Among patients with a patent foramen ovale (PFO) who have had a cryptogenic stroke, closure of the PFO reduces the risk of recurrent stroke, compared with medical therapy alone, according to three studies published in the September 14 issue of the New England Journal of Medicine. PFO closure, however, entailed increased risk of atrial fibrillation and, in two of the studies, venous thromboembolism.
In prior trials, PFO closure did not have a statistically significant effect on stroke risk, although the results suggested potential benefit. In an editorial accompanying the new trial results, Allan H. Ropper, MD, said that various limitations of the prior studies, including inclusion of patients whose prior stroke would not benefit from PFO closure, could help explain the positive results of the current studies—the CLOSE and Gore REDUCE trials and extended follow-up from the RESPECT trial. Dr. Ropper is Professor of Neurology at Harvard Medical School and Raymond D. Adams Master Clinician and Executive Vice Chairman of the Department of Neurology at Brigham and Women’s Hospital in Boston.
Together, the trials indicate the importance of considering the characteristics of a PFO when assessing whether a patient may be an appropriate candidate for the procedure, Dr. Ropper said. In the CLOSE trial, patients had to have a large interatrial shunt at rest or an atrial septal aneurysm. While rates of stroke in the PFO closure groups in all of the studies were low, “in the CLOSE trial, no patient in the PFO closure group had a stroke, whereas stroke occurred in 6% of the patients in the antiplatelet-only group.”
The Gore REDUCE trial represented a “middle ground” in that most patients (81%) had a moderate or large interatrial shunt. In that trial, PFO closure was associated with significantly reduced risk of recurrent stroke, compared with antiplatelet therapy alone (1.4% vs 5.4%).
The primary analysis of the RESPECT trial, published in 2013, suggested a potential benefit, but the primary result was not statistically significant. The trial nevertheless provided a reasonable assurance of safety and effectiveness, and the FDA approved the device studied in the trial, the Amplatzer PFO Occluder (St. Jude Medical, St. Paul), in October 2016. The primary analysis included a median of 2.1 years of follow-up, whereas the current analysis included a median of 5.9 years of follow-up. Through the extended follow-up, 3.6% of patients in the PFO closure group had recurrent ischemic stroke, compared with 5.8% of patients in the medical therapy group.
“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive,” Dr. Ropper said. “Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer.”
In the CLOSE trial, Jean-Louis Mas, MD, Professor of Neurology at Paris Descartes University and Head of the Neurology Department at Sainte-Anne Hospital in Paris, and colleagues enrolled patients who had had a recent cryptogenic stroke attributed to a PFO with an associated atrial septal aneurysm or large interatrial shunt.
The investigators assigned in a 1:1:1 ratio patients age 16 to 60 to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. The primary outcome was occurrence of stroke. In all, 663 patients were randomized and followed for a mean of 5.3 years.
“No stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03),” the researchers said. “Procedural complication from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%). The number of serious adverse events did not differ significantly between the treatment groups.” The trial was underpowered to determine the effects of oral anticoagulant therapy versus antiplatelet therapy.
Unlike in prior studies, CLOSE “included only patients who had PFO features that have been associated with cryptogenic stroke” and researchers “used a standardized evaluation to define a previous cryptogenic stroke,” the authors noted.
In the Gore REDUCE trial, investigators enrolled patients with a PFO who had had a cryptogenic stroke. Lars Søndergaard, MD, of the Department of Cardiology at Rigshospitalet, University of Copenhagen, and colleagues randomly assigned patients 2:1 to undergo PFO closure (with the Helex Septal Occluder or Cardioform Septal Occluder; W.L. Gore and Associates, Newark, Delaware) plus antiplatelet therapy or to receive antiplatelet therapy alone. Patients underwent brain imaging at baseline and 24 months. Coprimary end points were freedom from clinical evidence of ischemic stroke through at least 24 months after randomization and the 24-month incidence of new brain infarction (ie, clinical ischemic stroke or silent brain infarction on imaging).