Using genetics to inform prescription of warfarin and thereby enhance patient safety
Submitting InstitutionNewcastle University
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Warfarin is an anti-coagulant drug prescribed to tens of millions of
people in the UK and US who are at high risk of developing blood clots.
Because individual sensitivity to warfarin varies in the population there
is a risk of overdosing the drug and causing serious bleeding and even
stroke in many people when starting treatment. In 1999 researchers at
Newcastle University were the first to demonstrate a statistically
significant link between a person's genotype and the appropriate dose of
warfarin. In 2010 the US Food and Drug Administration (FDA) mandated
inclusion of a table of dose recommendations based on genotype in the
warfarin prescribing information leaflet accompanying the drug. Newcastle
research forms the basis of the 2009 international standard algorithm for
gene-guided dosing of warfarin. This approach has been adopted by large US
medical centres and the FDA states that it will prevent 17,000 strokes a
year in the US.
Key Newcastle University researchers
At the time of the research Professors Ann Daly and Farhad Kamali were
both Senior Lecturers in the Department of Pharmacological Sciences.
Warfarin is an anti-coagulant drug used to prevent and treat many
clotting disorders, that otherwise can lead to severe outcomes such as
stroke. It is very commonly prescribed: over 10.1 million prescriptions of
warfarin were written in 2012 in England, with approximately 1% of the UK
population being prescribed this drug at any given time. 33.9 million
prescriptions of the drug were dispensed in 2011 at retail pharmacies in
the US (data from the NHS Information Centre and IMS Health).
It has long been known that age, race, gender, weight, and the presence
or absence of co-morbidities (and associated medications) all influence
patient sensitivity to warfarin. Choosing the correct starting dose of
warfarin is a complex decision and once started, the dose will be adjusted
to the optimum level by closely monitoring the clotting ability of the
patient's blood over the course of several weeks. Overdosing a patient
with warfarin dramatically increases the risk of bleeding, and can
potentially also cause a stroke. Such overdosing is most likely in the
first few months of treatment. The Food and Drug Administration reported
in 2007 that warfarin was the second most common drug (insulin was the
first) implicated in emergency room visits in the US, amounting to tens of
thousands of trips per year (Lesko 2008 PMID: 18714317). Newcastle
University researchers, in collaboration with American colleagues,
realised that variable patient sensitivity to warfarin might have a
genetic component and explored this in a clinical study.
Newcastle University researchers were partners in the first clinical
study, led by the National Cancer Institute in the USA, which explored the
association between warfarin sensitivity and one variant allele of the
gene CYP2C9 (which encodes a liver enzyme that breaks down warfarin).
Although the results (Furuya et al. 1995 PMID: 8747411) did not reach
statistical significance they showed an association between genotype and
warfarin dose requirement. Subsequent research revealed that there are
actually two common variant alleles relevant to warfarin sensitivity.
These findings led Daly and others to refine the clinical study
methodology and explore more clearly the link between genotype and
warfarin sensitivity. By focussing on a group of patients with a
requirement for low doses of the drug they were, in 1999, the first to
demonstrate a statistically significant association between CYP2C9
genotype and sensitivity to warfarin (R1). The study also confirmed that
this group of patients needing a low dose of warfarin were significantly
more likely to have suffered serious bleeding events whilst taking the
In a 2005 study of 297 patients, each of whom was on a stable maintenance
dose of warfarin, Newcastle researchers assessed the genetic contribution
of sensitivity to the drug, relative to known factors of age and body
size. Consistent with their previous findings, patients with two copies of
the most common allele of CYP2C9 required significantly higher doses than
those possessing one or more variant alleles. The same study also reported
a significant association between allelic variants of another gene -
VKORC1 (which encodes the target of warfarin) - and warfarin dose
requirement. On the basis of these results a novel warfarin dosing regimen
incorporating CYP2C9 and VKORC1 genotype information, age and body size
was developed and validated (R2). Newcastle researchers were then closely
involved with the International Warfarin Pharmacogenetics Consortium in
the production of a refined algorithm, published in 2009, following a
trial involving 4,043 patients (R3).
