Trials Clarify Benefit of PFO Closure After Stroke

The investigators enrolled 664 patients (mean age, 45.2). During a median follow-up of 3.2 years, clinical ischemic stroke occurred in six of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23). The incidence of new brain infarctions was lower in the PFO closure group than in the antiplatelet-only group (5.7% vs 11.3%), but the incidence of silent brain infarction did not differ significantly between the study groups.

Serious adverse events occurred in 23.1% of the patients in the PFO closure group and 27.8% of the patients in the antiplatelet-only group. Serious device-related adverse events occurred in six patients (1.4%) in the PFO closure group. Atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs 0.4%). Most cases of atrial fibrillation or flutter were detected within 45 days after the procedure and resolved within two weeks after onset.

RESPECT

In RESPECT, among patients age 18 to 60 who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Jeffrey L. Saver, MD, Director of the University of California, Los Angeles Comprehensive Stroke Center and Professor of Neurology at the David Geffen School of Medicine at UCLA, and colleagues randomly assigned patients who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO with the Amplatzer PFO Occluder or to receive medical therapy alone (ie, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole). After the device was implanted, patients in the PFO closure group received aspirin plus clopidogrel daily for one month, followed by aspirin monotherapy for five months. Subsequent antithrombotic therapy was at the site investigator’s discretion.

The investigators enrolled 980 patients (mean age, 45.9) at 69 sites and followed patients for a median of 5.9 years. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group (3.6%) and in 28 patients in the medical-therapy group (5.8%), resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs medical therapy, 0.55).

“The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure),” the authors said. “Nonetheless, the cumulative absolute benefit had clinical relevance, since patients in this trial were younger … than the general population of patients who have stroke and thus faced a longer period of risk for recurrent stroke.”

Venous thromboembolism (ie, pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. Among patients in the PFO closure group, those with a history of overt deep-vein thrombosis had a higher incidence of venous thromboembolic events. A lower intensity of antithrombotic therapy, including less common use of anticoagulant agents, in the PFO closure group, compared with the medical therapy group, “may have contributed to the higher rate of venous thromboembolism in the PFO closure group,” the researchers said. “These findings provide indirect support for the recent revision in the national management guidelines that endorsed lifelong anticoagulation therapy in patients with overt deep-vein thrombosis.”

In addition, seven periprocedural events of atrial fibrillation occurred in the PFO closure group, all of which resolved before the patients’ discharge from the hospital.

Assessment by Neurologist and Cardiologist Is Key

“The key to appropriate device use is comprehensive clinical assessment by both a neurologist and a cardiologist to confirm the diagnosis of ischemic stroke and exclude other possible causes,” said Andrew Farb, MD, of the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, and colleagues, in a perspective accompanying the RESPECT trial results. The Amplatzer PFO Occluder’s labeled directions for use outline the recommended evaluation, which includes brain MRI or CT, transesophageal echocardiography, prolonged cardiac rhythm monitoring, intracranial and extracranial arterial imaging, and assessment for a hypercoagulable state. “Clearly, a deliberate, systematic assessment of the patient’s underlying conditions and the risks associated with ischemic stroke is needed before closure of a PFO can be recommended,” Dr. Farb and his coauthors said. The published results of the REDUCE and CLOSE trials “appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder,” they said.

—Jake Remaly

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