By Tom Jenkins
For July 2019, we have selected a scientific paper: RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage: a randomised open label trial. Lancet 2019; May 21 [Epub ahead of print]
A common clinical dilemma is the patient who has suffered a cerebral haemorrhage, but also has risk factors for ischaemic disease and was taking aspirin or clopidogrel before the event. This pragmatic trial addresses this issue and found that restarting medication a median of 76 days after the event was not associated with a greater bleeding risk. This has important implications for clinical practice.
The authors of this multicentre collaborative study recruited patients from 122 hospitals across the UK. Patients older than 18 years who has survived at least 24 hours after radiologically-confirmed spontaneous intracerebral haemorrhage were included. They were taking either antiplatelet or anticoagulant treatment for the prevention of occlusive vascular disease, and therapy was discontinued at the time of the haemorrhage. The patient and clinician had to be uncertain about whether to start or avoid antithrombotic treatment. Patients with head injury, haemorrhagic transformation of ischaemic infarcts, intracranial haemorrhages without intracerebral haemorrhage, pregnancy, breastfeeding, or childbearing age not taking contraception were excluded.
A computerised minimisation randomisation system was used to balance allocation to the two groups, either to restart or avoid antithrombotic treatment, equally weighted for the following characteristics: lobar vs non-lobar haemorrhage, time since symptom onset (1-6 days, 7-30 days, >30 days), specific antiplatelet therapy (aspirin alone vs other antiplatelet therapy), age (above or below 70 years), and predicted probability of being alive and independent at 6 months (above or below p=0.15). Treatment allocation was open to participants and clinicians and masked to follow-up staff and outcome adjudicators.
Within 24 hours of randomisation, either aspirin, dipyridamole or clopidogrel was restarted in the treatment group (alone or in combination, doses at the discretion of the treating physician). Patients were permitted to start or discontinue antiplatelet or anticoagulant treatment during follow-up if clinically indicated, regardless of treatment allocation. Follow-up was by postal questionnaire and/or telephone to general practitioners, patients and carers for 5 years.
The primary outcome was recurrent symptomatic intracerebral haemorrhage. The secondary outcomes were a composite of all major haemorrhagic events and a, composite of all major vascular occlusive events (including venous as well as arterial thromboses), both at any body site.
The target was 720 participants with 2 years follow-up. Cox proportional hazards models were used unadjusted and adjusted for the minimisation covariates, and hazard ratios reported.
Five hundred and sixty two participants were recruited. Recruitment proved difficult, and planned follow-up was extended by a year to attempt to accrue sufficient follow-up to power the study. In the final cohort, the median age was 76 years, two thirds were male and 92% were white. Sixty two percent had lobar haemorrhages. Allocation occurred at a median of 76 days from haemorrhage (inter-quartile range 29 to 146 days). Half were taking aspirin, a quarter clopidogrel and a fifth oral anticoagulants at the time of haemorrhage. In 97%, there was no underlying structural or macrovascular cause for the haemorrhage. Follow-up rates of 99% at 2 years and 94% at 4 years were achieved. Adherence to allocated treatment was 89% at 2 years and 82% at 4 years.
Four percent of patients who started and 9% patients who did not start antiplatelet therapy suffered a recurrent intracerebral haemorrhage (adjusted HR 0.51 (95%CI 0.25-1.03, p-0.060). There was no difference in 30 day case fatality between groups. There were no differences in secondary outcomes between groups. The details of the specific antiplatelet therapy restarted were not reported.
Limitations included difficulties recruiting to target (75% of the target number of participants was achieved) and a relatively low proportion of females in the final cohort. The study was not powered to determine the appropriate time interval at which to restart treatment.
The authors concluded that the results excluded all but a very modest increase in the risk of intracerebral haemorrhage with antiplatelet therapy. Further randomised trials and meta-analyses are planned.
“This pragmatic study provides the best evidence to date to guide physicians faced with this difficult dilemma”, said Professor Hugh Markus from the University of Cambridge. “It appears that restarting antiplatelet therapy after an intracerebral haemorrhage is lower risk than previously considered. Further studies are required to define the precise time-scales”
Prof Natan Bornstein, Tel Aviv University, commented: “This study addresses an important question. The difficulties in recruitment the authors experienced illustrate the challenges inherent to studying a complex clinical scenario in which practice varies, and highlight the current uncertainty about the best thing to do for the patient. In these patients who suffered a primary intracerebral haemorrhage and were at high risk of thrombotic events, it appeared safe to restart antiplatelet therapy after a median interval of between 2-3 months.”
Dr Tom Jenkins is Editor in Chief of EAN Pages and Member of the EAN eCommunicatipn Board and Senior Clinical Lecturer, Consultant Neurologist, Co-director of MND Care Center and MSc Course Lead at the Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, United Kingdom