COCROACH
(2023)Objective
To estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation using prospective individual participant data meta-analysis of randomised trials
Study Summary
• OAC significantly reduced ischaemic major adverse cardiovascular events (4% vs 19%, HR 0.27, 95% CI 0.13–0.56, p=0.0004)
• No significant increase in haemorrhagic events (7% vs 5%, HR 1.80, 95% CI 0.77–4.21) or death from any cause (18% vs 15%, HR 1.29)
Intervention
Starting oral anticoagulation (99% DOAC) vs avoiding oral anticoagulation (67% no antithrombotic, 33% antiplatelet monotherapy)
Inclusion Criteria
Participants from registered randomised trials with spontaneous intracranial haemorrhage and atrial fibrillation assigned to start or avoid long-term oral anticoagulation
Study Design
Arms: Start oral anticoagulation vs Avoid oral anticoagulation
Patients per Arm: 212 start vs 200 avoid
Outcome
• Ischaemic MACE significantly reduced with OAC (HR 0.27, 95% CI 0.13–0.56)
• No significant subgroup interaction by ICH location, age, sex, CHA2DS2-VASc score, or timing
Bottom Line
Oral anticoagulation (99% DOACs) significantly reduced ischaemic major adverse cardiovascular events (HR 0.27) in ICH survivors with atrial fibrillation, but had uncertain effects on the composite of any stroke or cardiovascular death (HR 0.68, not significant), haemorrhagic events, and functional outcome. No significant subgroup interactions were found, including by ICH location. The absolute ischaemic benefit appeared to exceed the potential haemorrhagic risk increase, but net benefit remains unconfirmed pending completion of 5 ongoing trials.
Major Points
- Prospective IPD meta-analysis of 412 participants from 4 completed RCTs (SoSTART, APACHE-AF, NASPAF-ICH, ELDERCARE-AF)
- 99% of participants assigned to start OAC received a DOAC (apixaban 130, edoxaban 61, dabigatran 12, rivaroxaban 6); only 3 received warfarin
- 33% of the avoid group received antiplatelet monotherapy; 67% received no antithrombotic therapy
- Primary outcome (any stroke or cardiovascular death): 14% vs 22%, pooled HR 0.68 (95% CI 0.42–1.10, p=0.12, I²=0%)
- Ischaemic MACE significantly reduced: 4% vs 19%, pooled HR 0.27 (95% CI 0.13–0.56, p=0.0004, I²=0%)
- Ischaemic stroke specifically reduced: 4% vs 16%, pooled HR 0.37 (95% CI 0.17–0.83, I²=0%)
- Haemorrhagic MACE not significantly increased: 7% vs 5%, pooled HR 1.80 (95% CI 0.77–4.21, I²=0%)
- All-cause death numerically higher with OAC: 18% vs 15%, pooled HR 1.29 (95% CI 0.78–2.11, I²=50%)
- No significant subgroup interaction by ICH location (lobar vs non-lobar), age, sex, timing, or CHA2DS2-VASc score
- ENRICH-AF Data Monitoring Committee stopped enrolment of lobar ICH and convexity SAH participants due to excess haemorrhagic stroke risk with edoxaban, contrasting with COCROACH findings
- Five ongoing trials (STATICH, A3-ICH, ASPIRE, ENRICH-AF, PRESTIGE-AF) may add ~2000 participants by 2028
- Death or dependence at 1 year was similar: 53% vs 51%, pooled OR 1.12 (95% CI 0.70–1.79, I²=0%)
Study Design
- Study Type
- Prospective individual participant data meta-analysis of randomised controlled trials
- Randomization
- Yes
- Blinding
- Three of four included trials were open-label (SoSTART, APACHE-AF, NASPAF-ICH); ELDERCARE-AF was placebo-controlled. All trials had independent outcome adjudication blinded to treatment assignment.
- Sample Size
- 412
- Follow-up
- Maximum 2–6 years across included trials
- Centers
- 67
- Countries
- UK, Netherlands, Canada, Japan
Primary Outcome
Definition: Any stroke (non-fatal symptomatic ischaemic stroke, haemorrhagic stroke, or stroke of unknown type) or cardiovascular death (death within 30 days of stroke, other ICH, extracranial haemorrhage, MI, or systemic embolism; sudden cardiac death; death from another vascular cause; or death of unknown cause)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 43/200 (22%) | 29/212 (14%) | 0.68 (0.42–1.10) | 0.12 |
Limitations & Criticisms
- Small total sample size (412 participants) insufficient to provide definitive evidence of superiority, non-inferiority, or heterogeneity in subgroups
- Three of four trials were open-label, conferring risk of performance bias
- Baseline covariates for ELDERCARE-AF were not fully available due to deidentification policy (sex, ethnicity removed)
- ELDERCARE-AF used low-dose edoxaban (15 mg daily) rather than full therapeutic dose, differing from the other 3 trials
- 33% of the control group received antiplatelet monotherapy, which may have attenuated effect sizes
- Incomplete adherence to OAC in open-label trials may have attenuated treatment effects
- Under-representation of Black and non-White ethnic groups (~76% White overall)
- No as-treated or per-protocol analyses performed
- Contrasting findings with ENRICH-AF safety signal in lobar ICH/convexity SAH raise uncertainty about ICH location effects
- Direction of effect reversed for fatal outcomes (HR 1.32) vs overall primary composite (HR 0.68), raising concern about severity of events in the OAC group
- Moderate heterogeneity (I²=50%) observed for all-cause death outcome
- Two participants from SoSTART opted out of data sharing
- Only 4 trials completed; 5 ongoing trials with ~2000 additional participants needed for definitive conclusions
Citation
Lancet Neurol 2023; 22: 1140–49