Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) trial

doi:10.1016/j.ahj.2015.11.004

American Heart Journal

Volume 172, February 2016, Pages 144-151

https://doi.org/10.1016/j.ahj.2015.11.004 Get rights and content

Background

Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF–-TIMI 48 trial.

Methods

The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years.

Results

Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS₂ and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023).

Conclusion

In the FDA-approved cohort of the ENGAGE AF–-TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

Section snippets

Methods

The ENGAGE AF–TIMI 48 study was a 3-group, randomized, double-blind, double-dummy multinational trial that compared 2 dosing regimens of edoxaban with warfarin in 21,105 patients with AF¹ (NCT00781391). A detailed description of the study population, randomization, and study design had been described previously.⁷ In brief, eligible patients were 21 years or older who had AF within 12 months prior to randomization, a CHADS₂ score of 2 or above, and planned treatment with anticoagulation. Key

Results

A total of 14,071 patients in the ENGAGE AF–TIMI 48 trial were randomized to either the higher-dose edoxaban regimen (60/30 mg) or warfarin. Of these 10,948 patients (77.8%) had a CrCl ≤95 mL/min at randomization. A total of 1,561 patients who were randomized to receive a reduced dose were not included in the FDA-approved cohort (Figure 1), leaving 9,387 patients included in this analysis. As compared with the 4,684 patients who constitute the nonapproved cohort (Table I), patients in the

Discussion

In this analysis of the FDA-approved cohort, once-daily edoxaban 60/30 mg was superior to well-managed warfarin for the prevention of SSE in patients with AF and a CrCl ≤95 mL/min. In addition, treatment with edoxaban compared with warfarin was associated with a reduction in cardiovascular death as well as in major bleeding events, with significant reductions in hemorrhagic stroke, intracranial, and fatal bleeding events. Edoxaban and warfarin prevented ischemic stroke to a similar degree,

Conclusion

In the FDA-approved cohort for edoxaban, with a CrCl 15-95 mL/min and no dose reduction for low body weight or potent P-glycoprotein inhibition, treatment with edoxaban 60/30 mg once daily is superior to well-managed warfarin in the prevention of SSE. This dosage is associated with lower rates of bleeding, including fatal bleeding and intracranial hemorrhage; it reduces cardiovascular death and provides superior net clinical outcomes. These favorable results now expand the pharmacotherapeutic

Disclosures

Drs Eisen, Nordio, Gogia, Awasty, and Henderson have no disclosures. Drs Mercuri and Rutman are employees of Daiichi Sankyo, which funded this trial. Dr Giugliano has served as a consultant and had received honoraria from Bristol-Myers Squibb, Janssen, Daiichi-Sankyo, Merck, and Sanofi, and grant support through his institution from Daiichi-Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Ruff reports grant support through his institution from Daiichi-Sankyo; has served as a

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Cited by (13)

