Exposure to non-therapeutic INR in a high risk cardiovascular patient: potential hazard reduction with genotype-guided warfarin (Coumadin[R]) dosing.
A case to illustrate the utility of genetic screening in warfarin
(Coumadin[R]) management is reported. A 45 year-old woman of Puerto
Rican ancestry was admitted to the emergency room twice within one month
with chest pain. she was diagnosed with congestive heart failure, which
was stabilized both times. At her second release, warfarin therapy was
initiated at 5 mg/ day to prevent thrombus formation and was lowered to
3.75 mg/day at day 7 by her primary physician. International Normalized
Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of
warfarin therapy were 4.5, 6.5, and 7.3, respectively--far in excess of
the therapeutic range, despite the lower dosage in effect from day 7
onward. the patient achieved target INR over the next 43 days after
downward adjustment of the dose to a dose of 1.5 mg/day by trial and
error. DNA-typing specific for the CYP2C9*2,*3,*4,*5,*6 alleles and
seven variants in the VKORC1 gene, including the VKORC1-1639 G>A
polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and
VKORC1-1639 G/A genotypes in this patient. entering the patient's
demographic and genotype status data into independent algorithms
available in the public domain to predict effective warfarin dose
yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably,
the prediction of 1.5 mg/day, which was generated by the online resource
www.warfarindosing.org, coincided with the patient's actual
effective warfarin dose. We conclude that the rapid rise in INR observed
upon the initiation of warfarin therapy and the final effective warfarin
dose of 1.5 mg/day, are attributable in some part to the presence of two
minor alleles in CYP2C9, which together significantly reduce warfarin
metabolism. Warfarin genotyping can therefore inform the clinician of
the predicted effective warfarin dose. The results highlight the
potential for warfarin genetic testing to improve patient care. [P R
Health Sci J 2010;4:402-408]
Key words: Warfarin (Coumadin[R]), Pharmacogenetics, Genotyping, INR, Minor alleles, CYP2C9, VKORC1, Dosing algorithm, Personalized Medicine
Se reporta un caso que ilustra la utilidad del cernimiento genetico en el manejo clinico de warfarina (Coumadin[R]). Una mujer puertorriquena de 45 anos de edad fue admitida a una sala de emergencias dos veces en un mismo mes con dolor de pecho. Ella fue diagnosticada con un fallo cardiaco congestivo, el cual fue estabilizado en ambas ocasiones. En su segunda visita, se inicio un tratamiento con warfarina en dosis diaria de 5 mg, para prevenir la formacion de trombos, que luego del septimo dia se redujo por su medico primario a 3.75 mg diarios. Los resultados de sus pruebas de INR en los dias 1, 7 y 10 fueron 4.5, 6.5 y 7.3, respectivamente. Estos valores estaban muy por encima del rango terapeutico, independientemente de la reduccion en la dosis a partir del septimo dia. La paciente alcanzo el INR requerido despues de 43 dias de ajustes de la dosis de warfarina, con reducciones diaria hasta los 1.5 mg, mediante tanteo y error. Una prueba de ADN especifica para los alelos CYP2C9*2,*3,*4,*5,*6 y otras siete variantes del gen VKORC1, incluyendo VKORC1-1639 G>A, revelaron la presencia en esta paciente de una combinacion de variantes alelicas en ambos genes que determinan el genotipo CYP2C9*2/*3 y VKORC1-1639 G/A. La dosis efectiva de warfarina para esta paciente fue estimada en el rango de 1.5 - 1.8 mg diarios, mediante un algoritmo farmacogenetico de dominio publico (www.warfarindosing. org), utilizando la informacion demografica y el genotipo de la paciente. Interesantemente, la dosis diaria de 1.5 mg estimada por el algoritmo coincidio con la verdadera dosis efectiva de warfarina para esta paciente. Podemos concluir que el rapido incremento de los valores de INR en esta paciente, observados durante la fase de iniciacion, asi como la baja dosis efectiva de 1.5 mg al dia, son atribuibles en parte a la presencia de dos variantes en el gen CYP2C9, lo cual reduce significativamente su capacidad para metabolizar la warfarina. Esta prueba genetica para warfarina puede entonces informar mejor al medico sobre la dosis mas efectiva en el paciente. Estos resultados resaltan el potencial de la prueba genetica de warfarina para mejorar el cuidado al paciente.
