The effects of long-term oral antithrombotic agents after intracranial haemorrhage: protocol for a prospective individual participant data meta-analysis of randomised controlled trials v1
Authors: Al-Shahi Salman Rustam , S. Anderson Craig , R. Benavente Oscar , Casolla Barbara , Chen Chen , Cheng Xin , J. Connolly Stuart , Cordonnier Charlotte , Glader Eva-Lotta , J. Hankey Graeme , U. Heuschmann Peter , Hofmeijer Jeannette , Kamel Hooman , Kerkhoff Henk , J.M. (Karin) Klijn Catharina , Kruuse Christina , Tveitan Larsen Kristin , Lewis Steff , Murthy Santosh , Pennlert Johanna , Pollock Roz , Morten Rønning Ole , Schreuder Floris , Sheth Kevin , Shoamanesh Ashkan , Song Lily , F. Tierney Jayne , Veltkamp Roland , Bart van der Worp H 
Published: March 2021

Introduction – Randomised controlled trials (RCTs) have shown that antiplatelet and anticoagulant (antithrombotic) agents reduce the risk of stroke and other major vascular events for a variety of patients despite increasing the risk of bleeding. However, patients with intracranial haemorrhage were not included in these RCTs, so the risks and benefits of antithrombotic agents after intracranial haemorrhage are uncertain. Methods and analysis – The Collaboration Of Controlled Randomised trials of long-term Oral Antithrombotic drugs after spontaneous intraCranial Haemorrhage (COCROACH) aims to perform an individual participant data meta-analysis (IPDMA) in order to provide reliable information about the effects of antithrombotic agents on the risks of major vascular events after spontaneous intracranial haemorrhage overall, and in clinically important sub-groups. The protocol of the corresponding Cochrane Review (8 April 2016) specified the methods used by this IPDMA for searching the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase, and online registries of RCTs. RCTs are eligible for inclusion in this IPDMA if they are registered with a trial registry, include participants with spontaneous intracranial haemorrhage who are allocated at random to long-term use of any oral antithrombotic agent(s) or to placebo, open control, another antithrombotic agent, or another intervention for the prevention of major vascular events, and their chief investigator agrees to share participant-level de-identified data. COCROACH was initiated at the European Stroke Organisation Conference on 17 May 2017 before the results of any RCTs were known. This protocol was agreed after the publication of one RCT of antiplatelet agents (RESTART ISRCTN71907627) and the presentation of one trial of an oral anticoagulant agent (NASPAF-ICH NCT02998905), but before the majority of RCT results were known. We will perform two-step IPDMA of included RCTs using their intention-to-treat datasets using fixed effects models as the primary analysis. We will conduct separate IPDMAs, grouping RCTs into distinct dyads of intervention (antithrombotic agent class) and comparator, as allocated by randomisation. The primary outcome for each IPDMA will be a composite outcome of major vascular events that are appropriate to the intervention-comparator dyad. Secondary outcomes will include major ischaemic events and major haemorrhagic events. We will assess interactions with the effects of antithrombotic agents on the primary outcome in demographic, clinical, imaging, and treatment-related sub-groups. Ethics and dissemination – All participant data will be shared with the University of Edinburgh by included RCTs with the intention of addressing the same research question for which they were acquired. Participant-level data will be de-identified and shared unless forbidden by individual participants or regulatory authorities. We will disseminate the results of this IPDMA in peer-reviewed journals.