Therapeutics
Edoxaban was noninferior to warfarin for preventing stroke or systemic embolism in atrial fibrillation
Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ H ★★★★★★★ Question In patients with atrial fibrillation (AF) who are at moderate-to-high risk for stroke, is edoxaban noninferior to warfarin for preventing stroke or systemic embolism?
Methods Design: Randomized controlled noninferiority trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48] trial). ClinicalTrials.gov NCT00781391. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, outcome adjudicators, {data collectors, data analysts, and manuscript writers}†). Follow-up period: Median 2.8 years. Setting: 1393 clinical centers in 46 countries. Patients: 21 105 adults ≥ 21 years of age (median age 72 y, 62% men) who had objectively documented AF in the past 12 months, CHADS2 score ≥ 2, and anticoagulation therapy planned for the trial duration. Exclusion criteria included AF due to a reversible disorder, estimated creatinine clearance (CrCl) < 30 mL/min, moderate-to-severe mitral stenosis, high bleeding risk, use of dual-antiplatelet therapy, acute coronary syndromes, coronary revascularization, other indications for anticoagulation therapy, or stroke within the past 30 days. Intervention: Edoxaban, 60 mg/d (n = 7035), or 30 mg/d (n = 7034), plus warfarin placebo; or warfarin, dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0, plus edoxaban placebo (n = 7036). Edoxaban doses were halved if patients had an estimated CrCl 30 to 50 mL/min; weighed ≤ 60 kg; or concomitantly used verapamil, quinidine, or dronedarone. Outcomes: Composite of ischemic or hemorrhagic stroke or systemic embolic event during the treatment period (noninferiority) and during the study period (superiority). The primary safety endpoint was major bleeding during treatment.
Patient follow-up: 99% for primary noninferiority outcome (intention-to-treat analysis).
Main results Median duration of treatment was 2.5 years. Both doses of edoxaban were noninferior to warfarin for the primary endpoint; neither dose was superior to warfarin (Table). Both doses of edoxaban resulted in less major bleeding than did warfarin (Table).
Conclusion In patients with atrial fibrillation who are at moderate-to-high risk for stroke, edoxaban was noninferior to warfarin for preventing stroke or systemic embolism and had less bleeding. *See Glossary. †Information provided by author.
Source of funding: Daiichi Sankyo Pharma Development. For correspondence: Dr. R.P. Giugliano, Brigham and Women’s Hospital, Boston, MA, USA. E-mail [email protected]. ■
Commentary
The ENGAGE AF-TIMI 48 trial of > 20 000 moderate-tohigh-risk patients with nonvalvular AF showed that edoxaban was noninferior to warfarin for preventing stroke or systemic embolism. Moreover, edoxaban had fewer major bleeding events, including intracranial hemorrhage, than warfarin. Warfarin patients spent a median 68% of time in the therapeutic range. ENGAGE AF-TIMI 48 studied 2 edoxaban doses, and > 25% of patients were randomized to the lower edoxaban dose based on prespecified criteria. Another 10% of patients had dose modification after randomization. Patients who received the lower edoxaban dose had fewer major bleeding events, without an increased risk for stroke or systemic embolism, compared with patients who had no dose reduction. This suggests that in patients with a higher bleeding risk, a lower edoxaban dose is safe without compromising efficacy. The investigators had a detailed plan for transitioning patients from edoxaban to open-label warfarin, and the transition was not associated with increased thromboembolic risk Edoxaban, 60 or 30 mg/d, vs warfarin in patients with atrial fibrillation as has been seen in other trials (1, 2). However, in routine who are at moderate-to-high risk for stroke‡ practice patients are often not transitioned from a novel Outcomes Edoxaban Event rate/y RRR/RRI P value for oral anticoagulant (NOAC) to warfarin. dose (97.5% CI) noninferiority/ The ENGAGE AF-TIMI 48 findings support the use NNT (CI) of edoxaban in nonvalvular