Ortiz-Rivera, Oscar J.
Seip, Richard L.
|Publication:||Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658|
|Issue:||Date: Dec, 2010 Source Volume: 29 Source Issue: 4|
In 2008, nearly 23 million warfarin (Coumadin[R]) prescriptions I
were written in the United States (1). Data from IMS I Health[TM] and
National Sales Perspective[TM] (2005) reveal that 2 million individuals
initiate warfarin therapy in the United States every year to prevent
blood clots, heart attacks and strokes (2). Warfarin is the second most
common drug, after insulin, implicated in emergency room visits for
adverse drug events (3). According to the U.S. Food and Drug
Administration (FDA), hemorrhage during warfarin therapy is a leading
cause of death in Western countries and related adverse events account
for 1 in 10 hospital admissions. Such events generate a mean hospital
stay of 6 days and healthcare costs of $16,000 per admission per year
(4), resulting in poor clinical outcomes and over 1 billion dollars in
health care services (2).
Despite over 50 years of clinical experience with warfarin, notable challenges persist when determining the optimal and safest dosage, which must be individualized for each patient (5). Warfarin is notoriously difficult to administer due to the highly variable optimal dose and multiple factors that influence dosage, including: patient age, body mass, gender, nutritional factors such as vitamin K intake, concurrent medications, indications, co-morbidities, and genetic variations (5). Also, warfarin has a very narrow therapeutic index making it all the more difficult to establish the correct dose (5). To assist in the management of warfarin dosing, physicians use a rate of change for blood coagulation as measured by the International Normalized Ratio (INR) value, which also has its limitations. These factors contribute to the need for frequent follow-up visits for INR tests and reassessment of the patient dosing regimen. Incorrect dosing especially during the induction phase (approximately the first 30-90 days of treatment) carries 10 times greater risk of severe bleeding (6).
In January 2010, FDA revised the warfarin label to include pharmacogenetics dosing recommendations based on gene polymorphisms (7). The main role of pharmacogenetics in warfarin therapy management is to provide the DNA-based information that can be used to achieve the patient's effective dose and target INR in a shorter period of time. Up to 45% of the variability in the effective warfarin dose depends o n variants in two highly polymorphic genes, cytochrome P450 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) (8-12). CYP2C9 polymorphisms include *2 and *3, which are associated with decrease in cytochrome p450 enzyme activity to approximately 12-70% and 5% ofthe normal level, respectively (6, 13-16). These polymorphisms lead to subsequent warfarin accumulation. Warfarin inhibits vitamin K epoxide reductase (VKOR), the enzyme responsible for activating an essential cofactor of clotting factors II, VII, IX and X (5). The VKORC1 -1639G>A polymorphism in the promoter region of the gene results in reduced enzymatic activity. A patient with one or more polymorphisms in either or both of these genes is at risk of supra-therapeutic warfarin dosing, increasing the risk of bleeding. This case presentation provides an example of the importance and utility of pharmacogenetic testing in the development of successful therapeutic regimens.
Here we describe a patient with a rapid increase in INR upon the initiation of warfarin therapy and a sustained elevation in INR despite conventional dose, the elevation of which, in response to the typical 5mg starting dose, is consistent with her genotype status: namely, the metabolic loss of function and decreased warfarin clearance anticipated with CYP2C9 *2/*3, and the decreased sites of drug action due to the presence of the -1639 G>A polymorphism.
