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 [CI], 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 [CI], 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:

Saver JL, 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, 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, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017;377:1033–42. doi:10.1056/NEJMoa1707404.

The original articles are available in the current issue of the New England Journal of Medicine.

References

  1. 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.
  2. 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.
  3. 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.