INTERACT3
The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial
Clinical Question
Does a goal-directed care bundle improve functional outcomes in patients with acute intracerebral hemorrhage (ICH)?
Study Overview
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.
Bottom Line
A goal-directed care bundle targeting early BP lowering (<140 mmHg), glucose and temperature control, and reversal of anticoagulation improved 6-month functional outcomes in acute ICH, with a favorable shift in mRS distribution (common OR 0.86, 95% CI 0.76–0.97, p=0.015).
Major Points
- Largest pragmatic ICH management trial: 7,036 patients randomized (6,255 in primary analysis) across 121 hospitals in 10 countries (9 LMICs plus Chile) using a stepped-wedge cluster randomized design.
- Care bundle targeted four modifiable physiological parameters: BP <140 mmHg within 1 hour, temperature <37.5°C, glucose 6.1–7.8 mmol/L in patients without diabetes (7.8–10.0 mmol/L in those with diabetes), and rapid anticoagulant reversal (INR <1.5 within 1 hour if on warfarin).
- Significantly improved functional outcomes: favorable shift in mRS distribution at 6 months (common OR 0.86, 95% CI 0.76–0.97, p=0.015; adjusted OR 0.84, 0.73–0.97, p=0.017).
- Lower odds of death at 6 months in the primary model (OR 0.77, 95% CI 0.63–0.95, p=0.015; crude 13.6% vs 16.6%), though this became non-significant after adjustment for country and patient characteristics (0.84, 0.65–1.07, p=0.16).
- Significantly fewer serious adverse events in the care bundle group (516/3221 [16.0%] vs 767/3815 [20.1%]; p=0.0098).
- Health-related quality of life EQ-5D utility score was significantly higher in the care bundle group (mean difference 0.04, 95% CI 0.02–0.07; p=0.0008).
- 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.
- Stepped-wedge design allowed every site to eventually receive the intervention, improving ethical acceptability.
- Only ~1% of patients were on anticoagulants (Table 1: 0.9% care bundle vs 1.0% usual care) — the anticoagulant reversal component contributed minimally; main drivers were likely BP and glucose management.
- Together with INTERACT2 and ATACH-2, defines the current approach to acute ICH management — INTERACT3 extended the evidence to bundled care in LMIC settings.
Design
Study Type: Pragmatic, international, multicentre, blinded endpoint, stepped-wedge cluster randomised controlled trial
Randomization: 1
Blinding: Open-label with blinded outcome assessment (PROBE)
Enrollment Period: December 2017 – December 2021 (patient recruitment)
Follow-up Duration: 6 months
Centers: 121
Countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, Chile
Sample Size: 7036
Analysis: Modified intention-to-treat with mixed-effects ordinal logistic regression (random effect for cluster, fixed effects for time period and group assignment)
Inclusion Criteria
- Adult patients (≥18 years)
- Presenting within 6 hours of symptom onset
- Imaging-confirmed spontaneous intracerebral hemorrhage
Exclusion Criteria
- ICH secondary to structural brain lesion (AVM, aneurysm, tumor, trauma, previous cerebral infarction)
- ICH related to reperfusion therapy (thrombolysis or thrombectomy)
- Unlikely to adhere to the study treatment or follow-up regimen per treating clinician
Arms
| Field | Control | Care Bundle |
|---|---|---|
| Intervention | Standard management per local guidelines without protocolized care bundle | SBP <140 mmHg within 1 h; temperature <37.5°C within 1 h; glucose 6.1–7.8 mmol/L (non-diabetic) or 7.8–10.0 mmol/L (diabetic); INR <1.5 within 1 h if on warfarin (fresh frozen plasma or prothrombin complex concentrate) |
| Duration | 6 months follow-up | 6 months follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Functional recovery measured by modified Rankin Scale (mRS) at 6 months, analysed as an ordinal shift across all categories (common odds ratio from ordinal logistic regression) | Primary | More unfavorable distribution of mRS | Shift toward lower (better) mRS scores | common OR 0.86 (unadjusted); common OR 0.84 (adjusted) | 0.015 (unadjusted); 0.017 (adjusted) |
| Death at 6 months | Secondary | 16.6% (crude); 14.3% (adjusted) | 13.6% (crude); 11.4% (adjusted) | OR 0.77 (0.63–0.95) primary model; 0.84 (0.65–1.07) fully adjusted | 0.015 (primary); 0.16 (fully adjusted) |
| Death or major disability at 6 months (mRS 3–6) | Secondary | 57.3% (crude) | 53.7% (crude) | OR 0.89 (0.78–1.02) | 0.10 |
| Serious adverse events | Secondary | 20.1% (767/3815) | 16.0% (516/3221) | 0.0098 | |
| EQ-5D overall health utility score (mean difference) | Secondary | reference | +0.04 (0.02–0.07) | 0.0008 | |
| Hospital discharge by day 7 | Secondary | reference | OR 0.72 (0.53–0.98) | OR 0.72 | 0.034 |
| Any Serious Adverse Event | Adverse | 20.1% | 16.0% | 0.0098 | |
| 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 (outcome assessment was masked).
- Cluster design relies on site compliance and fidelity to all four bundle components — variable implementation across 121 sites in 10 countries limits internal validity.
- Mortality benefit in the primary model (OR 0.77, p=0.015) lost statistical significance after adjustment for country and patient characteristics (0.84, p=0.16) — raising questions about robustness.
- 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 the majority of patients) — generalizability to other regions' ICH populations and healthcare systems is uncertain.
- Only ~1% on anticoagulants — the reversal component, which has the strongest individual evidence base, contributed minimally to the observed effect.
- COVID-19 pandemic overlap (enrolment ended Dec 2021) affected care patterns, hospital resources, follow-up completeness, and site recruitment timing.
- The proportional-odds assumption for the primary ordinal analysis was violated (treatment effect not constant across mRS categories).
- Extended recruitment in the intervention group (due to pandemic delays) may have introduced selection bias, partially addressed by post-hoc calendar-time adjustment.
Funding
Joint Global Health Trials scheme (UK Department of Health and Social Care, Foreign, Commonwealth & Development Office, Medical Research Council, Wellcome Trust); West China Hospital; NHMRC (Australia); Sichuan Credit Pharmaceutic and Takeda China
Based on: INTERACT3 (The Lancet, 2023)
Authors: Ma L, Hu X, Song L, et al.
Citation: Ma L, et al. Lancet. 2023;402:27-40.
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