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ENGAGE AF-TIMI 48: Edoxaban dose reduction improved clinical outcomes
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BARCELONA, Spain — In a subgroup analysis of the ENGAGE AF-TIMI 48 trial, patients with clinical factors known to increase risk for bleeding due to higher drug exposure who were administered a reduced edoxaban dose had decreased drug concentrations and anti-factor Xa activity, rates of stroke or systemic embolic events consistent with those who did not receive a dose reduction and greater relative reductions in bleeding compared with warfarin.
“This is the first analysis of a novel oral anticoagulant that evaluates edoxaban dose, concentration, anti-factor Xa activity, and the relationship with efficacy and bleeding outcomes,” Christian T. Ruff, MD, MPH, from the TIMI Study Group, associate physician at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, said in a press release.
The ENGAGE AF-TIMI 48 trial compared two once-daily edoxaban (Daiichi Sankyo) treatment strategies vs. warfarin in patients with nonvalvular atrial fibrillation: a high dose of 60 mg (30 mg dose-reduced) and a low dose of 30 mg (15 mg dose-reduced). Patients were followed for a median of 2.8 years.
Among patients randomly assigned edoxaban, 25.4% were dose-reduced based on prespecified clinical factors including:
- Creatinine clearance of 30 mL/min to 50 mL/min;
- Body weight <60 kg;
- Concomitant use of certain P-glycoprotein inhibitors.
Regardless of treatment status, patients who met clinical criteria for dose reduction had higher rates of stroke or systemic embolic events and major bleeding, according to the press release.
Among those eligible for inclusion in the subgroup analysis, the researchers measured trough edoxaban concentration in 6,780 patients and anti-factor Xa activity in 2,865 patients. A fourfold edoxaban dose range —15 mg to 60 mg — was associated with a threefold gradient of the mean edoxaban trough concentration and a 2.4-fold gradient of mean anti-factor Xa activity, according to the press release.
A 50% dose reduction in selected patients based on clinical factors resulted in a decrease in mean edoxaban trough concentration of 29% to 35% and a decrease in mean anti-factor Xa activity of 20% to 25%, Ruff said during a presentation at ESC Congress.
According to results of the prespecified analysis, in the high-dose group vs. warfarin, the relative risk reduction of stroke/systemic embolic events observed in patients receiving 60 mg (HR=0.78; 95% CI, 0.61-0.99) was consistent with that observed in patients receiving dose reduction to 30 mg (HR=0.81; 95% CI, 0.58-1.13; P for interaction=0.85). The researchers observed a lower incidence of major bleeding in patients assigned the 60-mg dose vs. warfarin (HR=0.88; 95% CI, 0.5-0.81), with a greater relative reduction observed in the dose-reduced 30-mg group (P for interaction=.02), according to the release.
In the low-dose group vs. warfarin, the relative risk for stroke/systemic embolic events observed in patients receiving 30 mg (HR=1.07; 95% CI, 0.86-1.34) was consistent with that observed in patients receiving dose reduction to 15 mg (HR=1.07; 95% CI, 0.79-1.46; P for interaction=.99). The researchers reported a lower incidence of major bleeding in the dose-reduced 15-mg group vs. warfarin (HR=0.31; 95% CI, 0.23-0.42), with a greater relative reduction observed in the dose-reduced 15-mg group (P for interaction=.002), according to the release.
These data “give us an idea that the therapeutic window of exposure differs between safety and efficacy. It is relatively steeper for major bleeding and more forgiving, or wider, for stroke/systemic embolic events and, reassuringly, very wide for intracranial hemorrhage.
“Tailoring the dose based on clinical features alone prevented excess edoxaban drug levels. Dose modification of edoxaban as studied in ENGAGE AF-TIMI 48 helped optimize the balance between ischemic and bleeding events without measuring drug levels or anticoagulation activity,” Ruff said.
For more information:
Ruff CT. Clinical Trial and Registry Update. Presented at: the European Society of Cardiology Congress; Aug. 30-Sept. 3, 2014; Barcelona, Spain.
Disclosure: Ruff reports receiving research support from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Intarcia, Merck and Sanofi Aventis, and serving as a consultant/advisory board member for Alere, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi Sankyo.
Perspective
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Manesh R. Patel, MD
The ENGAGE AF-TIMI 48 investigators have to be congratulated for rigorously conducting and collecting at least 2,865 patients or more with samples of the actual drug concentration at 1 month, the anti-factor Xa activity, and then the clinical events of bleeding, stroke/systemic embolic events and intracranial hemorrhage. It is important to recognize that the majority of the dose reduction from the main paper in NEJM was driven by renal function. Renal function is going to be an important story for patients with AF. Here, we see that 19% of the 25% of patients who had a dose reduction at least met the criteria for having reduced renal function.
The planned dose reduction did lead to a decrease in trough concentration and anti-Xa activity. It is important to recognize that even though they reduced the dose with the idea of keeping the concentration high, there was still some reduction in the trough concentration and some reduction in the anti-factor Xa activity. This tells me that despite all the knowledge we have about pharmacokinetics, there is not always a direct relationship.
I would caution against anyone using these data to go out and buy a factor Xa assay to try to individually patient-dose the novel oral anticoagulants for several reasons. First, there doesn’t seem to be exactly a direct relationship with reduced concentration and effect. Second, there are relative values for each patient regarding their risk for bleeding vs. ischemic events; it is hard to understand how you would balance that with an assay. We have failed in the past with platelet function testing. What we have from these data are great information on the dose reduction with edoxaban, learnings surrounding intracranial hemorrhage and caution against using our own assays to individually dose patients.
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