TIMING
(2022)Objective
To investigate whether early (≤4 days) initiation of NOAC is noninferior to delayed (5-10 days) initiation after acute ischemic stroke in patients with atrial fibrillation
Study Summary
• No symptomatic ICH occurred in either group during 90-day follow-up
• Numerically lower rates of recurrent stroke (3.1% vs 4.6%) and death (4.7% vs 5.7%) with early initiation
Intervention
Early NOAC initiation (≤4 days from stroke onset) vs Delayed NOAC initiation (5-10 days from stroke onset); choice of NOAC at physician discretion
Inclusion Criteria
Adults ≥18 years with atrial fibrillation and acute ischemic stroke within 72 hours of symptom onset, eligible for NOAC treatment
Study Design
Arms: Early initiation (≤4 days) vs Delayed initiation (5-10 days)
Patients per Arm: Early: 450, Delayed: 438
Outcome
• Recurrent ischemic stroke: 3.11% vs 4.57%
• Symptomatic ICH: 0% vs 0%
Bottom Line
Early initiation of NOAC (≤4 days) was noninferior to delayed start (5-10 days) after acute ischemic stroke in patients with atrial fibrillation. No symptomatic intracerebral hemorrhage occurred in either group, and there were numerically lower rates of ischemic stroke and death with early initiation, supporting early NOAC initiation as safe for acute secondary stroke prevention.
Major Points
- Primary composite outcome occurred in 6.89% (early) vs 8.68% (delayed) (risk difference -1.79%, 95% CI -5.31% to 1.74%, P_noninferiority=0.004)
- No patient in either group experienced symptomatic intracerebral hemorrhage during 90-day follow-up
- Ischemic stroke rates were numerically lower with early initiation: 3.11% vs 4.57% (HR 0.67, 95% CI 0.34-1.33)
- All-cause mortality was numerically lower with early initiation: 4.67% vs 5.71% (HR 0.81, 95% CI 0.45-1.44)
- Early start was not superior to delayed start (P_superiority=0.38)
- NOAC was initiated on average at day 3 (66.8 hours) in early group vs day 5 (116.8 hours) in delayed group
- Major bleeding at 28 days: 7 events (early) vs 3 events (delayed), including 3 asymptomatic hemorrhagic transformations
- Results were consistent across all prespecified subgroups
- First randomized controlled study evaluating clinical outcomes of NOAC timing within 10 days post-stroke
Study Design
- Study Type
- Registry-based randomized controlled noninferiority trial, open-label, blinded end-point
- Randomization
- Yes
- Blinding
- Open-label for treatment allocation; blinded end-point evaluation. Patients and physicians aware of treatment group but outcome events verified through medical record review.
- Sample Size
- 888
- Follow-up
- 90 days
- Centers
- 34
- Countries
- Sweden
Primary Outcome
Definition: Composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage (≥10mm with NIHSS increase ≥4 points or ≥2 points in one category), or all-cause mortality at 90 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 8.68% (38/438 patients) | 6.89% (31/450 patients) | 0.78 (0.48 to 1.25 (for HR); -5.31% to 1.74% (for risk difference)) | 0.004 (noninferiority); 0.38 (superiority) |
Limitations & Criticisms
- Smaller than preplanned sample size (888 vs target 3000) due to recruitment challenges and COVID-19 pandemic
- Open-label design for treatment allocation, though end-point evaluation was blinded
- Lack of brain imaging data (MRI with DWI) to assess lesion size
- Stroke physicians' preference to start early may have introduced selection bias
- Enrollment coincided with transition from VKA to NOAC era, with concurrent observational studies supporting early NOAC safety
- Subgroup findings (potential harm in thrombectomy and NIHSS >15 patients) are hypothesis-generating only
- Study not powered to demonstrate superiority
- Registry-based design may have limitations despite strength in consecutive enrollment
- 17 patients (1.9%) did not start NOAC treatment (4 early, 13 delayed)
Citation
Circulation. 2022;146:1056-1066