First overall stroke reduction with closure reported in two trials
The two trials reported at the European Stroke Organisation Conference (ESOC) in Prague are the first to find overall stroke reduction with the procedure.
Earlier results from the RESPECT trial gained FDA approval for the Amplatzer PFO Occluder based on a reduction in PFO-related second strokes without any effect on overall stroke risk, as was the case in the PC Trial with the device.
In the three-arm open-label CLOSE trial, which randomized 663 of a planned 900 patients to PFO closure with various investigational devices or to antiplatelet treatment or antithrombotic therapy, the hazard ratio for fatal or nonfatal stroke was 0.03 with closure versus antiplatelet therapy alone (95% CI 0-0.25, P<0.001; 0 versus 14 strokes over mean 5.3 years). The two medical arms didn't differ.
In the open-label REDUCE trial, randomizing 664 patients 2:1 to PFO closure with the Helex Septal Occluder or Cardioform Septal Occluder plus antiplatelet therapy versus antiplatelet therapy alone, the device intervention reduced recurrent clinically-apparent stroke (HR 0.23, 95% CI 0.09-0.62, P=0.001) and new brain infarction on MRI (RR 0.51, 95% CI 0.29-0.91, P=0.024).
Both trials showed an increase in largely periprocedural atrial fibrillation, as in prior trials.
"These data will change clinical practice in patients with cryptogenic stroke with atrial septal aneurysm or a large shunt," Jean-Louis Mas, MD, PhD, of Hôpital Sainte-Anne in Paris, said in a release from ESOC. "I also believe the question of whether or not to close a PFO in this subset of patients has been answered by these data – the answer is yes."
Heinrich Mattle, MD, of Bern University Hospital in Switzerland, agreed, saying "this will change secondary prevention in cryptogenic stroke," in his interview with Mas released by the conference organizers.
The REDUCE trial "looks impressive on the surface," commented Sanjay Kaul, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles. The "5.6% absolute difference in silent brain infarct is pretty good; 76% relative difference in recurrent stroke also looks good, the latter has a more robust P value!"
"To what extent is the large treatment effect driven by the choice of the control (antiplatelet therapy) remains an open question. The 2016 AAN practice advisory leaned towards favoring antiplatelet over anticoagulant therapy for this scenario (level C recommendation). There is no randomized, controlled trial evidence conclusively supporting anticoagulant over antiplatelet therapy. So, if the data pass muster, they could be potentially practice changing!" Kaul said.
An effect that large is unlikely to be by chance, he suggested, but why these new trial results differ from RESPECT's wasn't clear given broadly similar inclusion criteria.
RESPECT included patients ages 18 to 60 who had a cryptogenic stroke but also had a PFO that could have been responsible for their index stroke.
CLOSE included patients ages 16 to 60 with cryptogenic stroke and PFO with atrial septal aneurysm or PFO with large shunt.
REDUCE included "highly selected" patients ages 18 to 60 with cryptogenic ischemic stroke or transient ischemic attack of presumed embolic infarction verified by a neurologist and PFO seen on positive bubble study with transesophageal echocardiography. No difference appeared in effect between patients with small versus large shunts.
While the prior trials were negative for overall stroke reduction "there were clues" in two of them -- trends that "just missed statistical significance," Mas noted in the ESOC interview.
Gore announced that it plans to submit the REDUCE data to the FDA later this year to seek a PFO indication for its Cardioform Septal Occluder.