Despite increased mortality, DOAC safety data offer reassurance

These agents could serve as safe alternatives to warfarin


A large, prospective open cohort, , assessed associations and risks among apixaban, dabigatran, and rivaroxaban compared with warfarin in patients both with and without atrial fibrillation (AF). Despite lower risk of major bleeds, increased risk of all-cause mortality was detected.


Previous investigations on direct oral anticoagulants (DOACs) demonstrated that they are at least as safe and efficacious as warfarin for stroke prevention and the prevention and treatment of venous thromboembolism (VTE). Nevertheless, these trials excluded subjects without AF and many populations requiring dose reductions. This has led to uncertainty regarding safety and efficacy between DOACs and warfarin in these patients. Having monitored nearly 200,000 patients from 2011 to 2016, this study offered reassurance that DOACs may serve as safe alternatives to warfarin in realistic settings.


Investigators at the University of Nottingham used data from two large U.K. primary care databases to identify 196,061 patients who were newly prescribed anticoagulants or restarted after a period of at least 12 months. Amid 103,270 (53%) subjects diagnosed with AF and 92,791 (47%) taking anticoagulants for other conditions, study drugs were assigned to 18,223 patients taking apixaban, 7,744 dabigatran, 37,863 rivaroxaban, and 132,231 warfarin. Main outcome measures included major bleeds leading to hospital admission or death, ischemic stroke, VTE, and all-cause mortality.

Data showed that, compared with warfarin, apixaban was associated with less major bleeding, particularly brain and gastric bleeds, in patients with and without AF. In patients with AF using dabigatran and in patients using rivaroxaban without AF, results indicated lower risk of brain bleeds than with warfarin.


Increased risk of all-cause mortality compared with warfarin was seen with rivaroxaban and low-dose apixaban in all patients. Study authors noted that closer monitoring of warfarin patients or unidentified underlying conditions may have contributed to these results.


“While there were signals that mortality with rivaroxaban and apixaban was higher compared to warfarin, particularly in the low-dose groups… the interpretation of this data must be done cautiously,” explained Robert J. DiDomenico, PharmD, BCPS-AQ Cardiology, FCCP, FHFSA, FACC, associate professor at the University of Illinois at Chicago College of Pharmacy. “These observations may be incidental or may reveal unforeseen or unexpected risks for death in patients exposed to these drugs. While the authors analyze outcomes based on the prescribed dose, there is no indication as to why lower doses were used or whether they were consistent with labeled dosing recommendations.”


Apixaban demonstrated the lowest numbers needed to treat for avoiding one major bleed (182 patients with AF and 138 without), compared with warfarin. Rivaroxaban provided the lowest numbers needed to harm for one additional death (202 with AF and 61 without).


Owing to the investigation’s strengths, various methods were employed to control for confounders and to account for differences in demographic variables, past medical history, social history, concomitant medications, and time. The study design presented some limitations, including challenges identifying specific indications for anticoagulation and possible misclassification due to patient nonadherence.


For the full article, please visit for the September 2018 issue of Pharmacy Today.