Advertisement

Clinical Research in Cardiology

, Volume 106, Issue 8, pp 565–572 | Cite as

The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight—a systematic literature review

  • Raffaele De CaterinaEmail author
  • Gregory Y. H. Lip
Review
First Online:

Abstract

The non-vitamin K antagonist oral anticoagulants (NOACs) exert their anticoagulant effect closely related to their plasma concentrations. Since their distribution volume is related to body weight (and its correlates, i.e., surface area and body mass index, BMI), extremes in body weight may affect their efficacy or safety. Four NOACs are currently available for long-term use, with few exceptions, in atrial fibrillation and venous thromboembolism: the direct thrombin inhibitor dabigatran etexilate, and the factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience in patients with low (<50 kg) or extremely high (>150 kg) body weight is still quite limited, as such patients were rare in registration trials and sometimes directly excluded. In general, increased bleeding and higher mortality rates are observed in patients weighing <50 kg compared with patients weighing 50–100 kg. This may however also be explained by the presence of underlying conditions such as cancer. At the opposite end of the spectrum of body weight, lower antithrombotic efficacy may occur, perhaps due to the dilutional effect of a higher distribution volume. In this article, we review the pertinent literature and analyze the effects of low or high body weight on anticoagulant activity and clinical outcomes of the NOACs, their dose recommendations, and areas of uncertainty.

Keywords

Non-vitamin K antagonist oral anticoagulants NOACs Body weight Body mass index BMI Obesity Bleeding Stroke Mortality 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

Disclosures

RDC has served as a Consultant for Bayer, Merck, Sanofi Aventis, BMS/Pfizer, Daiichi-Sankyo, Lilly, Novartis, Roche, Portola, and Boehringer-Ingelheim; has received grants (to his University) from Boehringer-Ingelheim, Bayer, BMS/Pfizer; and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer-Ingelheim, Daiichi-Sankyo. G.Y.H.L. has served as a Consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer-Ingelheim, Microlife and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer-Ingelheim, Microlife, Roche, and Daiichi-Sankyo.

