Abstract
BackgroundAspirin is of moderate overall benefit for patients with acute disabling ischemic stroke. It is unclear whether functional outcome could be improved after stroke by targeting aspirin to patients with a high risk of recurrent thrombosis or a low risk of haemorrhage.AimsWe aimed to determine whether patients at higher risk of thrombotic events or poor functional outcome, or lower risk of major haemorrhage had a greater absolute risk reduction of poor functional outcome with aspirin than the average patient.MethodsWe used data on individual ischemic stroke patients from three large trials of aspirin vs. placebo in acute ischemic stroke: the first International Stroke Trial (n = 18 372), the Chinese Acute Stroke Trial (n = 20 172) and the Multicentre Acute Stroke Trial (n = 622). We developed and evaluated clinical prediction models for the following: early thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis and pulmonary embolism); early haemorrhagic events (significant intracranial haemorrhage, major extracranial haemorrhage, or haemorrhagic transformation of an infarct); and late poor functional outcome. We calculated the absolute risk reduction of poor functional outcome (death or dependence) at final follow‐up in: quartiles of early thrombotic risk; quartiles of early haemorrhagic risk; and deciles of poor functional outcome risk.ResultsIschemic stroke patients who were older, had lower blood pressure, computerized tomography evidence of infarct or more severe deficits due to stroke had increased risk of thrombotic and haemorrhagic events and poor functional outcome. Prediction models built with all baseline variables (including onset to treatment time) discriminated weakly between patients with and without recurrent thrombotic events (area under the receiver operating characteristic curve 0·56, 95% CI:0·53–0·59) and haemorrhagic events (0·57, 0·52–0·64), though well between patients with and without poor functional outcome (0·77, 0·76–0·78) in the International Stroke Trial. We found no evidence that the net benefit of aspirin increased with increasing risk of thrombosis, haemorrhage or poor functional outcome in all three trials.ConclusionsUsing simple clinical variables to target aspirin to patients after acute disabling stroke by risk of thrombosis, haemorrhage or poor functional outcome does not lead to greater net clinical benefit. We suggest future risk stratification schemes include new risk factors for thrombosis and intracranial haemorrhage.
Highlights
Aspirin is of moderate overall benefit for patients with acute disabling ischemic stroke
The absolute reduction in thrombotic events across trials was 6 per 1000, the absolute increase in haemorrhagic events across trials was 5 per 1000 and the absolute reduction in poor functional outcome by six-months across trials was 12 per 1000
Our study had a number of methodological strengths: we analyzed almost all the patients randomized to early aspirin vs. control in acute stroke trials; we modeled harms and benefits separately; we used an outcome measuring disability, rather than just events, so avoiding problems assigning weight to events of different severities; we did not implicitly assume linearity or additivity in our clinical prediction models; we accounted for missing data using multiple imputation avoiding the potential biases of a complete case analysis; we left continuous predictors continuous; and we did not remove insignificant predictors in our models or screen predictors at a univariate level, which would risk the problems with data-dependent selection [14]
Summary
Aspirin is of moderate overall benefit for patients with acute disabling ischemic stroke. When clopidogrel and aspirin were targeted to Chinese patients with a high risk of recurrent ischemic stroke, and low risk of haemorrhage – patients with recent TIA – the more intensive regime led to a net clinical benefit: fewer ischemic strokes, with no increase in intracranial haemorrhage [2]. This hypothesis is of great interest in recent TIA, and being explored in different populations (Platelet Orientated Inhibition in New TIA, POINT, NCT00991029) and with more intensive antiplatelet regimes (Triple Antiplatelets for Reducing Dependence After Ischaemic Stroke, TARDIS, ISRCTN47823388)
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