INTERACT3
(2023)Objective
Determine whether a care bundle targeting multiple physiological variables improves outcomes in patients with acute intracerebral hemorrhage.
Study Summary
• In patients with acute spontaneous ICH presenting within 6 hours, a goal-directed care bundle (targeting SBP <140 mm Hg, glucose, temperature, and INR control) improved 6-month functional outcomes versus usual care. This is the first phase 3 RCT to show improved outcomes from acute treatment of ICH.
Intervention
Stepped-wedge cluster randomized trial across 121 hospitals in 10 countries. Hospitals transitioned from usual care to a care bundle consisting of: • SBP <140 mm Hg within 1 hour • Blood glucose control (6.1–7.8 mmol/L non-DM; 7.8–10.0 mmol/L in DM) • Antipyrexia (temperature ≤37.5°C) • INR <1.5 (if on warfarin) Primary outcome: mRS at 6 months.
Study Design
Arms: Array
Outcome
• Favorable shift in mRS distribution: OR 0.86 (95% CI 0.76–0.97); p=0.015
• Mortality: 13.6% (care bundle) vs. 16.6% (usual care); OR 0.77; p=0.015
• Serious adverse events: 16.0% vs. 20.1%; p=0.0098
• Improved EQ-5D utility score; p=0.0008
• Number needed to treat to prevent one death or major disability = 35
• No significant differences in INR reversal or glycemic/pyrexia endpoints
• Mortality: 13.6% (care bundle) vs. 16.6% (usual care); OR 0.77; p=0.015
• Serious adverse events: 16.0% vs. 20.1%; p=0.0098
• Improved EQ-5D utility score; p=0.0008
• Number needed to treat to prevent one death or major disability = 35
• No significant differences in INR reversal or glycemic/pyrexia endpoints
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.
Study Design
- Study Type
- Pragmatic, multicenter, stepped-wedge cluster randomized trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 7976
- Follow-up
- 6 months
- Centers
- 121
- Countries
- China, India, Vietnam, Mexico, Brazil, Chile, Peru
Primary Outcome
Definition: Functional outcome measured by modified Rankin Scale (mRS) at 6 months
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| More unfavorable distribution of mRS | Shift toward lower (better) mRS scores | - (0.75–0.99) | 0.04 |
Limitations & 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.
Citation
Anderson CS, et al. Lancet. 2023;401(10389):102–113.