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Warfarin tablets Photo from Intermountain Medical Center
Warfarin tablets
Photo from Intermountain
Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 – 0.95). The relative rate was 0.24 (95% CI, 0.05 – 1.14) for major bleeding, 0.71 (95% CI, 0.51 – 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 – 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said. ht-logo-end


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