PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation

Summary

Participation Requirements

Description

Stroke is one of the largest public health challenges worldwide. Its societal impact is expected to further increase in the coming decades due to the aging of population. Importantly, stroke is a heterogeneous disease comprising various subtypes with distinct mechanisms. The variability of individua...

Stroke is one of the largest public health challenges worldwide. Its societal impact is expected to further increase in the coming decades due to the aging of population. Importantly, stroke is a heterogeneous disease comprising various subtypes with distinct mechanisms. The variability of individual risks demands that more specifically targeted and better personalised approaches are developed to tailor stroke prevention for particular stroke types and individual patients. Intracerebral haemorrhage (ICH) is a particularly severe type of stroke affecting 10-15% of all stroke patients. Importantly, ICH carries even higher mortality and more severe disability than other stroke types. While mechanisms of ICH and ischaemic stroke are distinct, many risk factors are shared and patients are often at increased risk of both ischaemic stroke and ICH. Atrial fibrillation (AF) is also a growing epidemic in aging populations and a major cause of ischaemic stroke due to thrombus formation in the heart migrating to and occluding intracerebral arteries. At least 20% of ICH survivors also suffer from AF and are, thus, at particularly high risk of ischaemic stroke. While ischaemic stroke in AF patients in general can be much more effectively prevented with oral anticoagulation than with antiplatelet agents (APA) concerns about ICH recurrence in ICH survivors are a major barrier for anticoagulation. The best approach to stroke prevention in ICH patients with AF is presently unknown. Current clinical guidelines, which are largely based on retrospective observational studies investigating anticoagulation with vitamin K antagonists (VKA), either recommend considering anticoagulation only in patients with non-lobar location of ICH or, in the absence of evidence from randomised controlled trials, refrain from making any recommendations at all. Anticoagulation with direct oral anticoagulants (DOAC) has proven efficacy and safety for stroke prevention in AF. DOACs may be a better alternative to VKA particularly in ICH patients because DOACs were associated with a 50% lower risk of ICH than VKA in previous clinical trials of stroke prevention in AF. However, patients with previous ICH were excluded from these trials. Although thousands of ICH survivors with AF every year worldwide need effective prevention of another stroke, the best antithrombotic therapy for these patients is currently unknown. PRESTIGE-AF will be the first sufficiently powered randomised controlled trial aiming to resolve the dilemma of stroke prevention in this challenging high-risk patient population. Specifically, it will answer the question whether DOAC with their well-documented lower risk of intracranial haemorrhagic complications, compared to VKA, provide both a more effective and an equally safe option for stroke prevention in patients with ICH and AF compared to no anticoagulant. Findings of the Study are expected to change management guidelines and future prevention research for ICH survivors with AF. PREvention of STroke in Intracerebral haemorrhaGE survivors (PRESTIGE-AF) will test whether preventive therapy with DOACs (intervention group) reduce the rate of ischaemic stroke (superiority) compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent ICH (non-inferiority) in patients with AF and a previous ICH within 6 months before enrolment. The Research Question is: Does preventive therapy with Direct Oral Anticoagulants (intervention group) reduce the rate of ischaemic stroke (superiority) compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent Intracerebral haemorrhage (non-inferiority) in patients with atrial fibrillation and a previous intracerebral haemorrhage within 6 months before enrolment. The Objectives of the study are: The main objective is to perform a randomised controlled trial to resolve the long-standing management dilemma of antithrombotic stroke prevention in intracerebral haemorrhage (ICH) survivors with comorbid atrial fibrillation (AF). Specifically, it will address the question whether direct oral anticoagulants (DOACs, intervention) provide a more effective option for prevention of ischaemic stroke and an equally safe option in terms of recurrence of ICH for antithrombotic stroke prevention in survivors of recent ICH compared to no anticoagulation (i.e. no antithrombotic therapy or antiplatelet therapy at Principal Investigator´s discretion). The secondary Study objectives are: To examine the effect of anticoagulation with DOAC versus no anticoagulation on major cardiovascular outcomes and mortality in ICH patient with AF To compare the effect of DOACs versus no anticoagulation on major systemic and intracranial bleeding in this Study population To examine the effect of DOACs versus no anticoagulation on net clinical benefit in ICH patients with AF The exploratory objectives are: • To explore the impact of DOAC vs. no anticoagulation on quality of life, cognition and psychological morbidity in patients with ICH and AF over time Study Design: PRESTIGE-AF is a phase 3b investigator-led, multicentre, parallel group, prospective randomised, open, blinded end-point assessment (PROBE) clinical trial comparing DOACs (interventional arm) against no anticoagulation (control arm) in patients with a recent ICH and comorbid AF. Randomisation will occur in a 1:1 ratio. Participants will be stratified according to two factors: lobar and non-lobar location of ICH and sex. Choice and dose of DOAC treatment as well as the use of concomitant medication during the study treatment will be at the Principal Investigator´s discretion within the spectrum of licensed doses labelled for stroke prevention in AF patients in Europe following the Summary of Product Characteristics (SmPC). The control group will receive no anticoagulant but the use of an antiplatelet agent is at the Principal Investigator´s discretion who will use their clinical judgment to initiate (or not) an antiplatelet drug of their choice. Baseline assessment will include capturing Participant's demographics, clinical characteristics, vital signs, medical history, and concomitant diseases as well as documentation of AF (previous history or newly detected). Results of routine diagnostic tests before Study enrolment will be also collected using an electronic case report form. The routine brain imaging data performed after the ICH and before Study enrolment will also be collected at baseline. After randomisation, Participants will be followed-up in person at various time points (1, 6, 12, 24, 36 months) for up to 3 years. At each visit, outcome events and adverse events will be captured.

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