Edith A. Nutescu

Drug and dietary interactions of warfarin and novel oral anticoagulants: an update

Clinicians and patients around the world have been intrigued by the concept of developing an oral anticoagulant with a broad therapeutic window and few drug and dietary interactions that can be administered at fixed doses with no or minimal monitoring. The recently approved oral direct thrombin inhibitor dabigatran, along with the emerging oral anti-factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have been developed to address many of the shortcomings of warfarin therapy. As warfarin is associated with extensive food and drug interactions, there is also a need to consider such interactions with the new oral anticoagulants. While to date few drug and dietary interactions have been reported with the new oral anticoagulants, it is still early in their development and clinical use cycle. Pharmacokinetic and pharmacodynamic profiles will have to be closely accounted for when determining the likelihood of a potential drug interaction prior to therapy initiation. As the list of drugs and supplements that interact with warfarin is continuously expanding, and the knowledge on drug interactions with the novel oral anticoagulants is still in its infancy, clinicians need to be vigilant when initiating any of these agents or when any changes in the patient’s medication profile occur and perform a close screening for potential drug and dietary interactions. The objective of this paper is to give an update on drug and dietary interactions with warfarin and the novel oral anticoagulants, dabigatran, rivaroxaban, apixaban, and edoxaban.

Genetic and Clinical Predictors of Warfarin Dose Requirements in African Americans

The objective of this study was to determine whether, in African‐American patients, additional vitamin K oxidoreductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), CYP4F2, or apolipoprotein E (APOE) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9*2 and *3 alleles and the VKORC1 −1639G>A genotype. In a cohort of 226 African‐American patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30–47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28–40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35–56) mg). The combination of CYP2C9 alleles, VKORC1 −1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9*5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1, CYP4F2, or APOE polymorphism contributed to the variance. The inclusion of additional CYP2C9 variants may improve the predictive ability of warfarin dosing algorithms for African Americans.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study

Summary Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10−8). This association was confirmed in the replication cohort (p=5·04×10−5); analysis of the two cohorts together produced a p value of 4·5×10−12. Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. Funding National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

Dosing and Monitoring of Low-Molecular-Weight Heparins in Special Populations

As a result of numerous clinical trials and meta‐analyses supporting the superior efficacy and relative safety of low‐molecular‐weight heparins (LMWHs) compared with unfractionated heparin (UFH), LMWHs are emerging as the antithrombotic agents of choice for the prevention and treatment of deep vein thrombosis and pulmonary embolism. In addition, data indicate that enoxaparin given with low‐dosage aspirin is more effective than UFH in treating acute coronary syndromes. Anti‐Xa activity can be used as a biologic marker of LMWH activity. Because of the more predictable anticoagulant response to subcutaneous administration of LMWHs compared with UFH, routine monitoring of anti‐Xa activity in clinically stable adults with uncomplicated disease is not recommended. Because the optimal dosage of LMWHs has not been established for patients with renal insufficiency or extremes of body weight, during pregnancy, or for children, anti‐Xa activity monitoring may be warranted in these subsets.

Warfarin and its interactions with foods, herbs and other dietary supplements

Despite its complex pharmacokinetic and pharmacodynamic profile, warfarin is still one of the most widely used oral anticoagulant agents. Attaining optimal anticoagulation with this agent is clinically challenging in view of its many food and drug interactions. Inappropriate anticoagulation control can expose patients to an increased risk of bleeding or thromboembolic complications, due to over and underanticoagulation, respectively. Fluctuations in dietary vitamin K intake can have a significant effect on the degree of anticoagulation in patients treated with warfarin. In addition, the explosion in use of various dietary supplements and herbal products can lead to undesired outcomes on anticoagulant levels. The aim of this review is to discuss the scope and the potential clinical impact of the most commonly reported food, dietary supplement and herbal interactions with warfarin therapy. Practical steps for patients and providers to minimise these interactions are highlighted.

Delivery of Optimized Anticoagulant Therapy: Consensus Statement from the Anticoagulation Forum

Objective: To provide recommendations, policies, and procedures pertaining to the provision of optimized anticoagulation therapy designed to achieve desired clinical endpoints while minimizing the risk of anticoagulant-related adverse outcomes (principally bleeding and thrombosis). Study Selection and Data Extraction: Due to this documents scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors who constitute the Board of Directors of The Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The Board is composed of physicians, pharmacists, and nurses with demonstrated expertise and significant collective experience in the management of patients receiving anticoagulation therapy. Data Synthesis: Recommendations for delivering optimized anticoagulation therapy were developed collaboratively by the authors and are summarized in 9 key areas: (I) Qualifications of Personnel, (II) Supervision, (III) Care Management and Coordination, (IV) Documentation. (V) Patient Education, (VI) Patient Selection and Assessment, (VII) Laboratory Monitoring, (VIII) Initiation and Stabilization of Warfarin Therapy, and (IX) Maintenance of Therapy. Recommendations are intended to inform the development of care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized anticoagulation therapy are intended to apply to all clinicians involved in the care of outpatients receiving anticoagulation therapy, regardless of the structure and setting in which that care is delivered. Conclusions: Anticoagulation therapy, although potentially life-saving, has inherent risks. Whether a patient is managed in a solo practice or a specialized anticoagulation management service, a systematic approach to the key elements outlined herein will reduce the likelihood of adverse events. The need for continued research to validate optimal practices for managing anticoagulation therapy is acknowledged.

