A Forum for Improving Drug Safety

Today is the last day to express your opinion on whether warfarin (Coumadin) DNA testing should be covered by insurance. Please post your comments on this important decision which will have far reaching effects on the field of personalized medicine and pharmacogenetics. Please go to http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?from2=viewtrackingsheet.asp&id=224& to learn more about this study. To post your comments scroll to the bottom of the page and click on view public comments, then click on the orange comments button on the upper right of the page. 

Here is what Genelex’s CEO, Howard Coleman posted:

Thank you for the opportunity to comment on the importance to patients of insurance reimbursement for warfarin DNA testing.

Warfarin (Coumadin) therapy is expanding rapidly in the elderly population because of the increasing prevalence of atrial fibrillation and longer life spans. Numerous studies have documented that warfarin is underutilized in eligible patients. Physicians, while knowing that warfarin is effective, have fear about bleeding that may prevent its use. Physicians also have been shown to reduce their prescribing of warfarin after one of their patients experiences a bleeding event. Approximately 5 million patients currently take warfarin and 500,000 start this medicine every year. It is the seventh most frequently prescribed medicine in the US. Many anticoagulation experts believe that up to 50% more patients could benefit from taking warfarin, but don’t because of the fear of the adverse outcomes of minor and major bleeds, or the inconvenience of frequent blood testing and the costs of travel and lost productivity.

Warfarin is a difficult and hazardous drug to prescribe because of its extremely narrow therapeutic index and twenty-fold variation in individual patient dose requirement. Non genetic factors, such as age, gender and body weight account for approximately 12% of this unusually wide variation in individual stable dose requirement. Most patients are started on 5mg per day and asked to return to the clinic weekly, or more frequently for INR blood testing (international normalization ratio based on prothrombin time) and dose adjustment, if needed. At the time of patient visits, prescribers don’t know if the blood levels of warfarin are stable, going up or going down. The result is an inefficient, trial and error process if multiple INRs and dosing adjustments are required to achieve a stable maintenance dose. It puts patients at risk, especially when initiating warfarin and can take weeks or months to get the maintenance dose reliably and consistently right.

The elderly are especially at risk which is not appreciably mitigated by prescribers taking age into account. The severity of the risks of taking warfarin leads to 58,000 emergency room visits by patients over age 65 every year. It is second only to insulin in precipitating medication related ER visits and is listed by the FDA’s Adverse Event Reporting System in the top ten of drugs with the greatest number of serious adverse events. The risks of warfarin therapy are so great that in 2006 the FDA added a “black box” warning to the label (see below). More information is needed in the elderly when starting warfarin in order to reduce costs and the reduction in quality of life resulting from adverse events.

Many studies in the last five years have demonstrated that patients prescribed warfarin and carrying variations in genes that reduce the clearance of warfarin via CYP2C9, or affect the sensitivity of its treatment target VKORC1 are at double or triple the risk for an adverse bleeding event or treatment failure (odds ratios up to 5X) in the time period after starting warfarin. Variation in these genes is the most important causal mechanism of warfarin intersubject variability. Therefore, the relationship between genotype and clinical outcomes of, INR control, number of INR blood tests required to reach a stable dose, number of dosing adjustments and time in therapeutic INR range is not empirical or due to chance.

These risk elevating genetic variations are present in the majority of patients seen by clinicians and as many as 60% of patients would benefit from genetic testing. Compared to patients without these variations they take as much as three months longer to reach a stable dose after starting warfarin, and spend more time at risky high doses or sub therapeutic low doses as dosing adjustments in response to unacceptable INRs are made by the prescriber. The quality of anticoagulant control, in turn, is related to the risk of having an adverse event. Mounting clinical studies from around the world, and between various ethnic groups, including large prospective trials, confirm the basic facts outlined here. These studies also point to the usefulness of genetic testing in helping patients avoid the personal hardship of a bleeding related hospitalization or recurrence of a stroke, myocardial infarction or thromboembolism. Compared to age, body weight and gender, genetic factors contribute three times more information about variability in stable dosage requirements, 35% for CYP2C9 and VKORC1 versus 12% for age, gender and body weight.

Some suggest that we wait for the conclusions to be reached by additional studies that are underway before taking action. These studies may further refine our knowledge of how best to prescribe warfarin, and are unlikely to overturn the conclusions of the many studies completed so far and cited below. In addition these studies, conducted under controlled conditions, may not be applicable to the primary or secondary medical care that is received by most warfarin patients in the US. Allowing these or other future studies to be the gatekeeper to the implementation of warfarin DNA testing is not in the best interest of patients.

