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

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 labels influence 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.

Genotypes Frequencies of Rs9923231 and Rs7294 Snps in the Vkorci Gene among Emiratis and Their Implications for Warfarin Dosage

Warfarin is the most commonly used oral anticoagulant medication given as a prophylaxis and/or treatment of venous and arterial thromboembolic disorders. Warfarin doses vary up to 10-fold among patients due to pharmacokinetics, pharmacodynamics and pharmacogenomics factors. In addition, Warfarin has a low therapeutic index with the risk of developing serious side effects such as severe bleeding or failure of therapy. Therefore, the main challenge to achieve the therapeutic goal in warfarin treatment is estimating the appropriate dose for each patient. It is estimated that pharmacogenomics factors contribute to more than 60% of dose variability. The gene encoding for the target enzyme of Warfarin, vitamin K epoxide reductase complex 1 (VKORCI), is a highly polymorphic gene and contributes to about 30% of this variability. The US Food and Drug Administration (FDA) recommends genetic testing to determine the VKORCI genotype prior to using Warfarin. However, there are no data on VKORCI alleles and genotypes or their frequencies among Emiratis. Therefore, the current approach is trial and error with warfarin doses which might lead to some serious complications for patients receiving this medication. In this thesis, we used PCR amplification and direct DNA Sanger sequencing to genotype the two most important variants in VKORCI gene (namely, rs9923231 and rs7294). The sample consist of 117 healthy Emirati nationals as control and 96 patients on stable Warfarin therapy. The alleles and genotypes frequencies were determined for both groups. In addition, the daily warfarin maintenance dose for patients was examined for associations with the VKORCI genotypes at the rs9923231 and rs7294 positions. There was no significant difference in allele frequencies between the controls and patients for either SNP. The genotypes frequencies for rs9923231 were 25%, 48.4%, 26% for GG, GA, AA genotypes, respectively. In addition, genotypes frequencies for rs7294 variant were 44%, 44%, 12% GG, GA, AA genotypes, respectively. Crucially, both VKORCI polymorphisms were found to be strongly associated with Warfarin doses required to achieve the target international normalized ratio INR (p \u3c 0.0001). The results of this study confirm the suitability of VKORCI genotyping to guide the use of the appropriate warfarin dosage for Emiratis. Keywords: Warfarin dosage, s9923231, rs7294, VKORCI, pharmacokinetics of Emiratis, Pharmacogenomic

Opposite Response to Vitamin K Antagonists: A Report of Two Cases and Systematic Review of Literature

Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high response variability hamper their management. Several patients experience fluctuations in dose–response and are at increased risk of over- or under-anticoagulation. Therefore, it is essential to monitor the prothrombin time/international normalized ratio to determine the so-called stable dose and to adjust the dosage accordingly. Three polymorphisms, CYP2C9∗2, CYP2C9∗3 and VKORC1-1639G>A, are associated with increased sensitivity to VKAs. Other polymorphisms are associated with a request for a higher dose and VKA resistance. We described the clinical cases of two patients who were referred to the Clinical Pharmacology and Pharmacogenetics Unit of the University Hospital of Salerno for pharmacological counseling. One of them showed hypersensitivity and the other one was resistant to VKAs. A systematic review was performed to identify randomized clinical trials investigating the impact of pharmacogenetic testing on increased sensitivity and resistance to VKAs. Although international guidelines are available and information on the genotype-guided dosing approach has been included in VKA drug labels, VKA pharmacogenetic testing is not commonly required. The clinical cases and the results of the systematically reviewed RCTs demonstrate that the pharmacogenetic-based VKA dosing model represents a valuable resource for reducing VKA-associated adverse events

Pharmacogenetic testing of patients with atrial fibrillation who required warfarin therapy

66 patients with atrial fibrillation from Smolensk region who needed warfarin therapy were recruited into the study. The significant variants of CYP2C9 and VK0RC1 genes (CYP2C9*2, CYP2C9‘ 3, VK0RC1 *2) were detected by real-time PCR. Among the study population the prevalence of warfarin sensitivity genotypes were widespread.Обследовано 66 пациентов с фибрилляцией предсердий, проживающих на территории Смоленской области и нуждающихся в назначении варфарина. У пациентов определялось наличие клинически значимых вариантов генов CYP2C9 и VK0RC1: CYP2C9*2, CYP2C9*3, VK0RC1 *2 методом ПЦР в режиме реального времени. Среди обследованной популяции выявлено широкое распространение полиморфизмов, определяющих повышенную индивидуальную чувствительность к варфарину

