Closure of patent foramen ovale versus medical therapy after cryptogenic stroke

N Engl J Med. 2013 Mar 21;368(12):1092-100. doi: 10.1056/NEJMoa1301440.

Abstract

Background: Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. We conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age.

Methods: In this prospective, multicenter, randomized, event-driven trial, we randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated.

Results: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two groups was unequal (1375 patient-years in the closure group vs. 1184 patient-years in the medical-therapy group, P=0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 95% confidence interval [CI], 0.22 to 1.11; P=0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort (6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P=0.03) and in the as-treated cohort (5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P=0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group (P=0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2%), but the rate of atrial fibrillation or device thrombus was not increased.

Conclusions: In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.).

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cardiac Catheterization / adverse effects
  • Embolism / etiology
  • Embolism / prevention & control
  • Female
  • Fibrinolytic Agents / adverse effects
  • Fibrinolytic Agents / therapeutic use*
  • Follow-Up Studies
  • Foramen Ovale, Patent / complications
  • Foramen Ovale, Patent / drug therapy
  • Foramen Ovale, Patent / mortality
  • Foramen Ovale, Patent / therapy*
  • Humans
  • Intention to Treat Analysis
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Risk
  • Secondary Prevention*
  • Septal Occluder Device* / adverse effects
  • Single-Blind Method
  • Stroke / etiology
  • Stroke / prevention & control*
  • Treatment Outcome

Substances

  • Fibrinolytic Agents

Associated data

  • ClinicalTrials.gov/NCT00465270