Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke

Team Representative:
David Thaler, MD, PhD, FAHA
Neurologist-in-Chief, Tufts Medical Center
E-mail: dthaler@tuftsmedicalcenter.org
Phone: 617-636-5848

Media Contact:
Rhonda Mann
E-mail: rmann1@tuftsmedicalcenter.org
Phone: 617-636-3265

Summary of findings in layman's terms:

Stroke kills nearly 130,000 people a year and is a leading cause of disability. Eighty-seven percent of strokes are ischemic, caused when an obstruction within a blood vessel interferes with the supply of blood to the brain. While atherosclerosis and other factors are known to account for the majority of ischemic strokes, a specific cause cannot be determined in about one out of four cases. Numerous prior studies have suggested that one cause for such cryptogenic strokes is the presence of a small opening in the wall between the left and right upper chambers of the heart that exists in some people. This hole, a patent foramen ovale (PFO) is present in everyone at birth but closes in the majority of people during infancy. In most of the 25% of the population thought to have a PFO, it causes no problems, but in some, it can allow a blot clot to travel to the brain, causing a stroke.

This study, the RESPECT trial, tested whether closing that hole with a catheter-inserted mechanical device can be helpful in preventing additional strokes in people with a PFO who had a stroke. The study, conducted in 69 centers across the US and Canada, randomly assigned participants, all between 18 and 60 years of age, to treatment using either the device or routine medical therapy, which centers on anticoagulant medications. The long-term follow-up results published this year constitute the most substantial clinical trial data on the topic to date. They show that the procedure significantly decreased the rate of recurrent ischemic stroke compared with medical therapy, and it thus offers an effective option for secondary stroke prevention in some people. 

Specific biological innovation of study:

A patent foramen ovale (PFO) provides a channel through which blood may shunt if the pressure in the right atrium exceeds that in the left. Usually the shunting is insignificant. However, PFOs are found in about 50% of stroke patients who have no other explanation for having had a stroke. Small venous blood clots that arrive in the right atrium are normally filtered out of the blood in the lungs; however if a PFO allows a small blood clot to bypass this lung filtration, it could arrive in the left atrium and then travel out into the body. Between 20 and 30% of ischemic strokes are considered cryptogenic, i.e. without a known cause despite extensive investigation for aortic and carotid atheroma, arterial dissection, atrial fibrillation, and other stroke causes.

Though first proposed long ago, the role of PFO in adverse vascular events has remained an open question. More recently, technical advances in PFO diagnosis, and the emergence of endovascular device closure as a treatment option have helped to stimulate considerable clinical interest in PFO management. Observational studies and meta-analyses suggest that closure is associated with a benefit but evidence from randomized trials, remained inconclusive, with most analyses based on only moderate durations of follow-up, averaging 2 to 4 years.

In our 2017 paper, we were able to report results from an extended period of follow-up (a median of 5.9 years, some as long as 12 years) for patients in the RESPECT trial, which compared closure with medical management in 980 patients (mean age, 45.9 years) at 69 sites. Our findings of a relative risk reduction with PFO closure vs. medical management of 45% (HR = 0.55; 95% CI, 0.305-0.999) for ischemic stroke provide conclusive evidence to settle the key question of whether device closure is helpful for cryptogenic stroke. 

Potential impact on patient care and/or how the findings contributed to an improved understanding:

By establishing the value of PFO closure for secondary stroke prevention, the long-term RESPECT Trial results have changed clinical practice paradigms for the management of cryptogenic stroke, directly informing clinical choices in about 10 percent of the 795,000 strokes that occur in the United States each year.

Several features of PFO and our study deepen the impact of these findings. In results analyses limited to strokes of undetermined cause – that is, excluding those recurrent ischemic strokes associated with a mechanism determined to be unrelated to the PFO -- PFO closure resulted in a 62% relative risk reduction in secondary stroke (95% CI 0.18-0.79) compared with medical management. Other analyses have suggested that there may be subgroups with a differential benefit, such as those with atrial septal aneurysm (rather than those without) and those with larger shunts.

The clinical impact of our results are especially profound in light of the need for effective secondary stroke prevention strategies for these young and middle-aged patients, who have many years of PFO-related risk ahead of them. 

Journal citation:

Saver, Jeffrey L., John D. Carroll, David E. Thaler, Richard W. Smalling, Lee A. MacDonald, David S. Marks, and David L. Tirschwell. "Long-term outcomes of patent foramen ovale closure or medical therapy after stroke." New England Journal of Medicine 377, no. 11 (2017): 1022- 1032.