Research involving Newcastle has continued, with Kamali and Daly leading
work packages within the EU-PACT European multi-site randomised controlled
trial of the safety and utility of genotype-guided dosing of
anticoagulants involving 455 patients. Newcastle University researchers
contributed to patient recruitment for the trial and led on (i) developing
and validating a rapid (~2hr) point of care test for genotyping (R4) and
(ii) developing an algorithm for genotype-guided dosing appropriate for
the study (R5). The EU-PACT study has shown that patients dosed with
warfarin based on CYP2C9 and VKORC1 genotype had on average a coagulation
rate within the desired range for 67.4% of measurements in the first 3
months of treatment compared with 60.3% of measurements in the controls
who received conventional dosing (R6). This difference was highly
significant (p<0.001). Genotyped patients exceeded the safe clotting
time in 2.3% of samples monitored, while the value for controls was 5.3%
(p<0.001). The study found that genotyping improves the safety of
warfarin treatment during initial dosing when adverse events are most
common; time to stable dosage was 44 days for genotyped patients and 59
days in controls (p<0.003) (R6).
References to the research
(Newcastle authors shown in bold. Citations from Scopus as at July 2013.)
R1. Aithal GP, Day CP, Kesteven PJL & Daly
AK (1999). Association of polymorphisms in the cytochrome P450
CYP2C9 with warfarin dose requirement and risk of bleeding complications.
Lancet 353:717-719. DOI: 10.1016/S0140-6736(98)04474-2. 807
R2. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood
P, Kesteven P, Daly AK & Kamali F (2005). The impact of CYP2C9
and VKORC1 genetic polymorphism and patient characteristics upon warfarin
dose requirements: proposal for a new dosing regimen. Blood
106:2329-2333. DOI: 10.1182/blood-2005-03-1108. 506 citations.
R3. The International Warfarin Pharmacogenetics Consortium (2009).
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N
Engl J Med 360:753-764. DOI: 10.1056/NEJMoa0809329. 558
R4. Howard R, Leathart JBS, French DJ, Krishan E, Kohnke H,
Wadelius M, van Schie R, Verhoef T, Maitland-van der Zee A-H, Daly AK
& Barallon R (2011). Genotyping for CYP2C9 and VKORC1 alleles by a
novel point of care assay with HyBeacon (R) probes. Clinica Chimica
Acta 412:2063-2069. DOI: 10.1016/j.cca.2011.07.013. 10
citations. (Daly is the corresponding author)
R5. Avery PJ, Jorgensen A, Hamberg A, Wadelius M, Pirmohamed M
& Kamali F (2011). A Proposal for an individualized
pharmacogenetics-based warfarin initiation dose regimen for patients
commencing anticoagulation therapy. Clinical Pharmacology and
Therapeutics 90:701-706. DOI: 10.1038/clpt.2011.186. 10
citations. (Kamali is the corresponding author and the first author
is Senior Lecturer, Department of Mathematics and Statistics, Newcastle
R6. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson
T, Kesteven P, Christersson C, Wahlström B, Stafberg C, Zhang E, Leathart
JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery
P, Kamali F, Wadelius M (2013). A Randomized Trial of
Genotype-Guided Dosing of Warfarin. N Engl J Med (publication
online Nov 2013). (Kamali is joint senior author with Wadelius)
Key research grants
European Commission Biomedical Programme. 1996-8. £33 512. Eurohepatotox.
GenoType Ltd. 2001-4. £35 000. A Study of Genetic Factors Affecting
Warfarin Dose Requirements.
European Commission FP7. 2007-13. £250 000 to Newcastle University. European
of Anti-Coagulant Therapy (EU-PACT) study design.
Details of the impact
Introduction of pharmacogenetic information to warfarin dosing advice
Several groups around the world made contributions to the body of
evidence about the role of genetics in determining the warfarin
sensitivity of patients, however it was the work published by Daly, Kamali
and others in Newcastle that has been recognised as being fundamental. The
Medical Director of the Barnes-Jewish Hospital Anticoagulation Service
(who is also Professor of Medicine at Washington University, St Louis,
USA) has said, `The seminal paper published by Ann Daly at Newcastle
University in 1999 [R1] ignited the field of
pharmacogenetic-based therapy' (Ev a). The importance of the 2005
study [R2] has also been acknowledged, with the University of Illinois
Hospital and Health Services Centre confirming that it `formed a
significant part of the evidence base that ultimately led to
international clinical trials of gene-guided dosing of anticoagulants
(including warfarin) being carried out' (Ev b).
