Ravinder-Jeet Singh, MBBS, DM

Moullaali TJ, Wang X, Martin RH, Shipes VB, Robinson TG, Chalmers J, et al. Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data. Lancet Neurol. 2019;18:857-864.

Approach to management of blood pressure during early hours after the onset of intracerebral hemorrhage (ICH) is heterogenous due to potential benefits vs. perceived risks of acute blood pressure lowering. The main rationale of acute blood pressure lowering is to reduce hematoma expansion, thereby, limiting early neurological deterioration and poor long-term outcome associated with hematoma expansion.1 Smaller hematoma expansion also leads to smaller final hematoma volume, therefore, lesser increase in absolute perihematomal edema and better outcomes.2 Conversely, acute blood pressure lowering might cause more cerebral insult by compromising perihematomal penumbra, a concept now widely debated.3 Aggressive blood pressure lowering is associated with systemic complications, especially remote ischemic cerebral lesions, which are associated with neurological deterioration4 and non-cerebral ischemia (especially cardiac ischemia and acute renal injury), worsening outcomes. Therefore, clinicians often face the questions “Where lies the right balance?” and “What’s the sweet spot of blood pressure target?” in an individual patient.

The literature on the topic is plagued by small or poor-quality studies. However, two recent large, international, multicenter, randomized controlled trials now provide additional evidence on the topic: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. However, the difference in the trial methodologies led to discordant results, resulting in uncertainty about the best strategy to manage blood pressure. In the September issue of Lancet Neurology, Moullaali et al. reported a preplanned pooled analysis of individual participant data of subjects enrolled into main phase of INTERACT2 and ATACH-II trial and performed multivariable analysis, not assessed in the previous meta-analysis using study-level data.6 The authors investigated three measures of systolic blood pressure (SBP) — magnitude of SBP reduction (the difference between SBP at randomization and lowest attained systolic blood pressure within 1 h), achieved SBP (the mean of the SBP measurements at five timepoints between 1 h and 24 h), and variability of SBP (the SD of the same measures between 1 h and 24 h) — for their association with the outcome. The primary outcome was functional status as defined by the distribution of scores on the modified Rankin Scale (mRS) at 90 days post-randomization. Secondary outcomes were good outcome (mRS 0-3) and functional independence (mRS 0-2); hematoma expansion (an absolute >6 mL 24 or relative >33% increase in hematoma volume from baseline to the 24 h CT scan); and death within 90 days. Safety outcomes were neurological deterioration (NIHSS increase of 4 points or more or GCS decrease of 2 points or more over 24 h compared to baseline); treatment-related symptomatic hypotension requiring therapy within 24 h; and any fatal or non-fatal, cardiac, or renal serious adverse events within 90 days.

A total of 3829 patients (mean age 63.1 years, 37% women, and 65% Asian) were randomized in these two trials; about two-thirds of patients were from INTERACT2 trial. Most enrolled patients had mild to moderate neurological deficit (median NIHSS of 11), relatively small deep hematoma (median volume 10·8 ml) and modest elevation of SBP (mean SBP 178 mm Hg). Patients were randomized at median 3·6 h from the onset of symptoms. The magnitude of systolic blood pressure reduction was 29, and achieved SBP was 147 with SBP variability being 14 mm Hg. Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio 0·90 [95% CI 0·87–0·94], p<0·0001). It was also associated with improved good outcome, functional independence, lower hematoma expansion, and mortality. Blood pressure reduction was safe with lower risk of neurological deterioration. The frequency of adverse effects was low; symptomatic hypotension occurred in 1% of patients, renal serious adverse events was seen in 1%, and cardiac serious adverse events occurred in 3% of patients.

The authors concluded that there are benefits to achieving early (first hour) and smooth control of systolic blood pressure (low variability) potentially to levels as low as 120–130 mm Hg in adults with acute (<6 hours) intracerebral hemorrhage having mild-moderate deficits. Further, the authors also found some evidence suggesting that a rapid and large reduction (≥60 mm Hg) within 1 h of the initiation of treatment might cause harm, though not conclusive. Of note, large and early drop in ATACH-II might explain why primary results of this trial were neutral.

Most notable limitations are inclusion of predominantly deep ICH, where BP appears to play a major role in ICH causation and ICH expansion; strategy of BP control in lobar hematoma remains still unclear. There is under-representation of ICH with poor prognosis as the trial protocols excluded subjects with very severe deficits (GCS <5) and large hematomas with significant midline shift; therefore, BP targets in these population remain unknown. In addition, the study was unable to provide evidence on the “best” antihypertensive drug and regime to achieve early and smooth blood pressure control. Finally, Asian population was overrepresented in the study, which compromises external validity of the results.

Overall, the study is important in providing new evidence demonstrating that systolic blood pressure control reduces hematoma expansion and improves functional outcome. Based on the meta-analysis, for now, a combination of intravenous and oral agent could be used to achieve the blood pressure targets. Future studies should define the role of blood pressure management in patients with poor prognosis and also the optimal agent/regime to achieve early/smooth blood pressure control. Further, usefulness of ultra-early (pre-hospital) blood pressure reduction in the ICH population remains to be established.

References:

  1. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–1181.
  2. Murthy SB, Moradiya Y, Dawson J, Lees KR, Hanley DF, Ziai WC. VISTA-ICH Collaborators. Perihematomal Edema and Functional Outcomes in Intracerebral Hemorrhage: Influence of Hematoma Volume and Location. Stroke. 2015;46:3088-92.
  3. Kate MP, Hansen MB, Mouridsen K, Østergaard L, Choi V, Gould BE, et al. ICHADAPT Investigators. Blood pressure reduction does not reduce perihematomal oxygenation: a CT perfusion study. J Cereb Blood Flow Metab. 2014;34:81-6.
  4. Buletko AB, Thacker T, Cho SM, Mathew J, Thompson NR, Organek N, et al. Cerebral ischemia and deterioration with lower blood pressure target in intracerebral hemorrhage. Neurology. 2018;91:e1058-e1066.
  5. Moullaali TJ, Wang X, Martin RH, Shipes VB, Robinson TG, Chalmers J, et al. Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data. Lancet Neurol. 2019;18:857-864.
  6. Boulouis G, Morotti A, Goldstein JN, Charidimou A. Intensive blood pressure lowering in patients with acute intracerebral haemorrhage: clinical outcomes and haemorrhage expansion. Systematic review and meta-analysis of randomised trials. J Neurol Neurosurg Psychiatry. 2017;88:339-345.