Elsevier

The Lancet Neurology

Volume 13, Issue 4, April 2014, Pages 364-373
The Lancet Neurology

Articles
Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial

https://doi.org/10.1016/S1474-4422(14)70018-3Get rights and content

Summary

Background

High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079).

Methods

INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150–220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2–7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles.

Findings

We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05–1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14–2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14–1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13–1·88; ptrend=0·0044).

Interpretation

Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure.

Funding

National Health and Medical Research Council of Australia.

Introduction

Stroke is a major cause of premature death and disability. The most serious and least treatable form—acute intracerebral haemorrhage—affects more than 1 million people each year worldwide.1 High blood pressure is a risk factor for stroke, particularly for both incident and recurrent intracerebral haemorrhage, but it also predicts a poor outcome when present in the first 24 h after the onset of intracerebral haemorrhage.2, 3, 4 Thus, early intensive control of blood pressure could be a safe and effective treatment for this disorder.5, 6 INTERACT2 showed improved functional outcomes with little risk for patients with intracerebral haemorrhage who received target-driven, early, intensive treatment to reduce blood pressure.7 However, the effects did not differ between patients who received treatment within 4 h and those who were treated at 4–6 h, which suggests that other aspects of blood pressure control might be important.

Most guidelines for the management of hypertension8, 9, 10, 11, 12 are based on usual or mean blood pressure, but the different efficacies of different antihypertensive drugs for reducing the risk of stroke and other cardiovascular events cannot be explained by reductions in mean systolic blood pressure alone.13, 14, 15 Blood pressure variability can be defined as the variation in blood pressure during a period of time (standard deviation [SD] or coefficient of variation), with or without adjustment for trends in underlying mean blood pressure (residual standard deviation) or the average absolute difference between successive readings (successive variation). An increase in blood pressure variability might predict outcome after acute stroke,13 but the few data available are conflicting. Some studies of patients with acute ischaemic stroke have shown that high beat-to-beat diastolic blood pressure is associated with a poor prognosis,16 and high systolic blood pressure variability is associated with high risks of death and early neurological deterioration.17 A small observational study18 has shown that systolic blood pressure variability independently predicts early haematoma growth and death or early neurological deterioration in patients with intracerebral haemorrhage. However, secondary analyses of two clinical trials—the Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS)19 and Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS),20 which included patients with intracerebral haemorrhage as well as those with ischaemic stroke—showed no significant association between blood pressure variability in the first 48 h after the onset of symptoms and death or dependency at 2 weeks.21 We assessed the clinical significance of blood pressure variability in the first 24 h (hyperacute phase) and during days 2–7 (acute phase) in patients with intracerebral haemorrhage who participated in INTERACT2.7

Section snippets

Study design and participants

We did this post-hoc analysis with data from INTERACT2 (ClinicalTrials.gov number NCT00716079). The design and main results of INTERACT2 have been outlined elsewhere.7, 22, 23 The study included 2839 adult patients with spontaneous intracerebral haemorrhage and high systolic blood pressure (150–220 mm Hg), without a clear indication or contraindication to early intensive treatment to reduce blood pressure. The patients were enrolled from 144 hospitals in 21 countries between 2008 and 2012.

Results

Of the 2839 participants in INTERACT2, 2645 were included in the analyses of the hyperacute phase and 2347 of the acute phase (figure 2). Baseline characteristics of patients at the time of randomisation were similar between the two phases (table 1). Mean age was 63·5 years, and 62·1% of participants were men, with 1381 participants (52·2%) having the primary outcome (death in 253, major disability in 1128) in the hyperacute phase, and 1179 (50·2%; death in 132, major disability in 1047) in the

Discussion

We have shown that within-patient variation in systolic blood pressure from visit to visit—in both the hyperacute (within 24 h) and acute (over the subsequent week) periods after intracerebral haemorrhage—is an important determinant of outcome, independent of mean systolic blood pressure. The greater the variation of systolic blood pressure, the stronger the association with a poor outcome at 90 days, defined either by the conventional measure of death or major disability, or by the level of

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