Vitamin K Antagonists Dose Research Articles

#3662 FREQUENCY OF INR TESTING IN HEMODIALYSIS PATIENTS ON VITAMIN K ANTAGONISTS: A RETROSPECTIVE STUDY

Abstract Background and Aims Despite the rising of direct oral anticoagulant agents’ use in the general population, vitamin K antagonists (VKA) are still used in hemodialysis (HD) French patients with atrial fibrillation. These HD patients on VKA have also poor levels of time in therapeutic range. It is recommended generally to follow patients with monthly INR, however there is lack of such evidence in HD. This study aims to analyze the frequency of INR testing needed in HD patients. Method This is a retrospective study of all patients treated with VKA in three French dialysis units between 1st January and 31st December 2022. Patients are followed with weekly INR. Variables collected included over twelve months the number of INR tests, their percentage within target, above target and below target, and number of VKA dose adjustment. Bleedings, transfusions, thrombotic events and antibiotic use were recorded. Linear regression analysis evaluated factors associated with number of VKA dose adjustment per year. This study was conducted in concordance with the Declaration of Helsinki 1975. Results Out of 160 HD patients, 45 (28.1%) were on VKA for paroxysmal or chronic atrial fibrillation. Their characteristics are summarized in Table 1. A total of 2609 INR tests were performed over a year with a mean of 57.9±18.6 per patient. The median number of VKA dose adjustment per year was 11 (8, 13). A significant correlation was found between the number of antibiotics and number of VKA dose adjustment (Spearman Rho = 0.360, p = 0.015). In univariate regression analysis, factors associated with higher numbers of dose adjustment were diabetes, sevelamer and blood flow (Table 2). Bleeding was not significantly different between those with high versus low VKA dose adjustment. Conclusion In this study, 22% of tests led to VKA dose adjustment. Patients with diabetes, on sevelamer, treated with antibiotics and with lower serum albumin needed frequent INR testing more than once monthly. These results could be helpful in contexts with limited resources.

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 variants influence vitamin K anticoagulant dosing in patients with mechanical prosthetic heart valves.

Background: Vitamin K antagonists (VKAs) are class I oral anticoagulants that are widely prescribed following surgical heart valve implantation. The objective of this studywas to quantify the relative effects of VKORC1, CYP2C9 and CYP4F2 genotypes in predicting VKA dosing. Materials & methods: A total of 506 South Indian patients with mechanical prosthetic heart valves who were prescribed oral VKAs, such as warfarin or acenocoumarol, were genotyped. The discriminatory ability of mutant genotypes to predict dose categories and bleeding events was assessed using regression analysis. Results: The VKORC1 rs9923231, CYP2C9*3 and CYP4F2*3 mutant genotypes significantly influenced VKA-dose requirements and explained 27.47% of the observed dose variation. Conclusion: Theseresults support pharmacogenetic screening for initial VKA dosing among South Indian patients with mechanical prosthetic heart valves.

