PDF: RESPECT
(2017)Objective
PFO closure to reduce the risk of recurrent ischemic stroke in patients with a prior cryptogenic stroke.
Study Summary
• PFO closure reduced the risk of recurrent ischemic stroke compared to medical therapy in patients with prior cryptogenic stroke; • PFO closure was associated with a higher risk of venous thromboembolism.
Intervention
Amplatzer PFO Occluder placement versus medical therapy (aspirin, warfarin, clopidogrel, or aspirin with dipyridamole).
Inclusion Criteria
Patients aged 18–60 with cryptogenic ischemic stroke and confirmed PFO. Excluded if another stroke cause was identified (e.g., large-vessel disease, hypercoagulability).
Study Design
Arms: PFO Closure vs. Medical Therapy
Patients per Arm: PFO Closure: 499, Medical Therapy: 481
Outcome
• Recurrent ischemic stroke: 0.58 vs. 1.07 per 100 patient-years (HR 0.55; 95% CI, 0.31–0.999; P=0.046). <br>• Cryptogenic stroke: HR 0.38 (P=0.007). <br>• Venous thromboembolism was more common with PFO closure.
Bottom Line
In this long-term follow-up of patients who had a cryptogenic stroke, PFO closure with the Amplatzer PFO Occluder was associated with a significantly lower rate of recurrent ischemic strokes compared to medical therapy alone. The benefit was most pronounced for strokes of undetermined cause. Venous thromboembolism was more common in the PFO closure group.
Major Points
- Landmark PFO closure trial — one of three RCTs published in 2017 (with CLOSE and REDUCE) that collectively established PFO closure as a treatment option for cryptogenic stroke. RESPECT was the longest-running, with median 5.9-year follow-up.
- Published in two phases: initial 2013 report was borderline negative (HR 0.49, p=0.08); the 2017 extended follow-up finally reached significance (HR 0.55, 95% CI 0.31–0.999, p=0.046).
- 980 patients randomized 1:1 across 69 US/Canadian centers. Used the Amplatzer PFO Occluder (St. Jude Medical/Abbott) — the first device specifically designed for PFO closure.
- Primary outcome: recurrent ischemic stroke was 0.58 vs 1.07 events per 100 patient-years (HR 0.55, NNT ~50 over median 5.9 years).
- Recurrent cryptogenic stroke (TOAST criteria) showed the strongest signal: HR 0.08 (95% CI 0.01–0.58, p=0.01), with only 1 event in closure group vs 11 in medical therapy — suggesting PFO closure specifically prevents paradoxical embolism.
- 48% of patients had a substantial right-to-left shunt, 36% had atrial septal aneurysm — both features that predicted greater benefit from closure.
- Venous thromboembolism was more common after closure: PE 0.41 vs 0.11 per 100 patient-years (HR 3.48, p=0.04), likely related to device endothelialization period.
- Device implantation success rate was 99.1%. Procedure-related serious adverse events occurred in 4.2% (21/499) of closure patients.
- Medical therapy was heterogeneous: aspirin, warfarin, clopidogrel, or aspirin-dipyridamole at investigator discretion — reflecting the lack of evidence-based guidance for ESUS at the time.
- FDA approved the Amplatzer PFO Occluder in 2016 based primarily on RESPECT data — the first PFO closure device to gain FDA approval.
Study Design
- Study Type
- Multicenter, randomized, open-label trial, with blinded adjudication of end-point events.
- Randomization
- Yes
- Blinding
- Open-label treatment with blinded endpoint adjudication.
- Sample Size
- 980
- Follow-up
- Median of 5.9 years.
- Centers
- 69
- Countries
- United States, Canada
Primary Outcome
Definition: The primary efficacy endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.07 events per 100 patient-years (28/481 patients) | 0.58 events per 100 patient-years (18/499 patients) | 0.55 (0.31 to 0.999) | 0.046 |
Limitations & Criticisms
- Initial 2013 publication was statistically negative — the 2017 extended follow-up publication achieved significance only with additional years of data, raising concerns about post hoc analysis.
- Dropout rate was markedly asymmetric: 33.3% medical therapy vs 20.8% closure — potentially biasing results if dropouts had different event rates.
- No mandatory prolonged cardiac monitoring to exclude occult atrial fibrillation — some 'cryptogenic' strokes may have been AF-related, diluting the treatment effect.
- Industry-sponsored (St. Jude Medical/Abbott) — the company that manufactured the Amplatzer PFO Occluder.
- Medical therapy arm was heterogeneous (4 different regimens, investigator choice) — no standardized comparator, making it unclear what optimal medical therapy should be.
- 270-day enrollment window (9 months from stroke) was the longest of any PFO trial — patients far from the index event may have different recurrence risk profiles.
- Higher VTE rate in closure group (PE HR 3.48) was an unexpected safety signal — possibly related to immobilization during procedure or device surface before endothelialization.
- The p-value of 0.046 is borderline significant — small changes in event adjudication could shift the result to non-significance.
- Limited to ages 18–60 — does not address PFO closure in older patients where age-related atrial fibrillation becomes more prevalent as a competing etiology.
Citation
N Engl J Med 2017;377:1022-32.