ENGAGE AF-TIMI 48 analysis highlights advantages, disadvantages of low- versus high-dose

Treating patients with atrial fibrillation with lower-dose edoxaban may increase their risk of stroke or systemic embolism compared with higher doses, but could also lower the incidence of mortality, bleeding, and the composite endpoint of major bleeding, stroke, and systemic embolism, according to a recent analysis of results from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.

Researchers led by Jan Steffel, MD, of Brigham and Women’s Hospital, Boston, sought to compare the net clinical outcome (NCO) of a lower dose edoxaban regimen (LDER; 30 mg once daily, reduced to 15 mg in select patients) with the higher dose edoxaban regimen (HDER; 60 mg once daily, reduced to 30 in select patients). Their findings were published in the Journal of the American College of Cardiology.

“Direct oral anticoagulants (DOACs) have become the preferred therapy for stroke prevention in atrial fibrillation (AFib), based on the outcomes of 4 pivotal phase III randomized clinical trials. Although they demonstrated at least similar (if not better) efficacy regarding stroke prevention, the risk of severe (including intracranial and fatal) bleeding was reduced compared with warfarin. As such, current guidelines recommend DOACs over vitamin K antagonists for stroke prevention in most patients with AFib. However, the inherent risk of severe bleeding, although less frequent with DOAC therapy than vitamin K antagonists, may affect the morbidity and mortality of patients,” wrote Steffel and colleagues.

“The fear of bleeding has resulted in a substantial overuse of unstudied ’off label’ reduced doses of all DOACs. However, there are no randomized clinical trial data to allow for any assessment of efficacy or safety of reduced doses of apixaban or rivaroxaban in patients who do not fulfill the respective pre-defined dose-reduction criteria,” they added.

Upon analysis, they found that the predefined NCO—which included stroke/systemic embolism (SEE), major bleeding, and death—occurred less frequently in patients treated with the LDER compared with HDER (7.26% vs 8.01%, respectively; HR: 0.90; 95% CI: 0.84-0.98; P=0.014). Secondary endpoints — disabling stroke, life-threatening bleeds, or all-cause mortality — were similar between the two groups, as were tertiary pre-defined NCOs, including stroke, SEE, life-threating bleeds, or all-cause mortality.

Unfortunately, patients treated with LDER had a significantly higher risk of stroke/SEE compared with those treated with HDER (2.04% vs 1.56%, respectively; HR: 1.31; 95% CI: 1.12-1.52; P <0.001). The differences between the two groups were primarily driven by a 43% increase in ischemic strokes in the LDER group (1.77% vs 1.24%; HR: 1.43; 95% CI: 1.21-1.69; P < 0.001). Similarly, patients treated with LDER had a significantly higher incidence of all strokes (1.92% vs 1.48%; HR: 1.3; 95% CI: 1.11-1.52 P=0.001) and systemic embolic events (0.15% vs 0.08%; HR: 1.92; 95% CI: 1.03-3.59; P=0.040).

The incidence of disabling and fatal strokes, however, were similar between the LDER and HDER groups (0.81% vs 0.69%, respectively; HR 1.18; 95% CI: 0.94-1.49; P=0.16). However, LDER patients also had a significantly lower incidence of major bleeding (1.82% vs 2.87%; HR: 0.64; 95% CI: 0.55-0.74; P <0.001), intracranial hemorrhage (0.25% vs 0.38%; HR: 0.65; 95% CI: 0.44-0.97; P=0.035), major gastrointestinal bleeding (0.87% vs 1.53%; HR: 0.57; 95% CI: 0.46-0.70; P < 0.0001), and life-threatening bleeding (0.38% vs 0.62%; HR: 0.61; 95% CI: 0.44-0.84; P=0.002) compared with the HDER group.

In all, 25% of patients qualified for dose reduction, and those who received reduced doses of LDER (15 mg) vs HDER (30 mg) had lower risks for hemorrhagic stroke and intracranial hemorrhage compared with patients in both groups who did not require dose reductions.

“In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the two dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation,” wrote Steffel et al.

“Similar studies with other DOACs would be welcome, particularly in light of the frequent off-label use of untested and unapproved low-dose DOACs in clinical practice. However, the approved DOAC dosing regimens remain the standard of care for stroke prevention in AFib,” they concluded.

Providing some context to the management of patients with atrial fibrillation with direct oral anticoagulants (DOACs) such as edoxaban, Jonathan L. Halperin, MD, of Mount Sinai Medical Center, New York City, and Eman R. Rashed, MD, PhD, resident at the University of Medicine and Dentistry of New Jersey, Cranford, New Jersey, noted:

“The 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society focused update of their 2014 guideline and the 2020 European Society of Cardiology guideline for management of patients with AFib provide dose-reduction recommendations for dabigatran, rivaroxaban, apixaban, and edoxaban based on risk factors such as age, kidney function, body weight, and bleeding risk. Although bleeding risk scores can facilitate evaluation and identification of modifiable and nonmodifiable risk factors, individualized assessment is crucial,” they wrote in an accompanying editorial.

Halperin and Rashed did, however, add a word of caution for clinicians in the management of these patients:

“In today’s clinical arena, more than 1 in 5 DOAC prescriptions are issued for lower doses, and almost one-half of these involve off-label dosing. Underdosing has been associated with increased rates of stroke, hospitalization, and death without appreciable reduction in major bleeding,” they wrote.

“Although low-dose edoxaban was associated with significantly less bleeding in ENGAGE-AF than the standard high-dose edoxaban regimen, this was accompanied by a reduction in all-cause mortality and frequency of ischemic events, and those, after all, represent the outcomes that anticoagulant therapy [are] designed to prevent. The new evidence reported with half-dose edoxaban in patients with AFib adds to the foundation of evidence regarding DOAC therapy, but in clinical practice, we must tread carefully to avoid falling through the floor,” they concluded.

Steffel and colleagues stressed that the use of lower doses of edoxaban is not approved for use in patients with atrial fibrillation, and that study limitations included the lack of generalizability of these results to all patients seen in clinical practice, failure to adjust for multiple comparisons, and the lack of powering of the trial for subgroup analyses.

  1. In patients with atrial fibrillation, a lower-dose edoxaban regimen was associated with a higher risk of stroke or systemic embolism than the higher-dose edoxaban regimen, but had lower rates of bleeding and the composite endpoint of major bleeding, stroke and systemic embolism, and mortality.

  2. Underdosing of target-specific DOACs is common in clinical practice, but after their analysis of results from the ENGAGE AF-TIMI 48 trial, researchers recommend caution and results from further clinical trials to help guide clinicians in their individualization of DOAC dosing.

Liz Meszaros, Contributing Writer, BreakingMED™

The ENGAGE AF-TIMI 48 trial was supported by Daiichi-Sankyo Pharma Development.

Steffel has received consultant and/or speaker fees from Abbott, Amgen, AstraZeneca, Bayer, BerlinChemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Medscape, Medtronic, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Pfizer, Portola, Saja, Servier, and WebMD; has ownership in CorXL; and has received grant support, through his institution, from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi-Sankyo, and Medtronic.

Halperin has received consulting fees involving the development of anticoagulant drugs from Bayer Healthcare, Boehringer Ingelheim, and Ortho-McNeil-Janssen; has served as a member of the Steering Committee for the ENGAGE-AF TIMI 48 trial, sponsored by Daiichi Sankyo; and has served on the Steering Committee of the CATALYST trial, sponsored by Abbott.

Rashed reported no disclosures.

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Topic ID: 74,2,730,2,913,38,192,925

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