Three separate trials examining the impact of closing a patent foramen ovale on the risk of stroke all point to endovascular closure offering a greater reduction in risk than with anticoagulant or antiplatelet therapy alone.
However, this benefit may be evident only in patients at higher risk of stroke associated with patent foramen ovale (PFO), and comes at the cost of an increased risk of atrial fibrillation and procedure-related adverse events, according to papers published in the Sept. 14 issue of the New England Journal of Medicine.
Closure plus anticoagulation vs. anticoagulation or antiplatelets alone
In the CLOSE trial, 663 patients aged 16-60 years who had experienced a recent stroke attributed to PFO and who had an associated atrial septal aneurysm or large interatrial shunt were randomized to transcatheter closure plus long-term antiplatelet therapy, antiplatelets alone, or oral anticoagulation alone.
After a mean follow-up of 5.3 years, Jean‑Louis Mas, MD, of Sainte-Anne Hospital, Paris, and his colleagues reported that there were no recurrent strokes in the closure group, but 14 of the 235 patients in the antiplatelets-only group experienced a stroke, representing a 97% reduction in the risk of stroke with endovascular closure (P less than .001). Patients in the antiplatelets-only group had a 4.9% overall probability of stroke, and no explanation other than PFO could be found for their recurrent stroke (), reported .
The study was not adequately powered to compare the outcomes of anticoagulant therapy with antiplatelet therapy alone.
The closure group also had a 61% lower risk of the secondary composite outcome of stroke, transient ischemic attack, or systemic embolism, compared with the antiplatelet-only group (P = .01).
However, closure of the PFO was associated with a higher rate of new-onset atrial fibrillation or flutter than antiplatelet therapy alone (4.6% vs. 0.9%, P = .02), and major procedural complications occurred in 5.9% of patients.
Closure plus antiplatelets vs. antiplatelets alone
In the second study – REDUCE – 664 patients with PFO who had experienced an ischemic stroke with no other obvious cause were randomized either to closure plus antiplatelet therapy or antiplatelet therapy alone ().
Over the median follow-up of 3.2 years, there were ischemic strokes in 1.4% of patients in the closure group, compared with 5.4% in the antiplatelet-only group; this was a 77% reduction in risk (P = .002), Lars Søndergaard, MD, of the University of Copenhagen, and his coauthors reported.
The closure group also had a 49% lower incidence of new brain infarctions, compared with the antiplatelet-only group, although the incidence of silent brain infarction was similar between the two groups.
While the risks of major bleeding, deep-vein thrombosis, and pulmonary embolism and serious adverse events were similar between the two groups, the closure group had a 2.5% rate of procedure-related serious adverse events and 1.4% rate of device-related serious adverse events. The closure group also had a significantly higher incidence of atrial fibrillation when compared with the control group (6.6% vs. 0.4%; P less than .001).
Closure vs. medical therapy alone
Finally, in the third paper, Jeffrey L. Saver, MD, of the University of California, Los Angeles, and his associates reported the long-term outcomes of the RESPECT trial of PFO closure versus medical therapy alone in 980 patients with PFO who had experienced a cryptogenic ischemic stroke ().
After a median follow-up of 5.9 years, there was a 45% lower risk of recurrent ischemic stroke in the closure group, compared with the medical therapy alone group. The overall incidence of recurrent ischemic stroke was 0.58 events per 100 patient-years after closure, compared against 1.07 events with medical therapy, which included aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole.
However, the rate of pulmonary embolism was more than threefold higher, and the rate of deep vein thrombosis was more than fourfold higher in the closure group, compared with the medical therapy group, although the latter was not statistically significant.
In an accompanying perspective on the three studies, Andrew Farb, MD, and his colleagues from the Center for Devices and Radiological Health at the Food and Drug Administration noted that the clinical benefit of closing a PFO has been an ongoing question for several decades, but the data on the Amplatzer PFO Occluder – a device for PFO closure – had met the agency’s approval threshold.
“The FDA concluded that although there were few recurrent strokes in both groups and some uncertainty regarding the reduction in stroke risk attributable to the device, preventing recurrent stroke is of high value,” the authors wrote ().
However, they stressed that because of the high prevalence of PFO, patients being considered for surgical closure should undergo comprehensive clinical assessment by a neurologist and cardiologist to ensure the ischemic stroke did not have any other possible cause.
The CLOSE trial was supported by the French Ministry of Health. Fourteen authors reported funding, grants, consultancies, and other support from the pharmaceutical industry. The REDUCE trial was supported by W.L. Gore and Associates, and 11 authors declared grants or fees from W.L. Gore and Associates. The RESPECT trial was supported by St. Jude Medical. Eight authors declared grants, fees, or nonfinancial support from St. Jude Medical. One also declared grants and fees from the pharmaceutical industry. The authors of the accompanying perspective had no conflicts of interest to declare.