title: Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.
abstract: ObjectiveTo examine clinical effectiveness and safety of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin among patients with atrial fibrillation who had not previously taken an oral anticoagulant.DesignPropensity weighted (inverse probability of treatment weighted) nationwide cohort study.SettingIndividual linked data from three nationwide registries in Denmark.ParticipantsPatients with non-valvular atrial fibrillation filling a first prescription for an oral anticoagulant from August 2011 to February 2016. Patients who filled a prescription for a standard dose non-vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight.InterventionInitiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin).Main outcome measuresPatients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events.ResultsAmong 55 644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38 893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.ConclusionIn this propensity weighted nationwide study of reduced dose non-vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.
authors.forename: Peter Brønnum
authors.initials: PB
authors.lastname: Nielsen
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.|Unit of Clinical Biostatistics, Aalborg University Hospital, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Skjøth
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.|Department of Cardiology, Aalborg University Hospital, DK-9000, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Søgaard
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.|Department of Cardiology, Aalborg University Hospital, DK-9000, Denmark.
authors.forename: Jette Nordstrøm
authors.initials: JN
authors.lastname: Kjældgaard
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.|University of Birmingham, Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark tobl@rn.dk.|Department of Cardiology, Aalborg University Hospital, DK-9000, Denmark.
authors.forename: Torben Bjerregaard
authors.initials: TB
authors.lastname: Larsen
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002545:Brain Ischemia / Q000453:epidemiology* / Q000517:prevention & control; D015331:Cohort Studies; D000069604:Dabigatran / Q000008:administration & dosage / Q000009:adverse effects; D003718:Denmark / Q000453:epidemiology; D004617:Embolism / Q000453:epidemiology* / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009026:Mortality; D057216:Propensity Score; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects; D000069552:Rivaroxaban / Q000008:administration & dosage / Q000009:adverse effects; D020521:Stroke / Q000453:epidemiology* / Q000517:prevention & control; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran