Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial
Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial
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DOI：
10.1016/s1474-4422(18)30128-5
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发表时间：
2018-06-01
期刊：
影响因子：
48
通讯作者：
Kang, Dong-Wha
中科院分区：
文献类型：
--
作者：
Kim, Bum Joon;Lee, Eun-Jae;Kang, Dong-Wha
背景 对于脑出血高风险的缺血性卒中患者的最佳治疗尚不清楚。我们在这些患者中评估了西洛他唑与阿司匹林（加或不加普罗布考）的疗效和安全性。 方法 在这项随机、对照、2x2 析因试验中，我们从三个亚洲国家的 67 个中心入组了有脑内出血病史或影像学表现或两次或以上微出血的缺血性卒中患者。患者被随机分配（1:1:1:1）接受口服西洛他唑（100 mg，每天两次）、阿司匹林（100 mg，每天一次）、西洛他唑加普罗布考（250 mg，每天两次）或阿司匹林加普罗布考，按中心分层集中治疗。西洛他唑与阿司匹林的比较进行了双盲研究；普罗布考治疗是开放标签的，但结果评估者对分配情况不知情。共同主要结局是卒中、心肌梗死或血管性死亡的复合发生率（疗效）和出血性卒中发生率（安全性），在意向治疗和改良意向治疗人群中进行评估。如果满足非劣效性，则通过非劣效性检验和优效性检验来分析功效。仅通过优效性测试评估安全性。该试验已在 ClinicalTrials.gov 注册，NCT01013532。结果 在 2009 年 8 月 1 日至 2015 年 8 月 31 日期间，我们将 1534 名患者随机分配到四个研究组之一，其中 1512 名患者接受了共同主要终点评估。在中位随访时间为 1.9 年（IQR 1.0-3.0）期间，接受西洛他唑治疗的患者复合血管事件的发生率为每 100 人年 4.27 例，接受阿司匹林治疗的患者为每 100 人年 5.33 例（HR 0.80，95% CI 0.57-1.11；非劣效性 p=0.0077；优越性 p=0.18）。接受西洛他唑治疗的患者脑出血发生率为每100人年0.61例，接受阿司匹林治疗的患者脑出血发生率为每100人年1.20例（HR 0.51，97.5% CI 0.20-1.27；优越性p=0.18）。普罗布考组的血管事件发生率为每 100 人年 3.91 例，而非普罗布考组为每 100 人年 5.75 例（HR 0.69，95% CI 0.50-0.97；优越性 p=0.0316）。普罗布考组脑出血的发生率为每 100 人年 0.72 例，非普罗布考组每 100 人年脑出血发生率为 1.11 例（HR 0.65，97.5% CI 0.27-1.57；p=0.55）。四个研究组的不良事件相似；最常见的事件是头晕、头痛、腹泻和便秘。 解读 在脑出血高风险的缺血性卒中患者中，西洛他唑在预防心血管事件方面不劣于阿司匹林，但并不能降低出血性卒中的风险。在阿司匹林或西洛他唑中添加普罗布考可能有利于降低心血管事件的发生率。版权所有 (C) 2018 爱思唯尔有限公司。保留所有权利。
Background The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients.Methods In this randomised, controlled, 2x2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532.Findings Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1.9 years (IQR 1.0-3.0), the incidence of composite vascular events was 4.27 per 100 person-years in patients who received cilostazol and 5.33 per 100 person-years in patients who received aspirin (HR 0.80, 95% CI 0.57-1.11; noninferiority p=0.0077; superiority p=0.18). Incidence of cerebral haemorrhage was 0.61 per 100 person-years in patients who received cilostazol and 1.20 per 100 person-years in those who received aspirin (HR 0.51,97.5% CI 0.20-1.27; superiority p=0.18). The incidence of vascular events was 3.91 per 100 person-years in the probucol group compared with 5.75 per 100 person-years in the non-probucol group (HR 0.69, 95% CI 0.50-0.97; superiority p=0.0316). The incidence of cerebral haemorrhage was 0.72 per 100 person-years in the probucol group and 1.11 per 100 person-years in the non-probucol group (HR 0.65,97.5% CI 0.27-1.57; p=0.55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation.Interpretation In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Copyright (C) 2018 Elsevier Ltd. All rights reserved.