Physicians' Academy for Cardiovascular Education

Real-world analyses show similar or better effectiveness and safety of NOACs compared to warfarin

Yao X et al., J Am Heart Assoc 2016

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation

Yao X, Abraham NS, Sangaralingham LR, et al.
J Am Heart Assoc 2016 doi:10.1161/JAH.116.003725


Atrial fibrillation (AF) is associated with a 3- to 5-fold increased risk of stroke [1]. Non-Vitamin K oral anticoagulants (NOACs) can reduce this risk and demonstrated at least equivalent efficacy compared to warfarin in large phase III clinical trials [2-4].
However the efficacy and safety observed in clinical trials may not necessarily translate to routine practice because of the differences in patient populations, the intensity of follow-up and the variations in care that patients receive. Furthermore, because anticoagulants are long-term preventive medications without serious ongoing symptoms, adherence is substantially lower in observational studies than in clinical trials [5-8].
Several observational studies have been performed comparing warfarin with dabigatran or rivaroxaban but only a few studies have been done with apixaban [8-11]. The longer of these medications now allows greater follow-up and better powered analyses.
Therefore, using a large patient population from a wide variety of health care settings, the stroke and bleeding outcomes were associated with dabigatran, rivaroxaban, and apixaban use by comparing each agent with warfarin. This retrospective analysis was done using administrative claims data from OptumLabs Data Warehouse (OLDW) in which 125,243 AF patients (age ≥18 yrs) who were anticoagulated between 2010 and 2015 (7698 on apixaban, 14,881 on dabigatran, 16,795 on rivaroxaban and 85,869 on warfarin). All results are based on 1:1 propensity score matching.

Main results

  • At baseline, dabigatran patients were younger than apixaban and rivaroxaban patients, had lower risk of stroke or bleeding and included a larger percentage of warfarin-naïve patients.
  • Compared to warfarin, apixaban was associated with a reduced risk of stroke or systemic embolism (S/SE) (HR 0.67; 95% CI: 0.46-0.98, P=0.04), which was mainly driven by the lower risk of haemorrhagic stroke (HR 0.35; 95% CI: 0.14-0.88, P=0.03).
  • Compared to warfarin, dabigatran was associated with a similar risk of S/SE (HR 0.98; 95% CI: 0.70-1.26, P=0.98), as was rivaroxaban (HR 0.93; 95% CI: 0.72-1.19, P=0.56).
  • Compared to warfarin, apixaban was associated with lower risks of major bleeding (HR 0.45; 95% CI: 0.34-0.59), intracranial bleeding (HR 0.24; 95% CI: 0.12-0.50) and gastrointestinal bleeding (HR 0.51; 95% CI: 0.37-0.70), all P<0.001.
  • Compared to warfarin, dabigatran was associated with lower risk of major bleeding (HR 0.79; 95% CI: 0.67-0.94, P<0.01) and intracranial bleeding (HR 0.36; 95% CI: 0.23-0.56, P<0.001).
  • Compared to warfarin, rivaroxaban was associated with a lower risk of intracranial bleeding (HR 0.51; 95% CI: 0.35-0.75, P<0.001) but a higher risk of gastrointestinal bleeding (HR 1.21; 95% CI: 1.02-1.43, P=0.03).
  • Subgroup analyses of dabigatran-warfarin showed a lower risk of major bleedings in dabigatran-treated patients with a CHA2DS2VASc score 2 or 3 (HR 0.46; 95% CI: 0.32-0.65, P<0.001) and in dabigatran-treated patients who were naïve for warfarin (HR 0.63; 95% CI: 0.50-0.79, P<0.01).
  • Subgroup analyses of rivaroxaban-warfarin showed an elevated risk S/SE and major bleedings in rivaroxaban-treated patients with prior warfarin-experience (HR 1.63, 95% CI: 1.01-2.62, P<0.01 and HR 1.48, 95% CI: 1.12-1.95, P<0.01, respectively).


In these real-world effectiveness and safety analyses, apixaban was associated with better effectiveness and safety, dabigatran was associated with similar effectiveness but better safety, whereas rivaroxaban was associated with similar outcomes for both effectiveness and safety, when compared to warfarin.  
Find this article online at JAHA


1. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 2002;113:359–364.
2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.
3. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.
4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.
5. Zalesak M, Siu K, Francis K, Yu C, Alvrtsyan H, Rao Y, Walker D, Sander S, Miyasato G, Matchar D. Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. Circ Cardiovasc Qual Outcomes. 2013;6:567–574.
6. Cutler TW, Chuang A, Huynh TD, Witt RG, Branch J, Pon T, White R. A retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center. J Manag Care Pharm. 2014;20:1028–1034.
7. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352.
8. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu T-C, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation.Circulation. 2015;131:157–164.
9. Maura G, Bloti_ere P-O, Bouillon K, Billionnet C, Ricordeau P, Alla F, Zureik M. Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensitymatched cohort study. Circulation. 2015;132:1252–1260.
10. Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G. Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study. J Am Heart Assoc. 2015;4:e001798 doi: 10.1161/JAHA.115.001798.
11. Abraham NS, Singh S, Alexander GC, Heien H, Haas LR, Crown W, Shah ND. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350:h1857 doi: 10.1136/ bmj.h1857.