A 45 year-old Puerto Rican female with a past medical history of congestive heart failure, hypertension, bronchial asthma, lupus, and substance abuse, was admitted to the emergency room with an acute onset of shortness of breath. The patient had a history of tobacco use and addiction to cocaine and heroin in the past. At the time of the admission she was taking only methadone and furosemide (Lasix[R], Sanofi Aventis US), with evidence of non-compliance regarding the latter. The patient denied nausea, vomiting, and fever at the time of admission.
Her diagnosis was congestive heart failure (CHF) exacerbation as a result of furosemide (Lasix[R], Sanofi Aventis US) noncompliance. The cardiac examination was unrevealing. Her laboratory studies revealed a brain natriuretic peptide (BNP) level of 1,511ng/L which implies severe CHF, a creatine kinase (CK) of 66U/L, and troponin levels of less than 0.01ng/ mL. Her chest x-ray indicated her heart was enlarged and the patient had diffuse pulmonary edema. The second set of cardiac enzymes revealed a CK of 1,531ng/L, CKMB of 3.2ng/ mL, and CKMB index
of 0.2. An echocardiogram showed a left ventricle that was markedly dilated and profoundly hypokinetic. The left ventricular ejection fraction was 10% to 15%, markedly decreased. PET scan showed anterior and lateral perfusion abnormalities and regional wall motion abnormalities. Computer tomography angiography was recommended; however, IV access was not obtained due to patient's refusal of IV. Due to the patient's low ejection fraction, it was considered that she was at an increased risk of a thrombus formation. She was started on heparin therapy; however, the heparin was discontinued because of chest pain. The patient did not receive aspirin due to self-reported allergy to this medication. Her discharge medications included lisinopril 10mg per os daily; carvedilol (Coreg[R], GSK) 6.25 mg per os twice a day; fluticasone propionate/salmeterol xinafoate (Advair[R] Diskus 250/50, GSK) inhaled twice a day; furosemide (Lasix[R], Sanofi Aventis US) 40 mg per os twice a day; methadone hydrochloride 75 mg per os daily; and albuterol sulfate as needed for asthma exacerbation.
A month after this visit the patient returned to the emergency room with the same complaints and similar clinical findings. The physical examination revealed irregular heart beats. The patient's PT and PTT were 23.3 and 55 sec., respectively. Cardiac enzymes were negative. BNP was elevated at 1,500ng/L and her chest x-ray showed mild pulmonary edema. The patient was discharged and prescribed warfarin at the standard dose of 5 mg/ day (per os) for prevention of thrombus formation. Consecutive INR values of4.46, 6.53, and 7.34 were measured on days 1, 7, and 10 of therapy, which demonstrated an incremental pattern (Figure 1). The baseline INR value for this patient was 1.21 (Table 1). In healthy people, the INR is by definition 1.0. For this patient the INR therapeutic range is between 2.0 and 3.0, based on the diagnosis of congestive heart failure. Warfarin dosage was changed four times in this patient during the course of 43 days. There were 7 INR assessments made before the patient reached target (Table 1). Six of the seven INRs exceeded target level, peaking at 7.34, suggesting a supra-therapeutic level of warfarin dosage, and exposing her to a higher risk of bleeding. Fortunately in this case, no minor or major life-threatening bleeding episodes were reported and dosage was eventually stabilized at 1.5 mg/ day, the lowest dose prescribed, at the time of achievement of target INR. In this patient, the initial warfarin dose of 5 mg/day resulted in successively higher INRs all of which exceeded the target range (Figure 1). At the initiation of therapy the dose was the highest dose given to the patient.
[FIGURE 1 OMITTED]
After almost three years on warfarin therapy, this patient underwent genotype testing as a volunteer participant in an IRB-approved research study conducted at Hartford Hospital-affiliated Brownstone anticoagulation clinic to investigate the frequency distribution of up to twelve common minor alleles in CYP2C9 and VKORC1 genes (5, 8) in the Puerto Rican population [i.e., five minor alleles in CYP2C9 (*2, *3, *4, *5, and *6) and seven minor alleles in VKORC1 (including -1639 G>A]. She signed an informed consent form approved by the Hartford Hospital Institutional Review Board. The HILOMet WARFARIN DNA-typing system (8) was used to run the test at the Laboratory of Personalized Health (LPH, Genomas Inc.), a CLIA-certified lab that is also licensed by the Connecticut Department of Health (CL-0644). DNA testing to infer patient's metabolic capacity and sensitivity to warfarin revealed this patient is a carrier of three major variants in these two warfarin-related genes: i.e., CYP2C9 *2 and *3 and the VKORC1-1639 G/A polymorphisms.
