PDF: RE-SPECT ESUS
(2019)Objective
Compare dabigatran versus aspirin for secondary stroke prevention in patients with embolic stroke of undetermined source (ESUS).
Study Summary
• Dabigatran was not superior to aspirin in preventing recurrent stroke in ESUS patients. Stroke recurrence and major bleeding rates were similar between groups, but dabigatran had higher rates of clinically relevant nonmajor bleeding.
Intervention
Dabigatran 150 mg BID (or 110 mg BID for patients ≥75 years or CrCl 30–50 mL/min) vs. aspirin 100 mg daily. Double-blind, randomized trial in 5,390 patients with recent ESUS. Median follow-up: 19 months.
Study Design
Arms: Array
Outcome
• Recurrent stroke: 6.6% (dabigatran) vs. 7.7% (aspirin); HR 0.85 (95% CI 0.69–1.03); P=0.10
• Ischemic stroke: 6.4% vs. 7.5%; HR 0.84 (95% CI 0.68–1.03)
• Disabling stroke: 0.6% vs. 0.9%; HR 0.59 (95% CI 0.36–0.96)
• Major bleeding: 2.9% vs. 2.4%; HR 1.19 (95% CI 0.85–1.66)
• Intracranial hemorrhage: 1.2% in both groups
• Clinically relevant nonmajor bleeding: 1.6% vs. 0.9%; HR 1.73 (95% CI 1.17–2.54)
• Composite of stroke, MI, or CV death: HR 0.88 (95% CI 0.73–1.06)
• Ischemic stroke: 6.4% vs. 7.5%; HR 0.84 (95% CI 0.68–1.03)
• Disabling stroke: 0.6% vs. 0.9%; HR 0.59 (95% CI 0.36–0.96)
• Major bleeding: 2.9% vs. 2.4%; HR 1.19 (95% CI 0.85–1.66)
• Intracranial hemorrhage: 1.2% in both groups
• Clinically relevant nonmajor bleeding: 1.6% vs. 0.9%; HR 1.73 (95% CI 1.17–2.54)
• Composite of stroke, MI, or CV death: HR 0.88 (95% CI 0.73–1.06)
Bottom Line
In patients with a recent embolic stroke of undetermined source, dabigatran was not found to be superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was similar between the two groups, but clinically relevant nonmajor bleeding events were more frequent with dabigatran.
Major Points
- Second major ESUS anticoagulation trial (after NAVIGATE ESUS). Both trials tested whether anticoagulation is superior to aspirin for ESUS — both were negative, effectively ending the ESUS anticoagulation hypothesis for the general ESUS population.
- Largest ESUS trial: 5,390 patients across 564 centers in 42 countries. Double-blind design (unlike NAVIGATE ESUS which was open-label) — the gold-standard design for drug comparison.
- Primary outcome: recurrent stroke 4.1%/yr dabigatran vs 4.8%/yr aspirin (HR 0.85, 95% CI 0.69–1.03, p=0.10) — a non-significant 15% relative risk reduction. Trend favoring dabigatran did not reach significance.
- Notably, disabling stroke showed a nominally significant reduction (HR 0.59, 95% CI 0.36–0.96, p=0.03), but this was not significant after hierarchical testing adjustment.
- Major bleeding was similar (1.7% vs 1.4%/yr, HR 1.19, p=NS) — a key difference from NAVIGATE ESUS where rivaroxaban showed significantly more major bleeding. Dabigatran appeared safer than rivaroxaban in the ESUS context.
- Clinically relevant non-major bleeding was higher with dabigatran (HR 1.73, 95% CI 1.17–2.54), but intracranial hemorrhage rates were identical (0.7%/yr in both groups).
- Dose-reduced dabigatran (110 mg BID) was used in patients ≥75 years or with CrCl 30–50 mL/min — a protocol feature not available in NAVIGATE ESUS (fixed-dose rivaroxaban).
- ESUS definition per Hart criteria: non-lacunar stroke on imaging, no ≥50% stenosis, no AF on ≥24h monitoring, no intracardiac thrombus, no other specific cause.
- 13% of patients had a PFO — these patients might have benefited from PFO closure rather than anticoagulation, potentially diluting the treatment effect.
- Together with NAVIGATE ESUS, established that empiric anticoagulation for ESUS is not beneficial — shifting focus to identifying specific ESUS subtypes (AF, PFO, cancer, aortic arch disease) for targeted therapy.
Study Design
- Study Type
- International, multicenter, randomized, double-blind trial.
- Randomization
- Yes
- Blinding
- Double-blind.
- Sample Size
- 5390
- Follow-up
- Median of 19 months.
- Centers
- 564
- Countries
- 42 countries
Primary Outcome
Definition: First recurrent stroke of ischemic, hemorrhagic, or unspecified type.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 7.7% (4.8% per year) | 6.6% (4.1% per year) | 0.85 (0.69 to 1.03) | 0.10 |
Limitations & Criticisms
- ESUS is a heterogeneous entity grouping PFO-related, occult AF, cancer-related, and aortic arch atheroma — treating all with one anticoagulant is likely to dilute any benefit in a specific subgroup.
- Only ≥24h cardiac monitoring was required to exclude AF — modern standards (30-day monitoring or implantable loop recorders) detect AF in 12–30% of cryptogenic stroke patients vs ~5% with 24h Holter.
- 13% of patients had a documented PFO — these patients may have benefited more from PFO closure than anticoagulation, confounding the intent-to-treat analysis.
- Industry-sponsored (Boehringer Ingelheim) — financial incentive to demonstrate superiority for dabigatran.
- Median 19-month follow-up was relatively short — longer follow-up might have allowed the trend (HR 0.85) to reach significance, as seen in RESPECT (initially negative at 2.6 years, positive at 5.9 years).
- No aortic arch imaging was mandated — aortic arch atheromas are a known but often undetected source of embolism in ESUS.
- The ESUS concept itself has been questioned after both NAVIGATE ESUS and RE-SPECT ESUS failed — some argue the entity should be abandoned in favor of more specific etiological classifications.
- Dose reduction criteria (age ≥75 or CrCl 30–50) may have undertreated some patients who could have tolerated full-dose dabigatran.
Citation
N Engl J Med 2019;380:1906-17.