Left atrial thrombus and smoke resolution in patients with atrial fibrillation or flutter under chronic oral anticoagulation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non–vitamin K antagonist (VKA) oral anticoagulant treatment (OAT) are scarce. Purpose The aim of this study was to explore retrospectively the resolution of LA/LAA spontaneous echo-contrast or thrombus in patients with nonvalvular atrial fibrillation (AF) or atrial flutter (AFL) after OAT in a real-world single center practice. Methods A single center retrospective analysis of patients with AF/AFL who underwent a transesophageal echocardiography (TEE) for an electrical cardioversion and/or atrial fibrillation ablation was performed. Patients showing LA/LAA echo-contrast or thrombus and with at least one TEE follow up to detect the resolution of LA/LAA echo-contrast/thrombus were included and analyzed. Results Among 277 TEE performed, 73 cases (26%) of LA/LAA echo-contrast or thrombus were detected in our hospital. Among them, a total of 53 patients showed LAA/LA echo-contrast (19%) and 20 (7%) patients showed a thrombus. Patients with echo-contrast or thrombus were usually male (78% vs 72%, p=0.05) with more comorbidities, as hypertension (90% vs 72%, p=0.03) and congestive heart failure (36% vs 17%, p=0.007) and with an overall higher CHA2DS2-Vasc score (3.5±1.5 vs 3±1, p=0.0001). All they were under chronic anticoagulation with a VKA (65%) or with a NOAC (35%), without differences between groups. (p=NS). At the TTE/TEE analysis, they showed a comparable ejection fraction (55±11 vs 55±22%, p=NS), a trend for an increased LA dilatation (27±8 vs 26±6 cm2, p=0.07) and a low LAA peak velocity (94% vs 19%, p=0.0001). The Echo-contrast Group maintained the same OAT strategy in 49 patients (93%), switching from VKA to NOAC in 3 cases (6%) and from NOAC to NOAC in 1 (1%). The Thrombus Group kept the same OAT strategy with a NOAC in 6 cases (30%) and changed the strategy in 14 patients (70%). Particularly, they titrated NOAC dose in 1 (5%) and the VKA dose in 4 (20%), switched from NOAC to VKA in 5 (25%), from VKA to NOAC in 3(15%) and from NOAC to NOAC in 1 (5%). Smoke resolution was observed in LA/LAA smoke group in 1/10 cases (10%) after a median time of 52 days (20-135) and LA/LAA thrombus resolution 8/15 (53%) after a median time of 45 days (25-180). Patients with the thrombus resolution had a lower CHA2DS2-Vasc score (3.5±2 vs 4±1, p=0.05), and showed a trend for a more frequent use of a NOAC (37.5 vs 28%, p=0.07) and a longer overall anticoagulation time (7.5 vs 4 months, p=0.08). At one-year follow-up, 1 ischemic stroke (1.9%) and 2 deaths (3.8%) were observed only in the Echo-contrast group. Conclusion(s) In OAT patients with an LA/LAA thrombus changing the OAT strategy is associated with thrombus resolution in more than 50% of cases, after an appropriate anticoagulation period and in lower CHAD2S2Vasc patients. Chronic OAT strategy confirmation, also with NOAC, is rarely effective, also in case of echo-contrast resolution.

Anticoagulant drug‐drug interactions: Highlighting the need for antithrombotic stewardship and shared decision making

When clinicians consider selecting an oral anticoagulant medication for their patient, a key advantage of the direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) is the fewer number of clinically significant drug‐drug interactions. Typically with VKAs, a drug interaction can be managed via monitoring of the international normalized ratio (INR) and subsequent adjustment of the VKA dose. With DOACs having primarily fixed‐dose regimens and laboratory testing that is not universally available or guideline recommended, drug interactions present a challenge to clinicians.

