PFO

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PFO Closure in PFO-related Stroke

Chayakrit Krittanawong, MD

Last week, Gore REDUCE study, a randomized open-label trial with a median duration of follow-up of 5.0 years [4.8 to 5.2] demonstrated that 1.8% of patients with PFO closure had recurrent ischemic strokes (hazard ratio, 0.31; 95% confidence interval, 0.13 to 0.76), compared with 5.4% patients who treated with an antiplatelet-only group (Figure).1 A patent foramen ovale (PFO) is far and away from the most common congenital heart defect with an estimated prevalence of 1 in 4 adults.  The FDA has previously approved the Amplatzer PFO Occluder device in 2016, however initial trials such as the RESPECT, PC, and CLOSER I trials did not show any benefit for PFO closure in the reduction of recurrent embolic stroke, compared to medical therapy. Interestingly, more recent trials conducted within the last 5 years, such as the DEFENSE‐PFO, REDUCE, CLOSE and RESPECT trials, demonstrated that PFO closure had reduced incidence of stroke compared to medical therapy. Given this influx of new evidence from recent trials, it has been suggested that PFO closure be considered in patients 60 years or younger with a PFO-related stroke. However, other potential etiologies such as atrial fibrillation (AF, requires at least 30 days of cardiac monitoring based on recent trials), autoimmune disorders, uncontrolled diabetes or hypertension must first be ruled out.

Last year, the 2020 practice advisory update summary by the American Academy of Neurology suggested that PFO closure probably reduces the risk of stroke recurrence with an HR of 0.41 with acceptable heterogeneity (I2 = 12%) and an absolute risk reduction of 3.4% at 5 years for patients with cryptogenic stroke and presence of a PFO based on meta-analyses using fixed-effect.2 This was unsurprising to me given the trends seen in the RESPECT and CLOSE trials. Interestingly, the report suggested an increased risk of developing AF with RR 3.12 in participants who received closure compared with those receiving medical treatment. This raised an interesting causality dilemma similar to the story of the chicken and the egg. Did these trials capture paroxysmal AF using 30 days of ambulatory monitoring and exclude those with paroxysmal AF prior to PFO closure? If that is the case, what was the primary mechanism for the development of AF after PFO closure? Atrial stunning? If a patient were to develop AF following PFO closure would that increase their risk of recurrent stroke?  And if so, is the risk of recurrent stroke higher or lower with PFO closure compared to those without PFO closure? Indeed, it would be interesting see which echo parameters are independent predictors of developing AF in PFO closure (after adjustment for potential confounders). Moreover, the American Academy of Neurology recommends (level C) that aspirin or anticoagulation may be considered in patients who opt to receive medical therapy alone without PFO closure.2 In fact, the comparison between PFO closure and systemic anticoagulation (e.g., DOAC) to prevent recurrent ischemic stroke remains unknown.

Switching gears, let us look at post-PFO closure management. Again, very limited data currently exists on the optimal duration of DAPT (dual antiplatelet therapy) after PFO closure. RESPECT and CLOSE used DAPT for 1 and 3 months, respectively, while some experts recommend ranges DAPT anywhere from 1 to 6 months. A European position paper on the management of PFO, suggested that following PFO closure patients should be on DAPT for 1-6 months followed by antiplatelet monotherapy for ≥5 years.3

In a nutshell, PFO closure should be considered for patients 60 years or younger with PFO-related stroke patients without the comorbidities of the previously mentioned risk factors.  A multidisciplinary discussion between neurology, geriatrics, and interventional cardiology are key in decision-making regarding PFO management.  Further research should include a randomized controlled trial regarding DAPT duration and the use of DOACs (direct oral anticoagulants) following PFO closure in patients with PFO-related left circulation embolism.

Credit: Figure from the New England Journal of Medicine 2021; 384:970-971

Reference

  1. Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjöstrand C, Roine RO, Hildick-Smith D, Spence JD, Søndergaard L; Gore REDUCE Clinical Study Investigators. Five-Year Outcomes of PFO Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2021 Mar 11;384(10):970-971. doi: 10.1056/NEJMc2033779.
  2. Messé SR, Gronseth GS, Kent DM, Kizer JR, Homma S, Rosterman L, Carroll JD, Ishida K, Sangha N, Kasner SE. Practice advisory update summary: Patent foramen ovale and secondary stroke prevention: Report of the Guideline Subcommittee of the American Academy of Neurology. Neurology. 2020 May 19;94(20):876-885. doi: 10.1212/WNL.0000000000009443. Epub 2020 Apr 29.
  3. Pristipino C, Sievert H, D’Ascenzo F, Louis Mas J, Meier B, Scacciatella P, Hildick-Smith D, Gaita F, Toni D, Kyrle P, Thomson J, Derumeaux G, Onorato E, Sibbing D, Germonpré P, Berti S, Chessa M, Bedogni F, Dudek D, Hornung M, Zamorano J; Evidence Synthesis Team; Eapci Scientific Documents and Initiatives Committee; International Experts. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J. 2019 Oct 7;40(38):3182-3195. doi: 10.1093/eurheartj/ehy649.
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Success Does Not Always Leave A ‘Footprint’

