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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)