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An analysis of data from the ENGAGE AF-TIMI 48 trial has shown that patients with a genetic sensitivity to warfarin had higher rates of bleeding during the first several months of treatment and benefitted from treatment with a different anticoagulant.
The research, published in The Lancet, suggests that using genetic analyses to identify patients who are most at risk of bleeding with warfarin could offer safety benefits, particularly in the first 90 days of treatment.
“We were able to look at patients from around the world who were being treated with warfarin and found that certain genetic variants make a difference for an individual’s risk for bleeding,” said study author Jessica L. Mega, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“For these patients who are sensitive or highly sensitive responders based on genetics, we observed a higher risk of bleeding in the first several months with warfarin, and consequently, a big reduction in bleeding when treated with the drug edoxaban instead of warfarin.”
The FDA label for warfarin notes that genetic variants in 2 genes—CYP2C9 and VKORC1—can assist in determining the right warfarin dosage. But a conclusive link between variation in these genes and bleeding has been debated.
By leveraging data from the ENGAGE AF-TIMI 48 trial—in which patients with atrial fibrillation received warfarin or 2 different doses of edoxaban—investigators were able to observe connections between genetic differences and patient outcomes.
A subgroup of patients was genotyped for variants in CYP2C9 and VKORC1, and the results were used to identify normal responders, sensitive responders, and highly sensitive responders to warfarin.
Dr Mega and her colleagues looked at data from 14,348 patients. Of the 4833 patients taking warfarin, 61.7% were normal responders, 35.4% were sensitive responders, and 9.2% were highly sensitive responders.
In the first 90 days of treatment, normal responders were over-anticoagulated a median of 2.2% of the time, compared to 8.4% of the time for sensitive responders, and 18.3% of the time for highly sensitive responders (Ptrend<0.0001).
Both sensitive and highly sensitive responders also had an increased risk of bleeding in the first 90 days when compared to normal responders. The hazard ratios were 1.31 for sensitive responders (P=0.0179) and 2.66 for highly sensitive responders (P<0.0001).
As a result, during the first 90 days, edoxaban was more effective than warfarin at reducing bleeding in sensitive and highly sensitive responders.
Compared with warfarin, both the higher and lower doses of edoxaban reduced bleeding more in sensitive and highly sensitive responders than in normal responders (Pinteraction=0.0066 and 0.0036 for the higher and lower doses, respectively).
“These findings demonstrate the power of genetics in personalizing medicine and tailoring specific therapies for our patients,” said Marc S. Sabatine, MD, also of Brigham and Women’s Hospital.
The ENGAGE AF-TIMI 48 trial was supported by research grants from Daiichi Sankyo, makers of edoxaban. 
An analysis of data from the ENGAGE AF-TIMI 48 trial has shown that patients with a genetic sensitivity to warfarin had higher rates of bleeding during the first several months of treatment and benefitted from treatment with a different anticoagulant.
The research, published in The Lancet, suggests that using genetic analyses to identify patients who are most at risk of bleeding with warfarin could offer safety benefits, particularly in the first 90 days of treatment.
“We were able to look at patients from around the world who were being treated with warfarin and found that certain genetic variants make a difference for an individual’s risk for bleeding,” said study author Jessica L. Mega, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“For these patients who are sensitive or highly sensitive responders based on genetics, we observed a higher risk of bleeding in the first several months with warfarin, and consequently, a big reduction in bleeding when treated with the drug edoxaban instead of warfarin.”
The FDA label for warfarin notes that genetic variants in 2 genes—CYP2C9 and VKORC1—can assist in determining the right warfarin dosage. But a conclusive link between variation in these genes and bleeding has been debated.
By leveraging data from the ENGAGE AF-TIMI 48 trial—in which patients with atrial fibrillation received warfarin or 2 different doses of edoxaban—investigators were able to observe connections between genetic differences and patient outcomes.
A subgroup of patients was genotyped for variants in CYP2C9 and VKORC1, and the results were used to identify normal responders, sensitive responders, and highly sensitive responders to warfarin.
