A practice advisory update from the American Academy of Neurology (AAN) warns against routinely offering percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic ischemic stroke outside of a research setting.

It adds, however, that in rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the Amplatzer PFO Occluder (St. Jude Medical Inc) if it is available.

The update was published online July 27 in Neurology.

Potentially Serious Complications

“Clinicians must counsel patients considering percutaneous PFO closure that having a PFO is common; it occurs in about 1 in 4 people; it is impossible to determine with certainty whether their PFOs caused their strokes or TIAs [transient ischemic attacks]; the effectiveness of the procedure [of closing the PFO] for reducing stroke risk remains uncertain; and the procedure is associated with relatively uncommon, yet potentially serious, complications,” the authors, led by Steven R. Messé, MD, University of Pennsylvania School of Medicine, Philadelphia, note.

“We issued this new guidance as we believe it is important for patients to be educated as to what we know about PFO closure and recurrent stroke risk. They need to know that PFO is common and the risk of stroke recurrence is low,” Dr. Messé told Medscape Medical News.

“There is some evidence that one closure device — the Amplatzer — may reduce risk of a subsequent stroke, but this evidence is weak and so we are not recommending routine PFO closure for this indication. In addition, the Amplatzer device is not currently available for this indication in the US — it is currently being reviewed by the FDA [Food and Drug Administration],” he added.

On the matter of ongoing preventive medical treatment, the advisory notes that there is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing recurrent stroke.

Therefore, it recommends that in the absence of another indication for anticoagulation, clinicians may routinely offer antiplatelet medications instead of anticoagulation to patients with cryptogenic stroke and PFO.
“There really isn’t enough data to recommend anticoagulation over antiplatelets in this population, and so we are sticking with the advice to use aspirin unless there is another indication for anticoagulation,” Dr Messé added.

The authors explain that these recommendations form an update to the 2004 AAN guideline for patients with stroke and PFO, which concluded that the optimal therapy for secondary stroke prevention in this population was unknown.

“Since that time, additional studies necessitated that we update our prior guideline,” they note.

PFO: What the Literature Says

From a systematic literature review, the authors identified three relevant studies on PFO closure.

The CLOSURE I study (Class I) was a multicenter, randomized, open-label trial of percutaneous closure with a STARFlexdevice (NMT Medical) compared with medical therapy alone in adult patients with PFO and a cryptogenic stroke/TIA.

Results showed similar rates of recurrent stroke in the two groups. And use of the STARFlex device was linked to a higher rate of atrial fibrillation and major vascular procedural complications.

The authors of the current AAN guidance conclude that the STARFlex device “possibly does not provide a large benefit in preventing stroke in place of medical therapy alone, possibly increases the risk of new-onset AF [atrial fibrillation], and probably is associated with a serious periprocedural complication risk.”

The Amplatzer PFO Occluder has been studied in two randomized trials that compared it with medical therapy.

The PC Trial showed a recurrent stroke rate of 0.5% in the closure group vs 2.4% in the medically treated group (P = .14). New-onset AF was reported in 2.9% in the closure group vs 1.0% in the medical treatment group, and bleeding adverse events occurred in 3.9% in the closure group and in 5.7% in the medically treated group.

In the second trial, RESPECT, the intention-to-treat analysis showed a recurrent stroke rate of 1.8% in the device group vs 3.3% in the medical group (P = .08).

A prespecified per-protocol analysis showed a statistically significant benefit favoring closure. The clinical AF incidence did not differ significantly between the two groups, but there were six pulmonary embolisms in the closure group compared with one in the medical group.

Pooled Analysis

The guidance authors conducted a pooled meta-analysis of the two Amplatzer studies that did suggest a significant reduction in recurrent stroke with PFO closure, with a number needed to treat of 56 to prevent 1 stroke during the 3 to 4 years of the studies.

“Although this result is significant…the precision of the pooled studies is consistent with a magnitude of benefit that many would deem unimportant,” they write.

They note that the meta-analysis also showed that serious procedural or device-related events occurred in 3.4% of patients undergoing closure, and also a significant increased risk for AF in the closure group.

They conclude that PFO closure with the Amplatzer device “possibly decreases the risk of recurrent stroke,” “possibly increases the risk of new-onset AF,” and “is highly likely to be associated with a procedural complication risk.”

“Because of the limitations of the efficacy evidence and the potential for serious AEs [adverse events], we judge the risk–benefit tradeoffs of PFO closure by either the STARFlex or Amplatzer PFO Occluder to be uncertain,” they add.

On the question of anticoagulation vs antiplatelet therapy for cryptogenic stroke patients with a PFO, the 2004 guideline identified one study relevant to this question.

PICSS Study

The PICSS study showed no significant difference in recurrent stroke or death at 2 years between patients receiving warfarin or those receiving aspirin, although there was a numeric reduction in the warfarin group. The authors note that the results are similar for patients without a PFO, suggesting that any effect was unrelated to the presence of a PFO.

Combining the two studies in a random-effects meta-analysis showed no significant difference between treatments, and the summary estimate of effect was a risk difference of 2% favoring antiplatelet treatment (95% confidence interval, –21% to 25%).

“For patients with cryptogenic stroke and PFO, there is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing recurrent stroke,” the authors conclude.

Finally, the authors suggest that it would be reasonable to consider trials of the new anticoagulants (factor Xa inhibitors and direct thrombin inhibitors), which have a lower bleeding risk and greater convenience than warfarin, in patients with stroke and a PFO.