Stroke is a leading cause of mortality and morbidity worldwide.¹ It is a clinically heterogeneous disease, and about 87% of cases are ischemic in nature.² It is estimated that about one-third of ischemic strokes are cryptogenic, which is defined as involving a brain infarction not clearly attributable to a definite cause (such as a cardiac embolism, large artery atherosclerosis, or small artery disease) despite extensive vascular, cardiac, and serologic evaluations. Thus, without clear etiology, the management of cryptogenic stoke is a major challenge and mostly involves an educated guess on the part of the clinician. Several observational studies have shown that patent foramen ovale (PFO) is associated with cryptogenic stroke, particularly in young patients.³ The mechanism by which PFO might cause a stroke is via a paradoxical embolism. Thus, it is plausible that percutaneous device closure of the PFO could reduce the risk of recurrent stroke, and observational studies have supported its efficacy.^4,5 However, the first three randomized controlled trials (RCTs) in this field, including CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale), PC (Percutaneous Closure of Patent Foramen Ovale Versus Medical Treatment in Patients With Cryptogenic Embolism), and RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), all failed to prove the superiority of PFO closure compared with medical therapy alone.^6-8 However, a patient-level meta-analysis of those trials did suggest that device closure of the PFO may be superior to the medical therapy alone for the prevention of recurrent stoke.⁹ This led the US Food and Drug Administration to approve the use of the AMPLATZER™ PFO Occluder (St. Jude Medical; St. Paul, MN) for recurrent stroke prevention in October 2016 despite a disagreement with the American Academy of Neurology regarding its use outside a research setting.¹⁰

The primary criticisms of those early RCTs have included poor patient selection, leading to a small number of events and relatively short follow-ups, which raised the probability of a type II error.¹¹ In addition, in the CLOSURE I trial, the STARflex Septal Occluder (NMT Medical; Boston, MA) was used, which is now considered too inferior because of its higher complication rate and lower procedural success rate. To address these limitations, RESPECT investigators followed their patients for an extended duration. Recently, with the longest (5,781 patient-year) follow-up data to date in this field, RESPECT investigators showed that that the AMPLATZER™ PFO Occluder decreased the risk of recurrent stoke by 45%, yet the absolute benefit was small (0.49 fewer events per 100 patient-years with a PFO closure). To overcome previous trial limitations, 2 new RCTs were performed: CLOSE (Patent Foramen Ovale Closure or Anticoagulants vs. Antiplatelet Therapy to Prevent Stroke Recurrence) and REDUCE PFO (Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke). The investigators' protocol mandated a thorough evaluation to identify true cryptogenic stroke.^12,13 Thus, with better patient selection, these two recently reported trials individually showed that PFO closure is superior to medical therapy alone for the prevention of recurrent stroke in patients with cryptogenic stroke.

We recently reported an updated, comprehensive meta-analysis by including data from these new positive trials.¹⁴ Our meta-analysis showed that transcatheter device closure of PFO compared with medical therapy alone reduced the absolute risk for recurrent stroke by 3.3% (risk reduction –0.033; 95% confidence interval [CI], –0.062 to –0.004; p = 0.037). However, no difference with respect to the risk for transient ischemic attack (risk reduction –0.004; 95% CI, –0.017 to 0.010; p = 0.46) or major bleeding groups (risk reduction –0.010; 95% CI, –0.037 to 0.016; p = 0.24) was found between the 2 treatment strategies (Table 1). Similarly, all-cause mortality was similar for the 2 strategies. We also found that device closure was associated with a higher risk of new-onset atrial fibrillation (AF) and vascular complications compared with medical therapy alone. However, one must be careful making any firm conclusions about the association of device therapy with new-onset AF because we found marked heterogeneity (I² = 81.9%) between trials, in addition to high values for confidence intervals in some instances.

