Intensive BP-Lowering for ICH Potentially Deadly in Chronic Kidney Disease

Erik Greb

July 15, 2021

Treating intracranial hemorrhage (ICH) with intensive blood-pressure control is potentially deadly in patients with impaired kidney function, new research shows.

A post-hoc analysis from the open-label ATACH-2 trial, which included almost 1000 participants, showed those with estimated glomerular filtration rates (eGFRs) signifying kidney dysfunction were at significantly higher risk for death and disability after an ICH than those with a normal eGFR.

In addition, for those with at least mild-to-moderate loss of kidney function who underwent intensive blood pressure reduction for ICH, the odds for death or disability was more than three times greater than for those who underwent standard blood pressure reduction.

"Although the common therapeutic approach for acute ICH is to quickly and drastically lower blood pressure, the effectiveness of this treatment might change, depending on kidney function," lead author Mayumi Fukuda-Doi, MD, PhD, chief of the Department of Data Science, National Cerebral and Cardiovascular Center, Osaka, Japan, told Medscape Medical News.

The findings were published online July 1 in Neurology.

Clarifying Conflicting Results

Among patients who experience a stroke, chronic kidney disease (CKD) is common and associated with worse outcomes. Although intensive blood-pressure lowering is a common treatment for ICH, this approach has raised concerns in the setting of CKD.

Results from the INTERACT2 trial suggest intensive blood-pressure lowering provided slightly greater benefits than standard lowering among patients with ICH. In addition, benefits did not vary significantly with patients' level of kidney function.

However, in the original ATACH-2 trial, intensive blood pressure lowering did not improve functional outcomes of ICH but increased the risk for renal adverse events (AEs).

To clarify the influence of kidney function on clinical outcomes and treatment of ICH, the current investigators performed a post-hoc analysis of data from the ATACH-2 trial.

That study included patients with ICH of less than 60 mL and systolic blood pressure (SBP) of greater than 180 mm Hg.

All were randomly assigned, within 4.5 hours of ICH onset, to intensive or standard blood-pressure lowering with intravenous nicardipine. The target SBP was 110 to 139 mm Hg for the intensive group and 140 to 179 mm Hg for the standard group.

Primary, Secondary Outcomes

A composite of death within 90 days or severe disability at 90 days was the primary endpoint. These outcomes were defined as a modified Rankin Scale (mRS) score between 4 and 6. The secondary outcome was death within 90 days.

CKD was defined as reduced eGFR. Using patients' baseline eGFR, the investigators categorized participants into three groups.

The first group had an eGFR of 90 mL/min/1.73 m2 or higher, the second had an eGFR between 60 and 89 mL/min/1.73 m2, and the third had an eGFR less than 60 mL/min/1.73 m2. Patients with kidney failure, defined as eGFR less than 15 mL/min/1.73 m2, and those with the highest 1% of eGFR values were excluded from the study.

The investigators analyzed data for 974 ATACH-2 participants. At baseline, median eGFR was 88 mL/min/1.73 m2. Approximately 46% of the population was in the group with the highest eGFR, 37% were in the middle group, and 16% were in the group with the lowest eGFR.

Compared with patients with normal eGFR, patients with decreased eGFR were older and more likely to have hypertension, dyslipidemia, atrial fibrillation, or diabetes. Baseline stroke severity was similar across eGFR categories.

Among patients who underwent intensive treatment, those with eGFR less than 60 mL/min/1.73 m2 maintained higher SBP than those with better renal function.

Small-Vessel Damage "Likely"

Results showed renal function was linked to outcomes of ICH. Rate of death or disability was 49.7% in the lowest eGFR category, 40% in the middle category, and 31.7% in the highest category (P <  .01).

After adjusting for covariates, the odds ratio (OR) of death or disability in patients in the lowest eGFR category was as high as 2.02 compared with patients in the highest eGFR category.

The combination of treatment and eGFR category had a significant effect on risk for death or disability (P = .02), but not on risk for death alone.

The OR of death and disability was also significantly higher in patients with decreased baseline eGFR who underwent intensive SBP-lowering therapy compared with those who underwent standard SBP-lowering therapy.

For example, the unadjusted OR of death and disability was 3.6 in patients with an eGFR less than 60 mL/min/1.73 m2 who underwent intensive SBP-lowering therapy.

Interestingly, acute kidney injury did not significantly influence the associations.

"Since the brain and kidneys share similar susceptibility to vascular injury, among those with decreased eGFR, the small vessels in the brain are likely to be damaged," said Fukuda-Doi.

"Therefore, these patients may be more susceptible to restricted cerebral perfusion by aggressive SBP lowering, resulting in delayed functional recovery," she added.

However, she cautioned that although post-hoc analyses can generate hypotheses, they should be interpreted carefully. Clarifying the mechanism of the association between decreased eGFR and increased risk for disability or death after intensive blood-pressure lowering therapy will require further studies.

"From ATACH-2, many other secondary analyses are being planned and conducted. It is hoped that further investigations will lead to the elucidation of a truly effective treatment for acute cerebral hemorrhage," Fukuda-Doi said.

A More Cautious Approach Warranted

Commenting on the findings for Medscape Medical News, Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales in Sydney, Australia, noted that about 1 in 5 patients have moderate-to-severe renal impairment at time of ICH.

He added that this impairment, presumably caused by the shared effects of chronic hypertension, predicts a worse recovery from ICH.

Dr Craig Anderson

The significant interaction between intensive blood-pressure lowering and poor functional recovery shown in the current study "raises issues of caution in the intensity of treatment in this subgroup of patients," said Anderson, who was not involved with the research.

He noted that although both ATACH-2 and INTERACT2 trials investigated intensive blood-pressure lowering as a treatment for acute ICH, comparing the trials is complicated because of the different approaches used for blood-pressure lowering and the different ways the data were reported.

Taken together, the trials suggest that "a more cautious approach to blood-pressure control of 1 hour, rather than 30 minutes, and avoidance of a substantial drop from SBP >220 mm Hg to the recommended target of <140 mm Hg, would seem reasonable," said Anderson.

A meta-analysis of individual patient data conducted by Anderson and colleagues, and published in 2019 in The Lancet Neurology, supports this recommendation, he said.

However, the current study's findings are mainly confirmatory and leave several questions unanswered, such as whether there is any benefit from intensive blood-pressure lowering initiated within 90 minutes of symptom onset in the ambulance, Anderson noted.

He added that the ideal drug for ICH has not been identified, nor have the mechanisms for any potential effect of hematoma expansion or secondary cerebral edema.

In addition, it is unclear whether avoiding large fluctuations in blood pressure over several days in the hospital provides additional benefits beyond targeted blood-pressure control in the first few hours following presentation, Anderson said.

The study was funded by the National Institute of Neurological Disorders and Stroke; the Japan Agency for Medical Research and Development; and the Japanese Ministry of Education, Culture, Sports, Science, and Technology. Fukuda-Doi has disclosed no relevant financial relationships. Anderson was principal investigator of the INTERACT studies, which investigated intensive blood-pressure lowering, and he has received funding from Takeda China for research on this topic.

Neurology. Published online July 1, 2021. Abstract

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