American Academy of Neurology advises not to routinely offer percutaneous PFO closure outside of a research setting



Steve Messe
Steven Messé

A practice advisory update from the American Academy of Neurology (AAN) suggests that percutaneous patent foramen ovale (PFO) closure to patients with cryptogenic ischaemic stroke “should not be routinely offered outside of a research setting”.

However, in cases of patients with recurrent stroke despite adequate medical therapy with no other mechanism identified, “clinicians may offer the Amplatzer PFO Occluder (St Jude Medical) if it is available,” the writing committee led by Steven Messé (University of Pennsylvania School of Medicine, Philadelphia, USA) advises.

This advisory, published at the end of July in Neurology, is an update from the 2004 AAN guideline on secondary stroke in PFO patients, which concluded that the “optimal therapy” for this patient population was “unknown”. Additional studies prompted the AAN to analyse whether percutaneous closure of PFO is superior to medical therapy alone and anticoagulation is superior to antiplatelet therapy for the prevention of recurrent stroke in patients who have had a cryptogenic ischaemic stroke or transient ischaemic attack (TIA).

In order to update the 2004 guidelines, a panel of neurologists, cardiologists, and an internist with expertise in stroke and PFO who had no financial conflicts performed a literature search on the subject. Messé et al identified three key studies on percutaneous PFO closure. The first was CLOSURE I, a multicentre randomised, open-label trial of percutaneous closure, which compared the StarFlex device (NMT Medical) with medical therapy alone in adult patients with PFO and a cryptogenic stroke. According to the results of the study—which found similar rates of recurrent stroke in the two groups, and linked the use of the StarFlex device to a higher rate of atrial fibrillation and major vascular procedural complications—the AAN committee concluded 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 atrial fibrillation, and is probably associated with a serious periprocedural complication risk.”

Two randomised studies compared the Amplatzer PFO Occluder with medical therapy. The PC trial reported recurrent stroke in one patient in the percutaneous closure arm and in five patients in the medically treated arm. New-onset atrial fibrillation was reported in 2.9% in the closure arm vs. 1% in the medical treatment arm, and bleeding events occurred in 3.9% in the closure arm vs. 5.7% in the medically treated group.

In the RESPECT trial, an intention to treat analysis showed that recurrent stroke occurred in 1.8% of patients assigned to percutaneous PFO closure with the Amplatzer device compared with 3.3% in the medical group. A pre-specified per-protocol analysis showed a statistically significant benefit favouring closure. The clinical incidence of atrial fibrillation did not differ significantly between the two groups. However, there were six pulmonary embolisms reported in the closure group compared with one in the medical therapy group.

Messé et al pooled the results of the PC and RESPECT trials in a random-effects meta-analysis and found that the risk difference (RD) of recurrent stroke significantly favoured PFO closure (RD ‒ 1.68%%, 95% CI ‒ 3.18% to ‒ 0.19%). The meta-analysis also demonstrated that serious procedural or device-related events occurred in 3.4% of patients who underwent closure. A significant increased risk of atrial fibrillation was also observed in this group.

In the update, Messé et al concluded that percutaneous PFO closure with the Amplatzer PFO Occluder “possibly decreases the risk of recurrent stroke, possibly increases the risk of new-onset atrial fibrillation and it is highly likely to be associated with a procedural complication risk.”

Anticoagulation vs. antiplatelet therapy

The 2004 guideline found one study which evaluated anticoagulation compared with antiplatelet therapy for the prevention of recurrent stroke in cryptogenic ischaemic stroke patients. The PICSS study was a sub-study of a randomised trial of warfarin vs. aspirin in patients with stroke or TIA not due to atrial fibrillation or extracranial carotid stenosis. The results showed no significant difference in recurrent stroke or death at two years between patients given warfarin and those given aspirin.

In this update, Messé et al identified a second randomised class II study comparing aspirin with warfarin for secondary prevention in patients with cryptogenic stroke and PFO. Results of the study suggest that there was no significant difference in ischaemic stroke risk or TIA risk between treatment groups.

The authors combined these two studies in a random-effects meta-analysis and found no significant difference between treatments, and the summary estimate of effect was a risk difference of 2% favouring antiplatelet treatment. In this update, they concluded that “there is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing stroke for patients with cryptogenic stroke and PFO.” Therefore, they advised 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.”

Messé et al note that currently there are at least three ongoing large randomised controlled trials comparing PFO closure with medications; however, they suggest that “because of the low number of events in the trials that have been completed thus far, it is possible that these ongoing trials may fail to provide definitive evidence for efficacy, and the aggregate data may not define patient population with a clear reduction in stroke risk and acceptable procedural risk profile.” Therefore, they comment that additional randomised controlled trials may be required and that these future studies “should make efforts to carefully select patients who have limited vascular risk factors and have undergone a thorough evaluation to exclude other stroke aetiologies.”

The authors also suggest the inclusion of novel anticoagulants in trials of stroke prevention in PFO patients as these medications have demonstrated “less bleeding risks, effective venous thrombosis prevention, and greater convenience than warfarin.”