The Risk of Paradoxical Embolism (ROPE) Study

描述(申请人提供)：超过三分之一的中风是“隐蔽的”；他们的原因是未知的，尽管测试。隐源性卒中(CS)患者卵圆孔未闭(PFO)的发生率约为50%，而在一般人群中仅为25%。这表明反常栓塞症(PE)是CS的主要原因。许多医生建议关闭PFO，特别是对年轻患者，但这种手术的好处尚未得到证实。对于患有CS和PFO的患者，尚不清楚PFO是否与中风或偶发中风有因果关系，中风复发在CS和PFO患者中并不常见(研究的平均年化风险为~2%)。虽然有些人的风险高于平均水平(例如，患有房间隔瘤的人)，但其他人的风险也必须低于平均水平。如何确定中风是由PE引起的，以及如何预测个体的复发风险尚不清楚。以前的研究一直受到以下因素的限制 用于检查与复发相关因素的统计能力极低，结果相互矛盾，甚至自相矛盾，可能是由于混淆了中风风险和其他原因，而没有对其进行适当的控制。为了向患者提供有关治疗的潜在益处的建议，需要一种方法来预测在单个患者中，PFO是指数事件的因果关系而不是偶然的可能性，以及这种事件再次发生的可能性。异常栓塞症风险(ROPE)研究的目标是确定：1)PE复发风险高的患者(不只是一般意义上的复发中风)，他们可以帮助进行PFO封堵；以及2)PE复发风险低的患者(偶发的PFO或良性自然病史)，他们不太可能从封堵中受益。我们假设，CS患者(有无PFO)的患者特征可以用来识别那些发现的PFO或多或少可能与中风有因果关系的人。此外，我们假设，在CS和PFO患者中，卒中复发的风险，特别是PE的复发，可以根据指示卒中时的临床、放射学和超声心动图变量进行预测。因此，ROPE研究的具体目标是：1)使用对接受TEE研究的CS患者的现有队列研究建立最大的CS数据库，无论有无PFO，足够稳健，以支持预测性风险建模；2.识别CS患者与存在(或不存在)PFO相关的患者特征；3) 在同时患有CS和PFO的患者中，开发一个预测模型，以根据临床、放射学和超声心动图特征估计特定患者的卒中复发风险；4)开发一个基于这些模型的指数，可以根据CS和PFO患者的条件概率对其进行分层，即PFO与中风指数和卒中复发风险有因果关系；5)应用这一评分对临床试验中的患者进行分层，以检验血管内封堵术与药物治疗的对比，从低预期受益到高预期受益，以及测试治疗效果之间的交互作用。公共卫生相关性普通人群中每四个人中就有一个心脏上有一个被称为卵圆孔未闭(PFO)的小孔，但在中风患者中，这些孔被发现在大约两个人中的一个，他们中的许多人都很年轻，没有解释为什么他们应该中风。在这些患者中，没有人知道如何判断PFO是否允许血栓通过并导致中风，或者是一个无辜的旁观者，中风是由其他原因引起的，许多医生认为，应该使用新的非手术方法关闭所有这样的孔洞，而不仅仅是血液稀释药。通过研究有史以来针对这一问题聚集的最大患者集合，ROPE研究团队旨在确定哪些患者应该关闭PFO以防止再次中风，同样重要的是确定PFO关闭对哪些患者不太可能有帮助，甚至可能导致伤害。

DESCRIPTION (provided by applicant): Over one-third of all strokes are "cryptogenic"; their cause is unknown despite testing. The prevalence of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is ~50%, yet only 25% in the general population. This suggests that paradoxical embolism (PE), venous emboli that access the arterial circulation via a PFO, is a major cause of CS. Many doctors advise PFO closure, especially for young patients, but the procedure's benefit is unproven. For someone with CS and PFO, it is not clear for that person if the PFO is causally related to the stroke or incidental, and stroke recurrence is uncommon in patients with CS and PFO (average annualized risk across studies is ~2%). While the risk is above average for some (e.g. those with atrial septal aneurysm), it must also be below average in others. How to determine that the stroke was caused by PE and how to predict recurrence risk for individuals is not known. Prior studies have been limited by extremely low statistical power for examining factors related to recurrence and have contradictory and even paradoxical findings, likely due to confounding stroke risk from other causes, which were not properly controlled for. In order to advise patients about the potential benefits of therapy, needed is a means of predicting, in the individual patient, the likelihood that the PFO was causal rather than incidental to the index event and the probability that such an event will recur. The goals of the Risk of Paradoxical Embolism (ROPE) Study are to identify: 1) patients at high risk for recurrent stroke from PE (not just recurrent stroke in general) who can be helped with PFO closure, and 2) patients who are at low risk of recurrence of PE (incidental PFO or benign natural history) who are unlikely to benefit from closure. We hypothesize that patient characteristics in those with CS (with and without PFO) can be used to identify those in whom a discovered PFO is more or less likely to be causally related to the stroke. Further, we hypothesize that, in patients with CS and PFO, the risk of stroke recurrence, and specifically recurrence from PE, is predictable from clinical, radiologic and echocardiographic variables available at the time of the index stroke. Thus, the specific aims of the ROPE Study are: 1) To build the largest database of CS using existing cohort studies of patients with CS studied with TEE, both with and without PFO, sufficiently robust to support predictive risk modeling; 2. To identify, CS patients, patient characteristics that are associated with the presence (versus the absence) of a PFO; 3) To develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics; 4) To develop an index based on these models that can stratify patients with CS and PFO by their conditional probability that the PFO was causally-related to the index stroke and the risk of stroke recurrence; 5) To apply this score to stratify patients in clinical trials testing endovascular PFO closure against medical therapy, from low-expected-benefit to high-expected-benefit, and to test for a treatment-effect-by-strata interaction. PUBLIC HEALTH RELEVANCE One out of every four people in the general population have a small hole in their heart known as a patent foramen ovale (PFO) but in patients with stroke, many of whom are young and with no explanation for why they should have had a stroke, these holes are found in around one in two people. In these patients, no one knows how to tell if the PFO allowed a blood clot to pass through it and cause a stroke or if it is an innocent bystander and the stroke was caused by something else and many doctors argue that all such holes should be closed, using new non-surgical methods, rather than just blood thinning pills. By examining the largest collection of patients ever assembled for this problem, the ROPE Study team aims to identify the patients who should have their PFO closed in order to prevent another stroke and equally importantly to identify those for whom PFO-closure would not be likely to help and may even lead to harm.