Timing of DAPT With Cilostazol Plays Role in Long-Term Recurrence of Ischemic Stroke

Author(s):

The recurrence of ischemic stroke was less common with dual antiplatelet therapy than with monotherapy in those treated within the 15–180-day window, and similarly common in the 8–14-day period.

Takenori Yamaguchi, MD, PhD

Long-term dual antiplatelet therapy (DAPT) with cilostazol (Pletal; Otsuka Pharmaceutical) was found to be more effective for secondary prevention of noncardioembolic stroke than monotherapy in high-risk patients who started the medication 15 days or later after stroke onset compared to those who started during the 8–14-day window.

CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination), a randomized controlled trial (NCT01995370), originally showed that cilostazol, coupled with aspirin or clopidogrel (Plavix; Sanofi), reduced the risk of recurrent ischemic stroke and had a similar risk of severe or life-threatening bleeding compared to aspirin or clopidogrel alone in high-risk patients for recurrent stroke over a median of 1.4 years.

In this subanalysis, senior author Takenori Yamaguchi, MD, PhD, president emeritus, American Heart Association (AHA), and colleagues evaluated whether the effect of DAPT changes based on the timing of starting medication. A cohort of 1879 patients were trichotomized according to the time of initiation of the trial medication: between 8 and 14 days (8-14D; n = 498), between 15 and 28 days (15-28D; n = 467), and between 29 and 180 days (29-180D; n = 914) after stroke onset.

Patients were randomized 1:1 to either monotherapy with aspirin (81 mg or 100 mg) or clopidogrel (50 mg or 75 mg) once daily or dual therapy with cilostazol (100 mg, twice daily) and either aspirin (81 mg or 100 mg) or clopidogrel (50 mg or 75 mg), once daily. At the conclusion of the analysis, there was a significant treatment-by-subgroup interaction observed for the primary efficacy outcome, or first recurrence of ischemic stroke, between assigned treatment and trichotomized groups (15-28D: P = .07; 29-180D: P = .022; and 15-180D combined: P = .012; all compared with the 8-14D group).

In the 8-14D group, ischemic stroke occurred in 15 patients (annualized rate, 4.5%) during follow-up in the DAPT group and 17 (4.5%) in the monotherapy group (crude HR, 1.02 [95% CI, 0.51-2.04]). In comparison, the recurrence of ischemic stroke was less common with DAPT than with monotherapy in the 15-28D group (annualized rate, 1.5% vs 4.9%, respectively; adjusted HR, 0.34 [95% CI, 0.12-0.95]) and the 29-180D group (1.9% vs 4.4%, respectively; adjusted HR, 0.27 [95% CI, 0.12-0.63]).

"The findings suggest the feasibility of a seamless DAPT strategy after stroke, switching from [aspirin + clopidogrel] in the acute to subacute stage to [cilostazol + aspirin] or [cilostazol + clopidogrel] at 15 days or later," the study authors concluded. “Clinical studies to prove this strategy are needed."

Secondary efficacy outcomes included any stroke (ischemic or hemorrhagic); a composite of stroke, myocardial infarction, and vascular death; all vascular events, including stroke, myocardial infarction, and other vascular events; and death from any cause. At follow-up, a similar occurrence of severe or life-threatening bleeding was found between patients on dual therapy and those on monotherapy in any of the trichotomized groups (8-14D: crude HR, 0.22 [95% CI, 0.03-1.88]; 15-28D: crude HR, 1.07 [95% CI, 0.15-7.60]; and 29-180D group: crude HR, 0.76 [95% CI, 0.24-2.39]). The composite of headache, palpitations, and tachycardia was similarly common between the 8-14D and 29-180D groups and somewhat less common in the 15-28D group.

Cilostazol, a phosphodiesterase 3 inhibitor, is currently recommended as a first-line antiplatelet agent for secondary stroke prevention in Japan and several Asian countries and was weakly recommended for stroke or transient ischemic attack attributable to moderate to severe intracranial artery stenosis in the US in the AHA’s 2014 guideline.²

REFERENCES
1. Toyoda K, Omae K, Hoshino H, et al. Association of timing for starting dual antiplatelet treatment with cilostazol and recurrent stroke: a CSPS.com trial post-hoc analysis. Neurology. Published online January 24, 2022. doi:10.1212/WNL.00000000000200064
2. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2014; 45:2160-2236. doi:10.1161/STR.0000000000000024