Smith is a 79 year old man who lives alone. He suffered a stroke two years ago so is taking Coumadin (warfarin) for non-valvular atrial fibrillation. His other significant medical history includes type 2 diabetes mellitus, hypertension, congestive heart failure and atrial fibrillation. His creatinine clearance (Crcl) is 52ml/min. He has been inconsistent with his warfarin use as it is not blister packed, which is commonly known to increase compliance. You consider starting him on a direct oral anticoagulant (DOAC, also known as novel oral anti-coagulant (NOAC)) but wonder which one to start with.
For stroke prevention in non-valvular atrial fibrillation, DOACs are considered superior to warfarin as they have fewer fatal bleeding events 1, 2, 3. For stroke prevention in atrial fibrillation, the Canadian Cardiovascular Society recommends DOACs as first line therapy 4, 5. And when comparing with warfarin in clinical trials, DOACs had significantly reduced all-cause mortality, cardiovascular mortality and intracranial bleeding 6, 7. What factors influence decision making when choosing a DOAC?
The commonly used DOACs in Canada are dabigatran, apixaban and rivaroxaban. They have predictable pharmacokinetic profiles allowing for fixed dosing and do not require INR monitoring, like the vitamin K antagonist warfarin. There are no known food interactions, though few defined drug interactions have been described, 8,9. Yearly monitoring of renal function to inform dose change or type of DOAC is recommended 4, 5.
The dose of dabigatran is 150 mg twice a day, orally. The 110mg dose is recommended for those 80 years or older or those 75-79 years but with an increased risk of bleeding10. Dabigatran should be avoided in patients with CrCl <30ml/min. When compared with warfarin a higher dose of dabigatran may be preferred in patients with a CHADS2 score of three or more as it provides the greatest risk reduction for stroke amongst the DOACs 11. In patients with dyspepsia or gastrointestinal complaints, apixaban or rivaroxaban is preferred. Local effects of dabigatran on the gastrointestinal (GI) mucosa is thought to account for the relative increase in of GI symptoms 12
The dose of apixaban is 5 mg twice daily, orally. The 2.5 mg dose is available for those with a serum creatinine of > 133 umol/L and either age 80 years or older or body weight of ≤60kg. It is not recommended in CrCl < 15ml/ min and there is no dose adjustment for CrCl 15-24 ml/ min 8. The results of the ARISTOTLE trial showed a reduced risk of stroke and non-central nervous system embolism in patients with atrial fibrillation and at least one other risk factor for stroke 2. There was a statistically significant reduced risk of bleeding when compared to warfarin for those aged 75 years and over 2. Apixaban may be used in patients with a high risk of bleeding or previous life-threatening bleeding.
The dose of rivaroxaban is 20 mg daily, orally. A dose reduction to 15 mg daily, orally is recommended for CrCl 30- 49ml/min. Avoid use in CrCl < 30ml/ min. 9. Rivaroxaban may be considered in patients with a CHADS2 score of three or more in whom dabigatran is contraindicated 3. The patient population in the ROCKET- AF trial for rivaroxaban had a higher mean CHADS2 score of 3.5 compared to the RELY and ARISTOTLE trials (2.1). A subgroup analysis of all three trials showed a comparable relative risk reduction for all the DOACs 10, 13. Once-daily dosing improves compliance with medications in patients on multiple medications.
While there have been no head-to-head trials directly comparing all three DOACs, indirect comparisons suggest similar efficacy with less risk of bleeding with apixaban when compared with dabigatran and rivaroxaban 14. The choice of DOAC is largely influenced by individual patient characteristics, including risk of stroke, bleeding and renal dysfunction 15.
- Connolly, S. J., Ezekowitz, M. D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., … & Wang, S. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 361(12), 1139-1151.
- Granger, C. B., Alexander, J. H., McMurray, J. J., Lopes, R. D., Hylek, E. M., Hanna, M., … & Bahit, M. C. (2011). Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 365(11), 981-992.
- Patel, M. R., Mahaffey, K. W., Garg, J., Pan, G., Singer, D. E., Hacke, W., … & Becker, R. C. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine, 365(10), 883-891.
- Skanes, A. C., Healey, J. S., Cairns, J. A., Dorian, P., Gillis, A. M., McMurtry, M. S., … & Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. (2012). Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Canadian Journal of Cardiology, 28(2), 125-136.
- Verma, A., Cairns, J. A., Mitchell, L. B., Macle, L., Stiell, I. G., Gladstone, D., … & Ivers, N. (2014). 2014 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. Canadian Journal of Cardiology, 30(10), 1114-1130.
- Dentali, F., Riva, N., Crowther, M., Turpie, A. G., Lip, G. Y., & Ageno, W. (2012). Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature.Circulation, CIRCULATIONAHA-112.
- Dogliotti, A., Paolasso, E., & Giugliano, R. P. (2013). Novel oral anticoagulants in atrial fibrillation: a meta‐analysis of large, randomized, controlled trials vs warfarin.Clinical cardiology, 36(2), 61-67.
- http://www.pfizer.ca/sites/g/files/g10028126/f/201511/ELIQUIS_184490_mkt_PM_E.pdf Accessed June 9th 2016.
- http://omr.bayer.ca/omr/online/xarelto-pm-en.pdf Accessed June 9th 2016.
- Harper, P., Young, L., & Merriman, E. (2012). Bleeding risk with dabigatran in the frail elderly. New England Journal of Medicine, 366(9), 864-866.
- Oldgren, J., Alings, M., Darius, H., Diener, H. C., Eikelboom, J., Ezekowitz, M. D., … & Wallentin, L. (2011). Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Annals of internal medicine, 155(10), 660-667.
- Eikelboom, J. W., Wallentin, L., Connolly, S. J., Ezekowitz, M., Healey, J. S., Oldgren, J., … & Diener, H. C. (2011). Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation, 123(21), 2363-2372.
- Hankey, G. J., Patel, M. R., Stevens, S. R., Becker, R. C., Breithardt, G., Carolei, A., … & Mas, J. L. (2012). Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. The Lancet Neurology, 11(4), 315-322.
- Mantha, S., & Ansell, J. (2012). An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thrombosis and haemostasis,108(3), 476-484.
- Douketis, J., Bell, A. D., Eikelboom, J., & Liew, A. (2014). Approach to the new oral anticoagulants in family practice Part 1: comparing the options.Canadian Family Physician,60(11), 989-995.