PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation

Atrial Fibrillation Clinical Trial

— PRESTIGE-AF  

Official title:

PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation (PRESTIGE-AF)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03996772
• Other study ID #: 17HH4268
• Secondary ID: 2018-002176-4175
• Status: Completed
• Phase: Phase 3
• Start date: June 3, 2019
• Est. completion date: May 31, 2024

Study information

• Verified date: June 2024
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Atrial fibrillation (AF) is the most common form of irregular heart rhythm. In people with AF, blood clots often form in the heart, which can travel to the brain. Blockage of brain arteries by these clots is a major cause of stroke. This type of stroke is called an ischaemic stroke and approximately 15% of all ischaemic strokes are caused by AF.

People with AF are often prescribed a medication called an anticoagulant, which makes it less likely for blood clots to form and thus can prevent ischaemic strokes. However, anticoagulants also increase the risk of bleeding, so they are not suitable for everyone.

Some people who have AF have had a different type of stroke which is caused by bleeding in the brain, an intracerebral haemorrhage (ICH). These people are at increased risk of suffering both an ischaemic stroke (due to AF) and another ICH. It is not known whether it is best for these people to take an anticoagulant medication or not, as previous research studies did not include this group of people.

PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation (PRESTIGE-AF) is a research study on the best stroke prevention in people with atrial fibrillation (AF) who have recently had a bleeding in their brain, (ICH). This is a trial where half of the participants will take an anticoagulant medication, preventing blood clot formation, and half will not receive an anticoagulant. The direct oral anticoagulants (DOACs) that will be used in this trial are all licenced for use in the United Kingdom and within the European Union (EU) to prevent strokes in people with AF. However, the current licence does not extend to use with people who have had an ICH because it has not been tested in this group with a randomised controlled trial. DOACs will be tested in ICH survivors with AF because previous research trials have shown that people are up to 50% less likely to have bleeding complications in the brain with DOACs than with Warfarin (another commonly used anticoagulant).

The aim of PRESTIGE-AF is to answer the question of whether people with ICH and AF should take an anticoagulant medication or if it is better for them to avoid it.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 319
• Est. completion date: May 31, 2024
• Est. primary completion date: May 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years

• Written informed consent obtained from the patient, or for patients who lack the capacity to consent this can be provided by an appropriate representative as defined in protocol

• Non-traumatic spontaneous ICH during the 12 months before enrolment. Patients become eligible 14 days after the date of their ICH.

• Documented evidence of AF (paroxysmal, persistent or permanent)

Exclusion Criteria:

• Fully dependent (mRS >4)

• Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period

• Women of childbearing potential (WOCBP see section 12.2 for definition) who are unable or unwilling to take measures for effective contraception (4.9)

• Enrolment occurring before 14 days after the date of ICH

• Enrolment occurring longer than 12 months after the date of ICH

• ICH resulting from trauma or vascular malformation

• Another indication for long-term anticoagulation

• Patient has hypertension, which in the opinion of the investigator, is uncontrollable with medication Any contraindication (except intracerebral haemorrhage) to treatment with apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC. Including any of the following:

• Hypersensitivity to the active principle or any of the excipients

• Clinically relevant bleeding in progress

• Liver disease associated with coagulopathy and a clinically relevant bleeding risk

• Injuries or conditions such as a significant risk of major bleeding

• Hepatic impairment or liver disease which can have an impact on survival

• Exclusion of patients with end-stage renal creatinine clearance CrCL, (CrCL <15 ml / min) or in patients undergoing dialysis

• Concomitant treatment with other anticoagulants

• Patients with a history of thrombosis and antiphospholipid antibody syndrome Special warnings and precautions for use for apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC should also be taken into account at randomisation.

• Absolute need for antiplatelet agent (APA) at enrolment, meaning that a patient randomised to receive DOAC who would require an APA is not eligible (single APA is permitted in control group only, at time of randomisation). Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO

• Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise

• Participation in any clinical study with an Investigational Medicinal Product within the past 30 days or 5 half-lives of the study drug (observational studies are permitted)

Related Conditions & MeSH terms

• Atrial Fibrillation
• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

Drug:
• Apixaban Oral Tablet
Factor Xa Inhibitor
• Dabigatran
Direct Thrombin Inhibitor
• Edoxaban Tablets
Factor Xa Inhibitor
• Rivaroxaban
Factor Xa Inhibitor

