Genetics and the clinical response to warfarin and edoxaban: findings from the
randomised, double-blind ENGAGE AF-TIMI 48 trial.
Author(s): Mega JL(1), Walker JR(2), Ruff CT(3), Vandell AG(4), Nordio F(3), Deenadayalu
N(3), Murphy SA(3), Lee J(4), Mercuri MF(4), Giugliano RP(3), Antman EM(3),
Braunwald E(3), Sabatine MS(5).
Affiliation(s): Author information:
(1)TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:
jmega@partners.org. (2)Celgene Corporation, Summit, NJ, USA. (3)TIMI Study Group,
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA, USA. (4)Daiichi Sankyo Pharma Development, Edison,
NJ, USA. (5)TIMI Study Group, Division of Cardiovascular Medicine, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:
msabatine@partners.org.
Publication date & source: 2015, Lancet. , 385(9984):2280-7
BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but
serious bleeding complications are common. We tested whether genetic variants can
identify patients who are at increased risk of bleeding with warfarin and,
consequently, those who would derive a greater safety benefit with a direct oral
anticoagulant rather than warfarin.
METHODS: ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients
with atrial fibrillation were assigned to warfarin to achieve a target
international normalised ratio of 2·0-3·0, or to higher-dose (60 mg) or
lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a
prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1.
The results were used to create three genotype functional bins (normal,
sensitive, and highly sensitive responders to warfarin). This trial is registered
with ClinicalTrials.gov, number NCT00781391.
FINDINGS: 14,348 patients were included in the genetic analysis. Of 4833 taking
warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as
sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared
with normal responders, sensitive and highly sensitive responders spent greater
proportions of time over-anticoagulated in the first 90 days of treatment (median
2·2%, IQR 0-20·2; 8·4%, 0-25·8; and 18·3%, 0-32·6; ptrend<0·0001) and had
increased risks of bleeding with warfarin (sensitive responders hazard ratio
1·31, 95% CI 1·05-1·64, p=0·0179; highly sensitive responders 2·66, 1·69-4·19,
p<0·0001). Genotype added independent information beyond clinical risk scoring.
During the first 90 days, when compared with warfarin, treatment with edoxaban
reduced bleeding more so in sensitive and highly sensitive responders than in
normal responders (higher-dose edoxaban pinteraction=0·0066; lower-dose edoxaban
pinteraction=0·0036). After 90 days, the reduction in bleeding risk with edoxaban
versus warfarin was similarly beneficial across genotypes.
INTERPRETATION: CYP2C9 and VKORC1 genotypes identify patients who are more likely
to experience early bleeding with warfarin and who derive a greater early safety
benefit from edoxaban compared with warfarin.
FUNDING: Daiichi Sankyo.
|
