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PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation

Periodic Reporting for period 2 - PRESTIGE-AF (PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation)

Reporting period: 2019-06-01 to 2020-11-30

Stroke is one of the leading causes of death and long-term disability worldwide, but its impact is expected to increase even further with the aging of populations in the future. Strokes that are caused by bleeding into the brain (called an Intracerebral haemorrhage or ICH) account for only 10-15% of all strokes but they are associated with a much higher risk of disability and death compared to strokes caused by a blood clot (ischaemic stroke). At least 20% of ICH survivors suffer from a cardiac arrhythmia (irregular heartbeat) called atrial fibrillation (AF) which can cause blood clots to form in the heart, and therefore is a major risk factor for ischaemic stroke. In patients with AF, ischaemic stroke can be effectively prevented by taking medications called oral anticoagulants. These lower the risk of a blood clot forming in the heart. However, survivors of ICH have a substantially increased risk of suffering another ICH, and there is a concern that starting anticoagulants because of AF may increase the risk of them having another ICH. Consequently, stroke prevention in ICH patients with AF has been an unresolved dilemma for decades.

The first main objective of the study is to determine whether ICH patients who have AF should be treated with anticoagulants for stroke prevention or not. Specifically, the PRESTIGE-AF Study will assess whether the treatment with a newer generation of anti-clotting drugs called Direct Oral Anticoagulants is more effective in preventing ischaemic stroke (compared to not taking an anticoagulant) without substantially increasing the risk of ICH recurrence.

The second main objective of the study is to improve the individual predictability of recurrent ischaemic and haemorrhagic events in ICH patients with AF. Thus, beyond the overall results of the trial, we intend to personalise the preventive strategy to individual patients using the results of risk modelling.

The third main objective is to address public health and health economic implications by estimating the effects of the trial data to the general stroke population in European and Asian populations. Using large-scale European and Asian registry data, we will model outcomes with effect sizes of the Direct Oral Anticoagulants in different ICH patient populations and will model the replication of the trial findings within real-life settings.

The fourth main objective is to investigate patient-centred aspects of preventive medicine in stroke patients. Specifically, we will study the potential impact that ICH patient attitudes towards antithrombotic therapy and their psychosocial status have on adherence to antithrombotic therapy and on clinical outcomes. Participants adherence to their medication will be monitored throughout the trial using questionnaires and blood drug levels. We will also strive to identify physician and patient factors that may underlie the under-representation of women in stroke prevention trials to inform future trials of cardiovascular prevention.
The PRESTIGE-AF Study was designed including the main randomised clinical trial, (where participants are randomly assigned to the groups) and 3 optional substudies. The study protocol has been approved by regulatory and ethics committees in all 6 participating European countries. All aspects of the trial infrastructure including data entry platforms, a safety reporting process, event adjudication, clinical data monitoring, and delivery of medication and other supplies, are firmly established. Of the 70 hospitals that will be recruiting for the trial, 47 have been completely setup with a further 10 in final stages and the remaining 13 sites expected to be open for patient enrolment in February 2021.

During the second reporting period, 30 participants have been enrolled across 5 countries. The consortium has received regular scientific advice from external scientific advisors and ethical advice from an ethics advisory board.

The ‘Predictive Modelling of Risk Substudy’ which is running alongside the main randomised controlled trial will extensively characterise participants at the start of the trial including medical history, brain imaging, blood-based biomarkers and genetics. Enrolment into the substudy is ongoing alongside the main trial.
To address public health impact, the project is using previously collected information from participants in the Global Burden of Disease (GDB) study and data sets from three registers of patients who have had strokes; the South London Stroke Register (SLSR), the European Registers of Stroke and the UK Sentinel Stroke National Audit Programme. Work on estimates of risk, and a range of outcomes, is ongoing, aiming at projection of ICH prevalence in the EU over the next 30 years, based on the data from GDB and SLSR.

Work for the qualitative exploration of the impact of physicians´ and patients´ attitudes toward their medication is ongoing in the UK and is expected to be started Italy in 2021. Adherence to study medication (i.e. Direct Oral Anticoagulants) is captured using questionnaires during the main trial. Additionally, the pharmacology substudy has received samples for blood levels of study drugs during study follow-up visits.

Dissemination of the project includes a regularly updated website, the development of a dissemination package, active engagement on social media, participating in relevant national and international conferences and workshops.
PRESTIGE-AF addresses an important unmet need for developing prevention concepts in a highly vulnerable group of stroke patients, namely those with ICH and AF. Effective prevention of recurrent strokes in these patients will prevent the devastating consequences for the individual and their families and will reduce societal and healthcare costs.

PRESTIGE-AF will deliver a randomised controlled trial to provide new guidance on effective treatment of ICH patients with AF overall. It will furthermore establish a personalised approach of individual risk prediction that integrates the knowledge of clinical characteristics as well as biological data including blood-based biomarkers, genetics and neuroimaging. The project will also simulate the population impact of the trial using data from large-scale registries derived from “real life” settings and perform health economic modelling.

PRESTIGE-AF will investigate patient-centred aspects including adherence to antithrombotic medication, patient and physicians´ attitudes towards anticoagulation. Concurrently, we are investigating and gender aspects that are essential for identifying implementation barriers in clinical routine and in prevention research.