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Cilostazol Works in DAPT for Secondary Stroke Prevention

HONOLULU — Stroke survivors taking dual antiplatelet therapy (DAPT) with the phosphodiesterase-3 inhibitor cilostazol (Pletaal) plus aspirin or clopidogrel (Plavix) for secondary prevention showed lower risk of recurrent stroke, relative to aspirin/clopidogrel monotherapy, with no trade-off in severe bleeding.

Rates of recurrent ischemic stroke were 2.2% per year with cilostazol DAPT versus 4.5% per year with monotherapy (HR 0.49, 95% CI 0.31-0.76), investigator Kazunori Toyoda, MD, of Japan’s National Cerebral and Cardiovascular Center in Suita, reported at a late-breaking trial session at the International Stroke Conference here.

Severe or life-threatening intracranial hemorrhage occurred at similar rates between groups (0.6% vs 0.9% per year; HR 0.66, 95% CI 0.27-1.60), Toyoda’s group found over 4 years of follow-up. However, only the DAPT arm developed headaches and palpitation or tachycardia.

“Addition of cilostazol to aspirin or clopidogrel is recommendable for the long-term use in the chronic stage of high-risk non-cardioembolic stroke for patients who are tolerable to headache and palpitation,” Toyoda concluded.

In the open-label trial, 1,839 Japanese patients already taking either aspirin or clopidogrel for secondary prevention were randomized to either stay on monotherapy or have cilostazol at 100 mg twice daily added to their regimen. Enrollment fell well short of the originally planned 4,000, despite an extension.

Patients accepted into the trial had a non-cardioembolic ischemic stroke in the 8-180 days prior to enrollment. They had to have at least 50% stenosis of a major intracranial artery or an extracranial artery, otherwise at least two risk factors for recurrent stroke.

Toyoda showed that combined stroke, MI, and vascular death rates went down with cilostazol (HR 0.52, 95% CI 0.35-0.77), but not hemorrhagic strokes or all-cause mortality.

There were more adverse events (27.4% vs 23.1%, P=0.038) and numerically more bleeds (4.1% vs 3.5%) with the PDE-3 inhibitor. Serious adverse events, however, were less common (9.3% vs 15.0%, P<0.001).

One in five patients in the DAPT group discontinued the trial medication within 6 months, Toyoda acknowledged.

‘Definitely an option now’

“The magnitude of effect without increased bleeding is very substantial and somewhat surprising in face of opposite results in previous dual antiplatelet studies,” commented James Grotta, MD, of Memorial Hermann-Texas Medical Center in Houston.

Toyoda noted that DAPT with aspirin and clopidogrel together has not been effective at preventing recurrent strokes in the long term and is associated with increased bleeding.

Cilostazol is “definitely an option now,” but the trial’s findings need to be duplicated in a non-Asian population, Grotta told MedPage Today.

What was shown in the trial may not be enough to change practice, Karen Furie, MD, MPH, of the Warren Alpert Medical School of Brown University in Providence, Rhode Island, told MedPage Today. She cited the trial’s flexibility of combining cilostazol with either clopidogrel or aspirin and the monotherapy group taking the same medications at different doses.

Concern about the comparison group not being a single antiplatelet regimen was also raised by Walter Kernan, MD, of Yale New Haven Hospital. “For this trial in particular, it will be important for all of us to see the final, published report before we can consider how the results might influence clinical policy,” he said.

On the other hand, the treatment effect is large enough that it couldn’t be explained by the “slightly inelegant” trial design, suggested Jeffrey Saver, MD, of the University of California, Los Angeles, who was not involved with the study. Saver told MedPage Today that Toyoda’s group achieved a “fantastic result” that can be put into practice right away.

If the findings are generalizable, cilostazol could be taken up more in the Western hemisphere, he said.

The study was funded by Otsuka Pharmaceutical Co.

Toyoda disclosed being a speaker for Bayer Yakuhin, Daiichi Sankyo, Brystol Meyers Squibb, and Nippon Boehringer Ingelheim.

Furie, Grotta, and Saver reported no conflicts of interest.


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