Cilostazol beats aspirin in secondary stroke prevention

MANILA, Philippines - Aspirin has been a popular agent for preventing stroke recurrence of ischemic origin. However, recent studies have shown that cilostazol – an anti-platelet, vasodilating agent – may be a more effective and safer alternative in preventing stroke and other vascular events among patients with high vascular risk for subsequent stroke, and those with previous transient ischemic attack.

A recent trial, titled the Cilostazol Stroke Prevention Study (CSPS 2), aimed to establish “non-inferiority” of cilostazol versus aspirin in the prevention of another recurrence of stroke.

The study was recently presented in detail by Dr. Dante Morales to the delegates of the 43rd Annual Convention and Scientific Meeting of the Philippine Heart Association Inc., together with the Philippine College of Cardiology.

The CSPS 2 trial evaluated patients aged 20-79 from 278 sites in Japan. They were allocated to receive 100 mg of cilostazol (n=1379) twice daily, or 81 mg of aspirin (n=1378) once daily for 1-5 years. Their primary endpoint would be the first occurrence of stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage).

Between December 2003 and October 2006, about 2,757 patients were enrolled in the study, with 1,337 on cilostazol and 1,335 on aspirin. The primary endpoint occurred at yearly rates of 2.76 percent (n=82) in the cilostazol group and 3.71 percent (n=119) in the aspirin group.

The researchers found that there were fewer hemorrhagic events in those who took Cilostazol (0.77 percent, n=23) versus those who received aspirin (1.78 percent, n=57).

“Cilostazol was significantly more effective than aspirin in preventing recurrence of stroke, with fewer hemorrhagic events,” said Morales.

“Therefore, cilostazol is recommended as an option for the prevention of stroke recurrence in non-cardioembolic stroke patients, who can tolerate long term administration of this drug,” he said.

Morales added that subgroup analysis and cost-effectiveness analysis are still ongoing.

Cilostazol is an anti-platelet drug that inhibits phosphodiesterase type-3, resulting in an increase in cAMP concentrations, thus inhibiting platelet aggregation. The drug has vasodilatory activities, inhibits vascular smooth muscle cell proliferation and protects the vascular wall.

Results from other trials confirmed the findings of the CSPS 2 study.

After a search of the Cochrane Stroke Group Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Cilostazol Stroke Prevention Study (CSPS 2) trials, researchers were able to pick randomized control trials wherein the participants were treated with either cilostazol or aspirin for at least one month, and subsequently they were followed up for the development of stroke, myocardial infarction or vascular death.

The researchers focused on two trials from Japan and China, with a total of 3,477 participants with a history of ischemic stroke of arterial origin. They discovered that Cilostazol had a significantly lower risk of vascular events (stroke, myocardial infarction, or vascular death; relative risk, 0.72; 95 percent CI, 0.57 to 0.91).

Furthermore, they found that the advantage of Cilostazol on ischemic or hemorrhagic stroke was 33 percent (95 percent CI, 14 to 48 percent), as opposed to aspirin. The treatment effect for each outcome was calculated using the Mantel-Haenszel method.

Cilostazol was also associated with a 74 percent risk reduction when it came to hemorrhagic stroke. Aspirin caused more bleeding with extra-cranial hemorrhage, compared to patients taking cilostazol.

Cilostazol, however, was associated with minor adverse reactions such as headache, palpitation, angina, and dizziness as compared to aspirin. 

With favorable effects and fewer bleeding events, cilostazol provides a good alternative in the secondary prevention of stroke of non-cardio embolic stroke.

Future randomized trials will focus on patients with ischemic stroke, to determine whether there is a reduction of vascular events after stroke, and whether or not this applies to non-Asian populations.