From a DOAC to Warfarin: Reasons Why Patients Switch

1. IntroductionThe introduction of direct oral anticoagulants (DOACs) has led to their widespread use for stroke prevention in patients with non-valvular atrial fibrillation (AF) and as first-line treatment in acute venous thromboembolism (VTE), and also as secondary thromboprophylaxis in patients with a history of VTE. In addition, many patients previously taking vitamin K antagonists (VKAs) have switched to a DOAC for reasons including erratic international normalised ratio (INR) control, medication interactions, convenience, possible lower major bleeding risk and possible improved stroke prevention rates. Although DOACs are well tolerated, little is known about the numbers of patients switching from a DOAC to (or back to) a VKA or the reasons for doing so.2. MethodsThis study was an analysis of prospectively-collected data from a four-year period surveying a computer-based VKA (warfarin) dose adjustment clinic in a large city centre hospital. The primary objective was to identify the reasons for patients switching from a DOAC to warfarin. Secondary objectives included assessing indication for anticoagulant therapy and choice of DOAC. The time in therapeutic range (TTR) once switched back to VKA and clinical events following commencement of warfarin were also determined.3. ResultsIn our VKA clinic with 1791 patients annually under review, 39 patients were identified as having switched from a DOAC to warfarin. The mean age of the patients was 68.5 years +/- 13.8 and the majority (N=24) were female. AF was the most common condition necessitating anticoagulation (N=24); VTE accounted for 12 cases; arterial thromboembolism (N=2) and cardiac thrombus (N=1) were less common causes and one patient had been started on a DOAC in the setting of valvular replacement. Of the patients who were switched to warfarin, seven (17.9%) had originally been anticoagulated with a VKA prior commencing on a DOAC. In terms of anticoagulant choice, the majority of patients (N = 27) were taking rivaroxaban with 6 patients each on dabigatran and apixaban. The causes for switching in this cohort are outlined in table 1. Interesting cases of note include one patient who had a splenic infarction while taking rivaroxaban for atrial fibrillation and one patient who developed a new thumb arterial embolus while taking rivaroxaban for a PE.Following warfarin commencement, there was a total of eight clinical events reported (21.1% of patients). There were seven bleeding events recorded with two serious events necessitating hospital admission and five minor events; in five of these (71.4%), the original reason for switching back to warfarin had been a bleed while on a DOAC. One further patient had a high INR necessitating administration of vitamin K. The mean TTR of this cohort was 61.4% +/- 22.3. 33 patients (84.6%) of patients still attend the warfarin clinic, with cessation of anticoagulant therapy having occurred in three patients (7.7%) and death occurring in one patient (2.6%); two patients (5.1%) have been recommenced on a DOAC.4. DiscussionDOACs have several advantages over warfarin for many patients; they do not require monitoring and the dose remains stable. Index trials have demonstrated at least non-inferiority to warfarin in stroke prevention in non-valvular AF and treatment of VTE, with at least no significant difference in bleeding outcomes. However, warfarin can be an attractive option in complicated cases as it can be rapidly reversed, and there continues to be greater levels of clinician experience with its use. In the present study, we report data regarding the switch back to warfarin in a DOAC cohort, an area into which little research has been conducted. There were only 39 patients reported over a four-year period; this represents only a small minority of the full cohort. As expected, the majority of patients required a switch because of re-thrombosis or a bleeding event. Patients also required an appropriate switch in situations outside of the licence of the DOACs i.e. renal deterioration or valvular AF. The authors are not aware of any data regarding arterial embolisation in rivaroxaban users, and acute hepatitis has been rarely described in rivaroxaban use. These data confirm that switching from a DOAC to warfarin is seldom deemed necessary by clinicians. However, familiarity and experience may guide therapy in complicated cases, and vigilance is required to ensure adherence to the licence when prescribing a DOAC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Maximising Time in Therapeutic Range with Vitamin K Antagonists in LVAD Patients

<h3>Purpose</h3> Time in Therapeutic range (TTR) is the percentage of time an anticoagulated patient has an INR between 2-3. While studies have demonstrated a link between low TTR, bleeding and thrombosis, the mean TTR in a VAD population is between 45 and 65%. We implemented a new anticoagulation protocol using point of care devices (POC, coagucheck©), with patient education and empowerment to control their own VKA (vitamin K antagonist) dosing. <h3>Methods</h3> Before discharge all VAD patients received anticoagulation education including drug and food interaction. Depending on INR stability, patients measured INR every 2-3 days and sent a text message to the VAD team for the appropriate VKA dose. After a minimum of 2 months post VAD, if the patient and team felt comfortable, VKA dosing was delegated to the patient. Patients updated the team weekly. <h3>Results</h3> Between February and October 2020, 24 patients were included (29% HM3, 71% HW, one Bi-VAD (HW)). Median follow-up was 131 days (IQR 88-163), cumulative follow up time was 3087day or 8.5 years. Median TTR was 90% (IQR 83-97), median INR 2.41 (IQR 2.2-2.4). INR was measured 3.6 times / week (IQR 3.3-3.8). In 15 cases (62%), the VKA dosing decision was delegated to the patient. Median TTR during patient management (96%, IQR 90-97) was significantly higher than the TTR during medical control (83%, IQR 78-88) (P<0.0001). There were no deaths, major bleeding events, pump thrombosis or strokes under patient management. Ten patients (41%) received one or more doses of enoxaparin (1mg/kg once a day) as bridge for INR < 1.8 for HW and 1.6 for HM3 pump. <h3>Conclusion</h3> A TTR higher than described in the literature is achievable in VAD patients using a POC device. If prerequisites are met, VAD patients can be empowered to control their VKA dosing with excellent TTR.

