Safety and efficacy of early versus delayed acetylsalicylic acid after surgery for spontaneous intracerebral haemorrhage in China (E-start): a prospective, multicentre, open-label, blinded-endpoint, randomised trial

Background: Patients with non-traumatic intracerebral haemorrhage have a substantial risk of major adverse cardiovascular and cerebrovascular events, including ischaemic stroke, after surgery. The optimal timing of antiplatelet therapy after surgery for spontaneous intracerebral haemorrhage in patients at high risk of postoperative ischaemic events has not been characterised. We aimed to investigate the safety and efficacy of early versus late initiation of antiplatelet therapy after surgery for spontaneous intracerebral haemorrhage.

Methods: This prospective, open-label, blinded-endpoint, randomised trial was done at eight stroke centres in China. Eligible patients were aged 18-70 years, undergoing surgery for the evacuation of spontaneous intracerebral haemorrhage, and had a high risk of postoperative ischaemic events. Using the minimisation method in an online randomisation system, patients were randomly assigned (1:1) to receive 100 mg acetylsalicylic acid once per day in either the early-start group (starting on the third day after surgery until the 90th day after surgery) or the late-start group (starting on the 30th day after surgery until the 90th day after surgery). Medication was taken orally or delivered via a feeding tube. The primary efficacy outcome was a composite of new major ischaemic cardiovascular, cerebrovascular, or peripheral vascular events within 90 days and the primary safety outcome was any intracranial bleeding within 90 days, both measured in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT04820972, and is complete.

Findings: From May 1, 2021, to May 1, 2023, 7323 patients were screened, of whom 269 (4%) were enrolled and randomly assigned: 134 to the early-start group and 135 to the late-start group. 195 (72%) patients were male, 74 (28%) were female, and the median age was 60·2 years (IQR 52·0-66·5). Haematomas were supratentorial and deep in most (170 [63%] of 269) patients. Ischaemic major cardiovascular, cerebrovascular, or peripheral vascular events occurred within 90 days after surgery in 27 (20%) of 134 patients in the early-start group and 42 (31%) of 135 patients in the late-start group (odds ratio 0·56 [95% CI 0·32-0·98]; p=0·041). Intracranial bleeding occurred in one (1%) of 134 patients in the early-start group and four (3%) of 135 patients in the late-start group. Non-bleeding serious adverse events occurred in 57 (42%) of 134 patients in the early-start group and 57 (42%) of 135 patients in the late-start group.

Interpretation: Starting acetylsalicylic acid on the third day after surgery for spontaneous intracerebral haemorrhage in Chinese patients at high risk of postoperative ischaemic events resulted in fewer postoperative ischaemic major cardiovascular, cerebrovascular, or peripheral vascular events than starting acetylsalicylic acid therapy at 30 days, with no increased risk of intracranial bleeding. Whether early initiation of acetylsalicylic acid therapy is safe and improves clinical outcomes for broader populations of patients with spontaneous intracerebral haemorrhage requires further research.

Funding: The National Key Research and Development Program of China.