RE-LY: Dabigatran Safe, Effective Across Range of Renal Function

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Two different doses of dabigatran are each as effective as warfarin regardless of renal function, according to a substudy of the RE-LY trial showing consistency with the overall study findings.  Published online December 9, 2013, ahead of print in Circulation, the analysis also shows that, using a new assessment of renal function, both dabigatran doses are associated with lower rates of major bleeding in patients with no renal impairment.

For the noninferiority RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial, researchers compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin in 18,113 patients at risk of stroke from nonvalvular A-fib.

After a median follow-up of 2 years, both doses of dabigatran proved noninferior to warfarin with regard to the primary endpoint of stroke or systemic embolism, with the higher dose showing superiority over warfarin. Based on RE-LY, dabigatran (Pradaxa, Boehringer-Ingelheim, Ridgefield, CT) 150 mg was approved by the US Food and Drug Administration for stroke risk reduction in patients with nonvalvular A-fib.

For the subanalysis, researchers led by Ziad Hijazi, MD, PhD, of Uppsala Clinical Research Center (Uppsala, Sweden), looked at glomerular filtration rate (GFR) in all patients with available creatinine at baseline (n = 17,951). Estimated GFR (eGFR) was calculated using the Cockcroft-Gault and new CKD-EPI equations and patients were stratified into 3 categories:

• No impairment: eGFR ≥ 80 ml/min (32.6% by Cockcroft-Gault; 21.6% by CKD-EPI)
• Mild impairment: eGFR 50 to < 80 ml/min (47.6% by Cockcroft-Gault; 59.6% by CKD-EPI)
• Moderate-severe impairment: eGFR < 50 ml/min (19.8% by Cockcroft-Gault; 18.8% by CKD-EPI)

Events Increase With Declining Renal Function

Overall, rates of stroke or systemic embolism (primary endpoint), major and intracranial bleeding, all-cause mortality, and net clinical outcome (stroke, systemic embolism, pulmonary embolism, MI, death, or major bleeding) increased as renal function decreased (table 1).

Table 1. Clinical Outcomes by Cockcroft-Gault eGFR

The rates of the primary endpoint were lower with dabigatran 150 mg and similar with 110 mg compared with warfarin without heterogeneity in subgroups defined by renal function (P for interaction > 0.1 for all).

Based on the Cockcroft-Gault equation, dabigatran 110 mg was associated with less major bleeding across the entire range of renal function (P for interaction = 0.0607). However, the CKD-EPI equation showed an interaction with renal function with a greater relative reduction in major bleeding with dabigatran 110 mg compared with warfarin in patients with no impairment (HR 0.41; 95% CI 0.27-0.62; P for interaction = 0.0012).

Regarding dabigatran 150 mg, there was no difference in major bleeds across renal function groups according to the Cockcroft-Gault equation, but the CKD-EPI equation showed less major bleeds with the novel anticoagulant vs. warfarin in patients with no renal impairment (HR 0.59; 95% CI 0.41-0.84; P for interaction = 0.005).

Irrespective of the level of renal function, dabigatran 110 mg had a similar net clinical benefit relative to warfarin using both equations. Dabigatran 150 mg was associated with fewer events without significant interaction by renal function using Cockcroft-Gault. However, the CKD-EPI equation demonstrated significant interaction for renal function with a greater relative reduction in net clinical outcomes using this dose compared with warfarin in patients with no impairment (HR 0.71; 95% CI 0.56-0.90; P for interaction = 0.0371).

Dose Tailoring Possible

“This study overall shows that it is possible to achieve effective and safe oral anticoagulation with dabigatran in a randomized and fully powered dose-comparison against warfarin without prespecified dose-reductions as was assigned in the ROCKET-AF and ARISTOTLE trials,” Dr. Hijazi and colleagues write. “For stroke prevention in [A-fib], dabigatran 150 mg [twice daily] is generally recommended over dabigatran 110 mg [twice daily] due to the superiority in reduction of ischemic and hemorrhagic strokes relative to warfarin as well as the superiority in net clinical benefit outcomes. However, by using information regarding age and eGFR, it seems feasible to attain a dose tailoring of dabigatran in special situations such as in patients with higher bleeding risk.”

Additionally, the results suggest that using the CKD-EPI equation “provides important and clinically useful information in regards to assessing renal function and tailoring oral anticoagulation in [A-fib],” they write.

Note: Study coauthor Michael D. Ezekowitz, MD, PhD, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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Source:
Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: A RE-LY trial analysis. Circulation. 2013;Epub ahead of print.

 

 

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