Official guidance: By late 2007 (and so having an impact on
practice from 2008 onwards) the US Food and Drug Administration had judged
that the evidence on warfarin pharmacogenetics was sufficiently strong to
warrant a change to the approved medication guide of warfarin (marketed as
Coumadin). Since approximately one third of the population carries at
least one genetic polymorphism that slows the breakdown of warfarin, there
was a significant opportunity to apply the research findings and protect
patient health by avoiding overdose. The regulator issued a safety alert
`FDA approved updated labeling to include pharmacogenomics information
to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION
sections of the prescribing information for the widely used
blood-thinning drug, Coumadin. This new information explains that
people's genetic makeup may influence how they respond to the drug.
Specifically, people with variations in two genes may need lower
warfarin doses than people without these genetic variations. The two
genes are called CYP2C9 and VKORC1' (Ev c)
In 2010 a substantial change was made to the drug medication guide that
is included in the drug packaging when, at the request of the US Food and
Drug Administration, a table displaying three ranges of warfarin doses
based on CYP2C9 and VKORC1 genotype information was added (Ev d and Ev e).
Assisting practitioners: In 2009 the international standard
algorithm for warfarin dosing was published in the New England Journal
of Medicine (Ev f). The algorithm was a product of the work of the
International Warfarin Pharmacogenetics Consortium. Newcastle University
researchers Daly, Kamali and Sconce all contributed data to the paper that
outlined the algorithm. Sources at centres in Chicago and Seattle have
confirmed that the international standard algorithm was `significantly
underpinned' (Ev b) by Newcastle research (R2) and that the
Newcastle researchers had published `the first algorithm on CYP2C9 and
VKORC1 gene-guided dosing of warfarin' (Ev g).
Application in the clinic
Interest in the pharmacogenetic approach to warfarin prescribing is
increasing in clinics across the US, with large academic medical centres
leading implementation. Since autumn 2010 the Vanderbilt University
Medical Center in the US has been running the PREDICT programme, which
aims to embed pharmacogenetic information in its approach to healthcare.
So far the programme `has included >12,500 subjects and
warfarin-CYP2C9/VKORC1 is one of five drug-gene interactions currently
[being] targeted.'(Ev h)
The University of Illinois at Chicago has also provided a statement
concerning practice at its medical centre:
`beginning in August 2012, all patients newly starting warfarin during
hospitalization at our medical center are automatically genotyped for
clinical care to assist with warfarin dosing. Nearly 300 patients have
been genotyped to date.' (Ev b)
Large-scale clinical trials
Clinical trials of gene-based dosing of warfarin, together involving
thousands of people in the US and Europe, are currently in progress. Daly
and Kamali contributed to the major European trial, EU-PACT (R6), which
involved 455 patients. In the US, two large studies are ongoing: the
WARFARIN study (approximately 3,800 patients, started August 2011) and the
COAG study (around 1,020 patients, started September 2009) (Ev i).
The US Food and Drug Administration has estimated that gene-based dosing
of warfarin will prevent 85,000 serious bleeding events and 17,000 strokes
a year in the US (Ev j).
Sources to corroborate the impact
Ev a. Correspondence from a Professor of Medicine, Washington University
Medical School, St Louis is available and contact details are available on
Ev b. Correspondence from an Associate Professor at the Department of
Pharmacy Practice, University of Illinois at Chicago is available and
contact details are available on request.
Ev c. US Food and Drug Administration (August 2007): Warfarin (marketed
as Coumadin) — safety alert.
Ev d. US Food and Drug Administration (January 2010): Coumadin (warfarin
sodium) tablet and injection. Detailed View: Safety Labeling Changes
Approved By FDA Center for Drug Evaluation and Research (CDER).
Ev e. Bristol-Myers Squibb website: Coumadin (warfarin) drug medication
(Dosing table on page 2, column 2.)
Ev f. The International Warfarin Pharmacogenetics Consortium (2009).
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N
Engl J Med 360:753-764. DOI:
10.1056/NEJMoa0809329. 558 citations
Ev g. Correspondence from a Professor and Chair of Medicinal Chemistry at
the Department of Medicinal Chemistry, University of Washington, Seattle
is available and contact details are available on request.
Ev h. Correspondence from the Director of the Oates Institute for
Experimental Therapeutics at the Vanderbilt School of Medicine is
available and contact details are available on request.
Ev i. Trial information at clinicaltrials.gov
Ev j. US Food and Drug Critical Path Initiative: Warfarin Dosing.