Which Strokes Need PFO Closure?

Once a stroke occurs, every attempt is made to determine its exact cause. The goal is to determine if additional strokes can be prevented.

Strokes fall into two categories: hemorrhagic and ischemic strokes. Hemorrhagic strokes are due to bleeding within the brain. Tests of the cerebral arteries may find an aneurysm which is the source of bleeding. Surgical correction of the aneurysm can prevent another episode of bleeding.

The majority ( around 70%) are ischemic strokes caused by obstruction of a cerebral artery by a thrombus, or by an embolus traveling from the heart to a cerebral artery (embolic strokes). Several different cardiac conditions may cause embolic strokes, and many embolic strokes can be prevented.

For example, the underlying cause could be atrial fibrillation (AF), a very common arrhythmia, especially in the elderly. AF can cause blood clots in the heart, which can embolize (travel) to the brain and occlude an artery, resulting in an embolic stroke.

Anticoagulation can reduce the chances of another embolic stroke by up to 80 percent. I believe that the reduction in the number of strokes in the last ten years is due to advising anticoagulants to AF patients who are at increased risk of stroke depending on their age and certain health factors.

Unfortunately, in 25 to 30% of ischemic strokes, a cause cannot be determined. These strokes, about 200,000 per year, are termed cryptogenic strokes.

In 1988, Lechat made a very important finding. He found that a patent foramen ovale is more likely to be found in patients with a cryptogenic stroke than in the general population. The foramen ovale is a small opening in the wall between the upper two chambers (atria). During pregnancy, the fetus does not breathe through its lungs. Blood from the placenta, rich in oxygen, bypasses the lungs by flowing into the right atrium. Then it flows through the foramen ovale into the left atrium, and then to the rest of the body. Upon birth, blood travels its usual route to the lungs. In about 75% of people, this foramen (opening) closes during infancy.

A foramen ovale that fails to close during infancy occurs is termed a patent foramen ovale (PFO). It causes no symptoms and cannot be detected on physical examination. However, it is easily detected by echocardiography. PFOs are a frequent incidental finding when an echocardiogram is performed to diagnose various forms of heart disease.

Physicians began to wonder if cryptic strokes might be due to a very unusual syndrome in patients with PFOs, termed paradoxical embolism. A paradoxical embolism occurs when a blood clot in a vein travels to the right atrium and then crosses a PFO to enter the left atrium. From there, it could travel to the brain and obstruct a cerebral artery, resulting in an embolic stroke.

This unproven hypothesis was widely believed to be a major cause of cryptic strokes. In 1986, a surgical closure of a PFO to prevent recurrent stroke was reported. Then a number of devices to close PFOs without cardiac surgery were developed. A special catheter is introduced to a vein and then advanced to the heart where the device closes the defect.

These devices cost between $2800 and $5000. The average cost of this procedure was more than $28,000 per patient. By 2006, more than 11,000 patients had undergone this unproven procedure.

Some clinicians voiced doubts about the probability that thousands of strokes were due to paradoxical emboli. Paradoxical embolism begins with venous thrombosis, leading to a major pulmonary embolism. Yet, very few cases of cryptic stroke have evidence of venous thromboembolism. A second issue was how a venous clot could cross a PFO when, normally, the right atrial pressure is less than left atrial pressure. Documented cases of paradoxical emboli are most common in patients in whom major pulmonary embolism causes the right atrial pressure to exceed left atrial pressure, thereby causing shunting from the right atrium to the left atrium.

Concerns about the validity of the hypothesis that thousands of strokes are due to paradoxical embolism led to the initiation of randomized clinical trials (RCT) comparing PFO closure to standard anticoagulant therapy. Randomized clinical trials are expensive, involving thousands of patients and take years to perform. Recruitment of patients to these trials was difficult because many physicians were convinced that PFO closure was effective.

The results of the first three RCTs were released in 2012 and 2013. After 2-4 years of follow-up, there was no significant difference in the rate of recurrent stroke in patients with PFO closure versus medical therapy.

Fortunately, the trials continued for a follow-up of 3 to almost 6 years. After this longer follow-up, the incidence of recurrent strokes was significantly less in patients who had PFO closure.

But there is more to the story. Approximately a third of patients with a PFO have another defect — an aneurysm of the atrial septum. These aneurysms are also detected by echocardiography. Some physicians have long suspected that these atrial septal aneurysms (ASA) could lead to clot formation which could result in paradoxical embolism and strokes. Analysis of these three later reports revealed that when the PFO was closed in patients without a septal aneurysm, there was no decrease in strokes. However, in 504 patients with a PFO and an atrial septal aneurysm, the incidence of strokes decreased from 9.0 % without closure to 1.2% after closure (P <.001). In patients without ASA, the incidence of stroke after PFO closure was the same as those without closure.

These results indicate that PFO closure prevents strokes in patients with a PFO and atrial septal aneurysm but is not effective, and therefore not indicated in PFOs without a septal aneurysm.

These findings are described in the article entitled Which Patent Foramen Ovales Need Closure to Prevent Cryptogenic Strokes? recently published in the American Journal of Medicine. This work was conducted by James E. Dalen and Joseph S. Alpert from the University of Arizona College of Medicine.

References

1. Lechat P, Mas JL, Lascault G. et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148-1152
2. Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022-1032.
3. Mas Jl, Derumeaux G, Guillon B, et al. Patent foramen closure or anticoagulation vs antiplatelets after stroke N Engl J Med 2017; 377: 1011-1022.
4. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377:1033-1042.
5. Dalen, JE Alpert JS. Which patent foramen ovales need closure to prevent cryptogenic strokes? Am J Med 2018:131; 222-225