Factors that Influence Prescribing Decisions

BACKGROUND Strategies to control the quality and cost of medication use are largely dependent on the ability to alter selection of medications. Previous models of prescribing behavior have focused on physicians. In the hospital setting, clinical pharmacists and formulary committee members are also key players in drug therapy decision-making. Differences between physicians, formulary committee members, and clinical pharmacists have not been compared. Knowledge of these differences could have importance in predicting the effectiveness of strategies designed to influence drug use in this setting. OBJECTIVE To describe and compare the opinions of physicians, clinical pharmacists, and formulary committee members with respect to key factors that influence medication prescribing in community hospitals. METHODS Physicians, clinical pharmacists, and formulary committee members were solicited to participate. A trained interviewer administered a standardized questionnaire designed to elicit opinions of participants regarding the importance of factors thought to influence drug prescribing. Responses were described using descriptive statistics, and differences between the groups were determined by post hoc analysis. RESULTS A total of 150 individuals participated in the study. Safety, effectiveness, formulary status, and restrictions on prescribing were considered highly influential by all participants. Physicians rated the availability of drug samples and personal experience higher (more influential on prescribing) than clinical pharmacists and formulary committee members. Clinical pharmacists and formulary committee members rated the influence of recommendations by clinical pharmacists, prescribing guidelines, and cost or cost comparisons higher than physicians. Factors that were drug-related or that involved policy-related programs tended to be more influential than indirect factors. CONCLUSIONS Those who seek to implement programs to alter medication use should recognize and employ factors that are most influential in the decision-making process. Further, it may be important to consider differences that exist between key participants in the medication use process.

Factors influencing warfarin dose requirements in African–Americans

INTRODUCTION African-Americans are under-represented in studies assessing contributors to warfarin response. Our primary objective was to determine whether the genes for cytochrome P450 (CYP) 2C9, nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase (NQO1) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are associated with warfarin dose requirements in African-Americans. PATIENTS AND METHODS The following factors were assessed: demographics; clinical data; the CYP2C9 Arg144Cys (*2), Ile358Leu (*3) and Asp360Glu (*5); NQO1 Pro187Ser (*1/*2); and VKORC1 G6853C genotypes were analyzed in 115 African-Americans on stable warfarin doses. RESULTS Allele frequencies were 0.05 for the CYP2C9 *2, *3 or *5 alleles; 0.20 for NQO1 *2; and 0.25 for VKORC1 6853C. Possession of a CYP2C9*2, *3 or *5 allele was associated with a 38% lower warfarin dose compared with the *1/*1 genotype (30 +/- 13 vs 48 +/- 18 mg/week; p = 0.003). Neither the NQO1 *1/*2 nor VKORC1 G6853C genotype was associated with warfarin dose requirements in the population as a whole or in CYP2C9*1 allele homozygotes. Multiple regression analysis revealed that CYP2C9 genotype (p = 0.015), age (p < 0.001) and body surface area (p < 0.001) were jointly associated with warfarin dose requirements, and together explained 33% of the variability in warfarin dose requirements among African-Americans. DISCUSSION Our data suggest that CYP2C9 genotype, age and body size are important determinants of warfarin dose requirements in African-Americans. Our data further suggest that the VKORC1 G6853C polymorphism alone may not be useful for predicting warfarin dose requirements in this racial group.

Rivaroxaban : An oral direct inhibitor of factor Xa

PURPOSE The mechanism of action, pharmacodynamics, pharmacokinetics, efficacy in clinical trials, interactions, adverse effects and toxicity, and place in therapy of rivaroxaban are reviewed. SUMMARY Rivaroxaban, the first oral, direct factor Xa (FXa) inhibitor to reach Phase III trials, inhibits thrombin generation by both the intrinsic and the tissue factor pathways. It has shown predictable, reversible inhibition of FXa activity, and it may have the ability to inhibit clot-bound FXa. Rivaroxaban is being evaluated for prevention of venous thrombosis in patients undergoing hip or knee arthroplasty, treatment of venous thrombosis, long-term use for secondary prevention of venous thrombosis, and prevention of stroke in atrial fibrillation. To date, only short-term trials have been reported, but rivaroxabans safety and efficacy appear to be at least equivalent to those of traditional anticoagulants. The results of four studies of primary prevention of venous thrombosis in patients undergoing orthopedic surgery suggest that rivaroxaban 10 mg daily is a promising alternative to low-molecular-weight heparins. Rivaroxaban appears to have a low potential for drug-drug or drug-food interactions. It offers the advantages of a fixed oral dose, rapid onset of action, and predictable and consistent anticoagulation effect, precluding the need for routine monitoring of anticoagulation. CONCLUSION Rivaroxaban is a promising alternative to traditional anticoagulants for the prevention and treatment of venous thromboembolism and for stroke prevention in atrial fibrillation; it offers once-daily oral administration without the need for routine monitoring.

Decreased Warfarin Clearance Associated With the CYP2C9 R150H (*8) Polymorphism

The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We conducted a pharmacokinetic study to examine whether the CYP2C9*8 allele impacts warfarin clearance in African‐American patients. We also conducted an in vitro kinetic study of S‐warfarin 7‐hydroxylation using complementary DNA (cDNA)‐expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S‐warfarin and a 25% lower R‐ to S‐warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with these findings, the in vitro intrinsic clearance of S‐warfarin was 30% lower with the cDNA‐expressed R150H protein as compared to the wild‐type protein. These data show that the R150H variant protein expressed by the CYP2C9*8 allele is associated with lower S‐warfarin clearance. This finding provides clinical and experimental evidence to explain the lower warfarin dose requirements in patients with the CYP2C9*8 allele.