The Risk of Paradoxical Embolism (ROPE) Study

描述（由申请人提供）：超过三分之一的中风是“隐源性”的;尽管进行了测试，但其原因尚不清楚。卵圆孔未闭（PFO）在隐源性卒中（CS）患者中的患病率约为50%，而在一般人群中仅为25%。这表明反常栓塞（PE），即通过PFO进入动脉循环的静脉栓塞，是CS的主要原因。许多医生建议关闭PFO，特别是对年轻患者，但该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与卒中是否存在因果关系，并且CS和PFO患者的卒中复发并不常见（研究中的平均年风险约为2%）。虽然对于某些人（例如房间隔动脉瘤患者），风险高于平均水平，但在其他人中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。以前的研究受到限制， 检查复发相关因素的统计功效极低，结果相互矛盾，甚至自相矛盾，可能是由于其他原因造成的卒中风险混淆，未得到适当控制。为了告知患者治疗的潜在益处，需要一种方法来预测个体患者中PFO与指示事件之间的因果关系而非偶发关系的可能性以及此类事件复发的概率。副动脉栓塞风险（ROPE）研究的目的是确定：1）PE导致的复发性卒中高风险患者（不仅仅是一般复发性卒中），可以通过PFO封堵术进行帮助; 2）PE复发风险低的患者（偶发PFO或良性自然史），不太可能从封堵术中获益。我们假设CS患者（有或无PFO）的特征可用于识别发现PFO或多或少可能与卒中有因果关系的患者。此外，我们假设，在CS和PFO患者中，卒中复发的风险，特别是PE复发的风险，可以从索引卒中时可用的临床、放射学和超声心动图变量中预测。因此，ROPE研究的具体目的是：1）使用经食管超声心动图研究的CS患者的现有队列研究（有和无PFO）构建最大的CS数据库，足够稳健以支持预测风险建模; 2.识别CS患者与PFO存在（与不存在）相关的患者特征; 3） 在同时患有CS和PFO的患者中，基于临床、放射学和超声心动图特征开发预测模型以估计患者特异性卒中复发风险; 4）基于这些模型开发指数，该指数可以根据PFO与指数卒中因果相关的条件概率和卒中复发风险对患有CS和PFO的患者进行分层; 5）应用该评分对临床试验中的患者进行分层，从低预期受益到高预期受益，并测试治疗效果与分层的相互作用。在普通人群中，每四个人中就有一个人的心脏上有一个小洞，称为卵圆孔未闭（PFO），但在中风患者中，其中许多人都很年轻，无法解释为什么他们应该中风，这些洞在大约两个人中发现。在这些患者中，没有人知道如何判断PFO是否允许血凝块通过并导致中风，或者如果它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，所有这些孔都应该使用新的非手术方法关闭，而不仅仅是血液稀释药片。通过检查有史以来最大规模的患者集合，ROPE研究小组旨在确定应该关闭PFO以防止再次中风的患者，同样重要的是确定PFO关闭不太可能帮助甚至可能导致伤害的患者。

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.