Cardiovascular Pharmacotherapies Focus: Are low doses of direct-acting oral anticoagulants justified and appropriate in patients with nonvalvular atrial fibrillation?

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare:

For permissions and non-commercial reprint enquiries, please visit to start a request.

For author reprints, please email
Information image
Average (ratings)
No ratings
Your rating

Disclosure:AMR has participated in scientific advisory boards or activities for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Daiichii Sankyo and has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer. GAD has received small speaker’s fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer, and research grants from the same companies.

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The novel direct-acting oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban and rivaroxaban overcome most drawbacks of vitamin K antagonists and have proven efficacious and safe in well-designed multicentre randomised clinical trials.1–4 Furthermore, the advantages of NOACs over vitamin K antagonists have been demonstrated in several specific groups of patients with atrial fibrillation (AF).5 Various cardiology societies now therefore recommend NOACs as first-choice oral anticoagulants in patients with nonvalvular AF.6–8

The four pivotal NOAC trials in patients with AF had very important differences in design, doses, population and results (see Table 1). Importantly, in the three trials comparing rivaroxaban (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation: ROCKET-AF), apixaban (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation: ARISTOTLE) and edoxaban (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation: ENGAGE-AF) with warfarin, different subgroups of patients received reduced doses of NOACs. In ROCKET-AF, the dose of rivaroxaban was reduced from 20 mg/d to 15 mg/d (a 25 % reduction) in patients with low creatinine clearance (30–49 mL/min).2 In ARISTOTLE, the dose of apixaban was reduced from 5 mg/12h to 2.5 mg/12h (a 50 % reduction) in patients with two or more of the following risk factors: age >80 years, weight <60 kg and serum creatinine >1.5 mg/ dL.3 ENGAGE-AF had three treatment arms: patients were randomised to receive warfarin or 60 mg/d edoxaban or 30 mg/d edoxaban, but the doses of NOAC were halved in patients with low creatinine clearance (30–50 mL/min), weight <60 kg or concomitant use of verapamil, quinidine or dronedarone, and the dose reduction could be reverted if its cause was transitory.4 Thus, except in ENGAGE-AF, the doses of NOACs were adjusted at baseline in relation to patient characteristics and could not be modified thereafter.

Unlike these three trials that compared the overall results of NOACs versus warfarin in mixed populations receiving full or reduced (between 25 % and 50 % reduction) NOAC doses, the Randomised Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial established three arms of similar size (each containing >6,000 patients) with enough statistical power to evaluate the noninferiority of each dose of dabigatran (150 mg/12h or 110 mg/12h) versus warfarin for preventing stroke and systemic embolism in nonvalvular AF.1 In this trial, the doses of dabigatran were maintained during the follow-up period. Thus, in the RE-LY trial all patients randomised to either dose of dabigatran received the full dose, whereas in the ROCKET-AF, ARISTOTLE and ENGAGE-AF trials, the dose of the NOAC was reduced at baseline (after randomisation) in 20.7 %, 4.7 % and 25.4 % of patients, respectively.

Since their approval, the NOACs’ advantages over warfarin have been reaffirmed in clinical praxis in diverse populations where confounding factors (e.g. concomitant drugs or diseases) may be present or patients might not follow the prescribed treatment.9–11 Subgroup analyses of lowdose regimens in the pivotal studies of NOACs in nonvalvular AF revealed no alert signs (clear differences in thromboembolic risk) versus the higher dose (non-significant interaction p-value).1–4 Nevertheless, physicians should be aware that only limited numbers of patients received the reduced doses of rivaroxaban, apixaban and edoxaban in the pivotal studies, and there was not enough statistical power to specifically compare the low doses against warfarin. Thus, the benefits of a very conservative approach with a low-dose NOAC to avoid bleeding must be carefully weighed against the risk of the thromboembolic complications of AF posed by inappropriately reduced doses of the NOAC. Reduced doses of NOACs are often prescribed in patients who do not meet the recommended criteria for dose adjustment.12 In addition to this, “good” renal function (creatinine clearance >80 mL/min) might decrease the efficacy of apixaban and edoxaban (but not rivaroxaban or dabigatran) in preventing a first ischaemic stroke (US Food and Drug Administration communication).13 Paradoxically, oral anticoagulants are particularly underused in patients with a high risk of stroke.14

Table 1: Overview of the Designs, Populations and Outcomes of the Four Pivotal Studies Comparing Novel Oral Anticoagulants (NOACs) with Warfarin