The target INR for patients diagnosed with heart failure is a range of 2.0-3.0. The recommended starting dose of warfarin is 5 mg/day. Many non-genetic factors, such as body size, sex, dietary change, and drug interaction, can contribute to an elevation in INR. Our patient denied significant dietary changes that would have altered Vitamin K intake. Furthermore, no pharmacokinetic or pharmacodynamic factors associated with the warfarin response such as drug-drug or drug-food interactions were found. Other factors to take into consideration are the medical condition of the patient and whether the patient complies with the drug regimen as prescribed. CHF exacerbation can increase the INR value due to an increase in hepatic congestion and decreased warfarin catabolism. However the patient's BNP was unaltered suggesting no change in CHF status. Also the non-compliance to furosemide therapy that was mentioned in the patient's history can put the patient at risk of future exacerbations and increase in INR values. It is conceivable but not likely that noncompliance to furosemide therapy contributed to the patient's elevated INR, because here the rapid rise in INR coincided with the onset of warfarin therapy. During the treatment course with warfarin, no drugs that interfere with CYP2C9 function were prescribed and there is no evidence of a change in diet that could have altered the intake of Vitamin K. The status of the CYP2C9 gene is consistent with decreased metabolic function and a high likelihood of warfarin accumulation. For these reasons, genetic polymorphisms in CYP2C9 and VKORC1 are the most likely explanations for the elevated INR, resulting from a supra-therapeutic warfarin dose.
Such unintended over-anticoagulation puts the patient at high risk for bleeding events. Severe bleeding complications do occur with warfarin therapy and are more likely during induction phase and with supra-therapeutic doses (17). According to a meta-analysis of 33 studies, major and fatal bleeding events occur at rates of 7.2 and 1.3 per 100 patient years, respectively (18). Even though our patient did not suffer any major bleeding event, she had some high risk factors for bleeding, which included: excessive anticoagulation (INR>4.0), highly variable INRs, hypertension, serious heart disease and genetic polymorphisms suggested significantly decreased enzyme activity (19). One randomized trial of 211 patients, found that 32 patients (15% of all patients) with INR values between 4.1-8.0 experienced a major bleeding event (20). It is important to note that the first three INR values ranged between 4.1 and 8.0 when a standard dosing initiation procedure was followed. Patients with more than four dose modifications within one year had approximately 25% more bleeding events than patients with less dose adjustments. Our patient's warfarin dose was changed four times during the course of 43 days, exposing her to a higher risk of bleeding. Reynolds et al. found that 83% of reported bleeding events occurred when patient INRs were above 3.0 (6). With each 1-point rise in the INR above 3.0, the risk of bleeding events increases by 42% (21). Our case report patient evidenced a total of six INRs above 3.0, the highest being 7.34. Patients at high risk of bleeding may need more frequent INR monitoring, which not only prolongs the dose adjustment period but also increases the health care spending.
The INR test has limitations with respect to clinical relevance especially in the initiation phase of warfarin therapy. There is a lag-time between the suppression of the synthesis or activation of vitamin K-dependent clotting factors by ingested warfarin and the increase in the INR6. This is due to differences in the biological half-life of active vitamin K-dependent clotting factors involved in coagulation, the reserve of these proteins when warfarin therapy is initiated, and the time needed for warfarin to accumulate to a sufficient therapeutic concentration (6). Factors that can promote an increase in INR value include 1) the use of concurrent medications that alter the metabolic activity of CYP2C9, 2) sudden reduction in vitamin K ingestion, and 3) polymorphisms in VKORC1 or CYP2C9.