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study

BackgroundVitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables.ObjectiveThe authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patientsMethodologyDNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0–3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910).ResultsThe clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability.ConclusionWe developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 (rs4244285), CYP1A2*1F (rs762551), GGCx (rs11676382), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP4F2 (rs2108622), VKORC1 (rs9923231), VKORC1 (rs7294), CYP3A4*1B (rs2740574), and ABCB1 (rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.

International Survey for Strategies Used for Oral Anticoagulation Reversal in Children

Background: Vitamin K antagonists (VKA) have been the main stay of oral anticoagulation (OAC) in pediatrics. However, VKA have multiple challenges. The pharmacological properties of direct oral anticoagulants (DOACs) suggest that they may have advantages particularly for children. The off-label use of DOACs is however on the rise within the pediatric population. The increasingly broad and varied use of DOACs, lack of published clinical guidance, and limited data on reversal strategies have created the imperative to identify strategies for OAC reversal in pediatrics. We conducted an online survey for strategies used for oral anticoagulants reversal in pediatrics. Study Design: Institutional review board approval was obtained and an online survey was developed using the RedCap. The survey was electronically distributed by International Society of Hemostasis and Thrombosis (ISTH) to its Pediatric/Neonatal Thrombosis and Hemostasis Subcommittee group members. The survey questions asked approach to common hypothetical clinical scenarios for OAC reversal.The data were analysed descriptively. Results: There were 76 respondents, majority from academic free-standing Children'sHospitals. Seventy-two percent reported having a hemostasis-thrombosis/anticoagulation service but only 29 % have a dedicated anticoagulation pharmacist. Approximately 40% do not have a formal protocol in place for VKA reversal. For a supra-therapeutic INR (INR &gt; 5) in a non-bleeding patient, 95% opted to manage by omitting the next dose of VKA while 18 % opted to give oral vitamin K alone or comitantly. For clinically relevant non-major bleeding, majority indicated using Vitamin K; oral (51%) or IV (37). For major bleeding on VKA, majority use either a combination of 4F-PCC and IV Vitamin K or plasma and IV Vitamin K (44/76 and 26/76 respectively). The presence of bleeding seemed to be the major driver for the choice of route (enteral versus parenteral) for Vitamin K for VKA reversal. Thirty-six of the 76 respondents indicated using DOACs; 94% used FXa inhibitors and 1/3 use dabigatran in their clinical practice. For non-urgent DOAC reversal, 97% indicated omitting the next dose. For non-major bleeding on DOAC, majority (29/36) indicated omitting the next dose/doses, some chose 4F-PCC (8/36) and only a few indicated use of specific reversal agents (3/36 and 1/36 for Dabigatran and Andexanet respectively). For major bleeding while on DOACs, the use of specific reversal agents (11/35, 6/35 for Andexanet and idarucizumab respectively) followed by 4F-PCC (9/35) was the major intervention indicated. Dilute thrombin time and partial thromboplastin time were the most commonly utilized tests to measure residual dabigatran activity. For Factor Xa inhibitors routine heparin assay rather than DOAC calibrated anti-Xa activity is utilized by most of the responders to assess presence of the plasma drug activity. Conclusion: Practices for oral anticoagulants reversal vary substantially in the pediatric population. Plasma is still used for urgent VKA reversal in many pediatric centers. The off-label use of DOACs in children is on the rise. Our results highlight the need for further studies to standardize OAC reversal in children. Disclosures Gupta: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Research Funding; Novartis: Honoraria, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarode:Portola: Honoraria; Octaphrarma: Consultancy; CSL Behring: Consultancy; Siemens: Research Funding. OffLabel Disclosure: The pharmacological properties of direct oral anticoagulants (DOACs) suggest that they may have advantages particularly for children. They are currently not approved in children. The off-label use of DOACs is however on the rise within the pediatric population.