Article image

Recently, Fay et al.15 presented data on the dosing patterns of NOACs for AF from more than 4,600 physicians’ prescriptions in France, Germany and the UK between January 2015 and November 2015. They reported that whereas only 4.7 % of the patients in the ARISTOTLE trial received the low dose of apixaban, in clinical practice 44 % of patients received the low dose. Similarly, whereas 49.7 % of the patients randomised to dabigatran in the RE-LY trial received only 110 mg dabigatran twice daily, in clinical practice 59.8 % received this dose and 2.9 % received only 75 mg twice daily; and whereas 20.7 % of patients in the ROCKET-AF trial received 15 mg/d of rivaroxaban, in clinical practice 32.4 % received this dose and 4 % received only 10 mg/d. These data point to the danger that the NOACs’ excellent results in preventing thromboembolic and haemorrhagic complications in nonvalvular AF observed during the pivotal studies1–4 could be distorted in clinical praxis if the doses are too low. This seems particularly important with apixaban and edoxaban, because the recommended reduced dose is only 50 % of the standard dose. Specific reversal agents for dabigatran16 and for anti-Xa anticoagulants (apixaban, edoxaban, and rivaroxaban)17 have been clinically evaluated, and the reversal agent for dabigatran (idarucizumab) is available in some countries.16 Although it is crucial to avoid bleeding complications – and low-dose anticoagulant regimens might very well achieve this objective – it is also crucial to avoid thromboembolic events, and the risks and benefits of using low doses must be carefully counterweighed in each individual patient.18–20

In summary, low-dose NOACs are justified in patients who present a high risk of bleeding for any reason. However, the reduction in haemorrhagic risk comes at the cost of lower antithrombotic protection. Moreover, strong evidence for a low fixed dose of NOAC only exists for dabigatran (110 mg twice daily). Patients must therefore be carefully evaluated before being prescribed low-dose NOACs and re-evaluated during the follow-up. Inappropriate application of low-dose NOAC regimens will probably lead to worse thromboembolic results than those observed in the large randomised clinical trials and will likely compromise patient safety. As is true for all drug classes, clinicians need to be educated in all aspects of NOAC treatment, from choosing the most appropriate drug and dose to managing possible complications.


  1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
    Crossref | PubMed
  2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
    Crossref | PubMed
  3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
    Crossref | PubMed
  4. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.
    Crossref | PubMed
  5. Martínez-Rubio A, Martínez-Torrecilla R. Current evidence for new oral anticoagulants in the treatment of nonvalvular atrial fibrillation: comparison of substudies. Rev Esp Cardiol 2015;68:185–9.
    Crossref | PubMed
  6. January CT, Wann LS, Alpert JS, et al.; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American college of Cardiology/American heart association task force on practice guidelines and the heart rhythm society. J Am Coll Cardiol 2014;64:e1–76.
    Crossref | PubMed
  7. Verma A, Cairns JA, Mitchell LB, et al.; CCS Atrial Fibrillation Guidelines Committee. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014;30:1114–30.
    Crossref | PubMed
  8. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;
    Crossref | PubMed
  9. Tamayo S, Frank Peacock W, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015;38:63–8.
    Crossref | PubMed
  10. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157–64.
    Crossref | PubMed
  11. Larsen TB, Skjøth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189.
    Crossref | PubMed
  12. Cardiovascular and Renal Drugs Advisory Committee, Edoxaban NDA 206316. Statistical Considerations, ENGAGE AF Trial. US Food and Drug Administration, 2014. Available at: AdvisoryCommittees/CommitteesMeetingMaterials / Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM421612.pdf (accessed 22.11.2016)
  13. Alamneh EA, Chalmers L, Berznicki LR. Suboptimal use oral anticoagulants in atrial fibrillation: has the introduction of direct oral anticoagulants improved prescribing practices? Am J Cardiovasc Drugs 2016;16:183–200.
    Crossref | PubMed
  14. Barra ME, Fanikos J, Connors JM, et al. Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 2016;129:1198–204.
    Crossref | PubMed
  15. Fay MR, Martins JL, Czekay B. Oral anticoagulant prescribing patterns for stroke prevention in atrial fibrillation among general practitioners and cardiologists in three European countries. Poster 2597 presented at the European Society of Cardiology Congress 2016, 27–31 August 2016.
  16. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.
    Crossref | PubMed
  17. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of Factor Xa inhibitor activity. N Engl J Med 2015;373:2413–24.
    Crossref | PubMed
  18. Lip GYH, Frison L, Halperin JL, et al. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41:2731–8.
    Crossref | PubMed
  19. Olesen JB, Lip GYH, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124.
    Crossref | PubMed
  20. Friberg L, Rosenqvist M, Lip GYH. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500–10.
    Crossref | PubMed