DNA-typing of the CYP2C9 and VKORC1 genes was performed at 12 variable sites, 5 SNPs in CYP2C9 and 7 SNPs in VKORC1. The assay employed PCR to amplify selectively these two genes without co-amplifying pseudogenes or other closely related sequences. The PCR-derived target DNA with 2 universally-tagged allele-specific primers, whose 3' ends define the corresponding alleles, were then used for running multiplexed Allele Specific Primer Extension (ASPE) reactions. A thermophilic DNA polymerase was used for primer extension and biotin-dCTP label incorporation. Following ASPE, tagged, extended products labeled with biotin were captured by their tag complements (anti-tags), which had been chemically coupled to spectrally addressable polystyrene microspheres. A fluorescent reporter molecule (streptavidin-phycoerythrin) was used to detect incorporated biotin. The fluorescent reporter signals generated for each bead population was measured on the Luminex xMAP[TM] platform (Luminex[R] Corp., Austin TX). Wild-types were assigned as a result of the absence of other SNPs.
Combinatorial genotyping analysis revealed CYP2C9*2/*3 and VKORC1 -1639 G/A genotypes, which classifies this patient as a carrier of three loss-of-function polymorphisms. Patients with *1 homozygous alleles are considered wild type and have a normal and fully functional CYP2C9 enzyme (5). A CYP2C9*2 allele variation produces a base pair exchange of cytosine to thymine (430 C>T) resulting in a Arg144Cys amino acid substitution reducing enzymatic activity (5, 17). A *3 variant (1075 A>C) causes an amino acid change at position 359 resulting in a null enzyme. For VKORC1, the transition from G to A at position -1639 in the promoter region leads to an altered transcription and, therefore, decreased amount of the enzyme with a subsequent higher patient's sensitivity to warfarin5. The CYP2C9 and VKORC1-1639 statuses by themselves accounts for approximately 15-20% and 20-25% of warfarin dose, respectively (10-11, 16, 22-23).
In Caucasian populations, the CYP2C9 polymorphisms are associated with 1.4-fold increased risk of excessive anticoagulation and a two- to three- fold increased risk of bleeding during warfarin induction phase specifically (16-17, 24-27). A recent study in African-Americans demonstrated an increased risk of hemorrhage during long-term therapy in patients with CYP2C9 minor variants (28). Even though our patient is neither Caucasian nor African-American, it is important to mention that her Puerto Rican ancestry background includes an admixture of Caucasian, African and Amerindian (Taino) heritage (29). The combinatorial genotype prevalence in Puerto Rican population for carriers of both the CYP2C9 and VKORC1 polymorphisms, as in our case report patient, is reported to be between 16%-18% (8, 30). Furthermore, nearly 5% of Puerto Rican population carried three polymorphisms (8). Duconge et al. showed that the predicted warfarin dose reduction (using 5mg/day as standard dose) for Puerto Rican patients having combinatorial CYP2C9 and VKORC1 genotypes ranged from 1.6 to 3.7mg daily (30). The reduction in effective warfarin dose for carriers of three polymorphisms compared with non-carriers is in the range of 34-47% (31). Patients with polymorphisms in VKORC1 and CYP2C9 are at high risk of over-anticoagulation compared to patients with 1 or no polymorphism (32).
Recent papers have published DNA-guided algorithms to predict effective warfarin dose (9-10, 14, 22, 31, 33-34). Also, computer based algorithms such as Couma Care[R], Coag Clinic[TM], INR star, and www.warfarindosing.org are available to guide clinicians in the incorporation of genotyping results relative to warfarin prescription. If any of these recently developed algorithms were employed, the patient's dosage might have been altered. Since genotyping analysis was performed three years after the patient started warfarin therapy, as part of a research study, it was not used to predict the patient therapeutic dose. We calculated the effective dose based on algorithms that incorporate gene status and compared the results with the actual effective dose of the patient. We tried different algorithms to calculate the predicted warfarin dose for our patient, including: Perini et al. model (34) for Brazilian patients; Sconce et al. model (10); Zhu et al. model (9); and warfarindosing.org (Table 2). The warfarin dose calculated by the website warfarindosing.org (http://www.warfarindosing. org/Source/Home.aspx) was 1.5 mg/day, which agrees precisely with the dose given when the patient reached target. In retrospect, had the dosage been reduced during the first few days of therapy, it is reasonable to expect the treatment course to have been altered.
