ARTICLE IN BRIEF
Two new studies showed no significant benefit to patent foramen ovale closure versus medical therapy for preventing stroke, but the data point in the direction of a potential benefit, though not one that reached overall statistical significance.
Closure of the patent foramen ovale (PFO) is not significantly better than medical therapy for preventing recurrent stroke in patients who had a cryptogenic stroke, according to two randomized clinical trials published in the Mar. 21 edition of New England Journal of Medicine (NEJM).
Those findings — coupled with results of a study published in 2012 that likewise showed no statistically significant benefit to PFO closure — could be interpreted as thumbs down for the procedure, which came into vogue as a prevention treatment over the past decade, often by off-label use of devices available to repair other heart anomalies. But the two new studies will not likely quiet the debate on the merits of the procedure, in part because the data point in the direction of a potential benefit, though not one that reached overall statistical significance.
A headline for a NEJM editorial that appeared along with the studies summed up that sentiment: “Still No Closure on the Question of PFO Closure.”
“We are left for the moment to make decisions under conditions of uncertainty,” wrote the editorialists Steven R. Messé, MD, assistant professor of neurology at the Hospital of the University of Pennsylvania and the Pennsylvania Hospital, and David M. Kent, MD, associate professor of internal medicine at Tufts University School of Medicine in Boston.
Closure of the PFO — a small flap-like opening between the right and left atriums of the heart that normally closes after birth — makes intuitive sense on several levels, the editorialists wrote. In about 30 percent of young people who survive a stroke, doctors are unable to identify anything that would explain why the stroke occurred, thus the use of the term “cryptogenic.” According to the editorial, PFO is found on transesophageal echocardiography in about half of those stroke patients, compared with about 25 percent of the general population. It is possible, the reasoning goes, that an embolism from the venous system can slip through the PFO and into systemic circulation, in turn travelling on to the brain. Closure of the PFO is done percutaneously.
The first of the two new studies, referred to by the acronym RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), enrolled 980 patients at 69 sites in the US and Canada. Patients were eligible for the trial if they were between 18 and 60 years old, had a cryptogenic ischemic stroke, and had a PFO identified by transesophageal endocardiography. Randomization to either the closure procedure (499 patients) or medical therapy alone (481 patients) occurred within 270 days of stroke.
The closure group underwent a procedure in which the Amplatzer PFO Occluder, made by St. Jude Medical, was inserted with fluoroscopic and echocardiographic guidance. In the medical therapy group, four therapies were permitted throughout the study: aspirin, warfarin, clopidogrel, and aspirin combined with extended-release dipyridamole.
The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. Patients were followed 2.6 years on average. The researchers first analyzed the data from the perspective of “intention to treat” — looking at what happened to all the patients in both arms of the study regardless of whether they ended up having the procedure or following the medical protocol as designed. Nine of the patients in the closure group and 16 in the medical therapy group had an event, all of which were nonfatal strokes. Those numbers represented a 51 percent reduction in stroke recurrence for the closure group, but that number did not reach statistical significance.
A statistical difference in favor of closure did emerge, however, when the researchers conducted pre-specified “per-protocol” and “as-treated” analyses. Closure seemed to be particularly beneficial for patients with an atrial septal aneurysm and a substantial shunt size.
The closure procedure had a high success rate technically, and the rate of serious adverse events (such as atrial fibrillation) was fairly similar for the two groups — 23 percent in the closure group and 21.6 percent in the medical therapy group. In the PFO closure study published last year, which involved a different make of device, atrial fibrillation was a problem.
John D. Carroll, MD, lead author for the RESPECT trial, told Neurology Today that he did not think the clinical trial should be viewed in the same spirit of a sporting event, “where there is a winner and a loser,” but rather as a means to advance knowledge of a disease and sort out treatment options, which may benefit some patients more than others. He said that in the case of the RESPECT trial, two of three analyses showed a statistically significant benefit to PFO closure over medical therapy, and the results were particularly favorable for patients with an atrial septal aneurysm and a large shunt size.
“I think clinicians will look at these trials and probably individualize their decision-making based on the profile of the patient,” said Dr. Carroll, an interventional cardiologist who is professor of medicine at the University of Colorado, Denver.
He said the RESPECT researchers are continuing to collect data to see if additional benefits in the treatments groups emerge over more time. In addition, the hope is that researchers from the three closure studies will come together to pool data and see if more striking conclusions can be drawn from a larger data set. It took a long time to get patients to enroll in the clinical trials, presumably because they could get the closure procedure with the off-label use of atrial septum closure devices.
The second new study, referred to as the PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism), was carried out at 29 sites in Europe, Canada, Brazil, and Australia and involved 414 patients under the age of 60 who were randomly assigned to closure or medical therapy. The study had broader eligibility criteria for PFO patients: they either had had an ischemic stroke, transient ischemic attack, or a peripheral thromboembolic event. The study used the same device tested in the other study, the Amplatzer PFO Occluder. The primary endpoint was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Participants were followed for an average of 4.1 years.
That primary endpoint was met for seven of the 204 patients (3.4 percent) in the closure group, compared with 11 of the 210 patients (5.2 percent) in the medical-therapy group. The difference was not statistically significant. Unlike with the RESPECT trial, atrial fibrillation was more common in the closure group.
NO NEED FOR ALARM
Anthony Furlan, MD, professor of neurology at Case Western Reserve University and principal investigator for the PFO closure trial published last year in the New England Journal of Medicine — CLOSURE I — agreed that the studies suggest “there is probably a small subset of patients who may benefit with a device. But you can't willy-nilly recommend closure of PFO for all patients.”
Gregory Albers, MD, professor of neurology and neurological sciences at Stanford University and director of the Stanford Stroke Center, said it's a hard thing for young stroke patients to be told that no definitive cause for their stroke can be identified.
“They are young and they had a stroke. They want to have an answer,” Dr. Albers told Neurology Today. At the same time, “some physicians will say: ‘You have a hole in your heart and that puts you in an incredibly dangerous situation. A PFO is like a ticking time bomb.’”
But he said the two new studies confirm other recent data that verify that the risk of recurrent stroke in young stroke patients is “typically very low. Patients should not be frightened or intimidated.”
Marc Fisher, MD, professor of neurology at the University of Massachusetts, said that the new studies will help inform conversations with patients who are debating what to do. “Now, what I would say is there is a suggestion that closing may be of some benefit and that the risk of the procedure is not much greater than treating medically,” he said. “But I would also explain to them that the risk of having another stroke [about one percent a year] is low,” regardless of what approach is taken.
Dr. Fisher said that sorting out who is most likely to benefit is important from both a medical and economic standpoint. “If you're going to spend a lot of money in the health care system, it would be nice to know you're having some benefit,” he said.
Researchers are waiting to see whether the Food and Drug Administration decides there is enough clinical benefit in the results to approve the Amplatzer PFO Occluder for clinical use.
“All eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards,” the NEJM editorial said.