Meta-analysis of Stroke and Bleeding Risk in Patients with Various Atrial Fibrillation Patterns Receiving Oral Anticoagulants
2019, American Journal of Cardiology
Oral anticoagulation therapy (OAT) is a mainstay for stroke prevention in atrial fibrillation (AF) patients. However, whether the risks of stroke/systemic embolic events (SEE) and bleeding events are affected by the type, duration, and frequency of AF in patients receiving OAT has been previously debated. We aimed to determine the risk of stroke/SEE and bleeding events associated with paroxysmal AF compared to persistent or permanent AF among patients who received OAT. Comprehensive literature searches of the Cochrane Library, PubMed/MEDLINE, and EMBASE databases were conducted from inception to July 2018. In total, 495 records were retrieved, of which 6 phase III randomized controlled trials (RCTs) focusing on the efficacy and safety of OAT in AF patients were ultimately evaluated and included. Among 70,447 AF patients, 15,028 (21.3%) patients had paroxysmal and 55,419 (78.7%) had persistent or permanent AF. Compared to persistent or permanent AF, the incidence of stroke/SEE was lower in paroxysmal AF patients (risk ratio [RR] 0.79, 95% confidence interval [CI] 0.71 to 0.88, P <0.00001, I² = 0%). Overall, all-cause mortality was also lower in paroxysmal AF than in persistent or permanent AF patients (RR 0.72, 95% CI 0.66 to 0.79, P <0.00001, I² =0%). Annualized major bleeding rates were similar across AF types (RR 1.06, 95% CI 0.96 to 1.17, P = 0.22, I ²= 35%). In conclusion, in patients with moderate-to-high risk of stroke receiving anticoagulation, those with paroxysmal AF have a lower risk of stroke, systemic embolism, and mortality but similar risk of major hemorrhage compared to persistent or permanent AF patients.
Influence of Renal Function on the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Non–Vitamin K Antagonist Oral Anticoagulants
2018, Mayo Clinic Proceedings
Citation Excerpt :
Notably, 36% of patients with moderate or severe renal impairment received the 20-mg dose rather than the label-recommended 15-mg dose, and for 34% of patients, information on renal function was missing. Turpie et al45 performed a subgroup analysis by renal function category using pooled data from the RECORD1, RECORD2, RECORD3, and RECORD4 studies (Table).12-50 Patients in the RECORD studies received rivaroxaban (10 mg OD) or enoxaparin (40 mg OD or 30 mg BID) for the prevention of VTE after THA or TKA.
With the growing integration of non–vitamin K antagonist oral anticoagulants (NOACs) into clinical practice, questions have arisen regarding their use in special populations, including groups that may have been underrepresented in clinical trials. Patients with renal impairment, particularly in the lower echelons of renal function, are one such group. In an effort to elucidate the current evidence regarding the use of NOACs in patients with renal impairment, a systematic assessment of the literature was performed. The MEDLINE database was interrogated for studies and analyses evaluating the influence of renal function on the pharmacokinetics, pharmacodynamics, efficacy, and safety of NOACs published from January 1, 2000, through August 2, 2017. The 82 relevant publications retrieved highlight the diversity in the NOAC class regarding the impact of renal function on drug clearance, drug exposures, and clinical trial outcomes. In several large clinical trials, subgroup analyses revealed no significant differences when patients were stratified by creatinine clearance as a measure of renal function. Efficacy findings, in particular, were largely aligned with the overall population in the included studies. However, relative risks of bleeding were shown to vary, sometimes driven by changes in bleeding event rates in the comparator arm (eg, warfarin, enoxaparin). With few exceptions, minimal influence of mild renal impairment was observed on the relative efficacy and safety of NOACs. Taken together, the evidence suggests that the presence of renal impairment merits careful consideration of anticoagulant choice but should not deter physicians from appropriate use of NOACs.
Appropriate doses of non-vitamin K antagonist oral anticoagulants in high-risk subgroups with atrial fibrillation: Systematic review and meta-analysis
2018, Journal of Cardiology
Citation Excerpt :
Two sensitivity analyses for each pooled analysis (Supplementary Appendices) were performed: (1) a pooled analysis of all data except the 30-mg edoxaban data. The rationale for this analysis was that the US Food and Drug Administration did not recommend low-dose edoxaban due to its worse efficacy trend compared to warfarin [22]. ( 2) After excluding the 30-mg edoxaban data, another pooled analysis was performed including only studies with median center-based TTR ≥66%.
We evaluated the dose-dependent efficacy, safety, and all-cause mortality of non-vitamin K antagonist oral anticoagulants (NOACs) in “atrial fibrillation (AF) patients who were OAC-naïve,” or “AF patients with prior-stroke history” with those who were known to be high-risk subgroups under OAC.
After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), five phase-III randomized trials comparing NOACs and warfarin in “OAC-naïve/OAC-experienced,” or “with/without prior-stroke history” subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risk (RR) for stroke/systemic thromboembolism (SSTE), major bleeding, intracranial hemorrhage, and all-cause mortality.
