Background and Purpose:Cilostazol, a phosphodiesterase 3’ inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression.Methods:A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742).Results:We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57–0.81]; P<0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29–0.64]; P=0.0001), deaths (OR=0.64 [95% CI, 0.49–0.83], P<0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54–0.99]; P=0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance.Conclusions:Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.

中文翻译：

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西洛他唑用于卒中和认知功能下降的二级预防：系统评价和荟萃分析。

背景与目的：西洛他唑是一种磷酸二酯酶3'抑制剂，在亚太地区的国家中用于预防中风，但在其他地方很少使用。除了弱的抗血小板作用外，它还可以稳定内皮细胞，在实验室模型中帮助髓鞘修复和星形胶质细胞-神经元能量转移，这种作用可能对预防小血管疾病的进展有帮助。西洛他唑可预防中风，认知能力下降或放射性小血管疾病病变进展。两名审稿人搜索了论文（2019年1月1日至2019年7月16日）并提取了数据。我们通过敏感性分析计算了复发性缺血，出血性中风，死亡，不良症状的Peto比值比（ORs）和95％CI。该评论已注册（CRD42018084742）。结果：我们纳入了20项随机对照试验（n = 10 505），缺血性中风18项（总n = 10 449）和2项认知障碍（n = 56）；大多数在亚太国家演出。西洛他唑减少了缺血性卒中的复发（17项试验，n = 10 225，OR = 0.68 [95％CI，0.57–0.81]；P <0.0001），出血性中风（16个试验，n = 9736，OR = 0.43 [95％CI，0.29–0.64]；P = 0.0001），死亡（OR = 0.64，[95％CI，0.49–0.83]，P < 0.0009），全身性出血（n = 8387，OR = 0.73 [95％CI，0.54–0.99]；P= 0.04），但与安慰剂，阿司匹林或氯吡格雷相比，头痛和心增加。长期（> 6个月）给予西洛他唑可减少复发性缺血性中风，而短期给予则不会增加出血，在腔隙性脑卒中比例更大（> 40％）的试验中。数据不足以评估其对认知，影像学，功能结局或耐受性的影响。结论：西洛他唑似乎可长期有效地预防继发性中风，而不会增加出血风险。但是，大多数与亚太地区患者相关的试验以及西方国家的更多试验应评估其对认知功能下降，功能结局和耐受性的影响，尤其是在腔隙性中风和其他小血管疾病表现中。