Cilostazol makes good in DAPT for recurrent stroke prevention in high-risk patients

Dual antiplatelet therapy (DAPT) with cilostazol performs better than either aspirin or clopidogrel alone at reducing the risk of recurrent stroke or vascular events without increasing the incidence of bleeding for patients with ischaemic stroke and intracranial arterial stenosis (ICAS), according to the results of the CSPS.com* trial.

Over a median follow-up of 1.4 years, DAPT with cilostazol halved the risks of ischaemic stroke (hazard ratio [HR], 0.47, 95 percent confidence interval [CI], 0.23–0.95; p=0.036), any stroke (HR, 0.47, 95 percent CI, 0.24–0.94; p=0.033), and the composite of vascular events (stroke, myocardial infarction, and vascular death; HR, 0.47, 95 percent CI, 0.25–0.90; p=0.022) as compared with single antiplatelet therapy (SAPT) with aspirin or clopidogrel. [ 2021;doi:10.1161/JAHA.121.022575]

Moreover, there was no between-group difference seen in the risk of severe or life‐threatening bleeding (HR, 0.59, 95 percent CI, 0.09–3.78; p=0.58).

“Cilostazol, a phosphodiesterase inhibitor, is known to have pleiotropic effects such as antiplatelet, vasodilating, anti‐inflammatory, and antiatherogenic effects, [as well as] protective effects on endothelial function. These effects might contribute to the long‐term stroke prevention and help to avoid bleeding risk,” explained a team of Japan-based researchers. [Arterioscler Thromb Vasc Biol 2008;28:1634-1639; Clin Exp Pharmacol Physiol 2020;47:432-438; Circulation 2010;121:2584-2591; Lancet Neurol 2010;9:959-968]

“The long‐term effect of cilostazol combined with clopidogrel or aspirin on recurrent stroke is similar to the effect of dipyridamole combined with aspirin. Interestingly, the Kaplan‐Meier curves for ischaemic stroke diverged gradually. Thus, the effects of cilostazol might be delayed and presumably more related to the pleiotropic effects rather than the direct antiplatelet effects,” the team added. [Lancet 2016;388:365-375]

The CSPS.com subgroup analysis included 547 Japanese ICAS patients, among whom 275 were assigned to receive DAPT with cilostazol (200 mg/day) and 272 to receive SAPT. There was a similar number of patients who used clopidogrel in the respective groups (58.2 percent and 59.3 percent; p=0.6575). Baseline characteristics were generally similar, except for chronic kidney disease, which was more common in the DAPT group.

The patients were required to meet at least one of the following criteria indicating a high risk for stroke recurrence: at least 50-percent stenosis of a major intracranial artery, the Sylvian segment of the middle cerebral artery, or the ambient segment of the posterior cerebral artery; at least 50-percent stenosis of an extracranial artery; and the presence of at least two risk factors for stroke.

As the researchers pointed out, the study population included both symptomatic and asymptomatic ICAS patients. This may explain why stroke rate in CSPS.com was lower than those in other clinical trials that included only patients with symptomatic ICAS, such as the WASID** and SAMPRIS⁺⁺ trials, with asymptomatic ICAS having been shown to contribute no increase in the short‐ or medium‐term risk of distal recurrent ischaemic stroke for patients receiving standard medical treatment. [Neurology 1995;45:1488-1493; N Engl J Med 2011;365:993-1003; JAMA Neurol 2020;77:947-954]

“ICAS is more common in Asian people than in White people, and the risk of first‐ever and recurrent stroke is high in patients with ICAS,” according to the researchers.

The takeaway from the present study, they said, is that cilostazol can be used in DAPT for the long‐term prevention of recurrent stroke and vascular events “without concern for increased bleeding in patients with symptomatic or asymptomatic intracranial arterial stenosis of at least 50 percent after ischaemic stroke.”

*Cilostazol Stroke Prevention Study for Antiplatelet Combination

**Warfarin‐Aspirin Symptomatic Intracranial Disease