Editor's Note: Commentary based on Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013; 369:2093-104.

Background

Patients with atrial fibrillation (AF) have a five to seven fold greater risk of stroke than the general population.^1-3 The incidence of stroke for non-anticoagulated AF patients averages 4 to 5% per year.⁴ Thromboembolism prevention with oral anticoagulation is recommended for patients with moderate or high risk of stroke.⁵ Edoxaban is an oral factor Xa inhibitor that was compared with warfarin for stroke prevention in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.⁶

Methods

This was a prospective, randomized, double-blind, and double-dummy study of 21,105 patients. Patients were randomized in a 1:1:1 ratio to dose-adjusted warfarin (INR goal 2.0-3.0), low dose edoxaban (30mg once daily), and high dose edoxaban (60mg once daily). Edoxaban doses were reduced by 50% at any point in the trial for creatinine clearance of 30 to 50 mL per minute, body weight ≤ 60kg, or use of potent P-glycoprotein inhibitors (verapamil, quinidine, or dronedarone). Patients had to have a CHADS2 score ≥ 2 to be included, and key exclusion criteria were creatinine clearance less than 30 mL per minute or moderate to severe mitral stenosis. Each edoxaban arm was evaluated for non-inferiority compared to warfarin for the primary efficacy endpoint of stroke or systemic embolism. The principal safety endpoint was major bleeding.6

Results

Both doses of edoxaban were non-inferior to warfarin for preventing strokes or systemic embolism. The superiority analysis for prevention of stroke or systemic embolism showed a trend towards superiority for the high dose of edoxaban (HR 0.87, 97.5% CI 0.73-1.04, p-value=0.08) and a negative trend for the low dose of edoxaban (HR 1.13, 97.5% CI 0.96-1.34, p-value=0.10). Both edoxaban arms had lower rates of major bleeding compared with warfarin with hazard ratios of 0.80 for the high dose (95% CI 0.71-0.91, p-value < 0.001) and 0.47 for the low dose (95% CI 0.41-0.55, p-value < 0.001). Similarly, both doses of edoxaban had decreased cardiovascular mortality versus warfarin with hazard ratios of 0.86 for high dose (95% CI 0.77-0.97, p-value=0.01) and 0.85 for low dose (95% CI 0.76-0.96, p-value=0.008). Edoxaban had lower rates of intracranial hemorrhage than warfarin with hazard ratios of 0.47 (95% CI 0.34-0.63, p-value < 0.001) and 0.30 (95% CI 0.21-0.43, p-value < 0.001) for high and low dose, respectively. The median time in therapeutic range for warfarin was 68.4%⁶.

Conclusion

High and low dose edoxaban were non-inferior to warfarin for the prevention of stroke or systemic embolism, and high dose was more effective than low dose edoxaban. Both doses had decreased rates of major bleeding, intracranial hemorrhage, and cardiovascular mortality.⁶

Commentary/Perspective

This study by Giugliano et al. is the fourth comparison of a novel oral anticoagulant to warfarin for stroke prevention in patients with atrial fibrillation.⁶ It convincingly shows that edoxaban, given once daily, is another effective and safe treatment for preventing stroke in atrial fibrillation.

While establishing the efficacy of warfarin versus control included a total of 2900 patients⁷ there have been more than 71,500 patients randomized in the RE-LY,⁸ ROCKET-AF,⁹ ARISTOTLE,¹⁰ and ENGAGE-AF⁶ trials. The average CHADS2 score of patients in ENGAGE-AF was 2.8, falling between ROCKET-AF and RE-LY or ARISTOTLE. The ENGAGE-AF trial sets a new standard for high quality with 182 patients (0.9%) withdrawing consent and having no known primary endpoint and not being dead, only one patient lost to follow-up, and median time in therapeutic range of 68% for patients on warfarin (versus 66% for RELY and ARISTOTLE and 58% for ROCKET). About 34% of patients stopped study drug (edoxaban or warfarin) prematurely.

For the prevention of stroke or systemic embolism, both doses of edoxaban were found to be non-inferior to warfarin, while the high dose edoxaban strategy tended to have better efficacy than warfarin and low dose edoxaban. Bleeding was lower with both doses of edoxaban than warfarin, with HRs of 0.80 and 0.47 for the high and low doses, respectively. Intracranial hemorrhage was also lower with edoxaban, with HRs of 0.47 (high dose) and 0.30 (low dose). As compared to warfarin, gastrointestinal bleeding was more common in the high dose edoxaban arm (HR 1.23, 95% CI 1.02-1.50, p-value=0.03), but it was lower with low dose edoxaban (HR 0.67, 95% CI 0.53-0.83, p-value < 0.001). Low dose edoxaban had lower all-cause mortality than warfarin (HR 0.87, 95% CI 0.79-0.96, p-value=0.006), although ischemic stroke was 41% higher with low dose edoxaban than with warfarin. High dose edoxaban trended towards lower all-cause mortality (HR 0.92, 95% CI 0.83-1.01, p-value=0.08), and both doses had lower cardiovascular mortality than warfarin.

Approximately 25% of patients had their edoxaban dose cut in half at baseline due to low body weight, chronic kidney disease, and/or concomitant use of potent P-glycoprotein inhibitors. An additional 7.1% of patients were dose-reduced, while 1.2% of patients were increased back to the standard dose, during the trial. The efficacy of edoxaban was consistent in the population that had dose reduction.

ENGAGE-AF demonstrated that edoxaban, compared with warfarin, has similar efficacy with stroke prevention, improved cardiovascular mortality, and decreased risk of bleeding, making edoxaban an attractive alternative to warfarin. For most patients the high dose appeared to be the optimal choice, with significantly lower risk of stroke or systemic embolism than the low dose and a tendency for lower risk of stroke or systemic embolism versus warfarin.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham Study. Arch Intern Med 1987;147:1561.
2. Wolf PA, Dawber TR, Thomas Jr HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke. Neurology 1978;28:973-7.
3. Flegel K, Shipley M, Rose G. Risk of stroke in non-rheumatic atrial fibrillation. Lancet 1987;329:526-9.
4. Hart RG, Pearce LA. Current status of stroke risk stratification in patients with atrial fibrillation. Stroke 2009;40:2607-10.
5. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.Circulation 2011;123:e269-367.
6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013;369(22):2093-104.
7. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med2007;146:857-67.
8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
10. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.

Keywords: Atrial Fibrillation, Creatinine, Factor Xa, Myocardial Infarction, Stroke, Thromboembolism, Verapamil, Warfarin

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