In August 2007, the FDA announced a warfarin label change recommending but not requiring testing for VKORC1 and CYP2C9 gene variants in patients receiving warfarin therapy (35). These tests are done in pharmacogenetic laboratories with an average turnaround time of four days, but 1 day turnaround time for warfarin genotyping is feasible (36). The necessity of a 1 day turn-around time is unclear since warfarin algorithms have focused on maintenance dose, rather than initiation dose (35). The impact of genetic variants on effective dose is well-known but the impact on the initiation dose or adjustment of initial dose has been given less attention (37). Schwarz et al (17) have shown that the CYP2C9 genotype is a significant predictor of time to first INR>4. Preliminary observations in our clinical practice indicate that double carriers of CYP2C9*2 and *3 compared to *2/*2 and non-carriers (unpublished data), increase INR quickly upon initiation of warfarin therapy. If this finding is confirmed, early knowledge of genetic testing results may expand prescribing options to include the early adjustment of the initial dose of 5 mg/day to a lesser dose, or initiation with a smaller dose.
Cost of Genetic Testing
Genetic testing for the presence of the most common VKORC1 and CYP2C9 minor alleles currently ranges in cost from $200 to $450, averaging $350 per test (2), while INR test costs an average of $50. For the case report patient six INR tests were ordered and performed before reaching target INR for a total approximately cost of $300. In addition to the INR cost it is important to add the cost of the laboratory personnel conducting the tests and the clinician making the dose adjustments. Estimates on cost savings suffer from a lack of hard data. If DNA typing were to be performed before warfarin is prescribed, one analysis estimated that 85,000 serious bleeding events and 17,000 strokes could be avoided annually in the US, saving over US $1.1 billion in health care (2). In contrast, another estimate based on genotype testing at the initiation of warfarin therapy, suggests lesser but still worthwhile cost savings, assuming the turn-around time for results is reduced to one day (38). Based on current estimates, the cost of warfarin per quality-adjusted life year is greater than $170,000, a number far too large to institute across the board. A more acceptable number for practical application is $50,000, which would require halving of the genotype costs and a return of results within 24 hours. In order to obtain this acceptable number, the utility would have to be in those with a very high risk for hemorrhage, like the patient in this case report, given the average annual estimate for warfarin-related intracranial bleeding being approximately 0.1%. Both public health improvement and significant reduction in the health care costs can be accomplished if clinicians can effectively incorporate pharmacogenetic into therapeutic management. The avoidance of adverse events for warfarin therapy such as bleeding, may soon justify the cost of genotyping, particularly in patients at high risk of bleeding complications.
Patients with polymorphisms in CYP2C9 and/or VKORC1 are more prone to develop supra-therapeutic levels of warfarin and usually require a prolonged dose adjustment period. The excess of anticoagulant can result in adverse events such as bleeding or hemorrhages. To improve patient's outcomes and reduce bleeding events we recommend genotyping for patients at high risk for bleeding.
(1.) 2008 Top 200 Generic Drugs by Total Prescriptions. Drug Topics, the Newsmagazine for Pharmacists; 2009: 4-6. Source: SDI/Verispan, VONA, full year 2008. http://drugtopics.modernmedicine.com/top 200gen (Accessed 2009 Dec 18).
(2.) McWilliam A, Lutter R , Nardinelli C. Health care savings from personalized medicine using genetic testing: The case of warfarin. [Working Paper 06-23, AE1-Brookings Joint Center for Regulatory Studies, November 2006]. www.aei-brookings.org/admin/authorpdfs/page.php?id=1337& PHPsEssID=7b3a3ae4b30d77cb76223e29535e7590. (Accessed 2009 Dec 18).
