Patent foramen ovale closure after cryptogenic stroke – assessing the evidence
Approximately 20 to 30 percent of ischemic strokes are cryptogenic, after ruled out a cardioembolic or large vessel source and small vessel disease. There is an increased prevalence of patent foramen ovale (PFO) in patients who have experienced a cryptogenic stroke, suggesting that paradoxical embolism through a PFO may be the cause of some cryptogenic strokes. However, the role of closure of PFO in preventing stroke recurrence in patients with a cryptogenic stroke was still an open question.
Three previously published randomized trials individually did not show a significantly lower risk of recurrent stroke with PFO closure than with medical therapy alone in the primary intention-to-treat analysis.
In the current issue of the New England Journal of Medicine, three articles were published regarding the use of occluder devices to reduce the rate of recurrent stroke: an exploratory analysis of data from the extended follow-up period of the RESPECT study by Sayer et al; the results from a multicenter, randomized, open-label study – the CLOSE trial by Derumeaux et al; and the results from the multinational REDUCE trial by Søndergaard et al.
The RESPECT trial was a multicenter, randomized, open-label, controlled clinical trial with blinded adjudication of end-point events, that included 980 patients – 499 participants randomly assigned to closure of the patent foramen ovale and 481 assigned to medical management. The results from the original trial were published in 2013, with a median follow-up pf 2.1 years, and showed no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke: the primary analysis of the intention-to-treat cohort showed a nominal 51% hazard rate reduction with closure, but the reduction did not reach significance. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks.
In this new article, Saver et al did an exploratory analysis regarding the data from a median 5.9 years follow-up of the RESPECT patients. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval , 0.31 to 0.999; P = 0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P = 0.007). Regarding safety, authors reported that venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group.
The CLOSE trial was a multicenter, randomized, open-label trial. It included a total of 663 patients, with 16 to 60 years of age, who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt. They were assigned in a 1:1:1 ratio to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative non-contraindicated treatment or to antiplatelet therapy (randomization group 2 and 3 respectively). The primary outcome was occurrence of stroke.
The mean follow up time was 5.3 years±2.0. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P = 0.02). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone.
The multinational REDUCE trial included a total of 664 patients with PFO who had had a cryptogenic stroke. The mean age was 45.2 years. They were randomly assigned in a 2:1 ratio to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). The co-primary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on follow-up imaging.
During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval , 0.09 to 0.62; P = 0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P = 0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P = 0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P = 0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure.
In conclusion, these three new articles suggested that the closure of a PFO in patients with a previous cryptogenic stroke may reduce the risk of recurrent strokes. Regarding safety, a low rate of serious adverse events associated with the devices occurred in the three trials.
Although in general there were few recurrent strokes in patients with a previous cryptogenic stroke and a PFO alone, the possibility of preventing is of high value, particularly in young patients.
Comment Author: Cristiana Silva and Diana Aguiar de Sousa, Department of Neurology, Hospital de Santa Maria, University of Lisbon, Portugal
Original Articles:
The original articles are available in the current issue of the New England Journal of Medicine.
References
- Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, et al. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N Engl J Med 2017;377:1022–32. doi:10.1056/NEJMoa1610057.
- Mas J-L, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med 2017;377:1011–21. doi:10.1056/NEJMoa1705915.
- Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017;377:1033–42. doi:10.1056/NEJMoa1707404.