What are the risks of intracerebral haemorrhage due to alteplase after acute ischaemic stroke? Results from an individual patient data meta-analysis of randomised trials

Journal article

Background: Randomised trials have shown that alteplase improves the odds of a good stroke outcome when delivered within 4.5 hours of acute ischaemic stroke. Alteplase also increases the risk of intracerebral haemorrhage, but the factors determining the proportional and absolute risks are uncertain.

Methods: We used data from the Stroke Thrombolysis Trialists’ (STT) meta-analysis of individual patient data from 9 randomised trials of alteplase versus placebo (or open control) involving 6,756 patients. We pre-specified assessment of 3 definitions of intracerebral haemorrhage: type 2 parenchymal haemorrhage (PH-2) within 7 days; SITS-MOST haemorrhage within 24-36 hours (PH-2 with at least 4 point deterioration in NIHSS); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. Exploratory analyses assessed mortality after intracerebral haemorrhage and examined the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days.

Findings: Alteplase increased the odds of PH-2 haemorrhage (231/3391 [6.8%] among patients allocated alteplase vs 44/3365 [1.3%] among patients allocated control; odds ratio [OR] 5.55, 95% CI 4.01–7.70; absolute excess 5.5% [95% CI 4.6% - 6.4%]); SITS-MOST haemorrhage (124/3391 [3.7%] vs 19/3365 [0.6%]; OR 6.67, 4.11-10.84; absolute excess 3.1% [2.4% - 3.8%]); and of fatal intracerebral haemorrhage (91/3391 [2.7%] vs 13/3365 [0.4%]; OR 7.14, 3.98–12.79; absolute excess 2.3% [1.7% - 2.9%]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1.5% (95% CI 0.8-2.6%) for strokes with NIHSS 0-4 to 3.7% (95% CI 2.1-6.3%) for NIHSS ≥22 (trend p=0.01). For those treated within 4.5 hours, the absolute increase in the proportion (6.8%) achieving a modified Rankin score of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2.2%) and the increased risk of any death within 90 days (0.9%).

Interpretation: Among patients treated with alteplase the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, on average, within 4.5 hours of stroke, the probability of achieving an excellent outcome clearly exceeds the risk of death, early treatment is especially important for those with severe strokes.

Authors: Emberson, J; Baigent, C; Whiteley, W; Lees, K; Blackwell, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Lancet
• Journal: Lancet Neurology
• Volume: 15
• Issue: 9
• Pages: 925–933
• Publication date: 2016-01-01
• Acceptance date: 2016-05-04
• DOI: 10.1016/S1474-4422(16)30076-X
• EISSN: 1474-4465
• ISSN: 1474-4422