References

  1. 1.
    Sorbera LA, Bozzo J, Castaner J (2005) Dabigatran/dabigatran Etexilate. Drugs Future 30:877–885CrossRefGoogle Scholar
  2. 2.
    Kubitza D, Becka M, Wensing G et al (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61:873–880CrossRefPubMedGoogle Scholar
  3. 3.
    Frost C, Wang J, Nepal S et al (2013) Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 75:476–487CrossRefPubMedGoogle Scholar
  4. 4.
    Camm AJ, Bounameaux H (2011) Edoxaban: a new oral direct factor Xa inhibitor. Drugs 71:1503–1526CrossRefPubMedGoogle Scholar
  5. 5.
    Scaglione F (2013) New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 52:69–82CrossRefPubMedGoogle Scholar
  6. 6.
    Raghavan N, Frost CE, Yu Z et al (2009) Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 37:74–81CrossRefPubMedGoogle Scholar
  7. 7.
    Piccini JP, Patel MR, Mahaffey KW et al (2008) Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs 17:925–937CrossRefPubMedGoogle Scholar
  8. 8.
    Stangier J, Clemens A (2009) Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 15 Suppl 1:9S–16SGoogle Scholar
  9. 9.
    Barba R, Marco J, Martin-Alvarez H et al (2005) The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE). J Thromb Haemost 3:856–862CrossRefPubMedGoogle Scholar
  10. 10.
    Legrand M, Mateo J, Aribaud A et al (2011) The use of dabigatran in elderly patients. Arch Intern Med 171:1285–1286CrossRefPubMedGoogle Scholar
  11. 11.
    Eriksson BI, Dahl OE, Feuring M et al (2012) Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis. Thromb Res 130:818–820CrossRefPubMedGoogle Scholar
  12. 12.
    Hartter S, Yamamura N, Stangier J et al (2012) Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost 107:260–269CrossRefPubMedGoogle Scholar
  13. 13.
    Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  14. 14.
    Boehringer-Ingelheim (2016) Pradaxa summary of product characteristics. https://www.medicines.org.uk/emc/medicine/24839 2016. Accessed 21 Dec 2016
  15. 15.
    Halton JMâ, Lehr T, Cronin L et al (2016) Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study. Thromb Haemost 116:461–471CrossRefPubMedGoogle Scholar
  16. 16.
    Kubitza D, Becka M, Zuehlsdorf M et al (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 47:218–226CrossRefPubMedGoogle Scholar
  17. 17.
    Young G, Kubitza D, Chan A et al (2015) Development of a rivaroxaban dosing regimen for treatment of VTE in children aged 12 to 18 years. J Thromb Haemost 13(Suppl. 2):37–S104 (Abstract)Google Scholar
  18. 18.
    Di Nisio M, Vedovati MC, Riera-Mestre A et al (2016) Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 116:739–746CrossRefPubMedGoogle Scholar
  19. 19.
    Upreti VV, Wang J, Barrett YC et al (2013) Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol 76:908–916CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Alexander JH, Andersson U, Lopes RD et al (2016) Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial. JAMA Cardiol 1:673–681CrossRefPubMedGoogle Scholar
  21. 21.
    Leil TA, Frost C, Wang X et al (2014) Model-based exposure-response analysis of apixaban to quantify bleeding risk in special populations of subjects undergoing orthopedic surgery. CPT Pharmacometrics Syst Pharmacol 3:e136CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bristol-Myers Squibb-Pfizer (2016) Eliquis summary of product characteristics. https://www.medicines.org.uk/emc/history/27220 2016. Accessed 21 Dec 2016
  23. 23.
    Yin OQ, Tetsuya K, Miller R (2014) Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol 70:1339–1351CrossRefPubMedGoogle Scholar
  24. 24.
    Lip GY, Agnelli G (2014) Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 35:1844–1855CrossRefPubMedGoogle Scholar
  25. 25.
    Buller HR, Decousus H, Grosso MA et al (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefPubMedGoogle Scholar
  26. 26.
    Giugliano RP, Ruff CT, Braunwald E et al (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104CrossRefPubMedGoogle Scholar
  27. 27.
    Niebecker R, Jonsson S, Karlsson MO et al (2015) Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism–the Hokusai-VTE phase 3 study. Br J Clin Pharmacol 80:1374–1387CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Krekels EH, Niebecker R, Karlsson MO et al (2016) Population pharmacokinetics of Edoxaban in patients with non-valvular atrial fibrillation in the ENGAGE AF-TIMI 48 study, a phase III clinical trial. Clin Pharmacokinet 55:1079–1090CrossRefPubMedGoogle Scholar
  29. 29.
    Nyberg J, Karlsson KE, Jonsson S et al (2016) Edoxaban exposure-response analysis and clinical utility index assessment in patients with symptomatic deep-vein thrombosis or pulmonary embolism. CPT Pharmacometrics Syst Pharmacol 5:222–232CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Park CS, Choi EK, Kim HM et al (2016) Increased risk of major bleeding in underweight patients with atrial fibrillation who were prescribed non-vitamin K antagonist oral anticoagulants. Heart RhythmGoogle Scholar
  31. 31.
    Vanassche T, Vandenbriele C, Peerlinck K et al (2015) Pharmacotherapy with oral Xa inhibitors for venous thromboembolism. Expert Opin Pharmacother 16:645–658CrossRefPubMedGoogle Scholar
  32. 32.
    Liesenfeld KH, Lehr T, Dansirikul C et al (2011) Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 9:2168–2175CrossRefPubMedGoogle Scholar
  33. 33.
    Schulman S, Kearon C, Kakkar AK et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352CrossRefPubMedGoogle Scholar
  34. 34.
    Mueck W, Borris LC, Dahl OE et al (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100:453–461PubMedGoogle Scholar
  35. 35.
    Mahlmann A, Gehrisch S, Beyer-Westendorf J (2013) Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis 36:533–535CrossRefPubMedGoogle Scholar
  36. 36.
    Thomas Z, Bareket Y, Bennett W (2014) Rivaroxaban use following bariatric surgery. J Thromb Thrombolysis 38:90–91CrossRefPubMedGoogle Scholar
  37. 37.
    Bauersachs R, Berkowitz SD, Brenner B et al (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510CrossRefPubMedGoogle Scholar
  38. 38.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–889CrossRefPubMedGoogle Scholar
  39. 39.
    Bayer Pharma AG (2016) Xarelto summary of product characteristics. https://www.medicines.org.uk/emc/medicine/255862016. Accessed 21 Dec 2016
  40. 40.
    Daiichi Sankyo UK Limited (2016) Lixiana summary of product characteristics. https://www.medicines.org.uk/emc/medicine/30506 2016. Accessed 21 Dec 2016
  41. 41.
    van Es N, Coppens M, Schulman S et al (2014) Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 124:1968–1975CrossRefPubMedGoogle Scholar
  42. 42.
    Steinberg BA, Shrader P, Thomas L et al (2016) Off-label dosing of non-vitamin k antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol 68:2597–2604CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.“G. d’Annunzio” University and Center of Excellence on Aging – CeSI-MetChietiItaly
  2. 2.University of Birmingham Institute of Cardiovascular ScienceBirminghamUK

Personalised recommendations

Cite article

Buy options