Locations

Country	Name	City	State
Germany	Klinikum Altenburger Land	Altenburg
Germany	Vivantes Hospital Neukolin	Berlin
Germany	University Hospital Cologne	Cologne
Germany	University Hospital Erlangen	Erlangen
Germany	Alfried Krupp Von Bohlen und Halbach-Krankenhaus	Essen
Germany	University Hospital Frankfurt	Frankfurt
Germany	Bezirkskrankenhaus Günzburg	Günzburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	University Hospital Heidelberg	Heidelberg
Germany	University of Leipzig	Leipzig
Germany	University Hospital Schleswig-Holstein Campus Luebeck	Luebeck
Germany	Johannes Wesling Klinikum Minden	Minden
Spain	Hospital Germans Trias I Pujol	Barcelona
Spain	Hospital Dr Josep Trueta	Girona
United Kingdom	East Kent Hospitals University NHS Foundation Trust	Ashford
United Kingdom	Northumbria Healthcare NHS Foundation Trust	Ashington
United Kingdom	Basildon and Thurrock University Hospitals NHS Trust	Basildon
United Kingdom	Cambridge University Hospitals NHS Trust	Cambridge
United Kingdom	Hull and East Yorkshire NHS Trust	Hull
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	Kings College Hospital NHS Foundation Trust	London
United Kingdom	St Helens and Knowsley Teaching Hospital NHS Trust	Prescot
United Kingdom	Taunton and Somerset NHS Foundation Trust	Taunton
United Kingdom	Mid Yorkshire Hospitals NHS Trust	Wakefield
United Kingdom	West Hertfordshire Hospitals NHS Trust	Watford

Sponsors (15)

Lead Sponsor

Collaborator

Imperial College London

Aalborg University, Alfried Krupp Krankenhaus, Azienda Ospedaliera di Perugia, Hospital Universitari Vall d'Hebron Research Institute, Imperial College Healthcare NHS Trust, Julius-Maximilians University, King's College London, Medical University of Graz, STROKE ALLIANCE FOR EUROPE, University Hospital Heidelberg, University Hospital, Bordeaux, University of Bordeaux, University of Liverpool, Wuerzburg University Hospital

Countries where clinical trial is conducted

Germany,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to the first incident ischemic stroke event.	Statistics: product-limit estimations of the time to event ("survival") functions in both study groups. Measure of association: hazard ratio under the proportional hazard assumption.	3 years
Primary	Time to the first recurrent intracerebral haemorrhage event.	Statistics: product-limit estimations of the time to event ("survival") functions in both study groups. Measure of association: hazard ratio under the proportional hazard assumption.	3 years
Secondary	Rate of all stroke events	Rate of all stroke events from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of systemic embolism	Rate of systemic embolism from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of major adverse cardiac events	Rate of major adverse cardiac events from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of all-cause mortality	Rate of all-cause mortality from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of cardiovascular mortality	Rate of cardiovascular mortality from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of major haemorrhage	Rate of major haemorrhage from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of any intracranial haemorrhage	Rate of any intracranial haemorrhage from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rates of events (all strokes, systemic embolic event, myocardial infarction, cardiovascular mortality and major bleeding)	Rates of events (all strokes, systemic embolic event, myocardial infarction, cardiovascular mortality and major bleeding) from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of myocardial infarction	Rate of myocardial infarction from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Rate of major bleedings	Rate of major bleedings from the index date as number of events per 100 person years under observation in the study	3 years
Secondary	Quality of life: EQ-5D	Quality of life: EQ-5D with 3 levels of severity for each of the 5 dimensions: EQ-5D-3L; Statistics at 12, 24 (if required) and 36 months (if required) in both study groups: Measures of central tendency and dispersion (mean and SD resp. median and interquartile range) for EQ VAS score (range 0 -100, higher values considered to be a better outcome) and for the EQ-5D-3L index score (range 0 - 1, higher values considered to be a better outcome) health profile: numbers and proportions reporting frequencies of the three levels within the EQ-5D dimensions in both study groups	enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 Months).
Secondary	Cognitive function: the Montreal Cognitive Assessment (MoCA)	Cognitive function: the Montreal Cognitive Assessment (MoCA) Total MoCA score: Range: 0 - 30, higher values considered to be a better outcome.; Statistics at 12, 24 (if required) and 36 months (if required) in both study groups: Measures of central tendency and dispersion (mean and SD resp. median and inter quartile range). Frequencies for the values of the subscores in both study groups	enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 Months).
Secondary	Psychological morbidity: the Hospital Anxiety and Depression Scale (HADS)	Psychological morbidity: the Hospital Anxiety and Depression Scale (HADS) Statistics at 12, 24 (if required) and 36 months (if required) in both study groups.; HADS anxiety and HADS depression score. For both scales range 0 - 21, smaller values considered to be a better outcome.; Median score and interquartile range for both scales in both study groups. Numbers and percentages of those patients classified as "non-cases", having mild disease, having moderate disease and having severe disease for both scales in both study groups according to the cut-off scores for HADS quantification.	enrolment visit, 6 months (min follow-up), 12 months, 24 months, 36 months, and End of Treatment Visit (between 6 and 36 months).