Could Genetics Improve Warfarin Dosing?
New Research Says Yes — Now for the Clinical Trial
In a large-scale study and an upcoming clinical trial, scientists
supported by the National Institutes of Health address one of the
trickiest issues in prescribing medicine — how to quickly
optimize each patient’s dosage of the common blood-thinning drug
warfarin.
One of the most widely prescribed drugs in the world, warfarin
is used to prevent dangerous blood clots that can lead to heart
attacks, strokes or even death. The drug is challenging for doctors
to prescribe because the ideal dosage for each person varies widely
and is hard to predict, yet is crucial for the patient’s safety.
Every year, an estimated 2 million Americans with certain heart
conditions or other risk factors start taking warfarin. Getting
the wrong amount of warfarin can be dangerous — if the dose
is too high, patients could bleed profusely; if it’s too low, they
could develop life — threatening clots.
Using information from thousands of genetically and geographically
diverse patients, an international team of researchers developed
a way to use genetic information from patients that could help
doctors better determine optimal warfarin doses. The results of
the analysis are published in an article titled " Warfarin
Dosing Using Clinical and Pharmacogenetic Data " in the Feb.
19 issue of The New England Journal of Medicine.
The article is accompanied by an editorial by Janet Woodcock and
Lawrence Lesko of the Center for Drug Evaluation and Research at
the Food and Drug Administration.
In an important step toward putting these findings into clinical
practice, NIH is launching the largest prospective, multi-center,
randomized clinical trial in the United States to test whether
a gene-based strategy for prescribing the initial warfarin dose
will improve patient outcomes. The clinical trial will use a dosing
strategy similar to that developed in the international study.
The trial will enroll 1,200 participants of diverse backgrounds
and ethnicities at twelve clinical sites, and is scheduled to begin
next month.
"In these investigations, NIH-funded basic research and
clinical trials are working hand in hand to improve the care of
the millions of patients on warfarin therapy, " said Raynard
S. Kington, M.D., Ph.D., acting NIH director. "More broadly, these
efforts showcase NIH’s firm commitment to building a future of
personalized medicine — a future in which doctors will be
able to prescribe the optimal dosage of medicine for each patient
right from the start."
Scientists Join to Address the Warfarin Problem
Each person responds differently to warfarin. One person may need
10 times more of the drug than another, so it’s challenging to
figure out where to start. Doctors typically select the initial
dose based on standard clinical factors — such as age, weight
and gender — then fine tune the dosage over a few weeks in
response to periodic tests of the blood’s ability to clot.
In 2007, the FDA worked with the makers of warfarin drug products
to modify the product label to indicate that a patient’s genetic
makeup may affect how he or she responds to the drug. Researchers
know that two genes, CYP2C9 and VKORC1, which vary slightly among
different individuals, can influence warfarin’s effectiveness.
However, scientists do not know whether information about these
genes can improve optimal dosage prediction for a wide range of
patients, regardless of race, ethnicity or other genetic differences.
To investigate this issue, researchers from more than 20 teams
in nine countries on four continents voluntarily joined to form
the International Warfarin Pharmacogenetics Consortium (IWPC).
The consortium was spearheaded by scientists involved in the NIH
Pharmacogenetics Research Network and PharmGKB (http://www.pharmgkb.org),
an online pharmacogenomics resource where data from the study is
now freely available to scientists.
By pooling their data, the consortium members had access to anonymized
information from about 5,700 people on stable dosages of warfarin.
The patients came from around the globe, including Taiwan, Japan,
Korea, Singapore, Sweden, Israel, Brazil, Britain and the United
States. This kind of study—one that includes a large, diverse data
set—is essential to draw conclusions that are applicable to a wide
range of patients.
For each patient, the data included demographic information like
age, gender and race; CYP2C9 and VKORC1 variants; and initial,
as well as optimized, warfarin dosages.
The scientists calculated warfarin dosages in three ways — one
that relied on the standard, clinical information, one that included
additional information about individual patient variation in CYP2C9
and VKORC1, and one that used a fixed dose per day. Then they checked
how closely their computational predictions matched the actual,
clinically derived stable warfarin dosage for each patient.
The results revealed that when genetic information was included,
the predictions of ideal dosages were more accurate, especially
for patients at the low or high ends of the dosing range. This
is meaningful because nearly half of those on warfarin are at the
extremes of the range, and these patients are typically at the
greatest risk for excessive bleeding or clotting. By quickly optimizing
dosages for these patients, doctors could minimize dangerous complications
and improve the effectiveness and safety of warfarin treatment.
"By sharing information and expertise, the consortium researchers
developed a way to dose warfarin that is based on data from patients
around the world," said Jeremy M. Berg, Ph.D., director of
the National Institute of General Medical Sciences (NIGMS), which
supported the study. "This is a highly commendable example
of international cooperation and data sharing and should increase
the potential utility of the results."
