Amrou Sarraj, MD: Evidence for PFO Closure vs Medical Management Alone in Reducing Stroke Recurrence

Amrou Sarraj, MD: Good afternoon. This is Dr Amrou Sarraj. I'm an associate professor of neurology at McGovern Medical School at UTHealth in Houston.

We're discussing an important subject to patients’ care, neurologists, cardiologists, and general practitioners, which is reducing stroke recurrence among patients with patent foramen ovale.

We will discuss the etiology and special characteristics of the patients with PFO. We will discuss how to approach these patients from a neurologist's standpoint.

We will also discuss the evidence around the treatment of strokes due to PFO, the different treatment methods, the evidence supporting the closure of the PFO, and in general, the expectations and how to approach these patients from the physician's standpoint, from the patient's, and what are the guidelines for practice in these patients.

Among patients with cryptogenic ischemic stroke and PFO, clinical trials have shown that the PFO closure reduces the risk of stroke recurrence compared to medical treatment alone, especially with antiplatelet therapy.

Those clinical trials that studied this population went through 2 generations of the trial, so to speak. The first generation of the trials actually did not show that the PFO closure would reduce the risk, and those trials included the CLOSURE-1 trial, the PC trial, and the initial RESPECT trial.

Then the second generation of the trials came and showed that closing the PFO with percutaneous closure devices does reduce the stroke recurrence. And so, how is that possible?

The answer to this is the initial trials–while they were well-designed, large, randomized, clinical trials that put patients either to PFO closure plus antiplatelet vs antiplatelets or anticoagulation alone–included all patients with PFO.

They did not specify size for the PFO. They did not specify other findings on the transesophageal echocardiogram, as in atrial septal aneurysm, which increased the likelihood of thromboembolism. The larger the PFO, the more likely that the shunting from the right to the left will happen and the clotting will happen.

So, the second generation of the trials came in and better selected the patients, and I will borrow here the same example from endovascular thrombectomy trials. We had several trials that showed no evidence initially because we enrolled all of the patients, and then as imaging improved and the patient selection improved, we identified this certain population where the treatment effect happened.

Same thing with the PFO closure trials. The second generation of the trials enrolled patients with larger PFOs and patients with atrial septal aneurysm, as I mentioned, that increased the risk of thromboembolism.

Those trials did show superiority in reducing stroke recurrence, as compared to medical management with antiplatelets. These trials were the RESPECT Long-Term trial, which actually is an extension of the initial RESPECT trial.

The initial RESPECT trial showed that 9 patients in the PFO closure had stroke recurrence, as compared to 16 patients in the medical management arm. Then the RESPECT Long-Term, which followed the patients up to 5.9 median years, showed 18 events in the PFO closure arm as compared to 28 events in the medical management arm with antiplatelets, which was statistically significant in reducing stroke recurrence.

The other trials that showed benefit were the Gore REDUCE trial, in which 6 events occurred in the PFO closure group, as compared to 12 events in the antiplatelets group, which was statistically significant, and the trial followed patients for a median of 3.2 years.

The length of the follow-up is important here because the longer that you have the PFO, the more likely that you may have a stroke mediated by it. So, the longer you follow the patients, the more likely you will have an event if you don't close the PFO.

The other trial that showed benefit of PFO closure was the CLOSE trial, which actually had no strokes occurring in patients who received percutaneous closure of the PFO, as compared to 14 events in 235 patients that were in the medical management arm.

And, there was a Korean trial, which is the DEFENSE-PFO trial. Only 2 Korean centers, 120 patients, and actually showed exclusively that events occurred in patients who did not have PFO closure. Not to criticize the trial, but there was no blindedness in the follow-up of the outcomes.

Again, in this second generation of the trial, if we focus on the RESPECT Long-Term trial, we see that the treatment effect, the benefit of PFO closure, occurred in patients with medium- to large-sized shunts, in patients with atrial septal aneurysm.

In terms of enrollment criteria, same thing with the Gore REDUCE trial. It included more than 80% with moderate to large shunts. And in the CLOSE trial, also, the baseline for enrollment was to have a large shunt or atrial septal aneurysm, so this is better identification of the patient.

So, based on all of these clinical trials, especially the second-generation trials, a meta-analysis was done. An analysis of these findings resulted in advisory AAN guidelines that recommend PFO closure for patients with a history of stroke, not TIA, and I want to focus here on that because clear evidence of having a stroke since TIA could be a subjective diagnosis without evidence of ischemia in the brain.

In the combination of this evidence recommended PFO closure in patients 18 to 60, with stroke, without determined reason, and underlying PFO, with an absolute recurrent stroke risk reduction of 3.4% over 5 years.

However, there are periprocedural complications, and the meta-analysis, in general, got those at around 3.9% increased absolute rate of complications, which is usually thromboembolism believed due to the device's insertion, there is increased risk of atrial fibrillation associated with these devices, and the combination of that from the trials was around increased risk of 0.33% per year–non-periprocedural atrial fibrillation, that is.

The number needed to treat to reduce 1 non-fatal stroke is 29 patients–so, PFO closure in 29 patients over medical management only, with a result in preventing 1 stroke over a 5-year period.

Thank you for listening to this podcast on an important subject for the general practitioner, the cardiologist, and the neurologist.