1. In OAC-naïve patients, standard-dose NOACs showed superior efficacy and safety with lower mortality [RR 0.90 (0.84–0.97), p = 0.008, I² = 0%] compared to warfarin.
2. For OAC-experienced patients, low-dose NOACs showed equivalent efficacy but reduced risk of major bleeding [RR 0.61 (0.40–0.91), p = 0.02, I² = 89%], and had lower all-cause mortality [RR 0.86 (0.75–0.99), p = 0.04, I² = 38%] compared to warfarin.
3. For patients with prior-stroke history, low-dose NOACs showed equivalent efficacy, but reduced risk of major bleeding [RR 0.58 (0.48–0.70), p < 0.001, I² = 0%] and all-cause mortality [RR 0.76 (0.66–0.88), p < 0.001, I² = 0%] compared to warfarin.
4. Among patients without prior-stroke history, standard-dose NOAC was superior to warfarin for both SSTE prevention [RR 0.78 (0.66–0.91), p = 0.002, I² = 43%] and all-cause mortality [RR 0.91 (0.85–0.97), p = 0.004, I² = 0%].
In conclusion, standard-dose NOAC showed lower all-cause mortality than warfarin in OAC-naïve patients with AF, and low-dose NOAC was better than warfarin among the patients with prior-stroke history in terms of all-cause mortality.
Non-vitamin K antagonist oral anticoagulants have better efficacy and equivalent safety compared to warfarin in elderly patients with atrial fibrillation: A systematic review and meta-analysis
2018, Journal of Cardiology
Citation Excerpt :
The characteristics of each study for age subgroups with different dose regimen, including time in therapeutic range (TTR) of warfarin-treated group, should be considered. Moreover, 30 mg regimen of edoxaban showed lower efficacy compared to warfarin in stroke prevention among AF patients with intact renal function [10]. Therefore, recently published pooled analyses have several limitations in comparing whether these outcomes differ between elderly and non-elderly populations: (1) dose-specific data were not reported [11,12]. (
To evaluate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in elderly patients (aged ≥75 years) with atrial fibrillation (AF), depending on dose and/or renal function.
After systematically searching the databases (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), 5 phase III randomized controlled trials and reported data according to subgroups of elderly/non-elderly AF patients, comparing any NOACs and warfarin were included. The primary efficacy and safety outcomes were stroke/systemic thromboembolism and major bleeding.
(1) NOACs showed better efficacy than warfarin in elderly patients [RR 0.83 (0.69–1.00), p = 0.04, I² = 55%], but equivalent efficacy in non-elderly patients. (2) NOACs reduced major bleeding compared to warfarin in non-elderly (p < 0.001) and had comparable safety to warfarin in elderly patients. (3) Even in elderly patients with moderately impaired renal function, NOACs had a safety profile comparable to that of warfarin for major bleeding if dose reduction was reached appropriately [pooled RR 0.82 (0.35–1.88), p = 0.63, I² = 63%]. (4) All-cause mortality was lower with NOACs in non-elderly patients [RR 0.89 (0.83–0.95), p = 0.001, I² = 0%], and with standard-dose NOAC group of elderly patients [RR 0.93 (0.86–1.00), p = 0.04, I² = 0%] compared to warfarin.
For elderly patients (aged ≥75 years), NOACs showed better efficacy and equivalent safety compared to warfarin even in those with moderately impaired renal function. All-cause mortality was lower with standard-dose NOACs compared to warfarin in the elderly patient group.
The protocol of this meta-analysis was registered on PROSPERO under CRD42016047922 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016047922).
Anticoagulation: The Successes and Pitfalls of Long-Term Management
2017, Physician Assistant Clinics
An Update on Anticoagulation in Atrial Fibrillation
2017, Heart Lung and Circulation
Citation Excerpt :
Although there were strong trends with dabigatran and rivaroxaban for reduction in total mortality compared with warfarin, apixaban was (nominally) statistically significant in this regard (p = 0.048). Edoxaban (which is not available in Australia) has also been studied in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study [31]. This was a double-dummy double-blind study looking 30 and 60 mg once daily edoxaban versus warfarin, with the same efficacy and safety endpoints as the other studies.
Cerebrovascular accidents related to atrial fibrillation (AF) are potentially preventable with anticoagulation. Until recently, warfarin was the only proven anticoagulant to be effective in stroke prevention, however the novel, direct acting oral anticoagulants (DOACs) are now available, triggering a paradigm shift in treatment philosophy. Today, physicians need to consider in which patients anticoagulation should not be used rather than, as in the past, deciding in which patients it should be used. Although warfarin will continue to have a place in managing some patients with AF, in the future, the DOACs should be the predominant therapy for stroke prevention in patients with non-valvular AF.

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: RCT #NCT00781391.

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Background

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Conclusion

Disclosures

Lancet

J Thromb Haemost

Best Pract Res Clin Haematol

Am J Cardiol

Chest

J Am Coll Cardiol

Antman EM; ENGAGE AF–TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation

N Engl J Med

Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers

J Clin Pharmacol

Modeling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation

Thromb Haemost