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INTERACT4

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke

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Year of Publication: 2024

Authors: G. Li, Y. Lin, J. Yang, ..., for the INTERACT4 investigators

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2024;390:1862-72.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2311377

PDF: https://trialsjournal.biomedcentral.com/...021-05860-y.pdf

Clinical Question

In patients with undifferentiated suspected acute stroke and SBP ≥150 mmHg within 2 hours of onset, does prehospital intensive IV antihypertensive treatment (targeting SBP 130-140 mmHg) improve 90-day functional outcomes vs usual care?

Bottom Line

Prehospital intensive BP reduction did not improve overall functional outcomes in undifferentiated stroke (OR 1.00; 95% CI 0.87-1.15). However, effects diverged by stroke type: worse in ischemic stroke (OR 1.30; 1.06-1.60) and better in hemorrhagic stroke (OR 0.75; 0.60-0.92). Does not support universal ambulance-based BP-lowering for undifferentiated stroke.

        Major Points
        Net null in undifferentiated stroke: OR 1.00 (95% CI 0.87-1.15) for 90-day mRS shift.
Divergent by stroke type: ischemic OR 1.30 (1.06-1.60, HARM); hemorrhagic OR 0.75 (0.60-0.92, BENEFIT).
SBP at hospital arrival: 159 vs 170 mmHg (−15 mmHg difference). Narrowed to −4 mmHg by 24h.
46.5% hemorrhagic, 53.5% ischemic among confirmed strokes — higher hemorrhagic proportion than Western populations.
Mortality identical: 22.5% vs 22.6%. SAEs similar: 27.5% vs 28.7%.
Urapidil (α-blocker) used in 98.2% of treated intervention patients — not widely available outside China.
89.5% of intervention group received ambulance BP treatment vs 9.7% in usual care.
Supports prehospital stroke imaging (mobile CT) to guide individualized BP management.
China-only, physician-staffed ambulances (99% Han Chinese). Limits Western generalizability.
Consistent with RIGHT-2 and MR ASAP: prehospital BP reduction in undifferentiated stroke is not beneficial overall.

      

Design

Study Type: Randomized controlled trial (open-label, PROBE design)

Randomization: 1

Blinding: Open-label; blinded 90-day outcome assessment. 1:1 with minimization algorithm stratified by region, age (≥65/<65), FAST score (≥3/2).

Enrollment Period: March 20, 2020 to August 31, 2023

Follow-up Duration: 90 days

Centers: 51

Countries: China

Sample Size: 2404

Analysis: ITT. Ordinal logistic regression (proportional odds confirmed P=0.16). Planned 2320; enrolled 2425.

Inclusion Criteria

Age ≥18 years.
Presumed acute stroke: FAST score ≥2 (must include arm motor deficit).
SBP ≥150 mmHg at ambulance assessment.
Able to initiate treatment within 2 hours of symptom onset or last known well.
Assessed by ambulance doctors.

Exclusion Criteria

Coma.
Severe coexisting disease.
Epilepsy.
Recent head injury.
Hypoglycemia.

Baseline Characteristics

Characteristic	Intervention (N=1,205)	Usual Care (N=1,199)
Age (mean±SD)	70±12	70±13
Male	719 (59.7%)	764 (63.7%)
SBP at randomization (mean±SD)	178±20 mmHg	178±22 mmHg
SBP at hospital arrival (mean±SD)	159±26 mmHg	170±27 mmHg
Time onset to randomization median (IQR)	63 (41-93) min	59 (41-93) min
Hypertension history	862/1,198 (72.0%)	834/1,195 (69.8%)
Previous stroke	232/1,198 (19.4%)	238/1,195 (19.9%)
AF	109/1,198 (9.1%)	98/1,195 (8.2%)
Diabetes	220/1,198 (18.4%)	195/1,195 (16.3%)
NIHSS at hospital median (IQR)	12 (6-18)	11 (6-17)
Final dx — Ischemic	599 (49.7%)	600 (50.0%)
Final dx — Hemorrhagic	522 (43.3%)	519 (43.3%)
Final dx — Stroke mimic	77 (6.4%)	77 (6.4%)

Arms

Field	Intensive Prehospital BP Reduction	Control
Intervention	IV urapidil 25 mg bolus over 1 min in ambulance, repeated once after 5 min if needed. Target SBP 130-140 mmHg within 30 min. Continue until hospital arrival. 89.5% received treatment; 98.2% used urapidil.	No active BP treatment in ambulance unless SBP ≥220 or DBP ≥110 mmHg. BP management commenced on hospital arrival per guidelines. 9.7% received ambulance BP treatment.
Duration	Prehospital + in-hospital continuation per guidelines	Standard care

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Distribution of mRS scores at 90 days (ordinal shift analysis)	Primary	mRS 0-6 distribution (see details)	mRS 0-6 distribution (see details)		NS
mRS 3-6 at 90 days \| 95% CI: 0.78-1.09	Secondary	721/1,177 (61.3%)	702/1,185 (59.2%)	OR 0.92
Death within 90 days \| 95% CI: 0.82-1.22	Secondary	266/1,178 (22.6%)	267/1,185 (22.5%)	OR 1.00
Ischemic stroke subgroup — poor outcome \| 95% CI: 1.06-1.60	Secondary	—	—	OR 1.30
Hemorrhagic stroke subgroup — poor outcome \| 95% CI: 0.60-0.92	Secondary	—	—	OR 0.75
SAEs	Adverse	344 (28.7%)	331 (27.5%)

Subgroup Analysis

10 prespecified subgroups. Stroke type was the only divergent subgroup: ischemic OR 1.30 (harm) vs hemorrhagic OR 0.75 (benefit). All other subgroups (age, sex, time, BP, hypertension hx, FAST score, region, care model, NIHSS) showed no significant interaction. Interaction P-values not individually reported.

