. 2018 Jun 17;7(12):e008356. doi: 10.1161/JAHA.117.008356

Table 1.

PFO Closure Versus Antithrombotic Therapy: Descriptive Summary of the Design of Randomized Trials Characteristics Included in the Meta‐Analysis

	Closure I (2012)7	PC Trial (2013)8	RESPECT (20139; 201710)	Gore REDUCE (2017)11	CLOSE (2017)12	DEFENSE‐PFO (2018)13
Trial design	Prospective, randomized, blinded adjudication of outcome events 1:1	Prospective, randomized, blinded adjudication of outcome events 1:1	Prospective, randomized, blinded adjudication of outcome events 1:1	Prospective, randomized, blinded adjudication of outcome events 2:1	Prospective, randomized, blinded adjudication of outcome events 1:1:1^a	Prospective, randomized 1:1
Main inclusion criteria	Age 18 to 60 y Cryptogenic ischemic stroke or TIA ≤6 months TEE‐verified PFO (with a bubble study showing right‐to‐left shunting at the atrial level during a Valsalva maneuver)	Age <60 y Cryptogenic IS or TIA or peripheral embolism; radiologically verified ischemic lesion mandatory TEE‐verified PFO	Age 18 to 60 y Cryptogenic ischemic stroke ≤270 d TEE‐verified PFO	Age 18 to 59 y Cryptogenic ischemic stroke ≤180 d TEE‐verified PFO	Age 16 to 60 y Cryptogenic ischemic stroke ≤6 mo TEE‐verified PFO with large interatrial shunt (>30 microbubbles) or ASA (septum primum excursion >10 mm)	Age 18 to 80 y Cryptogenic ischemic stroke ≤6 mo TEE‐verified PFO with atrial septum hypermobility (excursion ≥10 mm) or ASA (excursion ≥15 mm) or large PFO size (≥2 mm)
Intervention group (PFO Closure)	Transcatheter PFO closure+ Clopidogrel, 75 mg/d for 6 mo AND aspirin, 81 or 325 mg/d for 2 y	Transcatheter PFO closure+ Aspirin 100 to 325 mg/d for at least 5 to 6 mo AND ticlopidine 250 to 500 mg/d OR clopidogrel 75 to 150 mg/d for 1 to 6 mo	Transcatheter PFO closure+ Aspirin 81 to 325 mg/d AND clopidogrel daily for 1 mo, followed by aspirin monotherapy for 5 mo	Transcatheter PFO closure+ Clopidogrel 75 mg/d for 3 d (with 300‐mg dose if necessary) and then same antiplatelet therapy as in the other study arm (site specific), for the rest of the trial	Transcatheter PFO closure^a+ Aspirin 75 mg/d AND clopidogrel 75 mg/d for 3 mo, followed by single antiplatelet therapy for the rest of the trial	Transcatheter PFO closure+ Aspirin 100 mg/d AND clopidogrel 75 mg/d for at least 6 mo after the procedure
Control group (antithrombotic therapy)	At the investigator's discretion: Warfarin, aspirin, or both	At the investigator's discretion: antiplatelet therapy or anticoagulation	At the investigator's discretion: aspirin or warfarin or clopidogrel or/and aspirin plus dipyridamole	Antiplatelet therapy. Aspirin OR aspirin plus dipyridamole OR clopidogrel	Antiplatelet therapy: aspirin OR clopidogrel OR aspirin plus dipyridamole	At the investigator's discretion: single or dual antiplatelet therapy or anticoagulation (warfarin)
Primary end point	Composite: stroke or TIA, all‐cause mortality within 30 d, and death from neurologic causes between 31 d and 2 y	Composite: death, nonfatal stroke, TIA, peripheral embolism	Composite: ischemic stroke or early death (closure arm: within 30 d after closure or 45 d after randomization; antithrombotic arm: within 45 d after randomization)	2 co‐primary end points: Freedom from clinical ischemic stroke through 24 mo Composite of clinical ischemic stroke or silent brain infarction	Stroke (fatal or nonfatal, ischemic or hemorrhagic)	Composite: stroke, vascular death, major bleeding
Hypothesis	Rate of primary end point at 2 y: 6% in the medical arm and 3% in the closure arm	Rate of primary end point: 3%/y in the medical arm and 1%/y in the closure arm	Rate of primary end point at 2 y: 4.3% in the medical arm and 1% in the closure arm	Rate of primary end point at 2 y: 2.9% in the medical arm. 55% lower rate of recurrent stroke in the closure arm	Rate of primary end point: 3.5%/y in antiplatelet arm 50% lower rate in closure or anticoagulation arm	Rate of primary end point at 2 y: 15% in the medical arm and 4% in the closure arm
Enrollment period	June 2003–Oct 2008	Feb 2000–Feb 2009	Aug 2003–Dec 2011	Dec 2008–Feb 2015	Dec 2008–Dec 2014	Sept 2011–Oct 2017
Sites	87 sites in the United States and Canada	29 sites in Europe, Canada, Brazil, and Australia	69 sites in the United States and Canada	63 sites in Canada, Denmark, Finland, Norway, Sweden, United Kingdom, and United States	34 sites in France and Germany	2 sites in South Korea
Sample size (PFO closure group; antithrombotic therapy group)	N=909 (447; 462)	N=414 (204; 210)	N=980 (499; 481)	N=664 (441; 223)	N=663^a (Groups “1” and “2” in the original publication: 238 vs 235)	N=120 (60; 60)
Closure device	Starflex only	Amplatzer only	Amplatzer only	Helex Or Cardioform	At the investigator's discretion: Amplatzer (59%), Intrasept, Premere, Starflex, Figulla, Atriasept, Gore septal occluder	Amplatzer only
Sponsor	Industrial (NMT medical)	Industrial (St. Jude Medical)	Industrial (St. Jude Medical)	Industrial (Gore)	Academic (French Ministry of Health)	Academic (Cardiovascular Research Foundation, Seoul, South Korea)

ASA indicates atrial septal aneurysm; 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; IS, ischemic stroke; N, number; 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; TEE, transesophageal echocardiography; TIA, transient ischemic attack; TTE, transthoracic echocardiography.

Another intervention group in the 3‐arm CLOSE consisted of oral anticoagulation, the control group being antiplatelet therapy.12 The oral anticoagulation group was not described in the present table focusing on the intervention of PFO closure.