Clinical trial NCT06322953: Timing to Restart Direct Oral Anticoagulants After Traumatic Intracranial Haemorrhage
Official title: A Randomised Trial of Timing to Restart Direct Oral Anticoagulants After Traumatic Intracranial Haemorrhage
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Traumatic Intracranial Haemorrhage
Keywords: Direct Oral Anticoagulants
Randomised Trial
Lead sponsor: Walton Centre NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Liverpool
name: National Institute for Health Research, United Kingdom
name: University Hospital Plymouth NHS Trust
First posted: 2024-03-21
Enrollment: 1084
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised Controlled Trial
Primary purpose: TREATMENT

Brief summary: Older people falling from a standing height is the most common cause of hospital admission for head injury. Up to 1 in 3 patients admitted are taking a tablet medication which thins the blood, known as an oral anticoagulant. This type of medication can increase the likelihood of bleeding in the brain. Many patients are taking oral anticoagulation due to having an irregular heartbeat (called atrial fibrillation) or because of having a previous stroke or blood clots. When a scan shows blood in the brain, oral anticoagulation is nearly always stopped. However, this leaves the question of when it is safe to restart them. The risk of making the bleeding in the brain worse must be balanced against the risk of having a stroke or blood clots. There is no clear evidence on the safest time to restart oral anticoagulation, but most neurosurgeons advise restarting them 1-4 weeks after head injury. The number of people who have a bleed on their brain after a head injury is increasing and further brain bleeding or a stroke can have a serious effect on patients' lives and their on-going healthcare needs. Public and patient groups have highlighted that many patients want to stop taking oral anticoagulation after a bleed but they may be unaware of the vital importance of restarting this medication to prevent strokes and blood clots. The most popular oral anticoagulation prescribed has changed in recent years from warfarin to newer medications called Direct Oral Anti-Coagulants (DOACs).

This trial will recruit 1084 people who are admitted to hospital with a bleed on the brain caused by a head injury who were taking oral anticoagulation before their head injury and have been prescribed a Direct Oral Anti-Coagulant (DOAC) for previously diagnosed medical condition. Patients on other Oral Anti-Coagulants, such as Warfarin may also be able to take part. The main purpose of the trial is to determine when is most beneficial time for people to start or restart a DOAC after their head injury. People will be asked to start the medication either 1 week or 4 weeks after their head injury. They will be then followed closely for 12 weeks and any major bleeding events or a blood clots (thrombotic events) such as a stroke or heart attack will be recorded. The study will also look at the person's overall quality of life, how they recover physically, the number of people who die, the costs of the treatment, and the attitudes of people and their caregivers to starting or restarting a DOAC.

Detailed description: Head injury in older patients is becoming increasingly common. The 2017 England and Wales trauma network review reports an older person falling from standing height as the commonest type of major trauma, and most frequently results in injury to the head. By 2050, 1 in 6 people will be aged over 65, and with approximately 30% of older adults falling each year, the incidence of head injury will rise. In conjunction, there is a high prevalence of oral anticoagulant (OAC) use in this older population, driven by increased incidence of atrial fibrillation (AF), the commonest heart rhythm disorder, which is related to aging. It increases the risk of stroke 5-fold and should be considered for treatment with oral anticoagulants OACs depending on risk factor assessment by the CHA2DS2VASc (C - Congestive heart failure (1 point) H - Hypertension (1 point) A2 - Age ≥75 years (2 points) D - Diabetes mellitus (1 point) S2 - Prior Stroke or transient ischemic attack (2 points) V - Vascular disease (e.g., peripheral artery disease, myocardial infarction, aortic plaque) (1 point) A - Age 65-74 years (1 point) Sc - Female sex category (1 point) score). OAC prescribing for such patients has more than doubled in the United Kingdom (UK) since 20008 and between 20-35% of older patients admitted with head injury causing intracranial haemorrhage (tICrH), are taking an OAC at the time of injury. Standard care dictates that OACs should be stopped in the majority of cases to reduce the risk of progressive or new ICrH. Despite a low risk of new or on-going Intracranial Hemorrhage (ICrH) 48 hours after injury, there is a reluctance from clinicians to restart OACs for fear of evoking re-bleeding. This must be balanced against the increased risk of thromboembolism in patients not taking their OAC, predisposing AF patients to increased risk of stroke, systemic thromboembolism and all-cause mortality. Currently there is no clear consensus on the optimal practice on the timing for restarting OACs post- traumatic intracranial hemorrhage (tICrH). OAC medications are traditionally divided into vitamin K antagonists (e.g., warfarin) and Direct Oral Anticoagulants (DOACs). DOAC prescribing has increased substantially over the last decade. Benefits include an immediate therapeutic effect, fixed dosing, fewer drug interactions and no monitoring when compared to warfarin. Previous meta-analyses and trials demonstrate that DOACs are at least as effective as warfarin in the prevention of stroke in AF patients, and have a lower rate of associated ICrH and mortality. DOACs (eg Apixaban, dabigatran, edoxaban and rivaroxaban) are recommended by The National Institute for Health and Care Excellence (NICE) for those over 65 with AF and a CHA2DS2VASc score of 2 or above and considered for men with AF and a CHA2DS2VASc score of 16. For those already taking a Vitamin K antagonist (VKA) (e.g., Warfarin) NICE recommends that the option of switching to a DOAC should be discussed. This study will focus on patients who are taking a DOAC or Vitamin K antagonist for AF or venous thromboembolism (VTE) at the time of tICrH which is stopped due to risk of further bleeding. Patients will then either be restarted on their DOAC, or the option of switching to a DOAC from their current Vitamin K antagonist will be discussed, as these have a superior safety profile (significantly reduced risk of haemorrhagic stroke and intracerebral haemorrhage compared to warfarin) and reflects best practice following tICrH.

