PFO Closure for Cryptogenic Stroke: Synthesis of the Data and Its Application to Clinical Practice

Educational Objectives

After completing the activity, the clinician will be better able to identify patients who are most likely to benefit from closure of a patent foramen ovale after cryptogenic stroke.

Summary

Interviewer: Douglas P. Zipes, MD, MACC

Take-home Messages:

• The patent foramen ovale (PFO) has long generated debate about its propensity for causing stroke by paradoxical embolism as well as its value as a target for stroke prevention.
• Recent randomized clinical trials (RCTs) suggest a tipping point has been reached, with data now strongly supporting device closure in properly selected patients.
• Enough data have been amassed in recent years to permit a general approach to guide clinical decision making when patients have cryptogenic stroke and a PFO.

The foramen ovale is part of normal physiology. During embryonic development, the foramen ovale functions as a one-way (right-to-left) valve that provides a way for blood to bypass the lungs in utero.¹ At birth, lung pressures drop and the blood pressure in the left atrium exceeds that of the right atrium. This change in pressure leads to apposition of the septum and complete sealing of the defect within hours of birth. Well, it does in about 75% of infants; in the other 25%, it remains patent.

The pathologic importance of a PFO has been unclear; consequently, transcatheter closure of a PFO after cryptogenic stroke has been a contentious issue.

While it has been estimated that PFOs contribute to ≈100,000 strokes a year, some question whether PFOs really serve as a path for paradoxical embolism. And for the longest time, the data did not help sort out the issue.

Inconsistent Results
There have been several relevant RCTs, but the results have been inconsistent. The CLOSURE I trial, for example, enrolled 909 patients with a PFO who had experienced a cryptogenic stroke or transient ischemic attack (TIA).² Investigators compared treatment with the STARFlex Septal Closure System plus antiplatelet therapy to medical therapy alone for preventing recurrent stroke and TIA.

At 2 years, the treatment groups did not differ in terms of the reduction in the risk of stroke, TIA, or death, either individually or combined in the primary outcome measure. Furthermore, closure of the PFO increased the risks of major vascular events (a 3.2% absolute increase); there was also more atrial fibrillation (AF; a 5% absolute increase). The 3% risk of stroke at 2 years in both groups was lower than anticipated, and strokes that did occur during follow-up were often attributable to a cause other than the PFO.

CLOSURE I was followed by the PC (n = 414) and RESPECT (n = 980) trials, which also failed to show a benefit of closure, although the latter came closer. In order, these 3 trials had p values for their primary outcomes of 0.37, 0.34, and 0.08. However, RESPECT eked out a win with long-term follow-up (median: 5.9 years).³ Still, there was a higher dropout rate in the medical therapy group; meaning the findings were based on an intent-to-treat analysis that showed fewer recurrent strokes with PFO closure compared to medical therapy (hazard ratio [HR]: 0.55; p = 0.046).

A Tipping Point?
More consistent data have been recently reported, including the REDUCE trial, based on 3.2 years of follow-up in 664 patients with a PFO and a cryptogenic stroke.⁴ Risk of subsequent ischemic stroke was significantly lower among those assigned to PFO closure plus antiplatelet therapy than among those assigned to antiplatelet therapy alone (relative risk [RR]: 0.51; p = 0.04). PFO closure was associated with higher rates of device complications and AF.

Another trial, CLOSE, had strict entry criteria centering on a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt.⁵ No stroke occurred among 238 patients in the PFO closure group compared to 14 of the 235 patients in the antiplatelet-only group (HR: 0.03; p < 0.001). However, once again, PFO closure was associated with an increased risk of AF (4.6% vs. 0.9%; p = 0.02).

RESPECT, REDUCE, and CLOSE were all published in the same 2017 issue of the New England Journal of Medicine and, according to an accompanying commentary, were thought to represent “a tipping point.”⁶ Allan H. Ropper, MD, called it that after noting: “How can we now have 3 trials showing that closure prevents recurrent stroke, given that in the past 5 years, the Journal published articles from 3 other trials that showed the opposite?”

Attack of the Meta-analysts
Investigators subsequently got really busy, and by Richard Krasuski’s count, as of October 2018 (1 year later), there had been 34 “updated” meta-analyses published in 26 journals. No need to call upon all 26 references here, but one of those evaluations was by Dr. Krasuski and colleagues.⁷ They analyzed data from 5 RCTs, covering a total of 3,630 patients, in which stroke was the primary efficacy endpoint, and bleeding and AF were primary safety endpoints.

