Timing to Restart Direct Oral Anticoagulants After Traumatic Intracranial Haemorrhage

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.