Intensive Blood Pressure Lowering Potentially Harmful in ICH

Intensive systolic blood pressure (SBP) lowering in patients with intracerebral hemorrhage (ICH) and excessively high initial SBP does not improve outcomes and is linked to safety concerns, new research shows.

Investigators found that ICH patients whose initial SBP was 220 mmHg and who underwent intensive BP lowering had twice the relative risk for neurologic deterioration at 24 hours without any reduction in hematoma expansion or 3-month risk for death and disability compared to their counterparts who underwent standard SBP lowering.

"The significantly higher rate of neurological deterioration associated with intensive treatment in patients with initial systolic blood pressure of 220 mm Hg or more warrants caution against broad recommendations for intensive systolic blood pressure reduction in patients with intracerebral hemorrhage," the investigators, led by Iryna Lobanova, MD, Zeenat Qureshi Stroke Institute, University of Missouri, in Columbia, write.

The study was published online September 8 in JAMA Neurology.

Efficacy Unknown

American Heart Association and American Stroke Association guidelines recommend lowering SBP to 140 mmHg for ICH patients whose SBP is between 150 mmHg and 220 mmHg. However, guideline authors note that the safety and efficacy of intensive SBP lowering for patients with SBP >220 mmHg "appears to be unknown."

To evaluate the safety and efficacy of intensive SBP reduction for ICH patients with excessively high initial SBP, the investigators analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage–II (ATACH-II) trial, which compared intensive and standard SBP reduction for patients with spontaneous supratentorial ICH.

Eligible participants had SBP >180 mmHg on two measurements. The first measurement that was recorded in the emergency department was considered the initial SBP.

Consistent with practice guidelines, treatment to lower SBP before randomization was permitted. The SBP measurement recorded immediately before randomization was the prerandomization SBP.

The treatment goal was to reduce SBP to a target range of 140 mmHg to 179 mmHg in the standard reduction group and 110 mmHg to 139 mmHg in the intensive reduction group over 24 hours.

The primary outcome was the proportion of patients who died or experienced severe disability at 90 days, defined as a Modified Rankin Scale score of 4 to 6.

Secondary outcomes included neurologic deterioration, as determined by the Glasgow Coma Scale or the NIH Stroke Scale, as well as hematoma expansion and hypotension.

Neurologic Deterioration

The study included 999 participants. Of these, 228 had an initial SBP of ≥220 mmHg. The mean age was significantly less in the excessively high SBP group than in the lower SBP group, at 59.0 and 62.8 years, respectively.

The mean minimum SBP at 6 to 7 hours and at 23 to 24 hours after randomization was significantly higher among the high SBP group than the lower SBP group.

Of the 228 patients whose initial SBP was ≥220 mmHg, 110 were randomly assigned to intensive SBP reduction, and 118 were assigned to standard SBP reduction. These two treatment groups did not differ significantly with respect to age or sex distribution.

Results showed that among participants with excessively high SBP, the rate of neurologic deterioration within 24 hours was greater among those who underwent intensive SBP reduction (15.5% vs 6.8%; relative risk, 2.28, 95% CI, 1.03 – 5.07; P = .04).

However, the rate of death and severe disability at 90 days did not differ significantly between the two groups (39.0% vs 38.4%; relative risk, 1.02; 95% CI, 0.73 – 1.78; P = .92).

The investigators speculate that clinical intervention may explain why 90-day outcomes between the two study groups did not differ.

"Treating physicians may have responded to neurological deterioration by adjustment in the rate of (or avoidance of any further) SBP decline, which could have prevented irreversible ischemia and long-term adverse outcomes," the investigators write.

Results showed that there was a significantly higher rate of adverse kidney events among ICH patients in the intensive SBP reduction group than among those in the standard reduction group (13.6% vs 4.2%; relative risk, 3.22; 95% CI, 1.21 – 8.56; P = .01), but there was no difference in the rate of serious adverse kidney events.

Of 771 participants whose initial SBP was <220 mmHg, 390 were randomly assigned to intensive treatment, and 381 were assigned to standard treatment. The rate of 24-hour hematoma expansion in this patient population was significantly lower in the intensive treatment group than in the standard treatment group (20.9% vs 29.2%; relative risk, 0.72; 95% CI; 0.56 – 0.92; P = .009).

The rate of kidney adverse events was also significantly higher in the intensive treatment group than in the standard treatment group (7.7% vs 3.9%; relative risk, 1.95; 95% CI, 1.07 – 3.57; P = .03).

In an exploratory analysis, the researchers evaluated 48 patients whose prerandomization SBP was ≥220 mmHg. In this subgroup, the rate of death or severe disability at 90 days was significantly higher among those who underwent intensive SBP reduction than among those who underwent standard SBP reduction (66.7% vs 29.2%; relative risk, 2.29; 95% CI, 1.15 – 4.53; P = 009).

In this population, the rate of hematoma expansion was similar between groups. The rate of neurologic deterioration within 24 hours was higher in the intensive treatment group, although the difference was not statistically significant.

"Our data provide additional insight and perhaps evidence for caution and the need for further studies in this unique patient population," the investigators write.

Overcorrection Harmful

In an accompanying editorial, Matthew B. Maas, MD, associate professor of neurology and anesthesiology at Northwestern University in Chicago, Illinois, noted that the study "contributes to a growing body of literature that explores whether the limited benefit of intensive blood pressure reduction observed in the general population of patients with ICH is because of limited biological effect or instead because potential benefits are being counterbalanced by harms."

Maas notes that in addition to randomized studies, observational data suggest that "the ideal SBP reduction trajectory depends on numerous individual factors, and overcorrection is harmful."

There is a window beyond which the potential benefit of SBP reduction may wane, Maas says. "Evidence suggests that initiating SBP reduction very early confers more benefit."

Commenting on the findings for Medscape Medical News, Kevin N. Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine and chief of neurocritical care and emergency neurology at Yale New Haven Hospital, New Haven, Connecticut, said that, given the post hoc nature of the analysis, the results must be confirmed in another dataset or in prospective studies.

These findings "should be viewed as hypothesis-generating data, but the methodologies and dataset are quite strong," he said.

The current results suggest that the question of when and how much to lower blood pressure in an individual patient, especially one who presents with higher blood pressure, is still unclear, he noted.

"We need to better understand why some patients present with very high blood pressure in the first place," said Sheth. "Is it because of chronic hypertension, acute autoregulation, or both? Are those situations the same? If blood pressure lowering is worse in terms of cause and effect, why is it that lowering leads to worse outcome?"

The study was supported by grants from the National Institute of Neurological Disorders and Stroke and the Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center. Lobanova has disclosed no relevant financial relationships. Maas receives support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Sheth has disclsoed no relevant financial relationships.

JAMA Neurol. Published online September 8, 2020. Abstract, Editorial

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