AF. Nevertheless, proper Edoxaban Warfarin patient selection and education remain imperative with Primary noninferiority 60 mg/d 1.2% 1.5% RRR 21% (1 to 37) < 0.001 any NOAC. Baseline assessment of renal function, endpoint§ weight, and interacting medications will identify patients who need dose reduction to balance potential safety and 30 mg/d 1.6% 1.5% RRI 7% (−13 to 30) 0.005 efficacy concerns. Intermittent assessment of drug comPrimary superiority 60 mg/d 1.6% 1.8% RRR 13% (−4 to 26) Not significant pliance, monitoring of renal and liver function, and endpoint|| ongoing education, particularly in higher-risk patients, 30 mg/d 2.0% 1.8% RRI 13% (−4 to 33) Not significant are also recommended. Major bleeding
60 mg/d
2.8%
3.4%
RRR 19% (9 to 28)¶
70 (48 to 155)¶
30 mg/d
1.6%
3.4%
RRR 52% (44 to 58)¶
26 (24 to 31)¶
‡Abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from warfarin event rates and hazard ratios (HRs) in article. §Ischemic or hemorrhagic stroke or systemic embolic event during treatment (from first dose of study drug until 3 d after last dose or end of double-blind treatment). Noninferiority criterion was met as the upper limit of the 1-sided 97.5% CI for the HR was ≤ 1.38: 60 mg/d HR 0.79 (CI 0.63 to 0.99); 30 mg/d HR 1.07 (CI 0.87 to 1.31) ||Ischemic or hemorrhagic stroke or systemic embolic event during study (from randomization until 3 d after last study dose or end of double-blind treatment). ¶95% CI.
18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Stacy A. Johnson, MD Matthew T. Rondina, MD University Healthcare Thrombosis Service University of Utah Salt Lake City, Utah, USA References 1. Granger CB, Alexander JH, McMurray JJ, et al; ARISOTLE Committees and Investigators. N Engl J Med. 2011;365:981-92. 2. Mahaffey KW, Hellkamp AS, Patel MR, et al. Circ Cardiovasc Qual Outcomes. 2013;6:470-8. © 2014 American College of Physicians
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JC7
Edoxaban was noninferior to warfarin for preventing stroke or systemic embolism in atrial fibrillation
Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ H ★★★★★★★ Question In patients with atrial fibrillation (AF) who are at moderate-to-high risk for stroke, is edoxaban noninferior to warfarin for preventing stroke or systemic embolism?
Methods Design: Randomized controlled noninferiority trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48] trial). ClinicalTrials.gov NCT00781391. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, outcome adjudicators, {data collectors, data analysts, and manuscript writers}†). Follow-up period: Median 2.8 years. Setting: 1393 clinical centers in 46 countries. Patients: 21 105 adults ≥ 21 years of age (median age 72 y, 62% men) who had objectively documented AF in the past 12 months, CHADS2 score ≥ 2, and anticoagulation therapy planned for the trial duration. Exclusion criteria included AF due to a reversible disorder, estimated creatinine clearance (CrCl) < 30 mL/min, moderate-to-severe mitral stenosis, high bleeding risk, use of dual-antiplatelet therapy, acute coronary syndromes, coronary revascularization, other indications for anticoagulation therapy, or stroke within the past 30 days. Intervention: Edoxaban, 60 mg/d (n = 7035), or 30 mg/d (n = 7034), plus warfarin placebo; or warfarin, dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0, plus edoxaban placebo (n = 7036). Edoxaban doses were halved if patients had an estimated CrCl 30 to 50 mL/min; weighed ≤ 60 kg; or concomitantly used verapamil, quinidine, or dronedarone. Outcomes: Composite of ischemic or hemorrhagic stroke or systemic embolic event during the treatment period (noninferiority) and during the study period (superiority). The primary safety endpoint was major bleeding during treatment.
Patient follow-up: 99% for primary noninferiority outcome (intention-to-treat analysis).
Main results Median duration of treatment was 2.5 years. Both doses of edoxaban were noninferior to warfarin for the primary endpoint; neither dose was superior to warfarin (Table). Both doses of edoxaban resulted in less major bleeding than did warfarin (Table).
