Timing of Off-Label Dosing of Direct Oral Anticoagulants in Three Large Health Systems.

 While direct oral anticoagulants (DOACs) may be viewed as simpler to manage then warfarin, they present their own unique management challenges resulting in frequent off-label dosing. It is unknown to what extent off-label dosing occurs when a patient is started on a DOAC versus later in their treatment.  We aimed to better characterize when off-label DOAC dosing is occurring and to evaluate the effectiveness of prescribing oversight using a registry-based intervention.  We evaluated data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry, a retrospective quality-improvement process using data abstractors, from 2018 to 2022 on the number of "alerts" that are generated in response to dosing deviating from the U.S. Food and Drug Administration instructions for atrial fibrillation (AF) and venous thromboembolism (VTE).  Among a sample of 789 to 1,022 annual AF patients and 381 to 484 annual VTE patients prescribed a DOAC in the MAQI2 registry, off-label dosing was relatively common. Over the 5-year period (2018-2022), there were 569 alerts for AF patients and 162 alerts for VTE patients. Alerts occurred more frequently during follow-up than at the time of initial prescribing in AF patients (78.2 vs. 21.8%), but more commonly at initial prescribing in VTE patients (59.9 vs. 40.1%). After initial review by quality-improvement abstractors, 19.3% of AF alerts and 14.8% of VTE alerts resulted in contact to the prescriber. When the prescriber was contacted, it led to an intervention about 75% of the time for both populations. The most common intervention was a change in DOAC dosing.  This study demonstrates the benefit of DOAC prescribing oversight using a registry-based intervention to monitor for off-label dosing for the entirety of the time period a patient is prescribed DOAC, particularly for patients with AF, as off-label prescribing occurs frequently during the follow-up period.

Herron GC ，DeCamillo D ，Kong X ，Haymart B ，Kaatz S ，Ellsworth S ，Ali MA ，Giuliano C ，Froehlich JB ，Barnes GD ... -  《-》

Pharmacist Use of a Population Management Dashboard for Safe Anticoagulant Prescribing: Evaluation of a Nationwide Implementation Effort.

Barnes GD ，Chen C ，Holleman R ，Errickson J ，Seagull FJ ，Dorsch MP ，Allen AL ，Spoutz P ，Sussman JB ... -  《Journal of the American Heart Association》

Comparing DOAC and warfarin outcomes in an obese population using the 'real-world' Michigan Anticoagulation Quality Improvement Initiative (MAQI(2)) registry.

Ardeshna N ，Feldeisen T ，Kong X ，Haymart B ，Kaatz S ，Ali M ，Barnes GD ，Froehlich JB ... -  《-》

Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial.

Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage. PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete. Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73-83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7-2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01-0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14-2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43-12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95-60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68-8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14-2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died. DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients. European Commission.

Veltkamp R ，Korompoki E ，Harvey KH ，Harvey ER ，Fießler C ，Malzahn U ，Rücker V ，Montaner J ，Caso V ，Sibon I ，Ringleb P ，Halse O ，Hügen K ，Ullmann S ，Schuhmann C ，Todd GP ，Haas K ，Palà E ，Debette S ，Lachaize M ，D'Aoust T ，Enzinger C ，Ropele S ，Fandler-Höfler S ，Haidegger M ，Wang Y ，Wafa HA ，Cancelloni V ，Mosconi MG ，Lip GYH ，Lane DA ，Haefeli WE ，Foerster KI ，Wurmbach VS ，Nielsen PB ，Hajjar K ，Müller P ，Poli S ，Purrucker J ，Laible M ，D'Anna L ，Silva Y ，de Torres Chacon R ，Martínez-Sánchez P ，Boulanger M ，Norrving B ，Paré G ，Wachter R ，Ntaios G ，Wolfe CDA ，Heuschmann PU ，PRESTIGE-AF Consortium ... -  《-》

Current Real-World Status of Off-Label Under- and Over-Dose of Direct Oral Anticoagulants After Atrial Fibrillation Ablation.

Off-label under- and overdosing of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is not uncommon in real-world practice. This study aimed to identify efficacy and safety of off-label DOACs dose after AF ablation. The RYOUMA registry was a prospective multicenter study of Japanese patients who underwent AF ablation between 2017 and 2018. DOAC prescriptions were categorized into on-label standard dose, on-label reduced dose, off-label underdose, and off-label overdose. The proportion of off-label doses among patients after AF ablation varied depending on the type of DOAC, ranging from 13.5% to 34.9%. Of 2821 patients, 366 (13.0%) were prescribed an off-label underdose and exhibited significantly higher CHADS2, CHA2DS2-VASc, CHA2DS2-VA, HELT-E2S2, and HAS-BLED scores, age, concomitant use of antiplatelets, and lower weight when compared to the on-label standard dose (n = 1809). While the incidence of ischemic stroke after 1 year of off-label underdose was notably low (0.28%), the rate of major bleeding was relatively high (1.7%). Off-label overdose was prescribed to 134 patients (4.8%), who showed a significantly higher incidence of major bleeding (3.0%) compared to on-label standard dose (0.91%; p = 0.02). The off-label overdose group did not have any particular background and its thromboembolic risk was, conversely, low. The most likely cause of off-label overdose was clinicians potentially overlooking dose criteria, including advanced age, low body weight, and low creatinine clearance. In patients after AF ablation, off-label DOAC overdose was infrequent, but significantly associated with higher incidence of major bleeding during the remote period after AF ablation. The study was registered as UMIN000026092 (University Hospital Medical Information Network-Clinical Trial Registry).

Kino T ，Nogami A ，Soejima K ，Uno K ，Kumagai K ，Kurita T ，Fukuzawa M ，Takita A ，Ishizu T ，Aonuma K ，and other members of the RYOUMA Registry Investigators ... -  《-》