The possible pathogenic relationship between patent foramen ovale (PFO) and paradoxical embolism was first suggested about 150 years ago,1 although the first epidemiological evidence linking PFO to cryptogenic stroke only emerged in 1988.2 Now, after 30 years of intense scrutiny, we have consistent evidence from multiple clinical trials that PFO closure is effective at preventing recurrence.3-6 To optimize this strategy, careful patient selection is essential.
Cryptogenic stroke is a negatively defined diagnosis that broadly includes strokes without an established cause. That definition problematically encompasses 3 groups: those with thorough diagnostic testing, but no cause is identified; those with incomplete diagnostic testing; and those with multiple causes. In the case of PFO, a thorough evaluation is critical, as PFO is a relatively common finding (15%-25% of the population2), yet it should be the only potential source of stroke before considering an invasive procedure such as closure.
At a minimum, patients should have brain imaging to confirm that the stroke has an embolic appearance (typically involving the cerebral or cerebellar cortex), cervical and cerebral arterial imaging to confirm that there is no clinically relevant stenosis, and cardiac evaluation, including both early rhythm monitoring and echocardiography, to exclude atrial fibrillation and other high-risk cardiac sources of embolism. In select patients, especially those with multiple strokes or other systemic illness, additional testing for uncommon causes of stroke may be warranted.
Even with thorough testing, declaring a PFO as the most likely culprit responsible for a cryptogenic stroke remains a challenge. One approach that aims to clarify which PFOs are pathogenic and which are incidental is encompassed in the Risk of Paradoxical Embolism score.7 Younger age, the absence of traditional vascular risk factors, and the presence of a superficially located infarction are associated with increasing prevalence of PFO, and therefore are suggestive that the PFO is the proximate cause. This intuitive but probabilistic model is reasonable as a guide, although its value in maximizing the benefit of closure remains to be proven.
Percutaneous closure of PFO became increasingly popular in the 1990s as a treatment option, although clinical evidence was lacking. Clinical trials aiming to establish efficacy were launched, but they recruited patients slowly, at least in part because of the widespread availability of off-label closure in practice. The CLOSURE trial in 2012 failed to show a difference in secondary stroke prevention between closure with the STARFlex device and medical therapy, likely related to suboptimal closure with the device and high rates of complications.8 The RESPECT9 and PC Trials10 reported in 2013 were individually unable to demonstrate a significant benefit of closure using the Amplatzer device, but together these 2 trials favored closure without major device-related concerns. In practice, opinions were sharply divided, often with cardiologists favoring closure and neurologists favoring noninvasive medical therapy, although all wanted more data.
The RESPECT investigators continued to follow participants for several years. The US Food and Drug Administration had been reviewing the data concurrently and approved the Amplatzer PFO Occluder in late 2016. Shortly thereafter, in 2017, the long-term results of RESPECT yielded a significant relative risk reduction of stroke of about 45% with closure.3 At the same time, 2 major trials announced positive results and compelling evidence of closure efficacy in their primary trial outcomes. The CLOSE trial enrolled patients with cryptogenic stroke and PFO and required them to have large right-to-left shunts or atrial septal aneurysms.4
The study allowed for 11 different devices and found that no patients had recurrent stroke after closure, which was superior to antiplatelet therapy, although the comparison to anticoagulation was unclear. The Gore REDUCE clinical study recruited patients with PFO and cryptogenic stroke, but allowed PFO of all sizes, and compared closure with the GORE HELEX or newer-generation GORE CARDIOFORM septal occluder device to antiplatelet therapy only.5 Closure significantly reduced the risk for recurrent stroke by 77%,5 the first trial to yield success and safety for a specific device. PFO closure also notably reduced the risk for potentially disabling stroke.
In April 2018, the US Food and Drug Administration approved the GORE CARDIOFORM septal occluder for closure of PFO. Similar to the other approval, the indication is explicitly stated to reduce the risk for recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke resulting from a presumed paradoxical embolism, as determined by a neurologist and cardiologist after an evaluation to exclude known causes of ischemic stroke. Finally, in 2018, the DEFENSE-PFO trial further confirmed that PFO closure reduced the risk for recurrent stroke, and meta-analyses of the trials have shown consistent benefits.6
The risk for device implantation is modest. Across all trials, major complications such as pericardial tamponade, device embolization, acute device thrombosis, and procedural stroke were rare. However, atrial fibrillation occurs in about 4% of patients,6 the clear majority of which occurs early after the procedure and is short lived. Patients and clinicians should be aware of this risk to detect and treat the arrhythmia, although the role of anticoagulation for periprocedural atrial fibrillation is uncertain. Persistent atrial fibrillation seems to occur in less than 1% of patients.
Overall, the clinical trial evidence in favor of PFO closure is clear and compelling. The US Food and Drug Administration has approved 2 devices with highly favorable efficacy and safety profiles. Neurologists and cardiologists must work together to educate patients about their options and share the decision-making process. Neurologists must carefully evaluate patients to confirm that the stroke is truly cryptogenic and attributable to the PFO, and cardiologists must choose and skillfully implant the device that ideally suits the anatomy. Further, as PFO closure increases in clinical practice, both groups must monitor the trends together to ensure efficacy and safety are optimized.
Disclosures: Dr Kasner reports a research grant from W. L. Gore & Associates.
- Lippman H, Rafferty T. Patent foramen ovale and paradoxical embolization: a historical perspective. Yale J Biol Med. 1993;66:11-17.
- Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med. 1988;318(18):1148-1152.
- Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022-1032.
- Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.
- Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033-1042.
- Lee PH, Song J-K, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: The DEFENSE-PFO trial. J Am Coll Cardiol. 2018;71(20):2335-2342.
- Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81(7):619-625.
- Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
- Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-100.
- Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-1091.