Structural Basis of Vitamin K Antagonism

The vitamin K cycle supports blood coagulation, bone mineralization, and vascular calcium homeostasis. A key enzyme in this cycle, vitamin K epoxide reductase (VKOR), is the target of vitamin K antagonists (VKAs). Despite their extensive clinical use, the dose of VKAs (e.g., warfarin) is hard to regulate and overdose can lead to fatal bleeding. Improving the dose regulation requires understanding how VKAs inhibit VKOR, which is a membrane-embedded enzyme difficult to characterize with structural and biochemical studies. Here we achieve a long-standing goal of obtaining crystal structures of human VKOR with warfarin, which represents coumarin-based VKAs; with phenindione, which represents indandione-based VKAs; with superwarfarins, the most commonly used rodenticides; and with vitamin K epoxide in a reaction intermediate state. We have also solved structures of a VKOR-like homolog with warfarin, with vitamin K substrates, and without ligand. These structures show that human VKOR adopts an overall fold with four transmembrane helices (TM) and a large ER-luminal region. VKAs are bound at the active site of HsVKOR, which is formed by the surrounding four-TM bundle and a cap domain on top. The cap domain is stabilized by a linked anchor domain that interacts with the membrane surface. VKOR binds specifically to VKAs through hydrogen bonding to their diketone groups. Mutating VKOR residues recognizing the diketones render strong warfarin resistance. Except the hydrogen bonds, the binding pocket is largely hydrophobic. This pocket is incompatible with warfarin metabolite, explaining the inactivation of warfarin through CYP2C9 metabolism; CYP2C9 and VKOR genotypes can explain 30-50% of the patient variability in warfarin dose. In addition, the high potency of superwarfarins is due to the interaction of their side group with a tunnel where the isoprenyl chain of vitamin K is bound. For VKOR catalysis, the same residues affording the VKA-binding specificity also facilitate substrate reduction Initiation of the catalysis requires a reactive cysteine to form a substrate adduct. Interactions from this stably bound adduct induces a closed conformation, thereby triggering electron transfer to reduce the substrate. Importantly, the open to closed conformational change during catalysis similar to that induced by the binding of VKAs. Taken together, VKAs achieve inhibition through mimicking key interactions and conformational changes required for VKOR catalytic cycle. Understanding of these mechanisms will enable improved strategy to regulate warfarin dose and have a broad impact on thromboembolic diseases and bone disorders. Disclosures No relevant conflicts of interest to declare.

Oral Anticoagulant Therapy-When Art Meets Science.

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.

2018 Korean Heart Rhythm Society Guidelines for Non-Vitamin K Antagonist Oral Anticoagulants

Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative to vitamin K antagonists (VKAs) and have emerged as the treatment of choice in Korea. However, several questions remain regarding the optimal use of these agents in specific clinical situations. In this paper we discuss 1) patients with atrial fibrillation (AF) and coronary artery disease, 2) avoiding confusion with NOAC dosing across indications, 3) cardioversion in a patient treated with a NOAC, 4) AF patients who present with acute stroke while on NOACs, 5) NOACs in special situations, 6) anticoagulation in AF patients with a malignancy, and 7) optimizing VKA dose adjustments. (Korean J Med 2019;94:57-82)

How to Generate a More Accurate Laboratory-Based International Normalized Ratio: Solutions to Obtaining or Verifying the Mean Normal Prothrombin Time and International Sensitivity Index.

