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Intensive Blood Pressure-Lowering Strategy Shows Promise for Treating ICH

ARTICLE IN BRIEF

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In a pilot trial, mean hematoma growth was 22.6 percent lower in patients who had intensive antihypertensive therapy to a target systolic blood pressure of 140 mm Hg than in patients who had standard blood pressure–lowering treatment to a target of 180 mm Hg.

NEW ORLEANS—Early, aggressive blood pressure lowering is well tolerated and shows promise for limiting bleeding in patients with acute intracerebral hemorrhage (ICH), investigators reported here at the American Stroke Association International Stroke Conference in February.

Results from the pilot phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) show that mean hematoma growth was 22.6 percent lower in patients who had intensive antihypertensive therapy to a target systolic blood pressure of 140 mm Hg than in patients who had standard blood pressure-lowering treatment to a target of 180 mm Hg.

While the difference in hematoma growth between the two groups did not reach statistical significance — the p value was 0.06 — “there was a strong trend that worked out in absolute terms to about 2.5 ml less blood [in the brain of patients who had aggressive blood pressure-lowering therapy],” said principal investigator Craig Anderson, MD, PhD, director of the Neurological and Mental Health Division at the Royal Prince Alfred Hospital and professor of stroke medicine and clinical neuroscience at the University of Sydney in Australia.

At 90-day follow-up, there was no difference in adverse events, including recurrent stroke or other vascular events, between the two groups.

”There is a signal, which we believe is robust, that indicates we can arrest bleeding in the brain. We fulfilled our goal, showing that intensive blood pressure lowering is feasible and that it can limit bleeding under control without excessive hazard,” Dr. Anderson said.

About 780,000 Americans have an acute stroke each year, of which 10 percent are hemorrhagic. Hypertension is a cause of ICH and is also frequently present in the acute stage, he said.

Every incremental increase in blood pressure, particularly systolic blood pressure, correlates with poorer outcome, Dr. Anderson said, and international guidelines for the management of blood pressure in stroke typically indicate that high blood pressure is detrimental.

LITTLE GUIDANCE ON LOWERING BLOOD PRESSURE

But there are also concerns that rapid blood pressure lowering will have adverse effects on the brain and other organs and worsen outcomes. As a result, clinicians have little guidance about when to begin or cease antihypertensive treatment, he said.

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DR. JOSEPH BRODERICK said the plan to expand the trial is warranted, because it will offer more information about how to lower blood pressure in ICH patients.

Joseph P. Broderick, MD, professor and chairman of neurology at the University of Cincinnati and lead author of the American Heart Association/American Stroke Association 2007 guidelines for the management of spontaneous ICH in adults, said: “Frankly we have never had a study that shows us the best way to manage blood pressure in ICH.”

The current AHA/ASA guidelines note that little prospective evidence exists to support a specific blood pressure threshold, he said. The recommendations call for initiating hypertension treatment only if systolic pressure is over 180 mm Hg or mean arterial pressure is over 130 mm Hg.

Dr. Anderson said the new approach is based on the concept that “high blood pressure increases brain bleeding and expansion of blood in the brain. So, theoretically, controlling blood pressure should arrest or control the bleeding in the brain.”

STUDY METHODS, FINDINGS

The proof-of-concept study involved 404 patients from 44 hospitals in Australia, China, and Korea who were seen within six hours of onset of CT-confirmed acute ICH. All had elevated systolic blood pressures of 150 to 220 mm Hg.

A total of 174 patients were randomly assigned to undergo aggressive blood pressure lowering in which clinicians titrated available intravenous agents to a target systolic blood pressure of 140 mm Hg. The rest received standard treatment based on American Heart Association/American Stroke guidelines and targeted to a systolic blood pressure of 180 mm Hg. The National Health and Medical Research Council of Australia funded the study.

At one hour, systolic blood pressure was an average of 14 mm Hg lower in the intensive therapy group than the guidelines group. Follow-up CT scans showed that hematomas grew an average of 13.7 percent in the intensive group versus 36.3 percent in the standard treatment group.

The absolute amount of bleeding in the brain increased 0.9 ml in the intensive group versus 2.7 ml in the standard group.

The frequency of substantial hematoma growth — defined as ongoing bleeding of more than one-third of initial volume — was a statistically significant 36 percent lower in the aggressive treatment group: 15 percent versus 23 percent in the standard arm.

However, there was no difference in clinical outcomes between the two groups at 90 days, Dr. Anderson said. Among the outcomes looked at were death, dependency, modified Rankin score, NIH Stroke Scale score, Barthel index score, and Mini-Mental Status Examination score.

Dr. Anderson said that the study “was not powered for clinical outcomes.” He added that the investigators hope to show that aggressive treatment translates into better outcome in a phase 3 study of 2,500 ICH patients dubbed INTERACT2 that will be launched later this year.

MORE STUDY IS WARRANTED

Commenting on the results, Dr. Broderick said that the planned phase 3 study is warranted, because “it will give us more information about how to lower blood pressure in ICH patients.”

There are two main strategies for reducing hematoma size and improving outcomes in ICH patients currently being tested: aggressive blood pressure lowering and the use of recombinant factor VIIa, he said.

Theoretically, an aggressive blood pressure-lowering strategy should help to reduce bleeding, he said, likening it to putting water in a balloon and squeezing. “The water comes out more quickly,” he said.

“It's a good study to do. Will it decrease hematoma growth? Maybe. But whether that will translate into better clinical outcome is unclear,” Dr. Broderick said.

He said that in the phase 3 trial of recombinant factor VIIa for acute ICH, “we had a much larger decrease in hematoma growth and were still unable to find a difference in clinical outcome.” (The study is in press for publication.) Dr. Broderick participated in the trial, whose phase 2 results showed that factor VIIa limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days. •

REFERENCES

Broderick J, Connolly S, Zuccarello M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update — A guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007;38:2001–2023.
Mayer S, Brun NC, Steiner T, et al., for the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777–785.