INTERACT3
Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial–3
Clinical Question
Does a goal-directed care bundle improve functional outcomes in patients with acute intracerebral hemorrhage (ICH)?
Bottom Line
A care bundle targeting early BP lowering, glucose and temperature control, and reversal of anticoagulation improved functional outcomes in acute ICH, especially in low-resource settings.
Major Points
- Largest pragmatic ICH management trial: 7,976 patients across 121 hospitals in 10 low- and middle-income countries using an innovative stepped-wedge cluster randomized design.
- Care bundle targeted four modifiable physiological parameters simultaneously: BP <140 mmHg within 1 hour, temperature <37.5°C, glucose 6.1–7.8 mmol/L (nonfasting)/4.4–6.1 mmol/L (fasting), and rapid anticoagulant reversal.
- Significantly improved functional outcomes: favorable shift in mRS distribution at 6 months (adjusted common OR 0.86, 95% CI 0.76–0.97, P=0.015).
- No significant reduction in 6-month mortality (11.3% vs 12.0%, P=0.32) — benefit was in disability reduction rather than survival.
- Most benefit observed in low-resource healthcare settings — the care bundle had greatest impact where baseline ICH management was most variable.
- Builds on INTERACT2 (2013, intensive BP lowering in ICH) by adding glucose, temperature, and anticoagulant reversal — a comprehensive 'bundle' approach rather than single-intervention.
- Implemented via site-based quality improvement with centralized training — a scalable model applicable to diverse healthcare systems worldwide.
- Stepped-wedge design allowed every site to eventually receive the intervention, improving ethical acceptability and maximizing learning from all enrolled patients.
- Only 3% of patients were on anticoagulants — the anticoagulant reversal component contributed minimally; the main drivers were likely BP and glucose management.
- Together with INTERACT2 and ATACH-2, defined the current approach to acute ICH management — INTERACT3 extended the evidence to bundled care and low-resource settings.
Design
Study Type: Pragmatic, multicenter, stepped-wedge cluster randomized trial
Randomization: 1
Blinding: Open-label
Enrollment Period: August 2017 – March 2022
Follow-up Duration: 6 months
Centers: 121
Countries: China, India, Vietnam, Mexico, Brazil, Chile, Peru
Sample Size: 7976
Analysis: Intention-to-treat with mixed-effects ordinal logistic regression
Inclusion Criteria
- Adult patients (≥18 years)
- Presenting within 6 hours of symptom onset
- Confirmed spontaneous ICH on imaging
Exclusion Criteria
- Primary intraventricular hemorrhage
- Contraindication to active BP lowering
- Planned surgical evacuation of hematoma
Arms
| Field | Control | Care Bundle |
|---|---|---|
| Intervention | Standard management per local guidelines without protocolized care bundle | BP <140 mmHg, temperature <37.5°C, glucose 6–10 mmol/L, anticoag reversal (if needed) |
| Duration | 6 months follow-up | 6 months follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Functional outcome measured by modified Rankin Scale (mRS) at 6 months | Primary | More unfavorable distribution of mRS | Shift toward lower (better) mRS scores | 0.04 | |
| Mortality at 6 months | Secondary | 12.0% | 11.3% | 0.32 | |
| Serious adverse events | Secondary | 5.1% | 4.3% | 0.11 | |
| Any Serious Adverse Event | Adverse | 5.1% | 4.3% | 0.11 | |
| Recurrent ICH | Adverse | 1.0% | 0.9% | 0.64 | |
| Hypoglycemia | Adverse | 0.4% | 0.6% | 0.49 |
Criticisms
- Open-label stepped-wedge design — sites knew when they transitioned to the care bundle, potentially introducing Hawthorne effect and performance bias.
- Primary outcome (mRS shift) is modestly subjective — open-label knowledge of allocation could influence assessors despite attempts at standardization.
- Cluster design relies on site compliance and fidelity to all four bundle components — variable implementation across 121 sites in 10 countries limits internal validity.
- No effect on mortality (11.3% vs 12.0%) despite functional improvement — raises questions about whether the bundle truly changes outcomes or simply improves documentation.
- Cannot determine which bundle component(s) drove the benefit — BP, glucose, temperature, or anticoagulant reversal contributions are impossible to disentangle.
- Predominantly Asian population (China contributed majority of patients) — generalizability to other regions' ICH populations and healthcare systems is uncertain.
- Only 3% on anticoagulants — the reversal component, which has the strongest individual evidence base, contributed minimally to the observed effect.
- COVID-19 pandemic overlap (enrollment ended March 2022) may have affected care patterns, hospital resources, and follow-up completeness.
- The stepped-wedge design introduces temporal confounding — secular trends in ICH management during the enrollment period could mimic treatment effects.
Funding
UK Department of Health, WHO, NHMRC (Australia), and multiple regional sources
Based on: INTERACT3 (The Lancet, 2023)
Authors: Anderson CS, Arima H, Wang JG, et al.
Citation: Anderson CS, et al. Lancet. 2023;401(10389):102–113.
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