DNA testing of CYP2C9 and VKORC1 to help determine the maintenance dose of warfarin has been available from licensed medical laboratories since before 2000. There are now several FDA approved DNA diagnostic tests of high quality for warfarin dosing on the market. These tests are readily available and with the short turnaround time needed during the initiation of warfarin therapy. Prescribers can act on the test results because algorithms that incorporate DNA testing results and a variety of currently recognized clinical factors and drug interactions are available that can account for up to 79% of the individual dose variation. They can also predict the maintenance dose to within a milligram per day. These tests do not replace INR testing but have been shown to reduce the frequency needed for INR tests by improving the prediction of stable maintenance dose. In August 2007 the FDA changed the Coumadin drug label to point out the impact individual genetic variation has on warfarin dose requirement and risk.

One of the last remaining barriers to the routine adoption and availability of warfarin dosing DNA testing to the elderly patient is reliable and consistent insurance reimbursement. Estimates of cost effectiveness suggest that almost $1000 per patient could be saved by routine use of warfarin DNA testing at a cost of $550 per test, consistent with the costs of other routinely prescribed genetic tests. As testing volumes increase the costs of warfarin genetic testing will drop, further increasing its cost-effectiveness. These estimates did not take into account the added costs of more frequent monitoring and dosing adjustments by health care providers or the personal costs to patients. In addition, the psychological impact on patients to improve warfarin compliance will be enhanced by knowing that their prescriber has done all they can to start warfarin safely.

If the Center for Medicare and Medicaid Services adopts a policy of reimbursement for warfarin DNA testing, the virtually unanimous body of evidence collected for more than a decade points to a net result of a reduction in adverse events, treatment failures and costs. If CMS declines to reimburse for warfarin DNA testing it will be a major set-back for pharmacogenetic based personalized medicine and more importantly the millions of patients who will be denied the utility of this test and suffer accordingly as we have seen by published reports of the risks and bleeding complications in elderly patients treated with warfarin.

In summary, the weight and quality of evidence supports genetic testing for 2C9 and VKORC1 gene variants in elderly patients before or shortly after starting warfarin to improve the quality of anticoagulation and define starting doses that are closer to the eventual stable maintenance doses of warfarin. I recommend that CMS seriously consider reimbursement for these tests.

Abstracts of key papers.

A recent summary of previous trials, the benefit of genetic testing to various measures of quality anticoagulation and their conclusions about risks of bleeding can be found in “The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics.” Clin Pharmacol Ther, 2008 Sep;84(3):301-3 by LJ Lesko, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA is available at http://www.nature.com/clpt/journal/v84/n3/full/clpt2008133a.html 

These papers were published following recent FDA labeling changes (see below for excerpts).  They have also not been included in previous assessments of genetic testing to guide warfarin therapy such as the California Technology Assessment Forum which covers published literature to December 2007.

The largest prospective warfarin-treated cohort supports genetic forecasting.

Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P.: Blood. 2008 Jun 23

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (p=6.63×10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (p=9.82×10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygozity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95%CI 9.46;50.42) and 4.56 (95%CI 2.85;7.30), respectively. One of eight patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (p=0.066). A multiple regression model using the predictors CYP2C9, VKORC1, age, gender and drug-interactions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. Clin Pharmacol Ther. 2008 Sep;84(3):326-31. Epub 2008 Feb 27

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients.

Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. Thromb Haemost. 2008 Aug;100(2):229-39

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.

 

Health Care Savings from Personalizing Medicine Using GeneticTesting: The Case of Warfarin

Andrew McWilliam, Randall Lutter and Clark Nardinelli Working Paper 06-23, November 2006 AEI-BROOKINGS JOINT CENTER FOR REGULATORY STUDIES.

Updated in Personalized Medicine (2008) 5(3): 279-284 confirming with sensitivity analysis that cost savings per patient who is tested genetically can be nearly $1000 per patient and improve health outcomes.

Executive Summary

Progress towards realizing a vision of personalized medicine—drugs and drug doses that are safer and more effective because they are chosen based on an individual’s genetic makeup has been slower than once forecast. The Food and Drug Administration has a key role to play in facilitating the use of genetic information in drug therapies because it approves labels, and labelsi nfluence how doctors use drugs. Here we evaluate one example of how using genetic information in drug therapy may improve public health and lower health care costs.

Warfarin, an anticoagulant commonly used to prevent and control blood clots, is complicated to use because the optimal dose varies greatly among patients. If the dose is too strong the risk of serious bleeding increases and if the dose is too weak, the risk of stroke increases. We estimate the health benefits and the resulting savings in health care costs by using personalized warfarin dosing decisions based on appropriate genetic testing. We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion.

