Shashank Shekhar, MD, MS
The successful outcomes from three open-label, randomized, multicenter clinical trials looking for benefit from the clinical closure of Patent Foramen Ovale (PFO) is going to receive a rapturous welcome from the cardiology community and possibly from the stroke community. PFO is present in >25% of general population; however, it can account for up to 50% in cryptogenic stroke group (Homma S, Circulation 2005). Until recently, there were no recommended guidelines as for how to treat patients with a cryptogenic stroke suspicious of PFO as an etiology. Previous trials including primary analysis of the RESPECT trial did not show a significantly lower risk of stroke after PFO closure when compared to anticoagulation (Furlan, NEJM 2012; Carroll, NEJM 2013; Meier, NEJM 2013). However, the recent long-term outcome of RESPECT and two additional trials, namely CLOSE and REDUCE, has been published in the New England Journal of Medicine, in the September 2017 edition. All three trials showed the benefit of PFO closure, but surprisingly all trials had the higher rate of atrial fibrillation in patients with PFO closure. Let’s discuss in brief the results from the CLOSE trial.
Patients between 16 and 60 years of age and who had a recent stroke with most likely etiology from PFO in the setting of an atrial septal aneurysm or large interatrial shunt were enrolled. Three groups were assigned a total of 664 patients in the ratio of 1:1:1.
Group 1: PFO closure follow by Antiplatelet therapy (daily 75mg aspirin plus 75mg clopidogrel for three months, thereafter daily 75mg aspirin or 75mg clopidogrel or aspirin combined with dipyridamole).
Group 2: Antiplatelet alone as in Group 1.
Group 3: Oral anticoagulation (daily vitamin K antagonist or direct oral anticoagulant).
Patients who had contraindications to oral anticoagulation or PFO surgery were randomly assigned to group 1 or 2 and group 2 or 3, respectively. The primary outcome was the occurrence of fatal or non-fatal stroke. Patients had a mean follow-up duration of 5.3 years.
The outcome suggests none of the patients in the group 1 (PFO closure) had stroke vs. strokes amongst 14 patients in group 2 (in the anti-platelet only) with HR, 0.03; 95% CI, 0-0.26; P<0.001. The subgroup analysis in the group 2 suggested 12.2% stroke in patients who had PFO with an atrial septal aneurysm and 3.1% who had large PFO alone. Procedural risk of PFO closure occurred in 5.9% patients. New onset atrial fibrillation and flutter was higher in the PFO closure group vs. antiplatelet only group (4.6% vs. 0.9%, p= 0.02).
This trial, although well planned and executed, however, lacked the strength in the number of patients. There was no significant difference observed between the PFO closure group vs. medical management with an anticoagulation group. In the setting of higher procedural risk, there was no benefit against anticoagulation. This study does suggest its superiority over antiplatelet therapy alone. In addition, it has opened a new question, “Why is there a higher risk of atrial fibrillation/flutter in the PFO group who received closure treatment?” Is it because of chance or procedure complication? Although there was only report of transient cardiac arrhythmia within a month in the PFO closure group, luckily not prolonged enough to cause the higher incidence of stroke. Another factor to consider is that increased risk of arrhythmia occurred at a later time and not immediately post-procedure but within a month. None of the patients were long-term monitored for cardiac arrhythmia. We can never be sure if PFO closure puts patient at higher risk of arrhythmia in the long run albeit transient. With the current usage of a loop monitoring device, we can expect to catch a higher percentage of cardiac arrhythmias.
Nevertheless, this trial has brought us hope with the successful outcome we hoped for a long time. In the future, there still is a need for long-term cardiac monitoring to confirm the safety of the procedure. While the procedure might benefit a select population — i.e. PFO with an atrial appendage in the setting of contraindication with anticoagulation — further evidence is required to change the practice of sending all of these patients for the procedure.