Physicians' Academy for Cardiovascular Education

Reduced doses NOAC show similar efficacy and bleeding risk but possibly higher mortality risk

Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.

Literature - Nielsen PB, Skjøth F, Søgaard M et al., - BMJ. 2017; 10;356:j510. doi: 10.1136/bmj.j510


Data of large, randomised trials evaluating non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin, showed similar efficacy and superior safety profiles of NOACs in the prevention of stroke in patients with atrial fibrillation (AF). The better safety profile is mainly driven by a reduction in the risk of intracranial haemorrhage.

NOACs do not require precise dose-adjustment as is necessary with warfarin treatment, but a clinical evaluation of appropriate dose is still necessary. Recommendations for dose reductions are given for instance in case of impaired renal function. It is possible that other characteristics like age, body weight or interacting drugs also require consideration for dose adjustment [1]. Indeed, age and chronic kidney disease enhance the risk of stroke and risk of bleeding during antithrombotic therapy in patients with AF [2].

Elderly AF patients and those with renal impairment were included in the landmark NOAC trials, but only comprised small patient numbers. Reduced dosing regimens have been formulated in guidelines for the different NOACs, but limited evidence on the efficacy of lower dose regimens in real world clinical practice has been reported. This study therefore examined effectiveness and safety of reduced doses of NOACs as compared with warfarin in a Danish nationwide cohort. The analysis included data of 55644 patients who had not taken OACs in the previous year. Population average time of follow-up was 2.3 years, with the shortest mean follow-up (1 year) in the apixaban group.

Main results

Inverse probability of treatment weight was applied to account for baseline differences, which resulted in comparable distribution of variables between treatment groups in this cohort, thus allowing for comparisons.

The subgroup of patients with an indication for dose reduction (n=21949), showed worse outcomes than the main analysis.


These propensity-weighted real world data on the effectiveness and safety of low dose NOAC regimens as compared with warfarin in patients with AF showed a non-significant trend towards higher thromboembolic events and similar rates of bleeding for apixaban (2.5 mg). Low-dose rivaroxaban (15 mg) and dabigatran (110 mg) showed a non-significant trend towards lower one year rates of ischaemic stroke or SE, and similar (rivaroxaban) and lower (dabigatran) rates of bleeding.

While standard dosing regimes have consistently favoured a NOAC over warfarin with regard to mortality, some of the current analyses on reduced doses indicated an increased mortality risk. Although inverse probability treatment weighting allows for causal inference on average treatment effects, it is possible that some unmeasured residual confounding and selective prescribing behaviour remain.


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