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

Abstract

BackgroundFor 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 therapy modifies the risks of recurrent ICH, major haemorrhagic events, major occlusive vascular events, or a composite of all major vascular events compared to avoiding antiplatelet therapy.Methods/designThe REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet therapy 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 occurred on 29 January 2019, after which the un-masked trial statistician conducted the final analyses according to this statistical analysis plan.DiscussionFinal results of RESTART will be analysed and disseminated in May 2019.Trial registrationISRCTN registry 71907627. Prospectively registered on 25 April 2013.Electronic supplementary materialThe online version of this article (10.1186/s13063-019-3270-2) contains supplementary material, which is available to authorized users.

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

“…The patient reference group for the Research to Understand Stroke due to Haemorrhage (RUSH) programme reviewed the study materials and progress. The trial steering committee and co-sponsors approved the trial protocol and the statistical analysis plan 17, 18…”

“…The secondary outcomes were a composite of all major haemorrhagic events and a composite of all major occlusive vascular events 17 . Major haemorrhagic events included recurrent symptomatic intracerebral haemorrhage (primary outcome), 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 .…”

“…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 18 . In the protocol, we had specified a composite secondary outcome of all major vascular events defined by the Antithrombotic Trialists' Collaboration (non-fatal myocardial infarction, non-fatal stroke [ischaemic, haemorrhagic, or uncertain cause], or death from a vascular cause) 4, 17…”

“…Without reference to data by randomised allocation or input from the unmasked trial statistician, the masked trial statistician (GDM) and chief investigator (RA-SS) prepared a statistical analysis plan that was approved by the trial steering committee before database lock, and then published 18 …”

“…We constructed an unadjusted Cox proportional hazards regression model and a second model adjusted for all five covariates included in the minimisation algorithm (which was the primary method of analysis) to calculate the hazard ratios (HRs). We prespecified a hierarchical testing of the primary outcome, key secondary outcomes, and other secondary outcomes, so we did not adjust the threshold of statistical significance for multiplicity 18 . We used the Mann–Whitney test to compare group summaries of modified Rankin scale scores by randomised group.…”