Four years after three major studies found insufficient evidence to conclude that patent foramen ovale (PFO) closure lowers the risk of stroke better than medical therapy, three new analyses are concluding that it does.

The newest studies “provide compelling evidence that PFO closure does reduce the risk of recurrent stroke in carefully selected patients where the PFO was the most likely cause of the first event,” Dr. Steven Messe at the University of Pennsylvania told Reuters Health by email. He had previously opposed PFO closure outside a clinical trial.

Still, although the new evidence shows the benefit of the procedure, he and other researchers interviewed by Reuters Health cautioned against overuse of closure in cases where the source of the stroke is not immediately clear.

About 25 percent of the population has a PFO, “so in most patients with a PFO and a stroke, the PFO was incidental and closing it won’t help,” said Dr. David Spence of Western University in Ontario, coauthor of one of the new studies, known as Gore REDUCE.

“Patient selection will be paramount to avoid recommending PFO closure in patients where the PFO was an ‘innocent bystander,'” said Dr. Messe, who was peripherally involved in Gore REDUCE. “Compared to almost any other stroke etiology, PFO appears to be low risk for recurrence, and thus if a competing cause is identified, it is probably the proximate cause, rather than the PFO.”

The three previous studies that showed no significant benefit involved 2,798 patients. They were published in the New England Journal of Medicine, and were known as CLOSURE I (2012), PC (2013) and RESPECT (2013).

But when those results were pooled, closure did show a significant benefit, Dr. Spence told Reuters Health in an email. The individual tests from 2012-2013 “were just under-powered to show benefit individually,” and too many patients were getting the PFO device who weren’t likely to benefit from them.

The three new studies, involving 2,307 participants, were released online September 13, again by the NEJM.

One of the new tests is a follow-up to the RESPECT study, and those researchers found it took time for the benefits of closure to show up. At the 2- to 4-year mark, the benefit was not statistically significant. But it was significant at a median follow-up of 5.9 years, reducing the ischemic stroke rate by 45 percent (P=0.046) compared to standard medical therapy.

“The longer-term follow-up, a median of nearly six years, indicates durable benefit from treatment,” chief author Dr. Jeffrey Saver of the University of California, Los Angeles, told Reuters Health by email.

The second study, known as CLOSE and led by Dr. Jean-Louis Mas, a professor of neurology at Paris Descartes University, compared closure to aspirin therapy. No strokes occurred among the 238 patients in the closure group, but 14 of the 235 controls had a stroke (P<0.001). Dr. Mas said in an email that the data "confirm the direct responsibility of the patent foramen ovale in the occurrence of cerebral infarction in patients with no other identifiable cause—and provides a clear therapeutic response to a frequent and serious medical problem." In about 30 percent to 40 percent of ischemic strokes, the cause is not known and is classified as “cryptogenic stroke.” "In previous studies, the definition of cryptogenic stroke was less stringent," Dr. Mas said. He stressed that a comprehensive workup is needed "to rule out other potential causes of stroke." Regarding the Gore REDUCE study, coauthor Dr. Scott Kasner of the University of Pennsylvania told Reuters Health by email that his group saw a 49 percent reduction in new brain infarctions. "We believe we were able to enroll patients whose stroke was most likely due to the PFO, and therefore closure of the PFO would most likely be beneficial," he said. "The PFO is most likely the cause of the stroke in patients who are younger and have few traditional risk factors for stroke, such as hypertension, diabetes, and smoking," he said. "This is critical, since PFO is a relatively common finding (25 percent of the population), and it is only worth closing if it was the probable cause of the stroke. We also used the Gore devices that have a favorable safety profile and a low risk of erosions." Dr. Saver said, "All of the five trials actually provide consistent findings. All showed fewer strokes numerically in the device group than the treatment group. The statistical strength of the findings is greater in the current three trials for several reasons, including larger study sizes; use of better devices than in the first trial; more-stringent selection of patients with definite strokes and no other source found; and different rates of use of antiplatelet agents versus anticoagulant agents in the medical, non-device arms (anticoagulants appear likely better than antiplatelet agents)." "Both of the treatment options to prevent recurrent stroke, placement of a closure device or use of medication alone, work pretty well; but for patients matching the trial populations, treatment with a closure device works a bit better and will often be a preferred strategy," Dr. Saver said.

Dr. Kasner said he would not recommend closure “for patients with multiple typical stroke risk factors (older age, hypertension, diabetes, smoking, etc.), patients with lacunes, patients with diffuse atherosclerosis, or other likely contributors to future stroke risk.”

But he said, “I am recommending closure for patients who meet the criteria used in the REDUCE study: generally under age 60 with an embolic-appearing stroke (typically a cortical or cerebellar infarct, not small deep infarcts), PFO, and no other cause for the PFO.”

Dr. Spence, a coauthor of REDUCE, was one of the doctors urging caution in applying the new findings. “I think there is substantial risk that in the United States, where inappropriate carotid stenting is rampant, there will be a flood of percutaneous closures of PFO in people who are more likely to be harmed than helped,” he said. “A lot of cardiologists are going to be throwing PFO devices into people who can’t benefit from them.”

“Among people with a stroke and a PFO, the PFO didn’t cause it in 80 percent of the cases,” said Dr. Spence. Among the best candidates for closure: people with larger holes, people whose strokes are associated with prolonged sitting, shortness of breath at the onset of a stroke, waking up with a stroke, or a history of deep-vein thrombosis. “I think most doctors aren’t aware of these factors,” he said.

The Gore REDUCE study was funded by W.L. Gore and Associates, the RESPECT study by St. Jude Medical, and the CLOSE study by the French Ministry of Health.