Excerpts from the most recent changes to the Coumadin (warfarin) labeling. The complete label is available at: http://www.fda.gov/cder/drug/infopage/warfarin/default.htm

Metabolism

The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4′-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin. NDA 9-218/S-105 Page 4

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these allelles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively¹. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).²

Table 1. Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients

CYP2C9 Genotype	N	S-Warfarin Clearance/Lean Body Weight (mL/min/kg) Mean (SD)a
*1/*1	118	0.065 (0.025)b
*1/*2 or *1/*3	59	0.041 (0.021)b
*2/*2, *2/*3 or *3/*3	11	0.020 (0.011)b
Total			188

 

Pharmacogenomics

A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.³ In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.⁴ NDA 9-218/S-105 Page 5 Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.⁵ About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients.⁵ Similar observations have been reported in Asian patients.^6,7

Selected References:

Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002;287:1690-8

Takahashi H, Wilkinson GR, Padrini R, Echizen H. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004;75:376-80.

Gage, B.F., Eby, C., Milligan, P.E., Banet, G.A., Duncan, J.R. & McLeod, H.L. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb. Haemost. 91, 87–94 (2004).

Aithal, G.P., Day, C.P., Kesteven, P.J.L. & Daly, A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).

Margaglione, M. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost. 84, 775–778 (2000).

Voora, D. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb. Haemost. 93, 700–705 (2005).

Rieder, M.J. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352, 2285–2293 (2005).

Wadelius, M. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 5, 262–270 (2005).

D’Andrea, G. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105, 645–649 (2005).

Yuan, H.Y. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Mol. Genet. 14, 1745–1751 (2005).

Aquilante, C.L. et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin. Pharmacol. Ther. 79, 291–302 (2006).

Linder, M.W. et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J. Thromb. Thrombolysis 14, 227–232 (2002).

Shine, D. et al. A randomized trial of initial warfarin dosing based on simple clinical criteria. Thromb. Haemost. 89, 297–304 (2003).

Caraco, Y., Blotnick, S. & Muszkat, M. CYP2C9 Genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin. Pharmacol. Ther. 83, 457–467 (2008).

Anderson, J.L. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116, 2563–2570 (2007).

Millican, E. et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood 110, 1511–1515 (2007).

Marsh, S., King, C.R., Porche-Sorbet, R.M., Scott-Horton, T.J. & Eby, C.S. Population variation in VKORC1 haplotype structure. J. Thromb. Haemost. 4, 473–474 (2006).

Aquilante, C.L., Lobmeyer, M.T., Langaee, T.Y. & Johnson, J.A. Comparison of cytochrome P450 2C9 genotyping methods and implications for the clinical laboratory. Pharmacotherapy 24, 720–726 (2004).

Ridker, P.M. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N. Engl. J. Med. 348, 1425–1434 (2003).

Sconce, E.A. et al. 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 (2005).

Herman, D., Peternel, P., Stegnar, M., Breskvar, K. & Dolzan, V. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb. Haemost. 95, 782–787 (2006).

Wu, A. Use of genetic and non-genetic factors in warfarin dosing algorithms. Pharmacogenomics 8, 865–872 (2007).

King, B.P., Khan, T.I., Aithal, G.P., Kamali, F. & Daly, A.K. Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. Pharmacogenetics 14, 813–822 (2004).

King, C.R. et al. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J. Clin. Pathol. in press.

Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest 2004;126:3 Suppl:204S-233S. [Erratum, Chest 2005;127:415-6.]

Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-9.

Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119: 1 Suppl:108S-121S.

White, R.H., Beyth, R.J., Zhou, H. & Romano, P.S. Major bleeding after hospitalization for deep-venous thrombosis. Am. J. Med. 107, 414–424 (1999).

Beyth, R.J., Quinn, L. & Landefeld, C.S. A multicomponent intervention toprevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Ann. Intern. Med. 133, 687–695 (2000).

Hirsh, J., Fuster, V., Ansell, J. & Halperin, J.L. American heart Aassociation/American college of cardiology foundation guide to warfarin therapy. Circulation 107, 1692–1711 (2003).

Ezekowitz, M.D., James, K.E., Radford, M.J., Rickles, F.R. & Redmond, N. Initiating and maintaining patients on warfarin anticoagulation: the importance of monitoring. J. Cardiovasc. Pharmacol. Ther. 4, 3–8 (1999).

Ansell, J. et al. Managing oral anticoagulant therapy. Chest 119 (suppl. 1), 22S–38S (2001).

Ageno, W., Squizzato, A., Dentali, F. & Crowther, M. Tailoring warfarin induction doses to reflect individual and disease-specific factors. Am. J. Med.118, 143–144 (2005).

Lenzini, P.A. et al. Optimal initial dose adjustment of warfarin in orthopedic patients. Ann. Pharmacother. 41, 1798–1804 (2007).