Cilostazol useful for prevention of recurrent stroke

The phosphodiesterase type 3 (PDE3) inhibitor cilostazol succeeds in long-term secondary stroke prevention without increasing the risk of haemorrhagic complications, according to the results of a meta-analysis.

However, “[d]espite its encouraging safety profile (lower bleeding risk and death), cilostazol causes several symptoms (headache, palpitations, diarrhoea, nausea), which may limit tolerance, requiring more data to guide future routine use,” the investigators said.

Also, “most data are from Asia Pacific countries where stroke aetiologies and other factors may differ from other world regions,” they added.

The meta-analysis included 20 randomized controlled trials (n=10,505), of which 18 involved patients with ischaemic stroke (n=10,449) and the remaining two included patients with cognitive impairment (n=56).

Pooled data showed that cilostazol reduced the recurrence of any stroke (18 trials, n=10,225; odds ratio [OR], 0.61, 95 percent confidence interval [CI], 0.523–0.72; p<0.00001), ischaemic stroke (17 trials, n=10,225; OR, 0.68, 95 percent CI, 0.57–0.81; p<0.0001), and haemorrhagic stroke (16 trials, n=9,736; OR, 0.43, 95 percent CI, 0.29–0.64; p=0.0001), without heterogeneity among studies. [Stroke 2020;doi:10.1161/STROKEAHA.120.029454]

The drug also conferred protection against deaths (18 trials, n=10,865; OR, 0.64, 95 percent CI, 0.49–0.83; p<0.0009), major adverse cardiovascular events (10 trials, n=8,948; OR, 0.66, 95 percent CI, 0.57–0.76; p<0.00001), and systemic bleeding (12 trials, n=8,387; OR, 0.73, 95 percent CI, 0.54–0.99; p=0.04). However, cilostazol was associated with increased headache and palpitations, compared with placebo, aspirin, or clopidogrel.

The stroke recurrence-risk reduction effects mostly occurred in trials that initiated treatment ≥2 weeks after stroke (median, 76 days), those that administered the drug for long term (≥6 months), and those that included larger proportions (>40 percent) of patients with lacunar stroke. There was limited evidence on the effect of the PDE3 inhibitor on functional outcome, cognitive decline, or radiological markers of small vessel disease.

“The increased benefit of cilostazol later after stroke may reflect that its mechanisms of action are more relevant to lacunar stroke where recurrence occurs late, [as] supported by increased benefit in trials including more patients with lacunar stroke,” the investigators pointed out.

“[Favourable effects on] lacunar stroke include endothelial stabilization, improved myelin repair, and better astrocyte-to-neuronal energy supply, all of which may take some time to accrue. The lower cerebral and systemic haemorrhage risks would also confer benefit over other antiplatelet drugs, which typically have higher bleeding risk the longer they are given,” they added. [Int J Stroke 2015;10:469-478; EclinicalMedicine 2019;11:34-43]

Cilostazol is used for stroke prevention in Asia Pacific countries, but in Western countries it is licensed for treating symptomatic peripheral vascular disease.

The investigators underscored the need for more evidence before the PDE3 inhibitor can be used more widely for recurrent stroke prevention in routine practice.