Tapan Mehta, MBBS, MPH
Literature on PFO (Patent Foramen Ovale) as an underlying etiology for acute ischemic stroke and outcomes of PFO closure hit an important landmark when recently CLOSE, REDUCE and RESPECT trials were reported in the New England Journal of Medicine. All three trials had difference in methods of randomization, treatment protocols, outcomes, and patient population, to an extent. This post will focus on the RESPECT trial (Saver et al).
RESPECT was a multicenter, randomized, and open-label with blinded adjudication of end point event trial with 1:1 randomization to PFO closure and medical (antiplatelet or anticoagulation) groups. Important inclusion criteria included age 18–60 years and ischemic stroke within 9 months (defined with imaging or neurological deficit attributed to ischemic stroke lasting for more than 24 hours) that is determined to be not related to any other cause but PFO. All patients included had a PFO determined with transesophageal echocardiogram; however, PFO characteristics including type of shunt and presence of atrial septal aneurysm were not a part of inclusion criteria, unlike the CLOSE trial. Although all of these patients received extensive investigations to determine etiology of their stroke, including hypercoagulable workup, they were not required to have 30-day or long-term cardiac monitoring.
The trial enrolled 980 patients from 2003 to 2011 with 5.9 years median follow up [median duration of safety follow up was significantly higher in the PFO closure group (3141 patient years – 20.8% dropout) compared to medical group (2669 patient years – 33.3% dropout)]. PFO closure was performed with only Amplatzer device. Pre-procedure Aspirin 325 mg was administered before 24 hours, and post closure patients remained on Aspirin and plavix for 1 month followed by Aspirin alone for 5 months and after that on antiplatelet medication at the discretion of the investigator. The medical group was allowed Aspirin only (46.6%), Coumadin only (25.2%), Clopidogrel only (13.9%), Aspirin + dipyridamole (8.1%), Aspirin + clopidogrel (6.2%) (allowed for only first three years, discontinued based on revised AHA guidelines published in 2006). There was no statistically significant difference in baseline characteristics of patients in all three groups, with average age 45–46 years, previous stroke history 10.6%, PFO with large shunt in 48–49%, PFO with large shunt and atrial septal aneurysm in 35–36%.
Efficacy outcome showed that 46 patients had a primary end-point event (recurrent nonfatal ischemic strokes), 18 patients in the PFO closure group (0.58 events per 100 patient-years) and in 28 patients in the medical-therapy group (1.07 events per 100 patient-years), with hazard ratio of PFO closure vs. medical therapy group (HR) 0.55 [(95% confidence interval (CI) – 0.31 to 0.999, (P=0.046)]. Recurrent ischemic stroke of undetermined mechanism (defined using ASCOD algorithm) occurred in 10 patients in the PFO closure group (0.32 events per 100 patient-years) as compared with 23 patients in the medical-therapy group (0.86 events per 100 patient-years) (HR 0.38; 95% CI, 0.18 to 0.79; P=0.007). The subgroup analyses determining potential heterogeneity of the treatment effect showed that the benefit of PFO closure as compared with medical therapy may have been higher with presence of an atrial septal aneurysm (HR 0.20, p=0.005), with a substantial right-to-left shunt (HR 0.26, p=0.005), and among patients in the medical group whose planned regimen included antiplatelets compared to whose planned regimen included anticoagulants (HR 0.38, p=0.007).
There were 7 deaths in the PFO closure group and 11 in the medical therapy group determined to be not related to the trial. There were 25 serious adverse events related to procedure or device occurred the PFO closure group and all of them resolved before discharge. Periprocedural atrial fibrillation/flutter rate (0.4%) was not significantly higher than the medical therapy group in this trial. However, the atrial fibrillation/flutter rates were significantly higher compared to the medical group in CLOSE (4.6%) and RESPECT (6.6%).
All three trials had differences in measures of variables and design; it is important to note that the CLOSE trial had the lowest hazard ratio for primary outcome (recurrent ischemic stroke). Although it could be by chance, interestingly, difference in vascular risk factors of patient population was noticeable among these three trials (See table below). Post PFO closure dual antiplatelet use was also longest in CLOSE (3 months) compared to REDUCE (3 day) and RESPECT (1 month). On the other hand, the RESPECT trial used only the Amplatzer device with lowest atrial fibrillation/flutter rates, which were not significantly different from that in the medical therapy group. Currently available data on PFO attributable strokes is convincing for PFO closure being superior to antiplatelet treatment (robust data comparing PFO closure with only anticoagulation is still lacking). However, appropriate patient selection for PFO closure is of utmost importance in addition to understanding of device efficacy and related upfront complications.