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（is）二级预防指南推荐的。对于已知心脏栓塞性IS患者，抗凝治疗（例如使用华法林）是抗血栓治疗的选择。对于所有其他IS，包括隐源性卒中（CS），首选抗血小板治疗（APT）。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（大部分）观察性数据，表明AC与APT相比，隐源性卒中（CS）和卵圆孔未闭（PFO）患者的相对风险可能降低50%。然而，这些结果受到统计效力低、指征混淆和缺乏强有力的方法来控制成分观察性研究中的非可比性的限制。该建议通过从成分研究中获取个体患者数据（IPD），并通过我们正在进行的悖论性栓塞风险（RoPE）研究（R01 NS062153）的数据大幅增加meta分析，解决了这些局限性。RoPE研究的重点是开发预测模型，用于选择可能从PFO关闭中受益的患者，包括估计指数卒中与PFO相关概率的模型。它包括12个CS患者的组成数据库，用于调查PFO。这些RoPE数据库中的7个将适用于拟议的TAcTiCS- PFO研究。这7项研究将与另外3 - 5个非rope数据库合并并协调，形成一个包含约2000名患者的数据库。这大约是我们最近基于文献的综合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将允许我们使用研究特定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可能提供实质性的益处，特别是在最有可能因矛盾栓塞而不是隐匿性动脉粥样硬化栓塞或腔隙性疾病而发生卒中的患者亚群中。目的1：评估APT与AC在PFO和CS患者中的比较疗效，使用最大的PFO医学治疗CS患者联合数据库和“强”方法来控制适应症的混淆。目的2：探讨异位栓塞概率高与低的CS合并PFO患者治疗效果（HTE）的潜在异质性。长期目标：本分析的结果旨在激励并为随机临床试验（RCT）提供信息。在没有随机对照试验的情况下，他们将为IS患者这一重要亚组选择合适的抗血栓治疗提供最明确的研究。公共卫生意义：在美国，中风是导致死亡和残疾的第三大原因。在每年约79.5万例中风患者中，约18.5万例为复发。因此，二级预防具有巨大的公共卫生重要性。在大多数系列中，约30%的中风被归类为CS，其中约50%为PFO，即每年约10万例。尽管如此，在这一人群中进行二级预防的最佳医疗方法尚未得到很好的研究。

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.