The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: statistical analysis plan for a randomised controlled trial

Abstract

Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs modifies the risks of recurrent ICH, haemorrhagic events, vaso-occlusive events, or a composite of all serious vascular events compared to avoiding antiplatelet drugs. Methods/design: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH. Recruitment began on 22 May 2013 and ended on 31 May 2018. Follow-up ended on 30 November 2018. This update to the protocol describes the statistical analysis plan (version 1.7, finalised on 25 January 2019). Database lock and un-blinding occured on 29 January 2019, after which the un-blinded trial statistician conducted the final analyses according to this statistical analysis plan. Discussion: Final results of RESTART will be analysed and disseminated in May 2019. Trial registration: ISRCTN registry 71907627. Prospectively registered on 25 April 2013. The trial is funded by a British Heart Foundation special project grant (SP/12/2/29422) and a travel fellowship (FS/13/72/30531). The trial sponsor is the Academic and Clinical Central Office for Research and Development (ACCORD), which is a partnership between the University of Edinburgh and NHS Lothian Health Board.

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

“…17 Major haemorrhagic events included recurrent symptomatic intracerebral haemorrhage (primary out come), other forms of symptomatic spontaneous or traumatic intracranial haemorrhage, and symptomatic major extracranial haemorrhage at any site (requiring transfusion or endoscopic treatment or surgery, or resulting in death within 30 days). 18 Major occlusive vascular events were ischaemic stroke; myocardial infarction; mesenteric ischaemia; peripheral arterial occlusion; deep vein thrombosis; pulmonary embolism; and carotid, coronary, or peripheral arterial revascularisation procedures. 18 The composite secondary outcome of all major haemorrhagic or occlusive vascular events combined these two composite outcomes.…”

“…The trial steering committee and co-sponsors approved the trial protocol and the statistical analysis plan. 17,18…”

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

“…In our protocol and statistical analysis plan, 20,21 we prespecified that the MRI substudy would focus on primary subgroup analyses, testing whether there was heterogeneity in the effects of antiplatelet therapy on the trial's primary outcome of recurrent intracerebral haem orrhage by the presence, number, or location of cerebral microbleeds. We collected other brain imaging features on MRI and CT for exploratory subgroup analyses of the effects of antiplatelet therapy on recurrent intracere bral haemorrhage or ischaemic stroke.…”

“…We prespecified that for categorical analysis of cerebral microbleed number, the split would be 0 or 1 versus 2-4 versus 5 or more. 21 We investigated whether cerebral microbleed presence and burden (as a continuous variable) were associated, as expected, 7,32 with the first recurrent intracerebral haem orrhage or ischaemic stroke in Cox proportional hazards regression models adjusted for the five covariates in the minimisation algorithm (qualifying intracerebral haem orrhage location, time since symptom onset, antiplatelet therapy preferred by the participant's physician if allocated to start, participant age at randomisation, and predicted probability of being alive and independent at 6 months). We analysed heterogeneity of the effects of antiplatelet therapy on the first recurrent intracerebral haemorrhage between subgroups using a statistical test of interaction, by including an interaction term between treatment group and each imaging feature in Cox proportional hazards regression models adjusted for the five covariates in the minimisation algorithm.…”

“…RESTART was an investigatorled, pragmatic, multicentre, prospective, randomised, openlabel, blindedendpoint, parallelgroup trial in 122 hospitals in the UK. Participant eligibility, consent, data collection, monitoring, approvals, procedures, and statistical analysis principles are described in detail in the protocol, 20 statistical analysis plan, 21 and primary report of the trial. 19 Briefly, patients were eligible for enrolment if they were aged 18 years or older, had survived at least 24 h after spontaneous intracerebral haemorrhage, and were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease at the onset of intracerebral haemorrhage, after which therapy was discontinued.…”