Fourth Intensive Ambulance-Delivered Blood Pressure Reduction in Hyper-Acute Stroke Trial - INTERACT4

Contribution To Literature:

The INTERACT4 trial showed that in patients with concern for acute stroke and elevated BP, an intensive prehospital antihypertensive strategy was not associated with improved long-term functional status compared with usual care.


The goal of the trial was to determine the effect of prehospital treatment of elevated systolic blood pressure (SBP) in patients with recent onset of symptoms concerning for acute stroke.

Study Design

  • Multicenter
  • Randomized
  • Open-label

Patients with acute stroke causing a motor deficit, elevated SBP, and symptom onset within 2 hours were randomized to receive ambulance-delivered antihypertensive therapy (n = 1,205) or usual care (n = 1,199). In the intervention arm, 25 mg of intravenous urapidil, an α1-adrenoreceptor antagonist and 5-HT1A receptor agonist, was administered to achieve an SBP of 130-140 mm Hg. A second dose could be administered at 5 minutes if SBP remained elevated. Prehospital BP management in the usual care arm was reserved for SBP or diastolic BP >220 or 110 mm Hg, respectively.

  • Total number of enrollees: 2,404
  • Duration of follow-up: 90 days
  • Mean patient age: 70 years
  • Percentage female: 38%

Inclusion criteria:

  • Age ≥18 years
  • FAST score (face [facial droop]–arms [inability to lift arms]–speech [slurred speech]– time [time to call emergency services]) ≥2 with new arm motor deficit
  • Symptom onset ≤2 hours prior to randomization
  • SBP ≥150 mm Hg

Exclusion criteria:

  • Glasgow coma score <5
  • History of epilepsy or new seizure at symptom onset
  • Any severe comorbidities (e.g., dementia, advanced heart failure or chronic obstructive pulmonary disease, limited functional status)
  • Head injury <7 days prior
  • Hypoglycemia <50 mg/dL

Other salient features/characteristics:

  • Previous stroke: 19.5%
  • Median time from symptom onset: 61 minutes
  • Mean BP at randomization: 178/98 mm Hg
  • Percentage with hemorrhagic stroke: 43.3%; ischemic stroke: 50%, other conditions mimicking stroke (migraine, seizure, functional weakness, syncope): 6.4%
  • Percentage of usual care receiving prehospital BP treatment: 10%

Principal Findings:

The primary outcome, odds of a worse modified Rankin scale (mRS) score at 90 days, for intervention vs. usual care, was: odds ratio (OR) 1.00, 95% confidence interval (CI) 0.87-1.15 (p = 0.16).

Secondary outcomes for intervention vs. usual care:

  • mRS score ≥3 (i.e., worse functional status) at 90 days: 59.2% vs. 61.3% (OR 0.92, 95% CI 0.78-1.09)
  • All-cause death at 90 days: 22.5% vs. 22.6% (OR 0.90, 95% CI 0.74-1.08)
  • Median National Institutes of Health Stroke Scale (NIHSS) score at 7 days: 8 vs. 9
  • EuroQol 5-dimension 3-level (EQ-5D-3L) overall health utility: 0.5 vs. 0.5

Subgroup analysis of primary outcome for intervention vs. usual care among subsets:

  • Hemorrhagic stroke: OR 0.75 (95% CI 0.60-0.92)
  • Acute ischemic stroke or transient ischemic attack: OR 1.30 (95% CI 1.06-1.60)


Prehospital intensive BP control with urapidil in suspected acute stroke was not associated with any difference in 90-day functional status compared with usual care in this trial. Exploratory data did suggest potential benefit in patients with intracerebral hemorrhage.

These findings contrast with prior subgroup analyses from MR ASAP and RIGHT-2 trials, suggesting harm in hemorrhagic stroke with prehospital transdermal nitroglycerin, though differences in population demographics (99% Han Chinese vs. European cohorts) and choice of antihypertensive agent limit effective comparison. Moreover, the current data also suggest potential for harm with aggressive ambulance-delivered antihypertensive therapy in ischemic stroke, which was ultimately diagnosed in 50% of all presentations. These findings therefore do not support the prehospital use of urapidil in undifferentiated stroke. Future studies of alternative rapid-acting antihypertensive agents in different populations may be warranted.


Li G, Lin Y, Yang J, et al., on behalf of the INTERACT4 Investigators. Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke. N Engl J Med 2024;May 16:[Epub ahead of print].

Edlow JA. Editorial: Lowering Blood Pressure in Stroke Patients in the Ambulance — A Bridge Too Close? N Engl J Med 2024;May 16:[Epub ahead of print].

Clinical Topics: Prevention, Vascular Medicine

Keywords: Blood Pressure Monitoring, Ambulatory, Stroke

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