Optymalizacja leczenia antagonistami witaminy K - rola polimorfizmów genowych

The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40-50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 - have been identified and they determined 99% of genetic variability of this enzyme. The presence of -1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8-12% and 3-8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile. Kardiol Pol 2010; 68, supl. V: 428-435Na wielkość stabilnej dawki antagonistów witaminy K (VKA) w leczeniu przeciwzakrzepowym, oprócz znanych czynników klinicznych, środowiskowych i demograficznych, duży wpływ mają również czynniki genetyczne. Ich udział w przewidywaniu dawki VKA ocenia się na 40–50%. Kluczowe znaczenie mają polimorfizmy genetyczne 2 enzymów uczestniczących w metabolizmie witaminy K i/lub VKA - podjednostka 1 reduktazy epoksydu witaminy K (VKORC1) i izoformy 2C9 cytochromu P450 (CYP2C9). Mniejsze lub niewielkie znaczenie mają genetyczne polimorfizmy innej izoformy P450 (CYP4F2), apolipoproteiny E (APOE) oraz γ-karboksylazy (GGCX). W populacji europejskiej wyróżnia się 3 haplotypy VKORC1: VKORC1*2, VKORC1*3 i VKORC1*4, determinujące 99% zmienności genetycznej tego enzymu. Obecność polimorfizmu VKORC1 -1639G>A wiąże się z większym zapotrzebowaniem na VKA. Warianty alleliczne CYP2C9*2 i CYP2C9*3 (występujące odpowiednio u 8-12% i 3-8% chorych) warunkują wolniejszy metabolizm VKA i tym samym zwiększają ryzyko krwawień, zwłaszcza na początku terapii. Dostępne algorytmy farmakogenetyczne uwzględniające polimorfizmy genów VKORC1 i CYP2C9 ułatwiają przewidzenie dawki VKA, szczególnie gdy zapotrzebowanie na lek jest małe lub umiarkowane. Wciąż jednak brak przekonujących danych o zmniejszeniu ważnych klinicznie powikłań leczenia VKA dzięki znajomości profilu farmakogenetycznego pacjenta. Kardiol Pol 2010; 68, supl. V: 428-43

Adaptive introgressive hybridization with the Algerian mouse (Mus spretus) promoted the evolution of anticoagulant rodenticide resistance in European house mice (M. musculus domesticus)

Song, Y., Endepols, S., Klemann, N., Richter, D., Matuschka, F.-R., Shih, C.-H., Nachman, M.W., Kohn, M.H

Optimalisation of treatment with vitamin K antagonists : the role of gene polymorphisms

Na wielkość stabilnej dawki antagonistów witaminy K (VKA) w leczeniu przeciwzakrzepowym, oprócz znanych czynników klinicznych, środowiskowych i demograficznych, duży wpływ mają również czynniki genetyczne. Ich udział w przewidywaniu dawki VKA ocenia się na 40–50%. Kluczowe znaczenie mają polimorfizmy genetyczne 2 enzymów uczestniczących w metabolizmie witaminy K i/lub VKA — podjednostka 1 reduktazy epoksydu witaminy K (VKORC1) i izoformy 2C9 cytochromu P450 (CYP2C9). Mniejsze lub niewielkie znaczenie mają genetyczne polimorfizmy innej izoformy P450 (CYP4F2), apolipoproteiny E (APOE) oraz g-karboksylazy (GGCX). W populacji europejskiej wyróżnia się 3 haplotypy VKORC1: VKORC1*2, VKORC1*3 i VKORC1*4, determinujące 99% zmienności genetycznej tego enzymu. Obecność polimorfizmu VKORC1 –1639G>A wiąże się z większym zapotrzebowaniem na VKA. Warianty alleliczne CYP2C9*2 i CYP2C9*3 (występujące odpowiednio u 8–12% i 3–8% chorych) warunkują wolniejszy metabolizm VKA i tym samym zwiększają ryzyko krwawień, zwłaszcza na początku terapii. Dostępne algorytmy farmakogenetyczne uwzględniające polimorfizmy genów VKORC1 i CYP2C9 ułatwiają przewidzenie dawki VKA, szczególnie gdy zapotrzebowanie na lek jest małe lub umiarkowane. Wciąż jednak brak przekonujących danych o zmniejszeniu ważnych klinicznie powikłań leczenia VKA dzięki znajomości profilu farmakogenetycznego pacjenta.The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40–50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 — have been identified and they determined 99% of genetic variability of this enzyme. The presence of –1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8–12% and 3–8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile

A Case of Azathioprine Induced Warfarin Resistance in Behçet’s Disease

Behçet’s disease is characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Thrombosis associated with vascular inflammation in patients with Behçet’s disease presents various clinical symptoms. Warfarin is usually administered for treatment of thrombosis. However, warfarin can interact with many medications that cause various problems. A 43-year-old woman with Behçet’s disease presented with a swollen right leg. Deep vein thrombosis (DVT) was confirmed, and treated with warfarin. Due to exacerbation of Behçet’s disease, she received azathioprine along with warfarin. Subsequently, the international normalized ratio (INR) decreased and DVT was exacerbated. Despite an increase in the warfarin dose, the patient did not reach the target INR. After discontinuation of azathioprine, DVT improved and the warfarin dose was decreased. There were no specific findings associated with a hypercoagulable status. This finding suggests the interaction of azathioprine and warfarin. Therefore, clinicians should be cautious regarding the possibility of drug interactions between azathioprine and warfarin.ope

Pharmacogenetics of warfarin - is testing clinically indicated?

Pharmacogenetics is genetic testing to optimise prescribing for individual patients. Warfarin is a potential candidate for pharmacogenetic testing as it is commonly used, has a narrow therapeutic window and its mechanism of action and elimination pathways involve receptors and enzymes that are polymorphic. Polymorphism is found in vitamin K epoxide reductase and cytochrome P450 2C9. Pharmacogenetic testing is not yet routine because alone it does not predict all the variability in a patient's response to warfarin so its contribution to improved clinical outcomes is uncertain