Using genetic testing to help personalize doses of warfarin therapy given to patients undergoing elective orthopedic surgery appears to lower the risk of combined adverse events compared with clinically-guided dosing, according to research presented by Brian F. Gage, MD, MSc, on March 18 at ACC.17 in Washington, DC. This is the first trial to quantify the benefit of pharmacogenetic dosing of warfarin on clinical events.

In the Genetic InFormatics Trial (GIFT) of warfarin therapy to prevent deep venous thrombosis (DVT), 1,597 participants aged 65 years or older undergoing elective knee or hip replacement surgery were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors) by the algorithms; they were also randomly assigned to a target 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 participants randomized to genotype-guided dosing. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

The rate of adverse events was 14.7 percent in the clinical arm and 10.8 percent in the genotype-guided arm, a 27 percent relative risk reduction. There was a significant reduction in INR values ≥ 4: from 9.8 percent in the clinical arm to 6.9 percent with genotype-guided dosing. However, in looking at the events, there was no significant reduction in DVT/pulmonary embolism or major bleeds between the two groups.

According to the researchers, the clinical dosing used in this trial was likely better than standard dosing because it 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. The trial also showed a statistically significant improvement in INR control, the study's secondary endpoint, among patients whose warfarin dose was determined based on genetic information in addition to clinical factors. Researchers said these findings could have implications for a broad population of patients starting warfarin therapy. They hope that genetic and clinical dosing algorithms will be integrated within electronic medical records.

"The GIFT trial is an example of personalized medicine," Gage said. "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. This approach is especially important for older patients. Warfarin is the medication that is most likely to cause elderly patients to go to the emergency room."

"It is disappointing that clinical events were not lowered by the intervention," said Kim A. Eagle, MD, MACC, editor-in-chief of ACC.org. "Until genetic-based management is shown to really impact patient outcomes, the cost of routine genetic testing is questionable."

Keywords: ACC17, ACC Annual Scientific Session, Arrhythmias, Cardiac, Algorithms, Arthroplasty, Replacement, Knee, Confidence Intervals, Genotype, Hemorrhage, International Normalized Ratio, Lower Extremity, Pharmacogenetics, Ultrasonography, Doppler, Venous Thromboembolism, Venous Thrombosis, Warfarin

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