Compared to medical management, pooled analysis showed that device closure was associated with a significant reduction in stroke (RR: 0.30; p = 0.34), but the difference in TIA did not reach statistical significance (RR = 0.73; p = 0.43). The lower stroke rate came at the cost of a significant increase in atrial arrhythmias (RR: 4.8; 95% confidence interval: 2.2 to 10.7), but no increased risk of bleeding (RR: 0.80; p = 0.87), mortality (RR: 0.76; p = 0.48), or “any adverse events” (RR: 1.08; p = 0.37).

Subgroup analysis revealed that device closure significantly reduced the incidence of the composite primary endpoint among male patients (RR = 0.22; p = 0.028 ) and patients who had moderate-to-large shunt sizes (RR: 0.22; p = 0.28). There was also a significant reduction of stroke in patients younger than 45 years of age (RR = 0.40; p = 0.01).

Where does that leave the clinician who is wondering whether PFO closure is worthwhile? According to Dr. Krasuski, the overall evidence suggests that benefit from PFO closure relies on careful patient selection: Individuals under the age of 60 years with few to no vascular risk factors and embolic-appearing stroke deemed cryptogenic after thorough evaluation.

According to Dr. Krasuski, selection is ideally overseen by a team that includes a neurologist, to make sure that the stroke was likely related to the PFO, and a cardiologist, who can confirm the patient does not have undiagnosed AF. The evaluation should include neurologic imaging and transesophageal echocardiography looking for other potential sources of the stroke. Plus, there should be a concerted effort to detect any unrecognized AF. Dr. Krasuski often sends the patient home with a monitor for 30 days looking for silent AF.

This is the approach recommended in a recent European position statement on managing patients with a PFO (the first such document).⁸ Along with information on patient selection and the patients at greatest risk for recurrent events (Table), the recommendations suggest that in patients at high risk for AF, an insertable cardiac monitor can be reasonably considered for 6 months to rule out AF before deciding on PFO closure. Plus, the document finds strong support for interdisciplinary assessment and decision making.

At this point the jury (i.e., the U.S. Food and Drug Administration) is no longer out, with the approval of the Gore Cardioform Septal Occluder and the Amplatzer PFO Occluder for PFO closure after a first paradoxical embolic event.

The bottom line, according to Dr. Krasuski: “We can conclusively now say that based on both the epidemiologic data and the randomized data there is about a 70% reduction in stroke” with PFO closure compared to medical management.

Identifying Patients at Highest Risk for Recurrent Events

Predictor	Number of Patients	Number of Studies	OR/HR
Older age	2,171	4	1.5
Atrial septal aneurysm	630	5	3.0
Aspirin use vs. OAC	1,235	5	2.5
Coagulation disorders	258	2	2.8
Stroke as index event	334	2	3.0
PFO diameter (continuous variable)	334	2	3.0

HR = hazard ratio; OAC = oral anticoagulation; OR = odds ratio; PFO = patent foramen ovale.

Readings

1. Krasuski RA. When and how to fix a ‘hole in the heart’: approach to ASD and PFO. Cleve Clin J Med 2007;74:137-47.
2. Furlan AJ, Reisman M, Massaro J, et al.; CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991-9.
3. Saver JL, Carroll JD, Thaler DE, et al.; RESPECT Investigators. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy After Stroke. N Engl J Med 2017;377:1022-32.
4. Søndergaard L, Kasner SE, Rhodes JF, et al.; REDUCE Clinical Study Investigators. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017;377:1033-42.
5. 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.
6. Ropper AH. Tipping Point for Patent Foramen Ovale Closure. N Engl J Med 2017;377:1093-5.
7. Riaz H, Khan MS, Schenone AL, Waheed AA, Khan AR, Krasuski, RA. Transcatheter closure of patent foramen ovale following cryptogenic stroke: An updated meta-analysis of randomized controlled trials. Am Heart J 2018;199:44-50.
8. Pristipino C, Sievert H, D’Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2018 Oct 25. doi: 10.1093/eurheartj/ehy649. [Epub ahead of print]

Disclosures

Richard A. Krasuski, MD, FACC
This author has nothing to disclose.

Interviewer: Douglas P. Zipes, MD, MACC
This author has nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC510702

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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