Although the landscape of anticoagulation therapy is evolving, vitamin K antagonists (VKAs) such as warfarin remain an anticoagulant of choice for many clinicians and their patients. Nevertheless, management of VKA therapy remains challenging, largely because of patient variability and drug and food interactions; thus, VKA dosing has to be personalized. This is achieved by regular monitoring using a test called the prothrombin time (PT), mathematically converted to an international normalized ratio (INR). The INR system is meant to harmonize laboratory test results by taking into account reagent and instrumentation variability that is otherwise expected to give rise to variable PT values, but which should accordingly lead to less variable INR values. Of clinical importance, too low an INR is suggestive of increased thrombotic risk and typically means the VKA dose should be increased, whereas too high an INR is suggestive of increased bleeding risk and typically means the VKA dose should be temporarily withheld and/or decreased. However, evidence continues to show that variability in INR values between laboratories remains unacceptably high. Given that modern instrumentation provides for robust analytical values-meaning highly reproducible intralaboratory clotting times or PTs in this case-the most likely cause of high INR variability is inconsistency in the INR test components-meaning the MNPT (mean normal PT) and ISI (international sensitivity index) values used by laboratories to generate a given INR. In other words, there are doubts as to the accuracy of some INR values because there are corresponding doubts about the accuracy of MNPT and/or ISI values that have been assigned by some laboratories for their reagent/instrument combination. The current report is intended to provide some solutions around the problems of inaccurate INRs, ISIs, and MNPTs, thus aiming to drive laboratory INRs closer to "truth," and thus promote better patient management. The novel strategies include a primary process of transference to obtain/verify MNPT and/or ISI values for a new reagent using an existing reagent as reference, and a secondary process whereby external quality assessment data can be used to correct bias or existing errors in assigned MNPT and/or ISI values.

Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants.

Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs).VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult. GWAs have been useful in finding genetic variants associated with VKAs response. The main genes involved in VKAs pharmacogenetics are: VKORC1, CYP2C19 and CYP4F2. Variants in these genes have been included in pharmacogenetic algorithms to predict the VKAs dose individually in each patient depending on their genotype and clinical variables.DOACs: Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for patients with AF. They have stable pharmacokinetics and do not require routine blood checks, thus avoiding most of the drawbacks of VKAs. Except for a GWAs performed in patients treated with dabigatran, there is no Genome Wide pharmacogenomics data for DOACs. Pharmacogenomics could be useful to predict the better clinical response and avoid adverse events in patients treated with anticoagulants, identifying the most appropriate anticoagulant drug for each patient. Current pharmacogenomics data show that the polymorphisms affecting VKAs or DOACs are different, concluding that personalized medicine based on pharmacogenomics could be possible. However, more studies are required to implement personalized medicine in clinical practice with OA and based on pharmacogenetics of DOACs.

The VKORC1 and CYP2C9 genotypes significantly effect Vitamin K antagonist dosing only in patients over the age of 20 years

Given the qualitative differences in the role of VKORC1 and CYP2C9 polymorphisms in Vitamin K antagonists (VKA) dosing variation between adults and children, we were interested in determining at what age these polymorphism begin to play a more significant role. A prospective cohort study of 190 patients aged 1-86years receiving VKA for treatment of venous thromboembolism. Blood samples were collected beyond the acute thrombotic event when patients were on stable targeted INR (2-3) for plasma testing and VKORC1/CYP2C9 genotyping. Patient demographics including VKA dose were collected. Simple and multiple linear regression was used to assess the relationship of VKA dose with polymorphisms and weight, adjusted for quality of anticoagulation (INR, D-Dimer), liver (AST, ALT) and renal function. In subjects 1-19years of age, weight explained 39.0% of dosing variation with VKORC1 and CYP2C9 playing a minor role. In contrast, in subjects 20-40years weight contributed 23%, VKORC1 44% and CYPC29 49% of the VKA dose variation. Until the age of 19, weight has a far greater effect on VKA dosing variation than VKORC1 and CYP2C9 polymorphisms. During the age of 20-40years, VKORC1 and CYP2C9 play a significant role.

