RESPECT (Long-Term): Extended Follow-up of PFO Closure with the Amplatzer Occluder for Cryptogenic Stroke (Saver et al., 2017)
In patients 18–60 with cryptogenic ischemic stroke and a PFO, does transcatheter closure with the Amplatzer Occluder reduce recurrent ischemic stroke compared with medical therapy over extended follow-up? Note: original 2013 primary analysis at 2.1 years missed ITT significance (P=0.08); this is the pre-specified extended-follow-up analysis at median 5.9 years.
Saver JL et al. (NEJM 2017;377:1022-1032) · doi:10.1056/NEJMoa1610057 · 980 patients
Population
Included
- Age 18–60 years
- Cryptogenic ischemic stroke within 270 days before randomization
- TEE-confirmed PFO
- Mechanism workup excluded large-vessel arteriopathy, established cardioembolic source, intrinsic small-vessel disease, arterial hypercoagulable state (antiphospholipid antibodies, hyperhomocysteinemia)
Core inclusion
- Age 18 to 60 years
- Cryptogenic ischaemic stroke
- PFO confirmed by transoesophageal echocardiography
- Able to undergo randomisation within 270 days after the index stroke
Excluded
- Identifiable competing stroke mechanism
- Age outside 18–60
- Inability to undergo randomization within 270 days of index stroke
Exclusions
- An identifiable mechanism for the qualifying stroke other than presumed paradoxical embolisation (large-vessel arteriopathy, a cardiac source of embolism, intrinsic small-vessel disease, or an arterial hypercoagulable state as indicated by antiphospholipid antibodies or hyperhomocysteinaemia)
- Age outside 18 to 60 years
- Inability to undergo randomisation within 270 days of the index stroke
Source: Saver et al., N Engl J Med 2017;377:1022-1032· Retrieved 2026-06-09
Primary Outcome
Recurrent ischemic stroke at median 5.9-year follow-up
Negligible absolute difference
Recurrent ischemic stroke at 5.9y
Study Arms
- Agent
- Amplatzer PFO Occluder (St. Jude Medical)
- Dose
- Single device implantation
- Route
- Percutaneous transcatheter implantation under fluoroscopic and echocardiographic guidance
- Frequency
- Single closure procedure within 21 days of randomisation
- Duration
- Permanent implant; antithrombotic therapy at site investigator discretion after the first 6 months
- Co-interventions
- Patients continued their prerandomisation antithrombotic regimen until placement; after implantation, aspirin 81 to 325 mg plus clopidogrel 75 mg daily for 1 month, then aspirin monotherapy for 5 months
Extended follow-up (median 5.9 years) of the intention-to-treat population from the original RESPECT trial.
- Agent
- Antithrombotic medical therapy
- Dose
- Site-chosen regimen
- Route
- Oral
- Frequency
- Daily
- Duration
- Throughout follow-up
- Co-interventions
- Permitted regimens were aspirin, warfarin, clopidogrel, or aspirin plus extended-release dipyridamole; aspirin plus clopidogrel was permitted initially but eliminated in 2006 to conform to a change in guidelines
Medical-therapy patients received substantially more anticoagulation over follow-up (21.6% of patient-years on anticoagulant versus 3.3% in the closure group).
Safety
Procedure-related atrial fibrillation/flutter
1.4%
0%
Procedure-related atrial fibrillation/flutter: 7 events in 499 PFO closure patients (1.4%), all resolved before discharge from the hospital. Source: Saver et al., NEJM 2017, Table 3.
Trial Design
Type
- Multicenter, randomized, open-label, controlled trial with blinded endpoint adjudication
- 1:1 PFO closure vs medical therapy
- Stratified randomization by site, planned antithrombotic regimen, and presence/absence of atrial septal aneurysm
- 69 sites in US and Canada
- Original primary analysis (Carroll JD et al., NEJM 2013;368:1092–1100) at median 2.1-year follow-up: HR 0.49 (95% CI 0.22–1.11, P=0.08). Did not meet ITT primary
- Extended follow-up (this paper) at median 5.9 years. Pre-specified as exploratory
- No alpha-spending adjustment applied to long-term P-value; group-sequential Lan–DeMets threshold for final analysis would have been 0.043
Timeline
Enrolled August 2003 to December 2011; original primary analysis reported 2013 at median 2.1y; extended follow-up database lock May 31, 2016, median 5.9y
N
980
Enrollment
980 patients (499 PFO closure / 481 medical therapy) at 69 sites in US + Canada. Enrolled August 2003 to December 2011. Original primary analysis 2013 at median 2.1y was borderline (P=0.08); extended follow-up reported here at median 5.9y. Published NEJM 2017.
ClinicalTrials.gov
NCT00465270Bedside Pearl
RESPECT (long-term): in patients 18–60 with cryptogenic ischemic stroke and PFO, Amplatzer Occluder vs medical therapy reduced recurrent ischemic stroke over median 5.9y (3.6% vs 5.8%, HR 0.55, P=0.046, NNT 42). The original 2013 primary at 2.1y was negative; benefit emerges with time. Read with CLOSE and REDUCE (same NEJM 2017 issue).
See also