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A New Treatment for Symptomatic Intracranial Atherosclerotic Disease?

Cilostazol shows promise in limiting atherosclerosis progression, although confirmatory studies are needed.

Intracranial atherosclerosis is responsible for 8% to 10% of all ischemic strokes and carries a recurrence rate of 8% to 12% per year. Currently available treatments are inadequate: Warfarin is no better than aspirin in preventing intracranial-disease–related stroke (NEJM 2005; 352:1305), and although drug-eluting stents may offer a more definite treatment for intracranial arterial stenosis (IAS) in the near future, both balloon angioplasty and bare-metal stents have been associated with high restenosis rates (Stroke 2004; 35:1388).

Cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet, vasodilating, antiatherogenic, and antiproliferative effects, has demonstrated efficacy in the secondary prevention of stroke and in preventing restenosis after coronary procedures. To assess the effect of cilostazol on the progression of IAS, researchers conducted a randomized, multicenter, double-blind, placebo-controlled, manufacturer-supported trial. The 135 participants received cilostazol (100 mg twice daily) or placebo within 2 weeks after an ischemic stroke. All participants received aspirin. Exclusion criteria included potential for cardioembolic events, NIH Stroke Scale Score 16, >50% extracranial stenosis proximal to the symptomatic lesion, and prior antiplatelet or anticoagulant therapy. IAS was assessed by MR angiography (MRA) and transcranial Doppler (TCD) at recruitment and 6 months later.

At baseline, the location and severity of symptomatic IAS were similar in both groups. Patients treated with cilostazol had significantly less progression of symptomatic IAS than those who received placebo (6.7% versus 28.8%). Also, IAS regression was more common in the cilostazol group (24.4% versus 15.4%), though the statistical significance of this finding is not reported. There were no strokes or transient ischemic attacks, but acute coronary events occurred in two participants in each group. No major side effects occurred.

Comment: These results suggest that cilostazol shows promise as an adjunctive therapy for patients with symptomatic intracranial arterial stenosis. However, this study had several limitations, including the small number of patients, a high dropout rate (25%), short follow-up, and a large proportion of mild stenosis as demonstrated by the absence of cerebrovascular events. The extent of IAS would have been better defined by either catheter angiography or the less-invasive CT angiography as opposed to 3-D time-of-flight MRA and TCD, which are less accurate flow-based techniques. Two additional findings deserve comment. First, there was a high rate of IAS regression in the placebo group (15.4%). Second, the progression rate of asymptomatic stenosis was not different between the two groups. These facts raise the possibility that the pathologic process that led to the apparent improvement in symptomatic stenosis might have involved not only true regression of atherosclerosis but also resolution of a local thrombus, either superimposed on an intracranial plaque or related to a cryptogenic embolus. As the authors acknowledge, further studies are required to address these questions and to confirm the efficacy of cilostazol in IAS.

— Raul G. Nogueira, MD

Dr. Nogueira is Assistant in Neurology, Massachusetts General Hospital, and Instructor in Neurology, Harvard Medical School, Boston.

Published in Journal Watch Neurology August 25, 2005

Citation(s):

Kwon SU et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: The multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke 2005 Apr; 36:782-6.

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