Studies suggest evidence of early tICrH expansion (within 48hrs) on routine repeat imaging occurs in 10-37% of patients on OAC, indicating the need to stop OAC. This risk reduces substantially over time. A recent trial assessing patients with a major bleed on OACs, reported re-bleeding rates of 4.3% within 30 days, when excluding the first 3 days from the initial bleed. The bleeding rate was only 4.5% in those who restarted their OAC within 2 weeks, with a net benefit (Hazard ratio 0.384 combining thrombosis, bleeding and death rate) when compared to those that did not restart OAC within 2 weeks. Another study focusing on tICrH reported a 5% readmission rate for re-bleeding within 30-days in patients who did not restart their DOAC. There is a paucity of high-level data on delayed (\>72hrs) haemorrhage rates after tICrH and withholding OACs results in an elevated risk of thrombotic events such as stroke, myocardial infarction (MI) and VTE. A trial of 352 patients suffering a major bleed whilst on a DOAC demonstrated that thrombotic events increase from around 4% at 1 week to 10% at 4 weeks. At 3 months, patients who have restarted OAC have fewer strokes \[Hazard Ratio (HR) 0.85, 95% confidence intervals (CI) 0.43-1.68\] and deaths \[HR 0.5, 95% CI 0.35-0.72\], despite increased bleeding \[HR 1.62, 95% CI 0.95-2.75\] compared to those who have not restarted OAC.

Eligibility criteria: Inclusion Criteria:

1. Informed consent obtained from participant / participants' legal representative / participants' Consultee and ability to comply with the requirements of the trial
2. Adult ≥18 years with traumatic intracranial haemorrhage (tICrH) in the past 1 week who were taking oral anticoagulants (OAC) prior to admission
3. Oral anticoagulants include any DOAC or Vitamin K antagonist (VKA) (e.g. Warfarin), prescribed for atrial fibrillation (AF) or venous thromboembolism (VTE) prior to admission for tICrH
4. At high risk for thromboembolic complications (CHA2DS2VASc ≥2 in men and ≥3 in women)

Exclusion Criteria:

1. Patients whose traumatic intracranial haemorrhage is a chronic subdural haematoma
2. Patients with mechanical heart valve
3. Patients with plan to start/restart anti-platelet therapy within 12 weeks of tICrH
4. Abbreviated Injury Scale other than head with a score \>3
5. Pregnancy
6. Participants with a hypersensitivity or contraindication to Direct Oral Anticoagulant (DOAC)
7. Participant with bleeding where it would be unsafe to restart DOAC at 1 week
8. Participant with clinical reason to restart DOAC before 4 weeks or complete within 12 weeks
9. Concomitant p-gp and CYP3A4 inducers/inhibitors
10. Indication to stay on VKA (Warfarin) rather than switching to DOAC (e.g. severe renal impairment)

Primary outcomes:
measure: Proportion of patients with haemorrhagic or thrombotic event within 12 weeks following tICrH.
timeFrame: 12 weeks
Secondary outcomes:
measure: Time to first haemorrhagic or thrombotic event.
timeFrame: 12 weeks
measure: Time to first haemorrhagic event
timeFrame: 12 weeks
measure: Time to first thrombotic event
timeFrame: 12 weeks
measure: Time to death
timeFrame: 12 and 26 weeks
measure: Functional outcome measured using modified Rankin Scale (mRS)
timeFrame: 12 and 26 weeks
measure: Functional outcome measured using Barthel Index
timeFrame: 12 and 26 weeks
measure: Functional outcome measured using extended Glasgow Outcome Scale (GOS-E)
timeFrame: 12 and 26 weeks
measure: Overall Quality of Life measured by EuroQol 5 Dimensions 5 Levels (EQ5D5L) questionnaire
timeFrame: 12 and 26 weeks
measure: Patient/caregiver attitudes to (re)starting OAC
timeFrame: Within the first 9 months of recruitment start
measure: Healthcare resource use
timeFrame: 6, 12 and 26 weeks
Other outcomes:
Locations:
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
state: Devon
city: Liverpool
country: United Kingdom
facility: The Walton Centre NHS Foundation Trust
state: Mersyside
Study officials:
affiliation: Northern Care Alliance NHS Foundation Trust
name: Catherine McMahon
role: PRINCIPAL_INVESTIGATOR
References: