Hint of Benefit From Cilostazol in Preventing Carotid Restenosis

February 25, 2020

LOS ANGELES ― The antiplatelet agent cilostazol (Pletal, Otsuka), used to treat symptoms of intermittent claudication for patients with peripheral vascular disease, may be effective in preventing restenosis after carotid stenting, a new study suggests.

For the primary endpoint, analysis showed a trend toward less in-stent restenosis after carotid stenting in treated patients, although the difference did not reach statistical significance.

The Carotid Artery Stenting With Cilostazol Addition for Restenosis (CAS-CARE) study was presented at the International Stroke Conference (ISC) 2020 by Hiroshi Yamagami, MD, Osaka National Hospital, Japan.

Yamagami explained that cilostazol, a phosphodiesterase 3 inhibitor, has several mechanisms of action that could be beneficial in preventing restenosis. It improves endothelial function, inhibits platelet aggregation, causes vasodilation, and mildly inhibits cell growth.

"This is the first trial to show potential effectiveness of medical management for the prevention of in-stent restenosis after carotid artery stenting," he said.

For the open-label study, 631 patients who were scheduled to undergo carotid artery stenting were randomly assigned to receive either cilostazol (50 mg or 100 mg twice per day in addition to other antiplatelet agents) or other antiplatelet agents without cilostazol, starting 3 days before stenting and continuing for 2 years.

Results of the primary analysis showed that in-stent restenosis occurred in 10.8% of patients in the cilostazol group compared with 19.6% of those in the non-cilostazol group during 2 years of follow-up, a result that did not quite reach statistical significance (hazard ratio, 0.64; 95% confidence interval, 0.41 – 1.02; P = .056).

Cardiovascular events occurred at rate of about 6% in both groups. There was no statistical difference in bleeding events between the two groups; such events occurred in 1.1% of those treated with cilostazol, vs 0.3% among those not treated with cilostazol.

Commenting on the study, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University, New York City, said: "We've seen other trials with cilostazol in a setting of stroke, and there's some evidence of benefit, but other trials haven't confirmed that. These results may prompt further study in this area."

Also commenting for Medscape Medical News, Bruce Campbell, MBBS, PhD, Royal Melbourne Hospital, Australia, said interpretation of the trial is complicated by differences in background antiplatelet therapy between groups.

"There was more than double the use of combined aspirin and clopidogrel in the non-cilostazol group, which was likely influenced by the nonblinded nature of the study and variability in how long those combination regimens were used as the patients progressed through follow-up. The between-group differences were mainly seen towards the end of the trial, when the number of patients remaining in the analyses was very small, less than 20% of the original sample size," he noted.

"Longer-term follow-up of these patients would have been interesting. There were no advantages of cilostazol in other outcome measures," he added. "These factors mean that the borderline statistically significant reduction in restenosis reported needs to be interpreted cautiously."

Also commenting on the CAS-CARE study, Michael Hill, MD, University of Calgary, Canada, said: "Our general experience is that in-stent restenosis is a relatively uncommon problem when patients are treated with high-dose statin therapy and they quit smoking. However, when it occurs, it is an intractable problem. It appears to be a more serious problem among the Japanese."

Hill described cilostazol as "an interesting molecule" that has a mechanism of action similar to that of dipyridamole. He noted that several studies suggest it yields long-term benefit in reducing atherosclerosis progression.

He added that he would like clarification on how the primary outcome was measured, because technical problems regarding measurement may have influenced the result.

"The survival analysis is less clear to me because this is an interrupted time series with endpoints at predetermined imaging time points. Thus, the survival function is not continuous, so I would like to understand the methodology of their statistics more clearly," Hill said.

The CAS-CARE study was funded by the Translational Research Center for Medical Innovation (TRI), a public interest foundation, and by Otsuka Pharmaceutical Co. Some of investigators received a reward from Otsuka for work not related to this research but have no financial relationship regarding CAS-CARE.

International Stroke Conference (ISC) 2020: Abstract LB21. Presented February 21, 2020.

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