See related article, p 3419

The relationship between the presence of a patent foramen ovale (PFO) and an increased risk of ischemic stroke was first recognized in 1988 when 2 case-control studies reported on a significantly increased PFO frequency in young patients who had experienced a stroke of otherwise unknown cause compared with stroke-free controls.^1,2 An increased risk, although of lesser magnitude, was then reported even in older patients.³ The purported stroke mechanism was paradoxical embolism or the embolization to the systemic circulation of a thrombus originating in the venous circulation via the right-to-left shunt allowed by the PFO. Since a PFO is present in approximately 1 in 4 adults, the PFO-related risk of stroke could have important health implications at a population level; however, population-based studies failed to detect a significant increase in stroke risk,^4,5 possibly because the increased risk present in a minority of individuals with PFO was diluted by the lack thereof in the majority of them. Primary prevention strategies for PFO-related first stroke were therefore unfeasible, given the virtual impossibility to identify individuals at high risk of stroke, other than those with relatively infrequent conditions that increase thrombus presence/formation (hypercoagulability and deep venous thrombosis) or facilitate a right-to-left shunt (pulmonary hypertension). However, effective secondary prevention strategies were clearly needed for patients with PFO who had already suffered a stroke. Since paradoxical embolism was the purported stroke mechanism, antithrombotic treatment was tested first. In a randomized trial of warfarin versus aspirin, both treatments were shown to decrease the frequency of recurrent stroke to a similar extent, bringing it down to rates very similar to that observed in patients without PFO⁶; however, younger patients, who are at the greatest risk of PFO-related stroke recurrence, were underrepresented in the study.

The introduction of devices that could be deployed via a transvenous catheter provided a simpler option for PFO closure, which had theretofore required open-heart surgery, and opened the way to a new possible approach for preventing stroke recurrence and, shortly thereafter, to clinical trials comparing the efficacy of PFO closure versus medical therapy. While the earlier trials failed to show a significant difference,^7–9 the most recent ones suggested a superiority of PFO closure^10–12; in a meta-analysis including 4 of the trials for a total 2531 patients followed from 3 to almost 6 years, PFO closure was associated with a stroke recurrence rate of 1.8%, compared with 5.1% for medical therapy.¹³ The benefit was observed especially, but not exclusively, in patients with particular PFO features (large shunts and coexisting atrial aneurysm).^11,12 PFO closure was associated with periprocedural complications (ranging from 3.2% to 5.9% across the trials) and with an increased frequency of atrial fibrillation (ranging from 2.9% to 7.3%, the majority occurring within the first 30 days after the procedure). The trials had limitations, including the relatively small number of primary outcome events and the open-label ascertainment of end points, which may have affected the results because of ascertainment bias. In the present issue of Stroke, Messe et al¹⁴ report on additional results from one of the trials, the Gore REDUCE trial, describing in detail the neuroimaging findings observed during the follow-up in the 2 treatment arms (PFO closure and antiplatelet therapy).¹⁴ Brain magnetic resonance imaging was performed at enrollment and during follow-up, either after the detection of stroke symptoms through a validated questionnaire, or at 2 years in patients that remained symptoms-free. PFO closure was associated with a reduced frequency of combined strokes and silent brain infarcts resulting from the reduced frequency of the former, but not of the latter; infarct number, size, and location did not differ significantly between treatment arms, or between clinically manifest and silent infarcts. The study provides an important objective validation of the clinical observation of a decreased stroke incidence in the PFO-closure group, thus minimizing the possibility that the ascertainment bias associated with the open-label study design may have affected the results; it also provides interesting data on the neuroimaging features of the newly developed brain lesions observed with each treatment. At the same time, it raises questions related to some unexpected, or not immediately clear, findings. The observation that PFO closure was superior to antiplatelet therapy alone in preventing infarcts associated with clinical symptoms but not silent ones is surprising and not easy to explain. The possibility that clinically manifest and silent infarcts may represent somewhat different entities, with the latter being less frequently embolic in origin, seems to be negated by the similar number, size, and location of both infarct types. As the Authors mentioned, some mild periprocedural strokes may have gone undetected, or their symptoms been considered secondary to anesthesia effects; this circumstance would decrease the treatment difference observed for clinical strokes and increase that for silent infarcts while leaving the combined end point, and therefore, the main conclusion of the study, unchanged. Finally, the minimum magnetic resonance imaging infarct size considered (3 mm), although established in the literature, may have led to the exclusion of smaller and more often asymptomatic lesions, whose frequency might have differed between treatments; in fact, the total number of clinically manifest and of silent infarcts in the study was very similar (17 and 20, respectively), which may suggest a certain underestimation of silent lesions. These considerations also serve as a reminder that the study results were based on a small number of end points, which suggests caution in their interpretation, especially when subgroup comparisons are concerned; this applies to the reported results of the lack of a relationship between shunt size or incident atrial fibrillation and the outcomes of interest, or of similar neuroimaging features between symptomatic and silent infarcts.

