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Intensive blood pressure lowering failed to prevent poor outcomes in patients with intracerebral hemorrhage (ICH), but had a positive effect on functional disability, a large randomized trial showed.

The risk of death or major disability decreased by 13% among patients whose systolic blood pressure was treated to a goal of less than 140 mmHg, but the difference did not achieve statistical significance compared with controls receiving standard care, according to Craig S. Anderson, MD, PhD, of the George Institute for Global Health in Sydney, Australia, and co-authors.

However, an analysis across the range of possible scores on the Rankin stroke scale showed as much as a 19% improvement with intensive blood-pressure lowering, resulting in an overall benefit that was statistically significant, they reported online in the New England Journal of Medicine.

The results of the trial, called INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage), were reported simultaneously at the European Stroke Conference in London.

Despite missing the primary endpoint, the 2,800-patient trial made a case for intensive treatment of blood pressure in patients with ICH, according to Jennifer Frontera, MD, of the Cleveland Clinic, the author of an accompanying editorial.

"Based on the [American Heart Association/American Stroke Association] guidelines, we treat patients with a systolic blood pressure over 160 or a mean arterial pressure greater than 110 [mmHg]," Frontera told 麻豆传媒. "[On the basis of the study], I think right from the get-go a systolic pressure over 140 is the trigger for initiating treatment."

Despite much research, ICH remains the most treatment-resistant type of stroke. Immediately following ICH, blood pressure often increases to dangerously high levels, which is an independent adverse prognostic factor, the authors noted.

Intensive blood pressure lowering in ICH has been a source of controversy for years, as a definitive result has not emerged from clinical trials.

Kenneth S. Butcher, MD, PhD, of the University of Alberta in Edmonton, Canada, and colleagues reported in February that intensive blood pressure lowering did not reduce the infarct size. However, it also did not affect blood flow in other areas of the brain, a finding that "supports the safety of ongoing acute blood pressure reduction trials in ICH."

For the current multi-country study, patients who arrived at hospitals within 6 hours of ICH symptom onset, had systolic blood pressure of 150 to 220 mmHg, and had no contraindications to blood pressure treatment were randomized to the intensive therapy arm.

The intervention included protocol-specified intravenous and oral therapy based on local availability of medications. Treatment to a goal of systolic pressure less than 140 mmHg began within 1 hour of admission and continued for 7 days.

Controls received guideline-based treatment that included the combination of an angiotensin-converting enzyme inhibitor and diuretic for 7 days with the goal of a systolic pressure less than 180 mmHg.

The primary objective was poor outcome, defined as death or major disability (a score of 3 to 6 on the modified Rankin scale) at 90 days.

After the trial started, ordinal analysis of the modified Rankin scale won favor as a method of statistical evaluation in stroke trials. As a result, investigators revised the protocol and specified analysis of physical function across all seven levels of the modified Rankin scale (0 to 6) as a secondary outcome. The change occurred before the start of data analysis.

The analysis of the primary outcome included 2,794 of 2,839 randomized patients. The 90-day results showed similar poor outcome rates in the intensive-therapy group and the control arm (52.0% versus 55.6%). The difference translated into an odds ratio of 0.87 (95% CI 0.75-1.01, P=0.06).

The ordinal analysis resulted in a significant shift in the distribution of scores. It yielded an identical odds ratio of 0.87, but the result met requirements for statistical significance (95% CI 0.77-1.00, P=0.04).

Overall mortality was about 12% in each group, and the proportion of deaths attributed to ICH did not differ significantly between the study (61.4%) and control (65.3%) groups. Hematoma growth rate and final hematoma volume did not differ between groups. Intensive treatment was associated with significantly better quality of life at 90 days (P=0.002).

Rates of adverse events and serious adverse events were similar in the treatment arms.

Despite the negative primary outcome, the trial "provides the best data, to date, on acute, targeted blood pressure control after spontaneous intracerebral hemorrhage," Frontera said in her editorial. The addition of the ordinal analysis did not unfairly sway the results in favor of intensive therapy because the analysis "has inherently better power to show effect."

Moreover, had the investigators chosen to define the primary endpoint as a Rankin score of 2 to 6 (used more widely compared with the range of 3 to 6), the results would have shown a 17% reduction in the primary endpoint, which would have achieved statistical significance (P=0.03), she noted.

Given the lack of significant differences in other parameters (such as hematoma growth and volume), the explanation for the trend toward better outcomes with intensive blood pressure lowering remains unclear, researchers noted.

Limitations of the study include the lack of data on the effects of other blood pressure medications and the potential for treatment bias because the trial was open and unblinded.

From the American Heart Association:

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