INTERACT2: Intensive Blood Pressure Lowering Benefits ICH

May 29, 2013

Early intensive blood pressure lowering in patients with intracerebral hemorrhage (ICH) appears to be related to less long-term disability, according to the results of the INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2) trial.

The results were presented today at the European Stroke Conference in London, United Kingdom, and simultaneously published online May 29 in the New England Journal of Medicine.

The trial compared lowering blood pressure to a target of less than 140 mmHg systolic within 1 hour with the guideline-recommended approach of lowering pressure to less than 180 mmHg.

The primary outcome (death or major disability defined as a score of 3 to 6 on the modified Rankin Scale [mRS]) at 90 days just missed significance (P = .06). But the key secondary endpoint — an ordinal analysis of the mRS score — did suggest a significant benefit (P = .04) in the intensive treatment group. Serious adverse events were similar in the 2 groups.

"Our results debunk the long-standing dogma over the neurological risk of reducing blood pressure in ICH," Craig Anderson, MD, from the George Institute for Global Health, Sydney, Australia, told attendees here. "They resolve the uncertainty, and provide evidence of safety and efficacy of intensive blood pressure lowering. My advice is 'go early, go intensive and go sustained — longer than 24 hours.'"

He added, "The strategy is widely applicable and inexpensive, so why not do it? I believe our results will lead to guidelines changing throughout the world."

Several other experts discussing the results agreed with Dr. Anderson that the INTERACT2 results should change the guidelines, given that very little solid data have been available before now.

But session chair, Philip Bath, MD, University of Nottingham, United Kingdom, was the lone voice urging caution. He said that because the primary endpoint just missed significance, he would rather wait for further trials, which are due to report soon. "Having said that, I suspect that these results will actually change the guidelines," he added.

Spontaneous ICH

For the study, 2839 patients who had had a spontaneous ICH within the previous 6 hours and who had elevated systolic blood pressure were randomly assigned to the 2 different blood pressure target groups, with physicians free to use any antihypertensive agents they wished.

The median time from the onset of symptoms to the start of intravenous treatment was 4 hours in the intensive treatment group vs 4.5 hours in the standard therapy group. The mean systolic blood pressures at 1 hour after start of treatment were 150 mmHg in the intensive treatment group and 164 mmHg in the standard treatment group.

At 90 days, the intensive group had a lower incidence of the primary endpoint, and this narrowly missed significance.

Table. INTERACT2: Primary Endpoint

Endpoint Intensive Therapy (%) Standard Therapy (%) Odds Ratio (95% Confidence Interval) P Value
Death or major disability 52.0 55.6 0.87 (0.75 -1.01) .06


However, the key secondary ordinal analysis showed a significant favorable shift in the distribution of mRS scores with intensive blood pressure–lowering treatment, with an odds ratio of 0.87 (P = .04) for a shift to a higher mRS score.

My advice is 'go early, go intensive and go sustained' … Dr. Craig Anderson

Quality-of-life assessment suggested that patients in the intensive treatment group had fewer problems and had significantly better overall health-related quality of life at 90 days than the standard treatment group.

In a subgroup who underwent brain imaging, there was a small reduction in hematoma growth in the intensive treatment group, but this finding was not significant.

Discussing the results, Jeffrey Saver, MD, from the University of California Los Angeles, who was not involved in the study, congratulated the INTERACT2 investigators for "bringing data on this important issue that we have wanted for so long."

He noted that the current guidelines recommend blood pressure to be lowered to 180 mmHg, but this recommendation is based not on solid data but rather on expert opinion, and they have only level C, class 4 status.

"As this trial just missed the primary endpoint, purists will say it was a negative trial, but the results still mean the treatment is 94% likely to be beneficial," he said. "And the ordinal analysis was significant. And at the moment this is the only data we have. This trial will not produce a level A, class 1 recommendation in the guidelines, but it is a big step forward in the right direction over what we had before, and I do think the guidelines will change to reflect this."

In terms of clinical benefit, Dr. Saver said this was "modest," with a benefit of 3.6% in the main outcome of death or major disability. "So treating 1000 patients would benefit 36, and the number needed to treat is 27."

But he pointed out that the ordinal analysis is a more comprehensive measure of benefit and suggested that 12.3 patients would need to be treated for 1 patient to have less disability. And 81 patients would have less disability for every 1000 treated. He said this fell into the realm of what clinicians thought was worthwhile, which has been suggested to be 50 patients benefitting for every 1000 treated.

Dr. Saver suggested that better results could be achieved if the treatment was started earlier. "We know time is brain for hemorrhagic stroke. In INTERACT1 we found that early treatment reduced ICH growth, and INTERACT2 supports this." Noting that the average time to the start of treatment was 4 hours in this study, and that patients often deteriorate catastrophically between the ambulance and hospital, he added, "I think we should be asking whether treatment should start in the ambulance."

Asked by a member of the audience what blood pressure level should be aimed for, Dr. Anderson said, "I would say aim for 140 as soon as possible, preferably within an hour and then keep in there for at least the next 24 hours."

Another member of the audience questioned the relevance of the study to the Western population given that most patients were enrolled in China and the drug most commonly used was urapidil, a popular drug in China but not used extensively in the West.

Dr. Anderson countered, "I believe it is the degree of blood pressure lowering which is important rather than which medication is used. I would say use a drug that you are familiar with."

A "Reasonable Option"

In an accompanying editorial, Jennifer A. Frontera, MD, from the Cerebrovascular Center, Cleveland Clinic, Ohio, points out some limitations of the study, including the previously discussed point about the use of urapidil in this mostly Chinese population. In addition, this population has an increased incidence of ICH — twice that of other populations. These issues might limit generalizability, although it's unclear whether they might have affected outcomes, she writes.

The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial is an ongoing North American complement to INTERACT2, Dr. Frontera writes. "This study also randomly assigns patients to a target systolic blood pressure of less than 140 mm Hg or less than 180 mm Hg but requires the use of nicardipine as the sole blood-pressure–lowering agent. It is hoped that this trial, which has similar primary and secondary end points and results due in 2016, will corroborate the results of INTERACT2."

Nonetheless, she concludes, "given that INTERACT2 showed a trend toward a reduction in the primary outcome of death or severe disability, significant improvement in secondary functional outcomes, and reassuring safety data, acute blood-pressure reduction to a target systolic blood pressure of 140 mm Hg or less appears to be a reasonable option for patients with spontaneous intracerebral hemorrhage."

N Engl J Med. Published online May 29, 2013. Abstract Editorial


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