Like for other similar trials, the results of the Gore REDUCE trial do not represent a comparison of PFO closure versus antiplatelet treatment, but rather of PFO closure plus antiplatelet treatment (which was continued for the entire duration of the follow-up) versus antiplatelet treatment alone; therefore, the real clinical decision is whether or not to add PFO closure to an already effective preventive treatment (cryptogenic stroke recurrence rate on medical therapy is estimated at 1% per year),¹⁵ weighing possible benefit (further increase in protection) against risk (periprocedural complications, including atrial fibrillation, which was observed in 7.3% of patients in this trial; unestablished long-term safety record). This decision must involve a multidisciplinary team (neurologist and cardiologist) to assess the appropriateness of PFO closure, taking into account the patient’s clinical characteristics (embolic-appearing index stroke; absence of other possible causes; suitable PFO morphology) and informed preferences, an approach that was also supported in the most recent practice advisory of the American Academy of Neurology¹⁵ and in the recently published American Heart Association/American Stroke Association guideline for the secondary prevention of stroke¹⁶; under these conditions, the American Academy of Neurology advisory supported PFO closure in patients with cryptogenic stroke, bearing in mind the periprocedural risk and a possible over 2.5-fold increase in serious nonperiprocedural atrial fibrillation,¹⁵ whereas the American Heart Association/American Stroke Association guideline also supported PFO closure in patients 18 to 60 years of age with a nonlacunar ischemic stroke of undetermined cause and high-risk PFO anatomic features but considered the indication as not well established when those features are absent.¹⁶ Both guidelines agreed that there is not enough evidence on whether PFO closure is superior to systemic anticoagulation in this setting.

Some aspects of the prevention of PFO-related stroke recurrence remain unresolved. Since almost all clinical trials were conducted in patients younger than 60 years, limited data on treatment comparisons are available in older patients. Also, as systemic anticoagulation was not systematically tested in most trials, it is unclear whether patients who need anticoagulation because of coexisting conditions might benefit from adding PFO closure to it, or just be exposed to possible adverse effects from both treatments. Trials comparing new oral anticoagulants versus aspirin may be warranted in older patients, currently excluded from PFO closure recommendations, and in younger patients unwilling to undergo the procedure.¹⁵ Even with these open issues, the field of prevention of PFO-related recurrent stroke has come a long way in recent years, with several effective preventative options being now available for application to patients with different risk profiles. Besides further refinement of these options, future research will hopefully investigate novel and better ways to identify individuals with a PFO who, because of individual characteristics or associated conditions, may be at increased risk of suffering a first stroke, an important topic that has received comparatively limited attention in recent years.

Disclosures None.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Disclosures, see page 3429.

参见相关文章，第 3419 页

卵圆孔未闭 (PFO) 的存在与缺血性卒中风险增加之间的关系于 1988 年首次得到认可，当时 2 项病例对照研究报告称，在经历过不明原因卒中的年轻患者中 PFO 频率显着增加与无卒中对照相比。^1,2即使在老年患者中，风险也会增加，尽管幅度较小。³所谓的中风机制是矛盾栓塞或通过 PFO 允许的右向左分流将起源于静脉循环的血栓栓塞到体循环。由于大约四分之一的成年人患有 PFO，因此与 PFO 相关的中风风险可能对人群产生重要的健康影响；然而，基于人群的研究未能发现卒中风险显着增加，^4,5可能是因为少数 PFO 患者的风险增加因大多数人缺乏 PFO 而被稀释。因此，对于 PFO 相关的首次中风的一级预防策略是不可行的，因为实际上不可能识别出中风高风险的个体，除了那些相对不常见的增加血栓存在/形成（高凝性和深静脉血栓形成）或促进右-向左分流（肺动脉高压）。然而，对于已经发生中风的 PFO 患者，显然需要有效的二级预防策略。由于自相矛盾的栓塞是所谓的中风机制，因此首先测试了抗血栓治疗。在华法林与阿司匹林的随机试验中，⁶ ; 然而，PFO 相关卒中复发风险最高的年轻患者在研究中的代表性不足。