Criticisms

Open-label — ambulance staff not blinded.
China-only (99% Han Chinese); urapidil not available outside China.
Divergent effects by stroke type but enrolled undifferentiated — net null is mixture of harm+benefit.
Ischemic stroke OR 1.30 concerning, especially for LVO where BP reduction may compromise penumbra.
COVID-19 pandemic disruption during enrollment.
Physician-staffed ambulances — not generalizable to paramedic systems.
No adjustment for multiple comparisons in subgroup analyses.
BP difference narrowed to −4 mmHg by 24h — very brief treatment window.
Partial industry sponsorship (Takeda, urapidil manufacturer).

Funding

NHMRC Australia (APP1149087); Shanghai East Hospital; Chengdu grants; Takeda Pharmaceuticals China (partial sponsor, no role in trial conduct).

Based on: INTERACT4 (The New England Journal of Medicine, 2024)

Authors: G. Li, Y. Lin, J. Yang, ..., for the INTERACT4 investigators

Citation: N Engl J Med 2024;390:1862-72.

Content summarized and formatted by NeuroTrials.ai.

INTERACT4

(2024)

Objective

To assess whether prehospital, intensive blood pressure reduction in suspected acute stroke improves 90-day functional outcomes compared to usual care.

Study Summary

• In patients with suspected stroke within 2 hours of onset, prehospital antihypertensive treatment did not improve outcomes overall. • In patients with hemorrhagic stroke, early BP lowering improved outcomes while in patients with ischemic stroke, it worsened outcomes

Intervention

IV urapidil initiated in ambulance to target SBP 130–140 mm Hg vs. usual care (hospital-based BP management) for suspected stroke within 2 hours of symptom onset.

Inclusion Criteria

Age ≥18, FAST score ≥2 (with arm weakness), SBP ≥150 mm Hg, and ≤2 hours from symptom onset; excluded if coma, seizure, recent head injury, or severe comorbidity.

Study Design

Arms: Prehospital BP Reduction vs. Usual BP Management

Patients per Arm: Intervention: 1205, Usual Care: 1199

Outcome

• Primary outcome (mRS 0–6 at 90 days): no overall difference (common OR 1.00; 95% CI 0.87–1.15). • Hemorrhagic stroke: improved mRS with intervention (OR 0.75). • Ischemic stroke: worse mRS with intervention (OR 1.30). • 90d death: 22.5% (intervention) vs. 22.6% (usual care). • Serious adverse events: 27.5% vs. 28.7%. • EQ-5D-3L score: 0.5 in both groups.

Bottom Line

Major Points

Net null in undifferentiated stroke: OR 1.00 (95% CI 0.87-1.15) for 90-day mRS shift.
Divergent by stroke type: ischemic OR 1.30 (1.06-1.60, HARM); hemorrhagic OR 0.75 (0.60-0.92, BENEFIT).
SBP at hospital arrival: 159 vs 170 mmHg (−15 mmHg difference). Narrowed to −4 mmHg by 24h.
46.5% hemorrhagic, 53.5% ischemic among confirmed strokes — higher hemorrhagic proportion than Western populations.
Mortality identical: 22.5% vs 22.6%. SAEs similar: 27.5% vs 28.7%.
Urapidil (α-blocker) used in 98.2% of treated intervention patients — not widely available outside China.
89.5% of intervention group received ambulance BP treatment vs 9.7% in usual care.
Supports prehospital stroke imaging (mobile CT) to guide individualized BP management.
China-only, physician-staffed ambulances (99% Han Chinese). Limits Western generalizability.
Consistent with RIGHT-2 and MR ASAP: prehospital BP reduction in undifferentiated stroke is not beneficial overall.

Study Design

Study Type: Randomized controlled trial (open-label, PROBE design)
Randomization: Yes
Blinding: Open-label; blinded 90-day outcome assessment. 1:1 with minimization algorithm stratified by region, age (≥65/<65), FAST score (≥3/2).
Sample Size: 2404
Follow-up: 90 days
Centers: 51
Countries: China

Primary Outcome

Definition: Distribution of mRS scores at 90 days (ordinal shift analysis)

Control	Intervention	HR/OR	P-value
mRS 0-6 distribution (see details)	mRS 0-6 distribution (see details)	- (0.87-1.15)	NS

Limitations & Criticisms

Open-label — ambulance staff not blinded.
China-only (99% Han Chinese); urapidil not available outside China.
Divergent effects by stroke type but enrolled undifferentiated — net null is mixture of harm+benefit.
Ischemic stroke OR 1.30 concerning, especially for LVO where BP reduction may compromise penumbra.
COVID-19 pandemic disruption during enrollment.
Physician-staffed ambulances — not generalizable to paramedic systems.
No adjustment for multiple comparisons in subgroup analyses.
BP difference narrowed to −4 mmHg by 24h — very brief treatment window.
Partial industry sponsorship (Takeda, urapidil manufacturer).

Citation

N Engl J Med 2024;390:1862-72.

View Original Publication →

INTERACT4

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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