Blood Pressure Management After Intracerebral and Subarachnoid Hemorrhage

The Knowns and Known Unknowns

Jatinder S. Minhas, MD; Tom J. Moullaali, MD, PhD; Gabriel J.E. Rinkel, MD, PhD; Craig S. Anderson, MD, PhD

Disclosures

Stroke. 2022;53(4):1065-1073. 

In This Article

Evidence to Support BP Lowering After ICH

Acute Phase

Differing results of the 2 largest RCTs of early intensive BP lowering in ICH, the second INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial) and ATACH-II (Antihypertensive Treatment of Acute Cerebral Hemorrhage), intensified debate over the safety and efficacy of this treatment.[21] However, a collaborative analysis that pooled IPD of the 3829 patients from these RCTs showed that achieving lower and more stable BP during 1 to 24 hours after ICH is associated with lower odds of hematoma growth and neurological deterioration and better functional recovery over the subsequent 90 days.[22] Moreover, there were no apparent cardiac or renal serious adverse events from achieving low systolic BP, with potential benefits evident to levels as low as 120 to 130 mm Hg in 1 to 24 hours.

However, in a broader systematic review and IPD meta-analysis of 5895 patients from 16 RCTs that tested various interventions to lower BP within 7 days of ICH, there was no overall effect of the treatment on functional outcome at 90 to 180 days, despite a reduction in hematoma growth at 24 hours in the subset of 2510 patients from 5 RCTs with complete imaging data.[10] Once again, the treatment was shown to be safe in regard to serious adverse events, including those separately defined as cardiac and renal, and for any early neurological deterioration.

Discordance between the effects of early intensive BP lowering treatment on the key outcome measures of hematoma growth and functional recovery may relate to several issues of study design and patient characteristics. First, ICH patients included in RCTs were randomized to BP lowering after a median of ≈4 hours from symptom onset, which is outside the window of most hematoma growth.[12] Second, these patients tended to have small-to-medium sized hematomas in deep brain locations (median ≈11 mL), which are less likely to grow substantially.[12] Third, there were only small differences in hematoma growth between treatment and control groups (absolute difference of ≈1 mL at 24 hours); this may not be clinically relevant for individual patients but more appropriate across groups of patients as part of a standard of care protocol. Fourth, as ICH patients tend to be elderly and have multiple comorbidities,[23] the modest benefit of treatment will be diluted by medical complications, which are common in the acute period after ICH.[24]

Understandably, therefore, guidelines have been conservative by providing an intermediate Grade 2a level to support to their recommendations for intensive BP lowering to a systolic BP target <140 mm Hg within 6 hours of symptom onset to reduce hematoma expansion and improve functional outcome after ICH.[7,25]

Timing of BP Lowering After ICH

A recent post hoc subgroup analysis of the ATACH-II trial showed that intensive BP lowering (systolic target, 110–139 mm Hg) with intravenous nicardipine delivered within 2 hours of ICH onset was associated with reduced hematoma growth and improved functional outcome.[26] However, there was no heterogeneity in the effect of BP lowering treatment according to time to randomization in a broader IPD meta-analysis of 16 RCTs;[10] but this included a substantial number of ICH patients (N=145) who received a glyceryl trinitrate (GTN) patch as part of a large prehospital ambulance-initiated treatment RCT (RIGHT-2) in patients with suspected acute stroke, and where subgroup analysis showed patients treated with GTN had greater hematoma growth and poorer outcomes than sham-GTN controls.[27] These data suggest that very early use of GTN might promote vasodilation or disrupt hemostatic mechanisms in ICH, and this may have modified the signal for potential benefits from other BP lowering interventions delivered within 2 hours of ICH onset in the IPD meta-analysis.[10] Thus, further data on the effects of ultra-early BP lowering are required, which is the basis of the ongoing the INTERACT4 (Intensive Ambulance-Delivered Blood Pressure Reduction in Hyper-Acute Stroke Trial; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03790800).[28]

Target Systolic BP Level After ICH

RCTs of BP lowering interventions within 7 days of acute ICH have tested various strategies and BP targets with mixed results. In the aforementioned IPD meta-analysis of 16 RCTs, there was heterogeneity in the treatment effect according to BP lowering strategy: ICH patients with titration of treatment to a systolic BP target appeared to have better outcomes than patients treated with a fixed agent without a specified target.[10] These data support the pooled IPD analysis of INTERACT2 and ATACH-II of potential benefits to systolic levels as low as 120 to 130 mm Hg.[22] However, a one-size-fits-all approach to up-, down-, or cross-titrate BP lowering to achieve an effective target, at the lowest dose, and without causing hypotension and other side effects, is often challenging in practice.[7,25] Avoiding a rapid, large reduction in systolic BP may be important: emerging data suggests systolic reductions of >≈70 mm Hg in 1 hour are associated with poor functional recovery after ICH, with a sweet spot for better outcome exists for reductions of between ≈30 and 45 mm Hg over 1 hour.[29]

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