Conclusion In patients with atrial fibrillation who are at moderate-to-high risk for stroke, edoxaban was noninferior to warfarin for preventing stroke or systemic embolism and had less bleeding. *See Glossary. †Information provided by author.
Source of funding: Daiichi Sankyo Pharma Development. For correspondence: Dr. R.P. Giugliano, Brigham and Women’s Hospital, Boston, MA, USA. E-mail [email protected]. ■
Commentary
The ENGAGE AF-TIMI 48 trial of > 20 000 moderate-tohigh-risk patients with nonvalvular AF showed that edoxaban was noninferior to warfarin for preventing stroke or systemic embolism. Moreover, edoxaban had fewer major bleeding events, including intracranial hemorrhage, than warfarin. Warfarin patients spent a median 68% of time in the therapeutic range. ENGAGE AF-TIMI 48 studied 2 edoxaban doses, and > 25% of patients were randomized to the lower edoxaban dose based on prespecified criteria. Another 10% of patients had dose modification after randomization. Patients who received the lower edoxaban dose had fewer major bleeding events, without an increased risk for stroke or systemic embolism, compared with patients who had no dose reduction. This suggests that in patients with a higher bleeding risk, a lower edoxaban dose is safe without compromising efficacy. The investigators had a detailed plan for transitioning patients from edoxaban to open-label warfarin, and the transition was not associated with increased thromboembolic risk Edoxaban, 60 or 30 mg/d, vs warfarin in patients with atrial fibrillation as has been seen in other trials (1, 2). However, in routine who are at moderate-to-high risk for stroke‡ practice patients are often not transitioned from a novel Outcomes Edoxaban Event rate/y RRR/RRI P value for oral anticoagulant (NOAC) to warfarin. dose (97.5% CI) noninferiority/ The ENGAGE AF-TIMI 48 findings support the use NNT (CI) of edoxaban in nonvalvular AF. Nevertheless, proper Edoxaban Warfarin patient selection and education remain imperative with Primary noninferiority 60 mg/d 1.2% 1.5% RRR 21% (1 to 37) < 0.001 any NOAC. Baseline assessment of renal function, endpoint§ weight, and interacting medications will identify patients who need dose reduction to balance potential safety and 30 mg/d 1.6% 1.5% RRI 7% (−13 to 30) 0.005 efficacy concerns. Intermittent assessment of drug comPrimary superiority 60 mg/d 1.6% 1.8% RRR 13% (−4 to 26) Not significant pliance, monitoring of renal and liver function, and endpoint|| ongoing education, particularly in higher-risk patients, 30 mg/d 2.0% 1.8% RRI 13% (−4 to 33) Not significant are also recommended. Major bleeding
60 mg/d
2.8%
3.4%
RRR 19% (9 to 28)¶
70 (48 to 155)¶
30 mg/d
1.6%
3.4%
RRR 52% (44 to 58)¶
26 (24 to 31)¶
‡Abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from warfarin event rates and hazard ratios (HRs) in article. §Ischemic or hemorrhagic stroke or systemic embolic event during treatment (from first dose of study drug until 3 d after last dose or end of double-blind treatment). Noninferiority criterion was met as the upper limit of the 1-sided 97.5% CI for the HR was ≤ 1.38: 60 mg/d HR 0.79 (CI 0.63 to 0.99); 30 mg/d HR 1.07 (CI 0.87 to 1.31) ||Ischemic or hemorrhagic stroke or systemic embolic event during study (from randomization until 3 d after last study dose or end of double-blind treatment). ¶95% CI.
18 March 2014 | ACP Journal Club | Volume 160 • Number 6
Stacy A. Johnson, MD Matthew T. Rondina, MD University Healthcare Thrombosis Service University of Utah Salt Lake City, Utah, USA References 1. Granger CB, Alexander JH, McMurray JJ, et al; ARISOTLE Committees and Investigators. N Engl J Med. 2011;365:981-92. 2. Mahaffey KW, Hellkamp AS, Patel MR, et al. Circ Cardiovasc Qual Outcomes. 2013;6:470-8. © 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929862/ by a Tufts University User on 07/25/2017
JC7
