Intensive Blood Pressure Reduction Safe in Intracerebral Hemorrhage

SYDNEY, Australia, April 4 -- Early, intensive reduction of blood pressure appears safe for patients with intracerebral hemorrhage and might help control hematoma expansion, researchers found.A systolic blood pressure target of 140 mm Hg -- rather than the guideline-recommended 180 mm Hg -- reduced proportional hematoma growth by 22.6% at 24 hours (P=0.04), reported Craig S. Anderson, Ph.D., of the University of Sydney, and colleagues online in The Lancet Neurology.More importantly, the randomized Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) showed no increase in neurological complications or adverse events.
The findings represent "the best evidence to date of the safety of such an intervention," said Mustapha Ezzeddine, M.D., of the University of Minnesota in Minneapolis, in an accompanying editorial.
American Stroke Association guidelines for early blood pressure management in intracerebral hemorrhage have been based primarily on expert opinion without evidence for when to initiate treatment or the extent to which blood pressure should be lowered, the researchers noted.
The question has remained, though, whether acute lowering of blood pressure would help, plausibly by reducing growth of the intracerebral hemorrhage, or harm, by possibly worsening ischemia around the hematoma, Dr. Ezzeddine said.
"Because intravenous treatment to lower blood pressure is relatively straightforward, is not hazardous, and is of low cost," the researchers said, "if applied widely these effects could translate into major absolute benefits."
The multicenter, open-label trial included 404 patients from Australia, China, and South Korea who had acute spontaneous intracerebral hemorrhage diagnosed by CT within six hours of onset and no definite indication or contraindication to treatment.
The patients, whose elevated systolic blood pressure ranged from 150 to 220 mm Hg, were randomly assigned to early intensive lowering of systolic BP to a target of 140 mm Hg or standard guideline-based management with a target of 180 mm Hg.
Blood pressure lowering medications were more common in the early intensive blood pressure lowering group with 67% of patients getting intravenous antihypertensives compared with 27% of patients in the guideline group.
Blood pressure declined in both groups during treatment but was significantly lower in the intensive treatment group at all time points from 30 minutes to seven days (P<0.0001).
From the first hour after randomization to 24 hours, blood pressure averaged 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (P<0.0001).
Lower blood pressure was associated with lower mean proportional hematoma growth at 24 hours (13.7% in the intensive group versus 36.3% in the guideline group, P=0.04).
But after adjustment for initial hematoma volume and time from onset to CT scan, the difference in this primary outcome was no longer significant (P=0.06).
Substantial hematoma growth of at least 33% or 12.5 mL was 36% less common in the intensive group than in the guideline group (P=0.05), with an absolute risk reduction of 8% (P=0.05).
Absolute hematoma volume tended to be lower with intensive blood pressure lowering as well (difference 1.7 mL, P=0.13). This would be expected to reduce the risk of death or disability 12% based on previous studies showing that each 1 mL hematoma growth increases risk of death or disability 7%, the researchers said.
However, there was no benefit for clinical outcomes in the trial. Death and dependency were equivalent between groups at 90 days (48% versus 49%, P=0.81). Cognitive and neurological scores were similar between groups as well.
"In view of the overall relatively small numbers," Dr. Ezzeddine said, "I am not too surprised that there was no reflection of the restriction of hematoma growth to clinical outcomes."
Intensive blood pressure lowering did appear safe, though, without an excess of adverse events at 90 days.
This contrasts with use of the hemostatic agent recombinant activated factor VII (rFVIIa) for which the potential clinical benefit from reduction in hematoma growth is offset by increased risk of thromboembolism, the researchers said. "Early intensive lowering of blood pressure holds promise as an intervention without major hazard."
Large clinical trials are now needed to determine whether there are long-term functional outcome benefits and whether the results can be generalized to a wider population of stroke patients and to other blood pressure lowering agents, Dr. Ezzeddine said.
The most commonly used drug in the trial was urapidil, which is not approved for use in the United States.
The study was supported by a grant from the National Health and Medical Research Council of Australia. Dr. Anderson reported receipt of consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, sanofi-aventis, and Servier. His co-authors reported conflicts of interest for Bayer, Omron, Pfizer, sanofi-aventis, Takeda, Mitsubish-Tanabe, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Servier, Merck, and Novo Nordisk. Automated blood pressure monitors used in Chinese hospitals were donated by Omron.
Dr. Ezzeddine reported no conflicts of interest.
Primary source: The Lancet NeurologySource reference:Anderson CS, et al "Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): A randomised pilot trial" Lancet Neurol 2008. Additional source: The Lancet NeurologySource reference: Ezzeddine M "Acute hypertensive response in intracerebral haemorrhage: is treatment safe and helpful?" Lancet Neurol 2008.