Dr Mega and her colleagues looked at data from 14,348 patients. Of the 4833 patients taking warfarin, 61.7% were normal responders, 35.4% were sensitive responders, and 9.2% were highly sensitive responders.
In the first 90 days of treatment, normal responders were over-anticoagulated a median of 2.2% of the time, compared to 8.4% of the time for sensitive responders, and 18.3% of the time for highly sensitive responders (Ptrend<0.0001).
Both sensitive and highly sensitive responders also had an increased risk of bleeding in the first 90 days when compared to normal responders. The hazard ratios were 1.31 for sensitive responders (P=0.0179) and 2.66 for highly sensitive responders (P<0.0001).
As a result, during the first 90 days, edoxaban was more effective than warfarin at reducing bleeding in sensitive and highly sensitive responders.
Compared with warfarin, both the higher and lower doses of edoxaban reduced bleeding more in sensitive and highly sensitive responders than in normal responders (Pinteraction=0.0066 and 0.0036 for the higher and lower doses, respectively).
“These findings demonstrate the power of genetics in personalizing medicine and tailoring specific therapies for our patients,” said Marc S. Sabatine, MD, also of Brigham and Women’s Hospital.
The ENGAGE AF-TIMI 48 trial was supported by research grants from Daiichi Sankyo, makers of edoxaban.
An analysis of data from the ENGAGE AF-TIMI 48 trial has shown that patients with a genetic sensitivity to warfarin had higher rates of bleeding during the first several months of treatment and benefitted from treatment with a different anticoagulant.
The research, published in The Lancet, suggests that using genetic analyses to identify patients who are most at risk of bleeding with warfarin could offer safety benefits, particularly in the first 90 days of treatment.
“We were able to look at patients from around the world who were being treated with warfarin and found that certain genetic variants make a difference for an individual’s risk for bleeding,” said study author Jessica L. Mega, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“For these patients who are sensitive or highly sensitive responders based on genetics, we observed a higher risk of bleeding in the first several months with warfarin, and consequently, a big reduction in bleeding when treated with the drug edoxaban instead of warfarin.”
The FDA label for warfarin notes that genetic variants in 2 genes—CYP2C9 and VKORC1—can assist in determining the right warfarin dosage. But a conclusive link between variation in these genes and bleeding has been debated.
By leveraging data from the ENGAGE AF-TIMI 48 trial—in which patients with atrial fibrillation received warfarin or 2 different doses of edoxaban—investigators were able to observe connections between genetic differences and patient outcomes.
A subgroup of patients was genotyped for variants in CYP2C9 and VKORC1, and the results were used to identify normal responders, sensitive responders, and highly sensitive responders to warfarin.
Dr Mega and her colleagues looked at data from 14,348 patients. Of the 4833 patients taking warfarin, 61.7% were normal responders, 35.4% were sensitive responders, and 9.2% were highly sensitive responders.
In the first 90 days of treatment, normal responders were over-anticoagulated a median of 2.2% of the time, compared to 8.4% of the time for sensitive responders, and 18.3% of the time for highly sensitive responders (Ptrend<0.0001).
Both sensitive and highly sensitive responders also had an increased risk of bleeding in the first 90 days when compared to normal responders. The hazard ratios were 1.31 for sensitive responders (P=0.0179) and 2.66 for highly sensitive responders (P<0.0001).
As a result, during the first 90 days, edoxaban was more effective than warfarin at reducing bleeding in sensitive and highly sensitive responders.
Compared with warfarin, both the higher and lower doses of edoxaban reduced bleeding more in sensitive and highly sensitive responders than in normal responders (Pinteraction=0.0066 and 0.0036 for the higher and lower doses, respectively).
“These findings demonstrate the power of genetics in personalizing medicine and tailoring specific therapies for our patients,” said Marc S. Sabatine, MD, also of Brigham and Women’s Hospital.
The ENGAGE AF-TIMI 48 trial was supported by research grants from Daiichi Sankyo, makers of edoxaban.