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

Objective To 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. Design Propensity weighted (inverse probability of treatment weighted) nationwide cohort study. Setting Individual linked data from three nationwide registries in Denmark. Participants Patients 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. Intervention Initiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin). Main outcome measures Patients 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. Results Among 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. Conclusion In 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.

Frequency and Outcomes of Reduced Dose Non–Vitamin K Antagonist Anticoagulants: Results From ORBIT‐AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II)

“…In the largest study of NOAC dosing and outcomes, a nationwide Danish analysis suggested differential outcomes among different reduced‐dose NOACs compared with warfarin, but none of the comparisons was statistically significant 18. Furthermore, it is not clear from that analysis what proportion of patients in each drug group qualified for the reduced dose based on regulatory recommendations—our US data suggest that more than half of these patients may be inappropriately underdosed, and this could certainly account for a difference in clinical outcomes across very large populations.…”

Oral anticoagulant therapy for older patients with atrial fibrillation: a review of current evidence

“…There is some evidence from observational studies that dose-adjusted DOAC therapy is often inappropriately prescribed, being underdosing more frequent than overdosing [100,101], and that this behavior might be associated with lower efficacy and safety outcomes [102].…”

Evaluating adherence to non-vitamin-K antagonist oral anticoagulants in post-approval observational studies of patients with atrial fibrillation

“…from those included in the strictly defined study populations in the pivotal RCTs that are carefully followed up at regular protocol-based intervals. In addition, clinicians may sometimes choose NOAC dosing regimens that were not well studied in the RCTs 4 . Notwithstanding their limitations, well conducted post-approval large observational studies are of key importance to provide data (so called "real-world" data, RWD) on the effectiveness and safety of NOACs used outside the RCTs, in a routine clinical setting 5 .…”