Table 1: Pooled Analysis of RCTs Comparing Device Closure of PFO With Medical Therapy Alone

Outcomes	Pooled Estimate
	Risk Reduction (95% CI)	p
Recurrent stroke	–0.033 (–0.062 to –0.004)	0.037
Transient ischemic attack	–0.004 (–0.017 to 0.010)	0.46
Major bleeding	–0.010 (–0.037 to 0.016)	0.24

Following our meta-analysis, a new RCT called the DEFENSE-PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale) trial was reported.¹⁵ The major limitation of this study was early termination because recent reports from several positive trials caused the DEFENSE-PFO investigator and treating physician to discontinue randomization of true cryptogenic patients to the medical therapy alone arm. In this trial, PFO closure was also superior to medical therapy alone for the prevention of recurrent stroke in cryptogenic patients with high-risk PFO characteristics (such as atrial aneurysm or a PFO size ≥2 mm).

Currently, robust evidence suggests that for patients with PFO and cryptogenic stoke, PFO closure with a device decreases the risk of recurrent stroke compared with medical therapy alone. However, we also learned from the RCTs that patient selection is critical. Therefore, the device should be used only after a patient has been carefully evaluated by a neurologist and a cardiologist and after other known causes of stroke have been ruled out (such as small-vessel disease, an intracardiac embolic source, major intracranial and extracranial vascular pathologies, and a hypercoagulable status). The main safety issue with device closure seemed to be an increased incidence of new-onset AF. However, the absolute risk is low. Many AFs are paroxysmal, and some are transient, occurring only during the procedure. In addition, the type of device used might play a role in the risk of post-procedural AF. This risk seems to be lower with the AMPLATZER™ PFO Occluder.⁹ Nevertheless, it is a critical safety issue. We may be substituting one risk of stroke for another. Patients must be informed about this potential risk during shared decisions because many them are young and, thus, may have to live with a potentially iatrogenic illness for decades.¹⁶ In addition, continued longer-term follow-ups for all trials are needed.

In conclusion, for younger patients with cryptogenic stroke, a shared decision about PFO closure should be made between patients and clinicians, keeping in mind patient expectations and potential long-term risks and benefits of the procedure.

References

1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-128.
2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation 2015;131:e29-322.
3. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55:1172-9.
4. Agarwal S, Bajaj NS, Kumbhani DJ, Tuzcu EM, Kapadia SR. Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. JACC Cardiovasc Interv 2012;5:777-89.
5. Khairy P, O'Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003;139:753-60.
6. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991-9.
7. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083-91.
8. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092-100.
9. Kent DM, Dahabreh IJ, Ruthazer R, et al. Device Closure of Patent Foramen Ovale After Stroke: Pooled Analysis of Completed Randomized Trials. J Am Coll Cardiol 2016;67:907-17.
10. Messé SR, Gronseth G, Kent DM, et al. Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2016;87:815-21.
11. Rengifo-Moreno P, Palacios IF, Junpaparp P, Witzke CF, Morris DL, Romero-Corral A. Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2013;34:3342-52.
12. Mas JL, Derumeaux G, Guillon B, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med 2017;377:1011-21.
13. Søndergaard L, Kasner SE, Rhodes JF, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017;377:1033-42.
14. Shah R, Nayyar M, Jovin IS, et al. Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale in Patients With Cryptogenic Stroke: A Systematic Review and Meta-analysis. Ann Intern Med 2018;168:335-42.
15. Lee PH, Song JK, Kim JS, et al. Cryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial. J Am Coll Cardiol 2018;71:2335-42.
16. Farb A, Ibrahim NG, Zuckerman BD. Patent Foramen Ovale after Cryptogenic Stroke - Assessing the Evidence for Closure. N Engl J Med 2017;377:1006-9.

Keywords: Angiography, Ischemic Attack, Transient, Foramen Ovale, Patent, Embolism, Paradoxical, Septal Occluder Device, Stroke, Anticoagulants, Research Personnel, Follow-Up Studies, Brain Ischemia, Standard of Care, Embolism, Brain Infarction, Atherosclerosis, Neurology, Arteries

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