Non-inferior overall but MI rates higher with PDE3 inhibitor
In the PICASSO trial, patients on cilostazol had a lower risk of any stroke than those randomized to aspirin, but they had a higher risk of myocardial infarction, Sun Kwon, MD, of Asan Medical Center in Seoul in South Korea, and colleagues reported during a press briefing at the International Stroke Conference.
At the same time, the PDE3 inhibitor didn't prove superior for diminishing the risk of bleeding, which was part of the potential appeal of the alternative agent, Kwon said.
The use of blood thinners for secondary prevention in ischemic stroke can also increase the risk of cerebral hemorrhage, so researchers have been looking for an alternative to these agents, especially for patients who have evidence of micro- and macrobleeds in the brain after stroke. These bleeds are associated with risk of future cerebral hemorrhage.
Cilostazol had been shown in some earlier trials to be tied to a lower risk of recurrent stroke and fewer hemorrhagic events compared with other antiplatelet agents, but results have been inconsistent. So Kwon and colleagues enrolled 1,534 patients from 67 centers in three Asian countries from August 2009 to August 2014 into their study, which had a 2x2 factorial design, randomizing patients to either cilostazol or aspirin, or to cilostazol plus probucol versus aspirin plus probucol. Results of the latter part of the trial were not presented at the meeting.
All of the patients had non-cardioembolic ischemic stroke or a transient ischemic attack (TIA) within 180 days, and all had evidence of previous macro- or microbleeds.
They used co-primary endpoints of efficacy and safety; efficacy was time to first occurrence of a composite of major vascular events including stroke, MI, and vascular death, while safety was the time to first recurrence of cerebral hemorrhage.
Overall, cilostazol met criteria for non-inferiority in terms of the efficacy co-primary outcome of composite cardiovascular events, with 63 occurrences in the cilostazol group and 80 in the aspirin group (HR 0.80, 95% CI 0.60-1.05, P=0.004 for non-inferiority).
But it didn't prove non-inferior for the safety co-primary endpoint of cerebral hemorrhage. While the incidence rate was lower by half with cilostazol, the difference wasn't significant because there were relatively few events (0.61% versus 1.20% per person-year, P=0.09).
Neither outcome met criteria for superiority to aspirin.
In terms of individual outcomes, there was a significant benefit for stroke overall (HR 0.67, 95% CI 0.46-0.96, P=0.03), but not for any of the others, including ischemic stroke, cardiovascular death, or other vascular events. And there were numerically more heart attacks with cilostazol (nine versus two).
The non-inferiority findings for the co-primary endpoint and for the individual stroke endpoint remained significant in multivariate analyses, researchers noted.