By Alan Z. Segal, MD
Synopsis: Effective treatment for acute intracerebral hemorrhage (ICH) has remained elusive, with inconclusive results from surgical evacuations, as well as blood pressure management. The investigators performed a pooled analysis of four INTERACT trials that studied the effect of aggressive blood pressure lowering in patients with acute ICH. Ultra-early treatment (< 3 hours from onset) may be beneficial, but most patients are not so quickly diagnosed or treated.
Sources: Wang X, Ren X, Li Q, et al; INTERACT Investigators. Effects of blood pressure lowering in relation to time in acute intracerebral haemorrhage: A pooled analysis of the four INTERACT trials. Lancet Neurol. 2025;24(7):571-579.
Werring DJ. Rapid blood pressure lowering after acute intracerebral haemorrhage: Time is brain, again. Lancet Neurol. 2025;24(7):558-559.
The past 10 years have produced a revolution in the treatment of ischemic stroke, largely driven by the dramatic benefits associated with embolectomy for large-vessel occlusions. In contrast, intracerebral hemorrhage (ICH) has proven to be a difficult challenge, with little positive traction in management despite multiple investigations. Trials of surgical evacuations have shown mixed results, some favoring lobar over deep locations, but others showing the reverse. Noninvasive techniques, such as stereotactic irrigation systems and endoscopic catheters, have shown promise but still provide inferior clot removal as compared to open craniotomy.
Studies of the optimal medical management of ICH have focused primarily on defining the optimal acute blood pressure management. Persistent hypertension may promote hematoma expansion, but overtreatment of blood pressure potentially can threaten tissue at the margins of the hematoma. There may be at least a salvageable penumbra similar to that of ischemic stroke.
The present investigation represents a pooled analysis of the four INTERACT (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage) trials. The experimental arm of these studies aimed for aggressive blood pressure reduction (mean < 140 mmHg) compared to standard therapy (mean < 180 mmHg).
The treatment groups did not differ in any significant way regarding hemorrhage characteristics. Most hemorrhages (80%) were deep (basal ganglia), with a significant number (30%) having intraventricular extension. The study was international, including Europe/North America and Australia, but these locations were only about 5% of the total cohort, with more than 85% of subjects enrolled in China.
A mean blood pressure of 149 mmHg was achieved in the intensive management group, compared to a mean blood pressure of 158 mmHg in the standard cohort. This was a modest difference, notable for the fact that a significant number of patients in the intensive management group never actually reached the goal of mean blood pressure < 140 mmHg. The INTERACT studies allowed for the use of any standard blood pressure medication. Urapadil (an alpha-1 antagonist) was the most commonly used agent (almost exclusively in China).
Across all the INTERACT studies, the average time to initiation of treatment was 2.9 hours. The INTERACT 4 trial was unique in that it aimed for ultra-early treatment of blood pressure, within two hours of symptom onset, treating patients in the ambulance prior to computed tomography (CT) scanning. Unfortunately, of the 2,404 patients treated in that study, more than half (53%) had an ischemic stroke rather than an ICH.
The odds ratio for a poor outcome (modified Rankin Scale score of 3-6) was 0.85, significantly favoring the study group as compared to controls. Similarly, the odds of deterioration within the first seven days were 0.76 for the study group. The likelihood of serious adverse events was 0.84 and the likelihood of death was 0.84.
Hematoma volumes were approximately 12 cc for both treatment groups. This size is relatively small compared to the overall ICH population. The National Institutes of Health Stroke Scale (NIHSS) averaged about 11, which also is lower than for ICH in general (mean NIHSS score of 16). Hematoma expansion as defined by a relative increase in volume of > 33% or an absolute growth of > 6 cc was not different between the treatment groups. When the subjects were dichotomized into early blood pressure treatment (< 3 hours) as compared to late, there was a benefit for aggressive blood pressure treatment. As the authors noted, despite initiation of antihypertensive medications at around the three-hour mark, many of the patients in the intensive therapy groups did not achieve blood pressures < 140 mmHg for up to 12 hours after symptom onset.
Of note, the ATACH II (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trial, which was overall a negative study, did show both clinical and radiological benefits in a subgroup of patients treated within two hours. ATACH II (which used only nicardipine in contrast to the flexibility of INTERACT) did achieve more rapid blood pressure lowering, in less than two hours in 73% of patients.
Commentary
The INTERACT cohort totals an impressive 11,312 patients recruited over a span of almost 20 years (INTERACT 1 was completed in 2007). This study volume is a far greater number than would typically be associated with a stroke trial — the National Institute of Neurological Disorders and Stroke intravenous (IV) tissue plasminogen activator (TPA) trial had 624 patients and all of the embolectomy trials combined enrolled only about 1,200 patients. However, despite this relatively massive dataset, a conclusion regarding optimal blood pressure lowering in ICH remains elusive.
As was noted in the editorial accompanying this study, the most striking result of the INTERACT trials is that the benefit of blood pressure lowering is highly time sensitive — a window of < 3 hours, even more stringent than for IV thrombolysis for acute ischemic stroke. Also noted was the harm associated with blood pressure lowering in ischemic stroke patients, when treatment was initiated before the distinction between red and white stroke could be made on CT. In INTERACT 4, the odds ratio for a worse functional outcome was 1.3 for the ischemic stroke patients treated with aggressive blood pressure lowering and there was an increased mortality rate (23% treated vs. 17% untreated).
This diagnostic and treatment challenge can be addressed in a mobile stroke unit (MSU), in which there is a CT scanner available in the ambulance. Unfortunately, MSUs are expensive to build and operate, and currently only about 5% of stroke patients in the United States receive their initial care in a stroke ambulance. MSU volumes in Western Europe are comparable to the United States. For the less-resourced world, a stroke ambulance will remain an unattainable luxury.
Alan Z. Segal, MD, is Associate Professor of Neurology, Weill Cornell Medicine.
