Two similarly controlled landmark trials provide conflicting results regarding the clinical guidelines for management of acute hypertension in individuals with intracerebral hemorrhage (ICH).1 While one concluded aggressive treatment was associated with improved outcomes, the other found no significant changes in rates of death or severe disability.

Alejandro A. Rabinstein, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota, acknowledges the limitations of these trials and important takeaways for clinicians in his editorial published in Stroke. He believes focusing exclusively on blood pressure (BP) targets may obscure a critical finding, specifically, the potential link between fluctuations in BP during the hyperacute phase and poor outcomes for individuals with ICH.1

Results of INTERACT-2 and ATACH-2 Trials

The INTERACT-2 (The Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial; ClinicalTrials.gov Identifier: NCT00716079) randomized controlled trial evaluated 2794 individuals experiencing acute hypertension within 6 hours of ICH onset. Treatment was focused on meeting a systolic BP target <140 or <180 mm Hg. For individuals in the intensive subgroup, the goal was to achieve target systolic BP within 1 hour. While there was no specific mandate on which mediations clinicians could use to treat acute hypertension, patients had to remain below their target BP for at least 7 days.1,2

Rate of death and moderate or severe disability (modified Rankin score of 3-6) after 90 days did not differ significantly between the 2 study arms. Further, rate of serious adverse event was similar within the respective groups. Findings from this trial suggest improved functional outcomes in the more intensive treatment arm.2 Using these findings, the AHA adjusted their guidelines for the management of acute hypertension in individuals with ICH, advising a target systolic BP below 140 mm Hg.1

These findings were not replicated in the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-II; ClinicalTrials.gov Identifier: NCT01176565) randomized controlled trial. Systolic BP targets in this trial were the same as that found in INTERACT-2 (<140 or <180 mm Hg); antihypertensive treatment, however, had to be initiated within 4.5 hours of hematoma onset. ATACH-2 also mandated the use of intravenous nicardipine as a first-line medication and a goal of maintaining BP target for 24 hours.3

The ATACH-2 trial, which enrolled 1000 participants, discontinued after an interim analysis failed to demonstrate significant differences between rate of death or severe disability (modified Rankin score of 4-6) at 90 days.1,3 Moreover, an increase in renal adverse events was found within 7 days, specifically in the intensive treatment arm.3 In his editorial, Dr. Rabinstein speculates this “could have been caused by excessive BP lowering on the first day.”1

The more pronounced reduction in BP the first day in ATACH-2 highlights the primary difference between these trials which, Dr Rabinstein suggests, may have been aggressive. Secondary analyses from the INTERACT-2 trial of individuals with BP less than 130 mm Hg suggest a worse prognosis as well.4 “Taken along with the lack of effect from intensive BP lowering on reducing hematoma expansion observed in both trials, these combined findings argue against overzealous BP lowering during the first few hours after an ICH,” noted Dr Rabinstein.1,3

Link Between BP Variability and Outcomes

Variability in BP may in fact be associated with unfavorable functional outcomes, as suggested by Dr Rabinstein, according results published in the same issue of Stroke. This study included data from 386 participants enrolled in the FAST-MAG trial (Field Administration of Stroke Therapy – Magnesium; ClinicalTrials.gov Identifier: NCT00059332), and emphasized BP changes within the hyperacute phase. Researchers evaluated BP variability within 24 to 26 hours after ICH and observed that greater BP variability was associated with unfavorable functional outcomes (modified Rankin score of 3-6) at 90 days.5

Individuals in the highest quintile of hyperacute BP variability had a three-fold to four-fold increase in the risk for an unfavorable outcome, even after adjusting for age, initial severity and mean systolic BP.5 They find that neither mean nor maximum BP during the hyperacute phase was associated with poor functional outcomes; instead, BP variability appeared to be a deciding factor for outcomes.

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Research Limitations

In his editorial, Dr. Rabinstein acknowledges that the findings from FAST-MAG could not be adjusted to account for all prognostic factors.1 Nevertheless, associations were well-documented and showed a clear link between BP variability and worse clinical outcomes.

It remains unclear to what extent the BP-lowering medications impacted findings from the FAST-MAG trial. Further, BP fluctuations may be more prominent with severe hematomas, and may serve as a confounding factor for the link between BP variability and poor clinical outcomes.1 As the cause-and-effect relationship is difficult to assess, guidelines for optimal management of acute hypertension after ICH remain undefined.

Recommendations for Clinicians

Despite the limitations of these findings, Dr. Rabinstein finds that the cumulative evidence provided by the INTERACT-2 and ATACH-2 trials, along with the findings published from the FAST-MAG trial, suggest rapid and aggressive BP reduction may be harmful for managing acute hypertension after ICH. He pronounced that, “BP fluctuations portend poor outcome and suggest that avoiding these fluctuations could represent a valid therapeutic target.”1

References

1. Rabinstein AA. Optimal blood pressure after intracerebral hemorrhage. Stroke. 2018;49(2):275-276.

2. Anderson CS, Heeley E, Huang Y, et al. INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355-2365.

3. Qureshi AI, Palesch YY, Barsan WG, et al. ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375:1033-1043.

4. Arima H, Heeley E, Delcourt C, et al. INTERACT2 Investigators. Optimal

achieved blood pressure in acute intracerebral hemorrhage: INTERACT2. Neurology. 2015;84:464-471.

5. Chung PW, Kim JT, Sanossian N, et al. FAST-MAG Investigators and Coordinators. Association between hyperacute stage blood pressure variability and outcome in patients with spontaneous intracerebral hemorrhage. Stroke. 2018;49:348-354.