(3.) Budnitz DS, Pollock DA, Weidenbach KN, et al. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006; 296:1858-66.
(4.) Fanikos J, Grasso-Correnti N, Shah R, et al. Major Bleeding Complications in a Specialized Anticoagulation Service. Am. J. Cardiol. 2005; 96(4): 595-598.
(5.) Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: Uncovering a piece of the warfarin mystery. Am J Health-Syst. Pharm. 2009; 66(15): 123-33.
(6.) Reynolds KK, Valdes Jr. R, Hartung BR, Linder MW. Individualizing Warfarin Therapy. Personalized Medicine 2007; 4(1):11-31.
(7.) Coumadin[R] (Warfarin) Label Revision, January 22, 2010. Princeton, NJ, Bristol-Myers Squibb Pharma Company. http://www.accessdata.fda. gov/drugsatfda_docs/label/2010/009218s108lbl.pdf
(8.) Ruano G, Thompson PD, Villagra D, et al. High carrier prevalence of combinatorial CYP2C9 and VKORC1 genotypes affecting warfarin dosing. Personalized Medicine 2008; 5(3):225-232.
(9.) Zhu Y, Shennan M, Reynolds KK, et al. Estimation of Warfarin Maintenance Dose Based on VKORC1 (-1639 G>A) and CYP2C9 Genotypes. Clin. Chem. 2007; 53:1199-1205.
(10.) Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005; 106(7): 2329-2333.
(11.) Hillman MA, Wilke RA, Caldwell MD, et al. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics. 2004; 14(8): 539-547.
(12.) Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 2005; 352: 2285-93.
(13.) Kamali F, Pirmohamed M. The future prospects of pharmacogenetics in oral anticoagulation therapy. Br. J. Clin. Pharmacol. 2006; 61(6): 746-751.
(14.) Linder MW, Looney S, Adams JE, III, et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J. Thromb. Thrombolysis. 2002; 14: 227-232.
(15.) Scordo MG, Pengo V, Spina E, et al. Influence of CYP2C9 and CYP2C19 genetic polymorphism on warfarin maintenance dose and metabolic clearance. Clin. Pharmacol. Ther. 2002; 72: 702-10.
(16.) Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb. Haemost. 2005; 93: 700-705.
(17.) Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. N. Engl. J. Med. 2008; 358(10): 999-1008.
(18.) Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta analysis. Ann. Intern. Med. 2003; 139: 893-900.
(19.) Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am. Fam. Physician. 1999; 59(3):635-646
(20.) DiMarco JP, Flaker G, Albert WL, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: Observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study. Am. Heart J. 2005; 149(4): 650-656.
(21.) van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch. Intern. Med. 1993; 153:1557-1562.
(22.) Klein TE, Altman RB, Eriksson N, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 2009; 360: 753-764.
(23.) Wadelius M, Chen LY, Eriksson N. Association of warfarin dose with genes involved in its action and metabolism. Hum. Genet. 2007; 121:23-34.
(24.) Joffe HV, Xu R, Johnson FB, et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb. Haemost. 2004; 91: 1123-1128.
(25.) Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-98.
(26.) Margaglione M, Colaizzo D, D'Andrea G, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost. 2000; 84: 775-778.
(27.) Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood. 2000; 96(5):1816-9.
(28.) Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic Complications in African-American and European-American Patients on Warfarin. Clin. Pharmacol. Ther. 2008; 83(2):312-21.
(29.) Ruano G, Duconge J, Windemuth A, et al. Physiogenomic Analysis of the Puerto Rican Population. Pharmacogenomics. 2009; 10(4): 565-577.
(30.) Duconge J, Cadilla CL, Windemuth A, et al. Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: Implications for Warfarin Management in Hispanics. Ethn. Dis. 2009; 19(4): 390-395.
