TIMING Trial: Early vs Delayed NOAC Initiation After AF-Related Ischemic Stroke
In patients with acute AF-related ischemic stroke, is early NOAC initiation within 4 days non-inferior to delayed initiation (5-10 days) for the composite of recurrent stroke, symptomatic ICH, or death at 90 days?
Oldgren et al. (Circulation 2022) · 888 patients
Population
Included
- Acute ischemic stroke with atrial fibrillation
- Indication for long-term oral anticoagulation
- Randomized via the Swedish Stroke Register
- Ability to initiate NOAC within 4 days or 5-10 days of stroke onset
Target population
- Adults at least 18 years of age
- Atrial fibrillation (paroxysmal, persistent, or permanent), either previously known or diagnosed during the index hospitalization
- Recent ischemic stroke within 72 hours of symptom onset
- Eligible for and willing to start non-vitamin K antagonist oral anticoagulant (NOAC) treatment
Conditional eligibility
- Patients on ongoing oral anticoagulant therapy at the index stroke were eligible only if NOAC therapy was interrupted for at least 2 days at the index stroke, or the international normalized ratio was 1.7 or below on prior warfarin
- After reperfusion therapy, control brain imaging had to be performed before the patient was considered eligible
Excluded
- Mechanical heart valve
- Prior therapeutic anticoagulation at time of stroke
- Severe renal failure (eGFR below 15 mL/min)
- High bleeding risk precluding any anticoagulation
Exclusions
- Contraindication to NOAC therapy (for example ongoing bleeding or mechanical heart valve prosthesis)
- Previous participation in the TIMING study
Source: Oldgren J et al., Circulation 2022· Retrieved 2026-06-09
Primary Outcome — Composite at 90 Days (Non-inferiority)
888 patients; early NOAC within 4 days vs delayed 5-10 days after AF-related stroke
Non-inferiority design
This trial tested whether early NOAC is no worse than delayed initiation, not whether it is better. Non-inferiority met (P=0.004 for NI). Zero symptomatic ICH in either arm.
Negligible absolute difference
Composite: Recurrent Stroke, sICH, or Death at 90 Days
Study Arms
- Agent
- Non-vitamin K antagonist oral anticoagulant (apixaban, dabigatran, edoxaban, or rivaroxaban)
- Dose
- Standard stroke-prevention dosing; specific agent and dose at the treating physician's discretion
- Route
- Oral
- Frequency
- Per product labeling for the chosen NOAC
- Duration
- Initiated within 4 days (on or before day 4) of stroke onset; long-term anticoagulation continued
- Co-interventions
- All four NOACs available and reimbursed in Sweden; choice of agent and exact day within the assigned window at physician discretion
Mean NOAC initiation was 66.8 hours (day 3) after stroke onset in the early group
- Agent
- Non-vitamin K antagonist oral anticoagulant (apixaban, dabigatran, edoxaban, or rivaroxaban)
- Dose
- Standard stroke-prevention dosing; specific agent and dose at the treating physician's discretion
- Route
- Oral
- Frequency
- Per product labeling for the chosen NOAC
- Duration
- Initiated 5 to 10 days after stroke onset; long-term anticoagulation continued
- Co-interventions
- All four NOACs available and reimbursed in Sweden; choice of agent and exact day within the assigned window at physician discretion
Mean NOAC initiation was 116.8 hours (day 5) after stroke onset in the delayed group. Noninferiority margin was 3 percentage points (absolute); early initiation was noninferior (P=0.004) but not superior (P=0.380)
Trial Design
Type
- Registry-based randomized noninferiority trial
- Early NOAC initiation <=4 days vs delayed initiation 5-10 days
- Patients with acute ischemic stroke and atrial fibrillation
- Open-label with blinded endpoint assessment
Timeline
Swedish Stroke Register, 2017-2020
N
888
Enrollment
888 patients randomized via the Swedish Stroke Register. Registry-based open-label randomized noninferiority trial. NOAC started within 4 days (early) or 5-10 days (delayed). Published Circulation 2022.
ClinicalTrials.gov
NCT02961348Bedside Pearl
TIMING met its non-inferiority margin and supports early NOAC initiation within 4 days after AF-related ischemic stroke as safe. This does not mandate same-day initiation; the early window was days 1-4. Individualize timing based on infarct size, hemorrhagic transformation risk, and NIHSS. OPTIMAS (N=3621) provides larger, more definitive evidence and reached the same NI conclusion with a delayed window of 7-14 days.
See also