Blood thinners, or anticoagulants, are often prescribed to help prevent blood clots that can lead to pulmonary embolism, heart attack, and stroke. Though effective at preventing these clots, warfarin can cause life-threatening bleeds. Warfarin has led to more emergency room visits for older people over the last decade than any other medication. This is because it can be difficult for doctors to determine the right dose.
When a patient first starts warfarin, doctors usually choose the dose based on clinical information, such as a patient’s age and weight. They then adjust that dose as needed based on blood testing. However, this trial-and-error dosing can be dangerous. Too much warfarin can cause excess bleeding; too little may not prevent dangerous blood clots.
A team of scientists led by Dr. Brian F. Gage at Washington University in St. Louis investigated whether genetic testing can help predict the best warfarin dose to give a patient. They compared outcomes for patients whose initial doses were based on clinical information alone to those whose initial doses were based on their genetic makeup (genotype) along with clinical factors. The trial was funded primarily by NIH’s National Heart, Lung, and Blood Institute (NHLBI). Results appeared in the Journal of the American Medical Association on September 26, 2017.
Patients who were starting warfarin after elective hip or knee replacement at six medical centers across the US were recruited to participate. They were randomly assigned to have warfarin prescribed based on either clinical information alone (819 patients) or based on clinical information plus genotype (831 patients). All participants were at least 65 years old; 63.6% were women; and 91% were white.
The researchers collected blood samples from the patients and screened for genetic differences in the genes VKORC1, CYP2C9, and CYP4F2, which are related to blood clotting and warfarin metabolism or sensitivity. Doctors monitored each group and adjusted the warfarin dosage to reach a target blood thinning level over 11 days. Warfarin was continued for 35 days. Adverse events were tracked for 90 days, including major bleeding, deep vein thrombosis, and pulmonary embolism.
There were fewer adverse events in the genotype-guided dosing group: 87 events, or 10.8% of the genetic group, vs. 116 events, or 14.7% of the clinically guided group. No patient died during the study.
“Warfarin is very effective in preventing blood clots, but it’s very difficult to regulate,” explains Dr. Anne R. Bass, a study co-author at Hospital for Special Surgery in New York City. “About half of the population, because of genetic variants, is very sensitive to warfarin or has a very unpredictable or delayed response to the drug. This is the first study to show that adjusting the dose based on these genetic variants makes warfarin safer for patients.”
“Although genetic testing is more expensive than clinical dosing, the cost is falling,” Gage says. “In our study, we estimated that genetic testing costs less than $200 per person, which is less than one month of a newer anticoagulant.”
A previous study didn’t find genotyping improved warfarin dosing. That study used two of these genes and was done in a group that was 27% African-American. More work is needed to investigate how genetic variants can help guide dosing in different populations.