(31.) Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of Genetic Factors for Warfarin Dose Prediction. Clin. Med. Res. 2007; 5(1): 8-16.
(32.) Schalekamp T, Brasse BP, Roijers JFM, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: Interaction between both genotypes affects overanticoagulation Clin. Pharmacol. Ther. 2006; 80: 13-22.
(33.) Wu AHB, Wang P, Haller C, et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics. 2008; 9(2): 169-178.
(34.) Perini JA, Struchiner CJ, Silva-Assuncao E, et al. Pharmacogenetics of warfarin: development of a dosing algorithm for Brazilian patients. Clin. Pharmacol. Ther. 2008; 84(6):722-8.
(35.) Coumadin[R] (Warfarin) Label Revision, August 7, 2007. Princeton, NJ, Bristol-Myers Squibb Pharma Company. http://www.fda.gov/cder/foi/ label/2007/009218s105lblv2.pdf.
(36.) Food and Drug Administration. FDA clears genetic lab test for warfarin sensitivity. FDA News, Posted September 18, 2007; http://www.fiercebiotech.com/press-releases/press-release-fda-clears- genetic-lab-test- warfarin-sensitivity (accessed 2009 Dec 18).
(37.) Hillman MA, Wilke RA, Yale SH, et al. A Prospective, Randomized Pilot Trial of Model-Based Warfarin Dose Initiation using CYP2C9 Genotype and Clinical Data. Clin. Med. Res. 2005; 3(3): 137-145.
(38.) Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients with Nonvalvular Atrial Fibrillation. Ann. Intern. Med. 2009; 150(2): 73-83.
Rosangela Rodriguez-Velez, PharmD Candidate *; Oscar J. Ortiz-Rivera, PharmD Candidate *; Bruce Bower, MD [dagger]; Krystyna Gorowski, BS [dagger]; Andreas Windemuth, PhD [dagger]; David Villagra, BA [dagger]; Mohan Kocherla, MS [dagger]; Richard L Seip, PhD [dagger]; Darrin D'Agostino, DO [double dagger]; Cunegundo Vergara, MD [section]; Gualberto Ruano, MD, PhD [dagger]; Jorge Duconge, PhD **
* Contributed equally to this article, University of Puerto Rico School of Pharmacy San Juan Puerto Rico; [dagger] Genomas Inc. and Genetic Research Center, Hartford, Connecticut; [double dagger] Department of Internal Medicine University of North Texas Health Science Center; [section] Brownstone Hospital; ** School of Pharmacy, University of Puerto Rico, San Juan, Puerto Rico
Dr Ruaho is founder and President of Genomas, Inc. Dr. Bower, Dr Windemuth, Dr Seip, Mr. Kocherla, Mr. Villagra, and Miss Gorowski are full-time employees of Genomas. The rest of the authors have no potential conflicts of interest to disclose.
Address correspondence to: Jorge Duconge, PhD, School of Pharmacy, University of Puerto Rico, Pharmacy Bldg, 4th floor, room 420. PO Box 365067, San Juan, PR 00936-5067. Email: firstname.lastname@example.org
Table 1. Warfarin Doses and INR Responses Day INR Current Dose (mg/day) 1 1.21 0 9 4.46 * 5 16 6.53 * 5/2.5 alt (3.75) 19 7.34 * 5/2.5 alt 21 3.34 * 2.5 22 1.84 2.5 37 3.62 * 2.5 43 3.69 * 2/1 alt (1.5) 52 2.93 ([section]) 2/1 alt 59 2.99 ([section]) 2/1 alt 80 2.27 ([section]) 2/1 alt Therapeutic Range 2.0-3.0 * Above therapeutic range ([section] Target achieved Table 2. Predictions based on published DNA-guided warfarin dosing algorithms Algorithms Predicted Warfarin Dose (mg/day) Perini et al. 1.8 Zhu et al. 1.3 Sconce et al. 1.3 warfarindosing.org 1.5
|Gale Copyright:||Copyright 2010 Gale, Cengage Learning. All rights reserved.|