Abhishek Sharma, MD

Stroke is one of the leading causes of mortality and morbidity in the United States (US). Approximately one‐third of all ischemic strokes are considered cryptogenic, i.e not attributed to large‐vessel atherosclerosis, small‐artery disease, or embolism despite extensive vascular, serological, and cardiac evaluation. Until recently, the relationship between patent foramen ovale (PFO) and cryptogenic stroke was highly debated. Prior to 2006, use of transcatheter based PFO closure procedures were only permitted under Food and Drug Administration (FDA) Humanitarian Device Exemption for recurrent cryptogenic stroke from a PFO after failed conventional medical therapy1. However, the number of eligible patients exceeded the regulatory mandated annual limit of 4,000 patients in 2006. Thus, the Humanitarian Device Exemption process was voluntarily withdrawn1.

In the past two decades, several randomized clinical trials using the Amplatzer PFO Occluder, the Starflex Septal Occluder (NMT Medical Inc, Boston, MA), and the Gore Cardioform Septal Occluder were conducted. Based on long term follow up results of the RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment] and REDUCE [GORE® Septal Occluder Device for PFO Closure in Stroke Patients] trials, US FDA approved the Amplatzer PFO Occluder in 2016 and the Gore Cardioform Septal Occluder in 20181,2.  FDA approval for these devices for PFO closure in the United States is “to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke2.”

Despite proven efficacy, the use of device based PFO closure techniques have potential risks of several early and late complications, including infection, thrombosis, device dislodgement, atrial wall erosion, perforation, fracture, migration-embolization, allergic reaction to nickel used in PFO occluder device, and induction of arrhythmias3,4. Further, there is need of post procedure antiplatelet therapy after implantation of these devices. These concerns lead to need for a ‘deviceless’ transcatheter system to close PFO. Ruiz et al have performed first-in-man transcatheter suture closure of a PFO in an 18-year-old female with chronic migraine with aura in 2008 without leaving ‘footprint’5.  Results of this novel approach were exciting; however, safety and efficacy of ‘deviceless’ transcatheter techniques on large scale was not established until early results of the NobleStitch EL Italian Registry were reported few months ago6. In this prospective registry, investigators successfully used suture based PFO closure system in 186 (out of 192) patients across 12 sites in Italy with no device related complication on 206±130 days follow-up6. FDA approves the NobleStitch™ EL for Vascular and Cardiovascular suturing in the US (interestingly the technique is not specifically labeled for treating PFOs).

Due to projected increase in numbers of left sided transcatheter interventions (e.g. left atrial appendage closure, arrhythmia ablation and mitral valve interventions), the deviceless technique could be a very attractive option in selected patient population as presence of interatrial septal prosthesis make trans-septal puncture more challenging. Though this technology has huge potential, we should still wait for long term data on safety and efficacy of this no foot print PFO closure system before advocating and supporting its widespread use.

 

References:

  1. Writing Group Members , American Heart Association Statistics Committee; Stroke Statistics Subcommittee . Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016; 133:e38–e360
  2. .https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm527096.htm
  3. Luermans JG, Post MC, Yilmaz A. Late device thrombosis after atrial septal defect closure. Eur Heart J. 2010;31:142
  4. Merkler AE, Gialdini G, Yaghi S, Okin PM, Iadecola C, Navi BB, Kamel H. Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale. Stroke. 2017;48:3073-7
  5. Ruiz CE, Kipshidze N, Chiam PT, et al. Feasibility of patent foramen ovale closure with no-device left behind: first-in-man percutaneous suture closure. Catheter Cardiovasc Interv. 2008 Jun 1;71(7):921-6.
  6. Gaspardone A, De Marco F, Sgueglia GA, et al. Novel percutaneous suture-mediated patent foramen ovale closure technique: early results of the NobleStitch EL Italian Registry. EuroIntervention. 2018 Jun 8;14(3):e272-e279.