In addition to NIGMS, the following NIH components supported the
consortium’s research: the National Heart, Lung, and Blood Institute
(NHLBI), the National Institute of Neurological Disorders and Stroke
(NINDS), and the National Center for Research Resources (NCRR).
Moving from the Computer to the Clinic
Although genetic tests are now available for doctors to use to
help determine the initial dose of warfarin, a large, randomized
clinical trial — the gold standard for testing medical therapies — is
needed to determine if the more precise, gene-based prescribing
strategy is the best option.
"With growing evidence on how certain genes affect the way
individual patients respond to warfarin, we are now ready to move
forward with a major clinical trial to test these strategies in
patients who are starting warfarin therapy," said Elizabeth
G. Nabel, M.D., director of NHLBI, which is supporting the new
study.
Called Clarification of Optimal Anticoagulation through Genetics
(COAG), the new clinical trial will test two approaches to determining
the initial dose of warfarin in patients who are expected to need
therapy for three months or longer. The trial will be conducted
at 12 sites, with one site each in California, Florida, Maryland,
Michigan, Minnesota, Missouri, New York, Pennsylvania, Tennessee,
Texas, Utah and Wisconsin. The COAG Coordinating Center is at the
University of Pennsylvania School of Medicine.
COAG researchers will apply prescribing strategies for initial
dosing similar to those used in the IWPC analysis. About one-half
of the participants will be randomly selected to have their initial
dose determined by clinical information alone. For the other half
of the participants, the initial dose will be determined by using
the clinical factors as well as information about the participant's
genetic makeup, specifically his or her variants of the CYP2C9
and VKORC1 genes. All participants will be monitored for six months.
"The COAG study will provide important evidence to determine
if genetic information gives added benefit for determining initial
warfarin doses above and beyond what can be obtained with clinical
information," added Nabel.
Researchers will assess how long participants in each group maintain
the desired level of blood thinning, as determined by a blood test,
at two and four weeks after starting therapy, as well as at three
and six months. Researchers will also review bleeding problems
and other complications, quality of life and cost of therapy.
"This new body of research and the prospective clinical trial
that will soon be launched by NIH builds on the warfarin labeling
changes that FDA put in place in 2007 to reduce the number of adverse
events associated with this dose-sensitive drug," said Frank
M. Torti, M.D., acting commissioner of Food and Drugs. "The
NIH research is precisely what is needed to advance the promise
of personalized medicine, ensuring that patients receive the safest
and most effective drug dose."
The COAG trial is supported by NHLBI, with additional funding
for genome analyses from the National Human Genome Research Institute
(NHGRI). Warfarin will be donated by Bristol-Myers Squibb, New
York City. The COAG trial is also working with the Critical Path
Institute, an independent, non-profit organization that fosters
partnerships between academia, government and the healthcare industry.
Further information about this trial (NCT00839657) can be found
at http://www.clinicaltrials.gov/ct2/show/NCT00839657.
To arrange an interview about the IWPC research study with NIGMS
director Jeremy M. Berg, Ph.D., contact the NIGMS Office of Communications
and Public Liaison at 301-496-7301 or info@nigms.nih.gov.
To arrange an interview about the COAG clinical trial with NHLBI
director Elizabeth G. Nabel, M.D., or other NHLBI spokespeople,
contact the NHLBI Communications Office at 301-496-4236 or at nhlbi_news@nhlbi.nih.gov.
NINDS (www.ninds.nih.gov)
is the nation’s primary supporter of biomedical research on the
brain and nervous system. For more information about stroke prevention
and treatment, see www.stroke.nih.gov.
NCRR, a part of NIH, provides laboratory scientists and clinical
researchers with the resources and training they need to understand,
detect, treat and prevent a wide range of diseases. NCRR supports
all aspects of translational and clinical research, connecting
researchers, patients and communities across the nation. For more
information, visit www.ncrr.nih.gov.
NHGRI supports grants for research and for training and career
development at sites nationwide. Additional information about NHGRI
can be found at its Web site, www.genome.gov.
NHLBI plans, conducts, and supports research related to the causes,
prevention, diagnosis and treatment of heart, blood vessel, lung
and blood diseases; and sleep disorders. The Institute also administers
national health education campaigns on women and heart disease,
healthy weight for children, and other topics. NHLBI press releases
and other materials are available online at www.nhlbi.nih.gov.
NIGMS is a part of NIH that supports basic research to increase
our understanding of life processes and lay the foundation for
advances in disease diagnosis, treatment and prevention. For more
information on the Institute's research and training programs,
see www.nigms.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov. |