Optimization of vitamin K antagonist drug dose finding by replacement of the international normalized ratio by a bidirectional factor: validation of a new algorithm

ESSENTIALS: We developed a new algorithm to optimize vitamin K antagonist dose finding. Validation was by comparing actual dosing to algorithm predictions. Predicted and actual dosing of well performing centers were highly associated. The method is promising and should be tested in a randomized trial. Oral vitamin K antagonists (VKAs) have a narrow therapeutic window and thus require frequent monitoring of its intensity by the international normalized ratio (INR). Improvement of VKA dosing defined as more time in therapeutic range (TTR) can reduce thrombotic disease and bleeding. Computerized decision support programs (CDSs) are used to optimize VKA dosing, but the effects are heterogeneous. CDSs significantly improve the proportion of time in the therapeutic INR range for initiation therapy but not the quality of anticoagulant management in an outpatient setting. One of the major problems of VKA dose finding is that the INR is a ratio and does not present linearity. We developed a new dose-finding algorithm, based on a novel bidirectional factor (BF). This BF is linear transformation of the nonlinear INR. We compared the outcomes of the new algorithm, called BF-N, with dose finding performed at three highly ranked Dutch anticoagulation centers, using both acenocoumarol and phenprocoumon. The outcomes of the BF-N algorithm showed a linear correlation with VKA doses of the three centers (y = 1.001x, r(2) 0.999 for acenocoumarol and y = 0.999x, r(2) 0.999 for phenprocoumon), with a standard deviation of 3.83%. The rate of automated dosage proposals increased to 100%. The BF-N algorithm performs well in real-life settings and increases the rate of automated dosage proposals. The algorithm can be easily built into existing CDSs. Experienced staff remains necessary for complicated situations. The new algorithm needs to be evaluated in a prospective trial.

Effect of Body Weight on Dose of Vitamin K Antagonists.

Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements. We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight. Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations. Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA.

Trends in antithrombotic drug use and adherence to non-vitamin K oral anticoagulants in the Netherlands.

Background Non-vitamin K oral anticoagulants (NOACs) became available in the Netherlands in 2008, providing another antithrombotic treatment besides vitamin K antagonists (VKAs) and antiplatelet agents (APAs). Objective To describe the patterns of antithrombotic drug use between 2008 and 2013 by examination of dispensing data form community pharmacies in the Netherlands; to determine the concomitant use of NOACs with VKAs and APAs and switching between the drug classes; and to compare adherence to NOACs with adherence to APAs. Setting An observational retrospective study was conducted using routinely collected dispensing data from Dutch community pharmacies. Methods For each calendar year, the numbers of NOAC, VKA, and APA users were calculated. Adherence was determined for NOACs and APAs by the percentage of days covered by medication (PDC). Information on the prescribed daily dose of VKAs was unavailable. Main outcome measures Comparison of age, sex, and co-medications of users of the three drug classes; concomitant use of different antithrombotic drug classes and switching between these in each year; and mean PDC and percentages of all users with a PDC above 80 %. Results NOAC use increased during the study period to 29,687 users in 2013. In that year there were 484,024 VKA users and 1313,032 APA users. Compared with users of VKAs, NOAC users were slightly younger and more frequently used antiarrhythmic drugs and beta blockers as co-medications. Substantial numbers of patients were dispensed potentially harmful combinations in 2013: 820 subjects were dispensed NOACs together with VKAs, and 684 subjects were dispensed NOACs, VKAs, and APAs concomitantly. Mean adherence to NOACs was 84.2 % compared with 87.3 % to APA. One in four NOAC users had a PDC lower than 80 % compared with one in five APA users. Conclusion Our findings show increasing use of NOACs by outpatients. The number of patients taking potentially harmful combinations of antithrombotic drugs was substantial. Adherence to NOACs in daily practice may be suboptimal to prevent thrombotic events.