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Higher Prevalence of Patent Foramen Ovale Reported in Cryptogenic Stroke

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About one-quarter of all people walk around with a patent foramen ovale (PFO). Most of the time, it means nothing to them, does nothing, and they don't know it's there. But among patients who have had a cryptogenic stroke, there seems to be a higher prevalence of PFO, and that may have caused the stroke.

Figure

A patent foramen ovale is a flap between the two walls in the upper chambers of the heart.

At one time, cryptogenic strokes related to PFO were thought to occur mainly in those younger than 55, but a Nov. 29 study in the New England Journal of Medicine found otherwise. The prevalence of PFO was significantly greater than in the general population among those with stroke of known cause, including both younger and older patients.

“We were surprised by the results,” said study author Andreas Harloff, MD, of the department of neurology and clinical neurophysiology at the University Hospital in Freiburg, Germany.

“We did not prove that PFO caused the stroke in these patients,” Dr. Harloff said. “However, the significantly higher incidence of PFO and atrial septal aneurysm [ASA] in patients with cryptogenic stroke over the age of 55 strongly suggested a causal relationship.”

PFO is not so much of a hole as it is a flap between the two walls in the upper chambers of the heart. It's more of an overlap, as if the door were too large for the frame, said Isaac Silverman, MD, a vascular neurology and medical director of the Stroke Center at Hartford Hospital in Connecticut. When someone has an ASA, it means that flap moves to and fro between the left and right chambers. That movement can increase the risk of a cryptogenic stroke.

It's unclear exactly why those with PFO, and particularly those with ASA, have more strokes. But researchers believe that if a clot forms, the opening allows the clot to go from the right side of the heart to the left and then up to the brain.

“The hypermobility of the ASA probably contributes to the physics of the blood flowing across,” said Dr. Silverman. In cardiac ultrasound studies, you can “see the shunting of the bubbles across the walls of the PFO with patients with ASAs — the walls of the flap may then act to literally guide bloodflow through the PFO.”

Study Protocols, Results

Investigators compared data on 503 patients who had had a stroke — 227 with an unknown cause and 276 patients with a known cause, including large-artery atherosclerosis, cardioembolism, small-vessel occlusion, and other known causes. They also compared data between the 131 patients younger than 55 years old and 372 patients older than 55.

The findings: 13.4 percent of younger patients and 15.2 percent of older patients with cryptogenic stroke also had a PFO and an ASA. And 44 percent of younger patients with unexplained stroke had a PFO versus 14 percent of younger patients with a known cause of stroke; in older patients the prevalence of PFO was 28 percent (for cryptogenic stroke) versus 12 percent for those with a known cause of stroke.

Implications for Treatment

But while doctors, who were not involved with the trial, say the study was strong, particularly since transesophageal echocardiography (TEE) was done on all the participants, it leaves them without answers about treatment.

“It's the gray area,” said Steven R. Messé, MD, a neurologist in the division of Stroke and Neurocritical Care at the Hospital of the University of Pennsylvania. “We're not sure what's best for these patients.”

There are two main paths: medical management and surgery to close the PFO. “With medical management you can give them aspirin, or possibly warfarin [Coumadin],” said Dr. Messé. “But then you run a higher risk of bleeding complications over time, a major concern with younger patients.”

The risk of recurrent stroke in patients who are found to have a PFO after the first one is about 1 percent a year, said Dr. Messé. This risk is about the same in patients with unexplained stroke and no PFO. But for those patients with both PFO and ASA, the risk of recurrent stroke is probably higher, about 3 percent, he said.

There are procedures to close the PFO, but surgery is not 100 percent effective, and there is a risk — around 1 percent — of a major complication.

Dr. Harloff, the study author, said the goal was not to evaluate secondary prevention. He noted that although several ongoing trials are comparing PFO closure with medical management, there are no clear guidelines based on randomized trials.

Decisions for the patients in the study were made individually and following the recommendations of the German Neurological Society. Those with PFO and first transient ischemic attack/stroke were given aspirin 300 mg a day after coagulation disorders and deep vein thrombosis were excluded. Those with PFO and ASA, or those with relapsing stroke while taking aspirin, were treated with warfarin for at least two years, he said.

Those who had a stroke despite warfarin treatment or those with contraindications against oral anticoagulant therapy had surgical closure of the PFO. To close the PFO, doctors use a cardiac catheterization procedure, in which a catheter is inserted in the groin and an occluder device — slightly larger than the defect — is placed around the PFO. Over time, usually three to six months, the patient's tissue grows around the device to seal the area. Howard S. Kirshner, MD, professor and vice chair of the department of neurology for Vanderbilt University in Nashville, TN, said that it is often unclear what to do. “I just had a 65-year-old patient with a TIA,” he said. “He has a PFO, and he had a heart transplant; the PFO was in the transplanted heart. We do not want to give him warfarin because they need to get cardiac biopsies to check on the transplant.”

Although the 2001 WARSS trial — reported in the New England Journal of Medicine—comparing the use of warfarin and aspirin showed that there were no significant differences between the treatment groups, Dr. Kirshner said larger clinical trials are needed to establish clearer guidelines for treatment: medical therapy versus closure of the PFO, particularly for those with ASA. Current guidelines do not recommend either routine warfarin anticoagulation or closure.

Dr. Silverman said his standard practice is that if a PFO is found in someone with a cryptogenic stroke, he gives warfarin for three or four months, and then switches to low-dose aspirin.

“One initially treats with warfarin for the concept of a hidden clot on the venous side of the body to prevent that clot from going into the bloodstream, through a PFO and into the brain,” he said.

In addition to the concerns about bleeding, taking warfarin is harder on the patient because they need bloodwork every one to four weeks to be certain they remain within the therapeutic range, he said.

The study's finding that PFO is often found in older patients throws a further wrench into treatment, doctors said. “We should be looking for PFO in older patients, because we always assumed that with older patients there were other causes, especially atherosclerosis of large arteries in the neck or cardiac sources, high blood pressure, and diabetes,” said Dr. Silverman. “We need to study these patients more, especially with TEE, and maybe the next generation of studies will address treatment.”

Dr. Messé said part of the problem is getting patients to join the studies. “Having a stroke is stressful, and to some people, being told that there is a hole in their heart demonizes it, and it's psychologically difficult to imagine not closing the PFO,” he said. “And then for some people, they say, ‘You are not going near me with that device.’”

“The bottom line is — what should we do for the patient? And we honestly do not know right now.”

References

• Handke M, Harloff A, Giebel A, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262–2268.
• Mohr J, Thompson JLP, Adams HP Jr, et al., for the Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451.