Targeted Antithrombotic Therapy in Cryptogenic Stroke with Patent Foramen Ovale

描述（由申请方提供）：指南建议抗血栓治疗用于缺血性卒中（IS）的二级预防。对于已知患有心源性栓塞性IS的患者，抗凝（AC）（例如华法林）是抗血栓治疗的首选。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，表明在隐源性卒中（CS）和卵圆孔未闭（PFO）患者中，AC与APT相比，潜在的相对风险降低50%。然而，这些结果受到统计把握度低、适应症混杂以及缺乏强有力的方法来控制组分观察性研究中的非可比性的限制。本提案通过从组分研究中获得个体患者数据（IPD）并使用我们正在进行的副动脉栓塞风险（RoPE）研究（R 01 NS 062153）的数据大幅增强荟萃分析来解决这些局限性。RoPE研究的重点是开发预测模型，用于选择可能受益于PFO闭合的患者，包括估计指数卒中与PFO相关的概率的模型。它包括12个成分数据库的CS患者调查PFO。其中7个RoPE数据库将适用于本拟定TAcTiCS- PFO研究。这7项研究将与3至5个额外的非RoPE数据库合并和协调，产生一个约2000例患者的数据库。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，IPD将允许我们使用研究特定的倾向模型来调整适应症的混杂因素。我们假设，在PFO和CS患者中，AC可能比APT提供实质性获益，特别是在最有可能因反常栓塞而非隐匿性动脉粥样栓塞或腔隙性疾病发生卒中的患者亚组中。目标1：评价APT与AC在PFO和CS患者中的比较有效性，使用最大的合并PFO的药物治疗CS患者数据库和“强”方法控制适应症的混杂因素。目标二：探讨具有高与低反常栓塞概率的CS伴PFO患者的治疗效果（HTE）的潜在异质性。长期目标：本分析的结果旨在激励和告知随机临床试验（RCT）。在没有RCT的情况下，他们将提供最明确的研究，为这一重要的IS患者亚组选择适当的抗血栓治疗。公共卫生意义：中风是美国第三大死亡原因和主要残疾原因。在每年约795 000名中风患者中，约185 000人复发4。因此，二级预防具有巨大的公共卫生意义。在大多数系列中，约30%的中风被归类为CS，其中约50%患有PFO（即每年> 100，000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充分研究。

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.