom from TLR and TVR was significantly higher in the cilostazol group than in the control group (87.2% vs 67.6%, p < 0.05; 84.6% vs 62.2%, p = 0.04, respectively). Binary restenosis was found in 43 (55.1%) patients (cilostazol 43.6% vs control 70.3%; p = 0.02), and eight had complete occlusion (cilostazol, 5.1% vs control, 16.2%; p = 0.12). Freedom from MACE was also significantly higher in the cilostazol group compared with the control group (79.5% vs 48.7%, p = 0.006). The resting ankle-brachial pressure index was significantly better at 24 months in the cilostazol group compared with the control group (0.81 vs 0.72, p < 0.05). Importantly, 89.7% of the cilostazol group took the drug as directed. Cilostazol was stopped in two patients for palpitations, and two other patients stopped or reduced the dose of the drug themselves. Soga et al concluded that cilostazol, in combination with aspirin, reduces restenosis and repeat revascularization after EVT for femoropopliteal disease in claudicant patients.

Commentary

Cilostazol is approved by the FDA at a dose of 100 mg twice daily for use in PAD. It has been shown to improve claudication symptoms in medically managed PAD and to reduce restenosis in bare-metal coronary artery stents. This study adds to the current literature by showing that cilostazol reduces restenosis in PAD managed by percutaneous intervention. Patients with PAD are at high risk of acute coronary syndromes, and stroke and anti-platelet therapy can reduce these risks. In this study, the benefits of cilostazol on restenosis and MACE were in addition to aspirin therapy. Stented patients received ticlopidine for four weeks after the procedure only. It is not known whether the benefits of cilostazol would persist in addition to longer-term ticlopidine, or in combination with clopidogrel, which is the more commonly used thienopyridine in the United States. Many PAD patients will be taking dual anti-platelet therapy for co-existent coronary or cerebrovascular disease, and it is not clear if the current results can be extrapolated to these patients.

It bears mentioning that cilostazol can precipitate or worsen heart failure, and is, therefore, contraindicated in patients with any degree of heart failure. Soga et al do not mention whether they screened patients for heart failure prior to enrollment, nor whether any heart failure developed during follow-up, but there was no excess of mortality in the cilostazol group. In addition, although this was a prospective, randomized study, it was open-label, which can introduce some reporting bias. Furthermore, the use of stents, and the type of stents used, was at the operators' discretion, which may also introduce some bias. Despite these limitations, this study adds to our knowledge base for PAD, and may help avoid restenosis and costly repeat procedures in patients undergoing peripheral interventions.