ARTICLE IN BRIEF
A large randomized trial found mixed results: Rapid, intensive lowering of intracerebral blood pressure (BP) did not appear to reduce death or severe disability in patients with intracerebral hemorrhage, but an analysis of modified Rankin scores indicated that patients who underwent intensive blood pressure BP-lowering had improved functional outcomes.
Rapid, intensive lowering of intracerebral blood pressure (BP) does not appear to reduce death or severe disability in patients with intracerebral hemorrhage, according to findings from the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT 2), published online before the June 20 print edition of the New England Journal of Medicine.
The international multicenter trial, which accrued 2,839 patients at 144 hospitals in 21 countries, randomized participants to either intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing.
Among the participants for whom outcome could be determined, 719 of 1382 participants (52 percent) receiving intensive treatment had a primary outcome event (death or major disability), as compared with 785 of 1412 (55.6 percent) receiving guideline-recommended treatment (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; p = 0.06).
Strictly based on primary endpoints, then, INTERACT 2 is a negative trial. But the take-home message from the study remains in question. A preplanned ordinal analysis of modified Rankin scores did indicate that patients who underwent intensive blood pressure lowering had improved functional outcomes. And the study found no major safety issues linked to aggressive lowering of intracerebral blood pressure.
“It's an interesting set of results,” observed Adnan Qureshi, MD, professor and executive director of the Zeenat Qureshi Stroke Research Center in Minneapolis, MN. “While the primary outcome came close to statistical significance, it did not achieve it. I think that one would have expected a greater benefit from the intensive BP reduction if the primary hypothesis was true. The investigators had anticipated a 7 percent absolute risk reduction for the primary endpoints, and in the end it was just 3.6 percent.”
One possible explanation is that, while the mean systolic blood pressure in the intensive BP-lowering group was indeed lower than the standard treatment group, it never reached the range that the investigators initially set out to achieve. Only 462 patients, or 33.5 percent, in the intensive group actually attained the target BP of <140 mm Hg after one hour of treatment.
“One wonders if blood pressure control had been more effectively reduced, perhaps they would have seen the magnitude of benefit that they were expecting,” said Dr. Qureshi, who was not involved with the INTERACT 2, but is one of the lead investigators of the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH II) trial. He noted that, given the number of countries involved in the trial, standardization of protocols for achieving BP reduction goals may have been particularly challenging.
The trial's underlying hypothesis rested on the theory that intense systolic blood pressure reduction reduces the rate of hematoma expansion. But that was also not borne out in the results. The difference in hematoma growth between the groups in the 24 hours after baseline was not significant either in relative (4.5 percent [95% CI, 3.1 to 12.7; p = 0.27], or absolute terms (1.4 ml [95% CI, 0.6 to 3.4; p = 0.18]).
“This question may need to be revisited,” Dr. Qureshi noted. “Perhaps a greater level of BP reduction is necessary to reduce the rate of hematoma enlargement, although the possibility of diminishing returns cannot be excluded. Based on prior studies, one would think that more is better, and it's also possible that given that there were fewer sites involved in those pilot studies, that blood pressure reduction was achieved in a more effective manner.”
Will the study change practice? That's hard to predict. Dr. Qureshi believes that the recommendation to reduce and maintain systolic BP <140 mm Hg may be premature because the INTERACT 2 reported on the risk-benefit profile of systolic BP slightly above 140 mm Hg — but not on the risk-benefit profile of systolic BP around 125 mm Hg, which is what would be expected if the majority of patients had a reduction in systolic BP <140 mm Hg. A greater benefit may be expected with larger magnitude of systolic BP reduction but the risk of cerebral, coronary, and renal ischemia may also be higher, he said.
“We do need to be cautious before we start advocating a relatively untested threshold,” he said. “This trial may not have ascertained the full magnitude of risk or benefit profile if you achieve the predefined threshold.”
But another leading stroke expert sees the INTERACT 2 results differently. “The trial nearly reached significance for its primary endpoint, and did achieve secondary endpoints in favor of the more aggressive treatment, with no observed safety differences,” said Joseph Broderick, MD, chair of the department of neurology at the University of Cincinnati and the director of Greater Cincinnati-Northern Kentucky Stroke. “That's a good thing.”
However, Dr. Broderick pointed out that the relatively small hematoma-volume reduction is confounding. “We were involved in trials with NovoSeven where the decrease in volume of hemorrhage was between 3–4 ccs, whereas the absolute difference after adjustment in this trial was 1.4 ccs. That's very small. It goes in the right direction, but you would like to understand the biology of an outcome and that finding makes it a little harder.”
Unlike Dr. Qureshi, however, Dr. Broderick believes that the trend toward a positive primary outcome, and achievement of significance on the secondary outcome, along with no identified major safety issues, may change practice. “I do think this will nudge people toward being more aggressive with blood pressure.”
Dr. Qureshi noted that the positive results for the intensive BP-lowering group did not begin to emerge until later follow-up. “If you look at the functional outcomes at one month, there's really no difference between the two groups. Only at the three-month mark is the difference manifested,” he says. “It's strange that a therapy that is so acute would not show an acute benefit, but rather a late benefit.”
“ … [T]here may be other mechanisms at play, such as neuroprotection or a reduction in edema, that result in the later positive clinical outcomes with this treatment,” the authors speculate as one possible explanation.
Another ongoing trial, ATTACH II, is expected to provide further information about the impact of intensive blood pressure lowering within 4.5 hours of the onset of a cerebral hemorrhage.
“Once that study is done, we will at least have a better idea of the risk-benefit profile of keeping blood pressure below 140 mm Hg,” he said. “We need to optimize parameters to make sure that we are looking at a clinically meaningful benefit with a clear understanding of the risks.”