RE-SPECT ESUS (PFO subgroup): Dabigatran vs Aspirin in the Patent Foramen Ovale Subgroup of RE-SPECT ESUS (Diener et al., Stroke 2021)
In embolic stroke of undetermined source with a detected patent foramen ovale, does dabigatran reduce recurrent stroke compared with aspirin? The interaction test was null.
Diener HC et al. (Stroke 2021;52(3):1065-1068); parent Diener HC et al. (NEJM 2019;380(20):1906-1917) · doi:10.1161/STROKEAHA.120.031237 · 680 patients
Population
Included
- Embolic stroke of undetermined source (ESUS)
- For the subgroup: a patent foramen ovale detected during standard workup
Verifier-confirmed inclusion
- Embolic stroke of undetermined source; 5,390 patients randomized
- For the PFO subgroup: a patent foramen ovale detected during workup (680 of 5,388 patients with PFO status recorded, 12.6%)
Excluded
- Atrial fibrillation on the monitoring performed before randomization
- An identified cardioembolic, large-artery or small-vessel stroke mechanism (the ESUS construct excludes these by definition)
Ascertainment note that functions as an eligibility caveat
- The trial did NOT mandate transesophageal echocardiography or bubble contrast, so entry into the PFO subgroup depended on whichever imaging the enrolling site happened to perform. A 12.6% detected prevalence, against the 33.8% PICSS detected in a cohort that did undergo transesophageal echocardiography, means the subgroup is incompletely and non-randomly ascertained. This is not a PFO-selected population.
Remaining exclusions (not recoverable)
- The full published exclusion list was not retrieved by the evidence packet. The ClinicalTrials.gov record (NCT02239120) was not mirrored, following the precedent set for the PFO-for-migraine cluster. Read this as a gap in what NeuroWiki can source, not as an absence of exclusion criteria in the trial.
Result in the PFO group
SUBGROUP, INTERACTION NULL
NO PER-ARM RATES EXIST FOR THIS SUBGROUP. The publication reports a hazard ratio only, and the arm-level figure in circulation comes from the AAN 2020 practice advisory rather than from the paper itself. NeuroWiki does not claim this subgroup analysis was prespecified: the evidence packet could not establish it.
Hazard ratio (AAN 2020 extraction)
0.88
95% CI 0.45 to 1.71
The interval includes 1, so no difference was demonstrated.
No arms are drawn because no per-arm event rates were published for this subgroup. The PFO-by-treatment interaction was p=0.8290: PFO status did not modify the treatment effect. This trial matters most for what it did to the pooled evidence. Adding it to the 2018 pooled analysis, by the same method and on the same set, moved the estimate from an odds ratio of 0.48 (0.24 to 0.96, significant) to 0.70 (0.43 to 1.14, not significant). No NNT is computed.
Study Arms
- Agent
- Dabigatran etexilate
- Dose
- 150 mg or 110 mg twice daily
- Route
- Oral
- Frequency
- Twice daily
Both dose strata were used in the parent trial. Safety was not presented for the PFO subgroup; overall, clinically relevant non-major bleeding was more common with dabigatran.
- Agent
- Aspirin
- Dose
- 100 mg daily
- Route
- Oral
- Frequency
- Once daily
Trial Design
Type
- PFO subgroup of RE-SPECT ESUS, a randomized superiority trial of dabigatran 150 or 110 mg twice daily against aspirin 100 mg daily
- Parent population: 5,390 patients with embolic stroke of undetermined source
- The parent trial RAN TO COMPLETION and its primary endpoint was NOT met
- The PFO subgroup has a DEDICATED publication in Stroke (2021), two years after the parent; it is NOT reported in the 2019 NEJM paper, and citing NEJM 2019 for it is a misattribution
- Whether the subgroup analysis was PRESPECIFIED could NOT be established, and NeuroWiki does not claim that it was
- The trial did NOT mandate transesophageal echocardiography or bubble contrast, so PFO ascertainment is incomplete and non-random
Timeline
Parent published NEJM 2019;380(20):1906-1917; PFO subgroup published Stroke 2021;52(3):1065-1068
N
680
Enrollment
5,390 patients randomized in the parent trial, which ran to completion and did not meet its primary endpoint. A PFO was documented in 680 of the 5,388 with PFO status recorded (12.6%). Dabigatran 150 mg or 110 mg twice daily against aspirin 100 mg daily. The PFO subgroup has a dedicated publication in Stroke 2021; do not cite the 2019 parent paper for it.
ClinicalTrials.gov
NCT02239120Bedside Pearl
RE-SPECT ESUS PFO subgroup (Stroke 2021, NOT the 2019 NEJM parent): dabigatran vs aspirin 100 mg in the 680 of 5,388 patients (12.6%) with a detected PFO. The interaction with treatment is flatly null, p=0.8290. Per-arm rates were never published, and the HR 0.88 (95% CI 0.45 to 1.71) in circulation is an AAN 2020 EXTRACTION, not a Diener 2021 figure. Prespecification could not be established, so NeuroWiki does not claim it. Adding this trial to the 2018 pool moved OR 0.48 (95% CI 0.24 to 0.96) to OR 0.70 (95% CI 0.43 to 1.14). Authors: there is insufficient evidence to recommend anticoagulation over antiplatelet therapy in ESUS with a PFO. No NNT.