可以通过经静脉导管部署的设备的引入为 PFO 闭合提供了一种更简单的选择，此前需要进行心脏直视手术，并为预防中风复发的新方法开辟了道路，随后不久将进行临床试验比较 PFO 闭合与药物治疗的疗效。虽然早期的试验未能显示出显着差异，但最近的^{7-9表明 PFO 闭合的优越性10-12}；在一项包括 4 项试验的荟萃分析中，总共 2531 名患者随访 3 至近 6 年，PFO 闭合与 1.8% 的卒中复发率相关，而药物治疗为 5.1%。¹³在具有特殊 PFO 特征（大分流和并存心房动脉瘤）的患者中尤其观察到这种益处，但不仅限于此。^11,12 PFO 闭合与围手术期并发症相关（在试验中从 3.2% 到 5.9%）和心房颤动频率增加（从 2.9% 到 7.3%，大多数发生在手术后的前 30 天内）。这些试验有局限性，包括相对较少的主要结果事件和终点的开放标签确定，这可能由于确定偏倚而影响了结果。在本期Stroke中，Messe 等人¹⁴报告其中一项试验 Gore REDUCE 试验的其他结果，详细描述了 2 个治疗组（PFO 闭合和抗血小板治疗）随访期间观察到的神经影像学结果。¹⁴脑磁共振成像在入组和随访期间进行，无论是在通过经过验证的问卷检测到中风症状之后，还是在 2 年保持无症状的患者中进行。PFO 闭合与合并中风和无症状脑梗塞的频率降低有关，这是由于前者的频率降低而导致的，但与后者无关；梗死数量、大小和位置在治疗组之间或在临床表现和无症状梗死之间没有显着差异。该研究为 PFO 闭合组卒中发病率降低的临床观察提供了重要的客观验证，从而最大限度地减少了与开放标签研究设计相关的确定偏倚可能影响结果的可能性；它还提供了有关在每种治疗中观察到的新开发的脑损伤的神经影像学特征的有趣数据。同时，它提出了与一些意想不到的或不是立即明确的发现有关的问题。在预防与临床症状相关的梗塞而不是无症状的梗塞方面，PFO 封闭优于单独的抗血小板治疗这一观察结果令人惊讶且不易解释。临床表现和无症状的梗塞可能代表一些不同的实体，后者在起源上栓塞的频率较低，这似乎被两种梗塞类型的相似数量、大小和位置所否定。正如作者所提到的，一些轻微的围手术期中风可能未被发现，或者它们的症状被认为是继发于麻醉效应；这种情况会减少临床卒中观察到的治疗差异，增加无症状梗塞的治疗差异，同时保持联合终点不变，因此研究的主要结论不变。最后，考虑的最小磁共振成像梗死面积（3 mm）虽然在文献中已经确定，但可能导致排除了较小且更经常无症状的病变，其频率可能在治疗之间有所不同；事实上，研究中临床表现和无症状梗塞的总数非常相似（分别为 17 和 20），这可能表明对无症状病变的估计存在一定程度的低估。这些考虑也提醒我们，研究结果是基于少数终点，这表明在解释时要谨慎，特别是在涉及亚组比较时；这适用于报告的分流大小或心房颤动与感兴趣的结果之间缺乏关系的结果，或症状性梗塞和无症状梗塞之间的类似神经影像学特征。

与其他类似试验一样，Gore REDUCE 试验的结果并不代表 PFO 封堵与抗血小板治疗的比较，而是 PFO 封堵加抗血小板治疗（在整个随访期间持续）与抗血小板治疗的比较独自的; 因此，真正的临床决策是是否在已经有效的预防性治疗中增加 PFO 封闭（药物治疗的隐源性卒中复发率估计为每年 1%），¹⁵权衡可能的益处（进一步增加保护）与风险（围手术期并发症，包括心房颤动，在本试验中 7.3% 的患者中观察到；未确定的长期安全记录）。该决定必须涉及多学科团队（神经科医生和心脏病专家）来评估 PFO 闭合的适当性，同时考虑到患者的临床特征（出现栓塞性卒中；没有其他可能的原因；合适的 PFO 形态）和知情偏好，这是一种方法这也得到了美国神经病学会最近的实践咨询¹⁵和最近出版的美国心脏协会/美国中风协会中风二级预防指南^16的支持; 在这种情况下，美国神经病学学会咨询支持对隐源性卒中患者进行 PFO 封堵，同时考虑到围手术期风险和严重的非围手术期房颤可能增加 2.5 倍以上，¹⁵而美国心脏协会/美国卒中协会指南还支持对 18 至 60 岁、原因不明的非腔隙性缺血性卒中和高危 PFO 解剖特征的患者进行 PFO 闭合，但认为当这些特征不存在时，该适应症尚不明确。¹⁶两个指南都同意，在这种情况下，没有足够的证据证明 PFO 关闭是否优于全身抗凝。

预防 PFO 相关卒中复发的某些方面仍未解决。由于几乎所有临床试验都是在 60 岁以下的患者中进行的，因此在老年患者中可获得的治疗比较数据有限。此外，由于在大多数试验中没有系统地测试全身抗凝，尚不清楚因共存疾病而需要抗凝的患者是否可能受益于添加 PFO 封闭，或者只是暴露于两种治疗可能产生的不良反应。对于目前被排除在 PFO 封堵建议之外的老年患者以及不愿接受该手术的年轻患者，可能需要进行比较新型口服抗凝剂与阿司匹林的试验。¹⁵尽管存在这些悬而未决的问题，但近年来预防 PFO 相关的复发性卒中领域取得了长足的进步，现在有几种有效的预防选择可用于具有不同风险特征的患者。除了进一步完善这些选项之外，未来的研究有望探索新的和更好的方法来识别患有 PFO 的个体，这些个体由于个体特征或相关条件可能会增加患第一次中风的风险，这是一个相对较受欢迎的重要话题近年来关注有限。

披露无。

本文所表达的观点不一定是编辑或美国心脏协会的观点。

有关披露，请参见第 3429 页。