Genetic Testing Improves Warfarin Dosing But Not
Optimal Dose in Second Study
Predicting right dose of warfarin for older patient
can be tricky; two studies of genetics use in warfarin therapy presented
at American Heart Association’s Scientific Session; patients with atrial fibrillation, venous
thromboembolism, and in second study stroke history
Nov. 19, 2013 — Obtaining genetic information before starting warfarin
therapy helped patients increase the effectiveness of treatment while
reducing the risk of over-anticoagulation and improper dosing in a
late-breaking clinical trial presented at the American Heart
Association’s Scientific Sessions 2013. Another study presented,
however, found genetics did not prove useful in predicting optimal doses
Helpful Before Warfarin Therapy
In a study conducted in Europe, genetic testing before beginning
warfarin therapy helped patients increase their time in
therapeutic range by 7 percent while reducing the need for
warfarin dose adjustments.
“We found that genotyping before starting warfarin
increased the time in therapeutic range by approximately 7 percent,
reduced over-anticoagulation, reduced the time required to reach
therapeutic range, improved the time required to reach stable dose and
reduced the number of
warfarin dose adjustments,” said
Munir Pirmohamed, M.D., Ph.D., lead author of the study and NHS Chair of
Pharmacogenetics at the University of Liverpool in the United Kingdom.
The EU Pharmacogenetics of Anticoagulant Therapy
(EU-PACT) Warfarin Study of 454 patients in Europe compared using
genetic tests to guide warfarin dosing with traditional methods, which
involves patients undergoing frequent blood testing to gauge whether
their warfarin levels are too high or too low.
The majority of patients were white, average age
67 years, 61 percent were male, 72 percent had atrial fibrillation
and the other patients had venous thromboembolism. All patients were
followed for three months, and were checked at days four, six, eight,
15, 22, 57 and 85 of the study. Adjustments to the patients' warfarin
doses were either based on genetic results or standard blood testing to
decide whether warfarin levels were too high, too low or just right.
Although warfarin has been approved for decades,
there is a lot of variability as to how patients will respond to
warfarin. Additionally, finding the right dosage can be difficult — too
little warfarin can lead to blood clots and too much can cause bleeding.
Researchers specifically looked for two genes
associated with the clotting process.
“Our study very much fits in with the concept of
personalized medicine, which aims to get the right drug, at the right
dose to the right patient,” Pirmohamed said.
“There is huge potential in the cardiovascular
field for personalizing therapy on the basis of genetic or non-genetic
tests,” he said. “For genetic testing, in some cases it may be possible
to undertake the testing at the bedside or in surgery, so called
point-of-care tests as we did in this trial. We need evidence from
randomized controlled trials to show the utility of genetic testing.”
Co-authors are Girvan Burnside; Jenni Stoddern;
Clare Prince; Cheng Hok Toh; Toby Nicholson; Patrick. Kesteven; Andrea
Jorgensen; Anne Daly; Anke-Hilse Maitland-van der Zee; Paula Williamson;
Niclas Eriksson; Peter Avery; Farhad Kamali and Mia Wadelius for the
EU-FP7 Programme funded the study.
to Take Guesswork Out of Warfarin Dosing
Genetic testing did not prove useful in improving blood
thinning control in patients on warfarin.
Both the group undergoing genetic testing and the standard
dosing group were within the appropriate therapeutic range —
meaning that the blood thinning was within the desired level
— 45 percent of the time.
Genetics did not prove useful in predicting optimal
doses of warfarin for patients in a late second late breaking
clinical trial presented at the American Heart Association’s Scientific
In the Clarification of Optimal Anticoagulation
through Genetics (COAG) trial, researchers divided 1,015 patients with
histories of stroke, venous thrombosis and atrial fibrillation, who took
the common blood-thinning drug warfarin into two groups.
Clinical information, such as age, weight, and
smoking status, was used for one group to measure how much warfarin they
would need while the second group used similar clinical information plus
During this multi-center, randomized,
double-blinded, controlled study, all patients received warfarin, but
one group received therapy based on clinical information, while the
other group received therapy guided by their genetic information. Each
group received an initial warfarin dose, and then four to five days
later, adjustments were made to their doses based on either genetic
information or standard clinical information.
Patients were followed for up to six months from
Regardless of whether or not genetic information
was used, the two groups of patients showed no significant differences
in outcomes; both groups were within the appropriate therapeutic range —
meaning that the blood thinning was within the desired range — 45
percent of the time over the first four weeks. In an additional finding
among African Americans, those receiving therapy based on genetics
didn’t do as well as those who did not use genetics.
Patients’ average age was 57 years; 51
percent were male; 27 percent were African American; 22 percent had
atrial fibrillation, and 58 percent had deep vein thrombosis in the legs
“This study demonstrates that until you do a
clinical trial, you really don't know what the answer is going to be,"
said Stephen Kimmel, M.D., lead study author and a professor of medicine
and epidemiology at the University of Pennsylvania School of Medicine.
"There's a lot of debate about when to bring
genetics into clinical practice, and whether or not you need clinical
trials before widely using genetics. For a drug as complex as warfarin,
the COAG trial demonstrates the utility of performing such trials.”
Predicting the right dose of warfarin for the
individual patient can be tricky; too much can lead to internal bleeding
and too little can lead to blood clots, some of which can be
life-threatening. Patients taking warfarin have to undergo frequent
monitoring to see whether their doses need to be changed. Identifying
certain genetic markers from a patient's blood sample is suggested to
help improve the initial dosing of warfarin and smooth out the many dose
changes often required during monitoring.
One gene is responsible for how warfarin is
metabolized by the liver. The other gene is about how the body responds
to warfarin. Identifying one or both of these two genes in a patient's
blood sample has been suggested to help physicians prescribe more
specific warfarin doses that better align with the patient's unique
The National Heart, Lung, and Blood Institute
funded the study. GenMark Diagnostics and AutoGenomics Inc. loaned
genotype platforms to the study and Bristol-Meyers Squibb donated the
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