Analyses Signal NOAC Benefit in Uncharted AF Populations

Patrice Wendling

March 08, 2017

BOSTON, MA — Edoxaban (Savaysa, Daiichi-Sankyo) may be a good alternative to warfarin in individuals with atrial fibrillation (AF) and bioprosthetic valves, a new analysis of the ENGAGE AF-TIMI 48 trial suggests[1].

The prespecified subgroup analysis includes just 0.9% of the 21,105 patients enrolled in the pivotal trial but is reportedly the largest prospective, randomized comparison of a novel oral anticoagulant (NOAC) with warfarin in this high-risk population, in whom current guidelines recommend against NOAC therapy due to a lack of data.

A second study, a new meta-analysis of randomized trial data[2], also supports the use of NOACs in AF patients with valvular heart disease (VHD) other than hemodynamically significant mitral stenosis and mechanical valves.

Biosynthetic Valves in ENGAGE AF-TIMI 48

As previously reported by heartwire , edoxaban at either of two dosages (60 mg and 30 mg) was shown in ENGAGE AF-TIMI 48 to be noninferior to warfarin for preventing stroke or systemic embolism but with significantly less overall risk of bleeding. Patients with mechanical valves or moderate-severe mitral stenosis were excluded.

Now with 2.8 years of follow-up in 191 bioprosthetic-valve patients, those treated with higher-dose edoxaban had similar rates of stroke or systemic embolism (hazard ratio [HR] 0.37, 95% CI 0.10–1.42; P=0.15) and major bleeding (HR 0.50, 95% CI 0.15–1.67; P=0.26) compared with warfarin.

Patients treated with lower-dose edoxaban, however, had similar rates of stroke/systemic embolism (HR 0.53, 95% CI 0.16–1.78; P=0.31) but lower rates of major bleeding, at 0.76% per year vs 6.27% per year with warfarin (HR 0.12, 95% CI 0.01–0.95; P=0.045).

Rates of the primary net clinical outcome of stroke/systemic embolism, major bleeding, or death were lower in both edoxaban groups than the warfarin group.

Finally, the rate of major adverse coronary events was more than halved in bioprosthetic-valve patients, from 11.07% per year with warfarin to 4.32% per year with higher-dose edoxaban (HR 0.36, 95% CI 0.15–0.87; P=0.03) but was similar between lower-dose edoxaban and warfarin (HR 0.64, 95% CI 0.30–1.35).

"Our analysis suggests that edoxaban appears to be a reasonable alternative to warfarin in patients with AF and remote bioprosthetic-valve implantation," lead author Dr Anthony Carnicelli (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) and colleagues write in the study, published recently in Circulation.

Meta-analysis Backs Benefit in VHD

The meta-analysis used data from secondary analyses of the ENGAGE AF-TIMI 48, ARISTOLE, RE-LY, and ROCKET-AF trials to examine the safety and efficacy of the NOAC drugs apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), dabigatran (Pradaxa, Boehringer Ingelheim), edoxaban, and rivaroxaban (Xarelto, Bayer/Johnson & Johnson) in AF patients with VHD other than hemodynamically significant mitral stenosis and mechanical valves.

Limited data exist specifically for this population, and many clinicians are hesitant to prescribe NOACs in patients with some degree of VHD, lead author Dr Konstantinos Siontis (Mayo Clinic, Rochester, MN) and colleagues write in a research letter, published in the February 14, 2017 issue of Circulation.

Among the 58,497 patients analyzed, the NOACs, also known as direct oral anticoagulants (DOACs), lowered the risk of stroke/systemic embolism compared with warfarin in patients with VHD (HR 0.70, 95% CI 0.58–0.86) and without VHD (HR 0.84, 95% CI 0.75–0.95).

The effect of the two drugs was similar in the two subgroups for major bleeding (P=0.11 for interaction), although a high level of treatment effect heterogeneity (I2>70%) was discovered. This finding was likely driven by increased bleeding rates with rivaroxaban in the VHD subgroup and decreased bleeding with apixaban in the non-VHD subgroup, the investigators suggest.

In other limitations, they note that the meta-analysis did not include individual patient data and may be subject to between-study variations in VHD definition, anticoagulation practices, outcome definition, and adjudication.

Still, the investigators conclude, "Our study provides evidence in support of the notion that the presence of VHD, aside from hemodynamically significant mitral stenosis and mechanical valves, should not preclude the use of DOACs. Their effectiveness and safety profile suggests they may be considered as first-line agents in patients with or without VHD."

ENGAGE AF-TIMI 48 was supported by a research grant from Daiichi Sankyo to Brigham and Women's Hospital. Carnicelli reported no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Siontis reported no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

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