Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta-Analysis, and New Insights From the CLOSE Study

Abstract

Background: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing patent foramen ovale (PFO) closure, anticoagulation, and antiplatelet therapy to prevent stroke recurrence in patients with PFO-associated cryptogenic stroke.

Methods and results: We searched Medline, Cochrane Library, and EMBASE through March 2018. The primary outcome was stroke recurrence. Pooled incidences, hazard ratios, and risk ratios (RRs) were calculated in random-effects meta-analyses. PFO closure was associated with a lower risk of recurrent stroke compared with antithrombotic therapy (antiplatelet therapy or anticoagulation: 3560 patients from 6 RCTs; RR=0.36, 95% CI: 0.17-0.79; I²=59%). The effect of PFO closure on stroke recurrence was larger in patients with atrial septal aneurysm or large shunt (RR=0.27, 95% CI, 0.11-0.70; I²=42%) compared with patients without these anatomical features (RR=0.80, 95% CI, 0.43-1.47; I²=12%). Major complications occurred in 2.40% (95% CI, 1.03-4.25; I²=77%) of procedures. New-onset atrial fibrillation was more frequent in patients randomized to PFO closure versus antithrombotic therapy (RR=4.33, 95% CI, 2.37-7.89; I²=14%). One RCT compared PFO closure versus anticoagulation (353 patients; hazard ratio=0.14, 95% CI, 0.00-1.45) and 2 RCTs compared PFO closure versus antiplatelet therapy (1137 patients; hazard ratio=0.18, 95% CI, 0.05-0.63; I²=12%). Three RCTs compared anticoagulation versus antiplatelet therapy, with none showing a significant difference.

Conclusions: PFO closure is superior to antithrombotic therapy to prevent stroke recurrence after cryptogenic stroke. The annual absolute risk reduction of stroke was low, but it has to be tempered by a substantial time at risk (at least 5 years) in young and middle-aged patients. PFO closure was associated with an increased risk of atrial fibrillation.

Trial registration: ClinicalTrials.gov NCT00562289.

Keywords: anticoagulation; patent foramen ovale; patent foramen ovale closure; stroke.

Figure 1

Pooled risk ratio (A) and hazard ratio (B) of recurrent stroke in patients randomized to PFO closure vs antithrombotic therapy (random‐effects meta‐analysis). The closure and antithrombotic columns denote the number of events divided by the total number of patients in each treatment group. The DEFENSE‐PFO trial was not included in (B) because no HR was reported in the original publication. CI indicates confidence interval; CLOSE, Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; CLOSURE I, STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; DEFENSE‐PFO, Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale; Gore REDUCE, Gore Helex septal occluder and antiplatelet medical management for reduction of recurrent stroke or imaging‐confirmed transient ischemic attack in patients with patent foramen ovale; HR, hazard ratio; PC trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; PFO, patent foramen ovale; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; RR, risk ratio.

Figure 2

Trial sequential analysis of the risk of recurrent stroke in patients randomized to PFO closure vs antithrombotic therapy. The cumulative Z‐curve crosses the monitoring boundary (red dashed line) before reaching the required information size (RIS, red vertical line), providing evidence for the superiority of PFO closure over antithrombotic therapy to prevent recurrent stroke.26 CLOSE indicates Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; CLOSURE I, STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; DEFENSE‐PFO, Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale; Gore REDUCE, Gore Helex septal occluder and antiplatelet medical management for reduction of recurrent stroke or imaging‐confirmed transient ischemic attack in patients with patent foramen ovale; PC trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; PFO, patent foramen ovale; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment.

Figure 3

Pooled risk ratio of recurrent stroke in patients randomized to PFO closure vs antithrombotic therapy, according to PFO anatomical features (random‐effects meta‐analysis). For the present meta‐analysis, we defined higher‐risk anatomical features as follows (Table S4): For CLOSURE I, PC trial and RESPECT: presence of an atrial septal aneurysm (ASA), regardless of shunt size, For CLOSE and DEFENSE‐PFO: presence of an ASA and/or a large shunt (i.e., all included patients), For Gore REDUCE: moderate or large shunt (Nota bene: presence or absence of ASA could not be analyzed because it was not recorded in patients randomized to the antiplatelet group). Number of recurrent strokes in each group were extracted from the original publications of the randomized trials or calculated using published data by Kent et al.33 The Closure and Antithrombotic columns denote the number of events divided by the total number of patients in each treatment group. CI indicates confidence interval; CLOSE, Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; CLOSURE I, STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; DEFENSE‐PFO, Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale; Gore REDUCE, Gore Helex septal occluder and antiplatelet medical management for reduction of recurrent stroke or imaging‐confirmed transient ischemic attack in patients with patent foramen ovale; PC trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; PFO, patent foramen ovale; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; RR, risk ratio.

Figure 4

Kaplan–Meier cumulative estimates of the probability of recurrent stroke in patients randomized to PFO closure vs anticoagulation therapy in the CLOSE trial. This post hoc analysis was performed in the intention‐to‐treat cohort. The inset shows the same data on an enlarged y axis. CI indicates confidence interval; CLOSE, Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; PFO, patent foramen ovale.