Targeted Antithrombotic Therapy in Cryptogenic Stroke with Patent Foramen Ovale

描述(由申请人提供)：抗血栓治疗是缺血性卒中二级预防指南推荐的治疗方法。对于已知的心脏栓塞症患者，抗凝(AC)(例如使用华法林)是首选的抗血栓治疗。对于所有其他IS，包括隐源性卒中(CS)，抗血小板治疗(APT)是首选。我们最近进行了一项荟萃分析，包括来自8项研究的随机和(主要)观察性数据，表明隐源性卒中(CS)和卵圆孔未闭(PFO)患者AC与APT的潜在相对风险降低50%。然而，这些结果受到统计能力低、受指征混淆以及缺乏强有力的方法来控制成分观察研究中的不可比较性的限制。这项建议通过从成分研究中获得个体患者数据(IPD)，并使用我们正在进行的反常栓塞风险(ROPE)研究(R01 NS062153)的数据大幅增强荟萃分析，解决了这些限制。ROPE研究的重点是开发预测模型，用于选择可能受益于PFO关闭的患者，包括估计指标性卒中与PFO相关的概率的模型。它包括12个CS患者的组件数据库，这些患者接受了PFO调查。这些绳索数据库中的7个将适用于这项拟议的战术--PFO研究。这7项研究将与另外3至5个非ROPE数据库结合并协调，产生一个拥有约2000名患者的数据库。这大约是我们最近基于文献的综合性研究水平荟萃分析中纳入的患者数量的3倍。更重要的是，拥有IPD将允许我们使用特定于研究的倾向模型来调整适应症的混淆。我们假设，在PFO和CS患者中，与APT相比，AC可能提供实质性的好处，特别是在最有可能因矛盾的栓塞性中风而不是隐匿性动脉粥样硬化或腔隙疾病而发生中风的患者中。目的：利用经内科治疗的CS合并PFO患者的最大数据库和按适应证控制混淆的“强”方法，评价APT和AC在PFO和CS患者中的比较效果。目的：探讨高发或低发血栓形成的CS患者治疗效果(HTE)的异质性。长期目标：这项分析的结果旨在激励随机临床试验(RCT)并为其提供信息。如果没有随机对照试验，他们将为在这一重要的IS患者亚组中选择适当的抗血栓治疗提供最明确的研究。公共卫生意义：中风是美国第三大致死和致残原因。在每年约79.5万名卒中患者中，约有18.5万人复发。因此，二级预防对公共卫生具有重大意义。在大多数系列中，约30%的中风被归类为CS，其中约50%有PFO(即每年&gt；100,000)。尽管如此，在这一人群中进行二级预防的最佳医学方法尚未得到很好的研究。 公共卫生相关性：在没有任何明显原因的中风患者中，约有一半被发现有卵圆孔未闭，这是心脏中一种常见的解剖异常，可能与中风有关，也可能与中风无关。目前还不知道对这些患者最好的药物治疗是什么。这项研究将通过构建此类患者的最大数据库，进行内科治疗，并使用严格的统计方法来比较治疗效果，来调查抗凝治疗是否优于抗血小板治疗。

DESCRIPTION (provided by applicant): Antithrombotic therapy is recommended by guidelines for secondary prevention in ischemic stroke (IS). For patients with known cardioembolic IS, anticoagulation (AC) (e.g. with warfarin) is the antithrombotic therapy of choice. For all other IS including cryptogenic stroke (CS), antiplatelet therapy (APT) is preferred. We performed a recent meta-analysis including both randomized and (mostly) observational data from 8 studies suggesting a potential 50% relative risk reduction for AC versus APT in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO). These results, however, are limited by low statistical power, confounding by indication and the lack of strong methods to control for non-comparability in the component observational studies. This proposal addresses these limitations by obtaining individual patient data (IPD) from the component studies and substantially augmenting the meta-analysis with data from our on-going Risk of Paradoxical Embolism (RoPE) Study (R01 NS062153). The RoPE Study focuses on the development of predictive models for the selection of patients that might benefit from PFO closure, including a model to estimate the probability that an index stroke is PFO-related. It includes 12 component databases of CS patients investigated for PFO. Seven of these RoPE database will be appropriate for this proposed TAcTiCS- PFO study. These 7 studies will be combined and harmonized with 3 to 5 additional non-RoPE databases, yielding a database with ~2000 patients. This is roughly 3-fold the number of patients included in our recent comprehensive literature-based study-level meta-analysis. More importantly, having IPD will permit us to use study-specific propensity models to adjust for confounding by indication. We hypothesize that, among patients with PFO and CS, AC may provide substantial benefit compared to APT, particularly in the subset of patients most likely to have stroke from paradoxical embolism, rather than occult atheroembolic or lacunar disease. Aim 1: To evaluate the comparative effectiveness of APT versus AC in patients with PFO and CS, using the largest combined database of medically-treated CS patients with PFO and "strong" methods to control for confounding by indication. Aim 2: To explore potential heterogeneity of treatment effect (HTE) in CS patients with PFO with a high versus a low probability of paradoxical embolism. Long term objectives: The results of this analysis are intended to motivate and inform a randomized clinical trial (RCT). Absent an RCT, they will provide the most definitive study available for selecting appropriate antithrombotic therapy in this important subgroup of IS patients. Public health significance: Stroke is the 3rd leading cause of death and leading cause of disability in the US. Among the ~795 000 people with stroke annually, ~185 000 are recurrent4. Secondary prevention is thus of enormous public health import. In most series, ~30% of strokes are classified as CS and about 50% of these have PFO, (i.e. >100,000 per year). Despite this, the optimal medical approach to secondary prevention in this population has not been well studied. PUBLIC HEALTH RELEVANCE: About half of patients who have a stroke without any apparent cause are found to have a patent foramen ovale, a common anatomic anomaly in the heart that may be related or unrelated to the stroke. It is currently not known what the best medical therapy for these patients is. This study will investigate whether anticoagulation therapy is bette than antiplatelet therapy by constructing the largest database of such patients, treated medically, and using rigorous statistical methods to compare treatment effects.