Managing transitions from oral factor Xa inhibitors to unfractionated heparin infusions.

PURPOSE: Published evidence regarding the effects of oral factor Xa inhibitors on anticoagulation monitoring tests is reviewed with a focus on monitoring concerns that can arise during transitions to i.v. heparin therapy. SUMMARY: Assays that measure inhibition of factor Xa activity (i.e., anti-Xa assays) are widely used in U.S. institutions to monitor i.v. heparin therapy and, in some cases, for monitoring other types of anticoagulation therapy. Clinicians have raised concerns that the use of anti-Xa assays to monitor heparin levels in hospitalized patients who must be transitioned from oral factor Xa inhibitor therapy to i.v. unfractionated heparin (UFH) infusions could yield unquantifiable or inaccurate results, leading to unnecessary UFH dose reductions and potential treatment failures; the manufacturer labeling of oral factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) does not provide specific guidance on this issue. Results of a literature review indicated that residual effects of oral factor Xa inhibitor use can result in substantial interference with the currently available chromogenic anti-Xa assays but negligible to moderate effects on global coagulation assays, which measure activated partial thromboplastin time (aPTT) or prothrombin time. Therefore, during the transition from an oral factor Xa inhibitor to i.v. UFH therapy, it may be prudent to consider an aPTT assay for anticoagulation monitoring. CONCLUSION: The use of oral factor Xa inhibitors appears to affect the accuracy of anti-Xa assay results, with results of global coagulation assays affected to a lesser degree.

Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. Despite the changing landscape of VTE treatment with the introduction of the new direct oral anticoagulants many uncertainties remain regarding the optimal use of traditional parenteral agents. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. This specific chapter addresses the practical management of heparins including low molecular weight heparins and fondaparinux. For each anticoagulant a list of the most common practice related questions were created. Each question was addressed using a brief focused literature review followed by a multidisciplinary consensus guidance recommendation. Issues addressed included initial anticoagulant dosing recommendations, recommended baseline laboratory monitoring, managing dose adjustments, evidence to support a relationship between laboratory tests and meaningful clinical outcomes, special patient populations including extremes of weight and renal impairment, duration of necessary parenteral therapy during the transition to oral therapy, candidates for outpatient treatment where appropriate and management of over-anticoagulation and adverse effects including bleeding and heparin induced thrombocytopenia. This article concludes with a concise table of clinical management questions and guidance recommendations to provide a quick reference for the practical management of heparin, low molecular weight heparin and fondaparinux.

Integrating electronic health records in the delivery of optimized anticoagulation therapy.

Integration of accepted practice standards into electronic health record systems can facilitate standardization of anticoagulation care delivery and result in improved anticoagulation safety. However, the majority of commonly used electronic health record systems are lacking the specialized features necessary for optimal anticoagulation management. The Task Force on Electronic Health Records of the New York State Anticoagulation Coalition provides such a Consensus Statement in this issue of the journal. The Anticoagulation Forum endorses these recommendations and advises the electronic health record industry and health information technology programmers at the institutional level to adopt these recommendations in a comprehensive and timely manner.

Rivaroxaban: practical considerations for ensuring safety and efficacy.

Rivaroxaban is the first agent available within a new class of anticoagulants called direct factor Xa inhibitors. Rivaroxaban is approved for use in the United States for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the prevention of deep vein thrombosis in patients undergoing total hip replacement and total knee replacement, for the treatment of deep vein thrombosis and pulmonary embolism, and for the reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism (with additional indications under review). Rivaroxaban dose and frequency of administration vary depending on the indication. As of result of predictable pharmacokinetics and pharmacodynamics, a fixed dose of rivaroxaban is administered without routine coagulation testing. Rivaroxaban has a short half-life, undergoes a dual mode of elimination (hepatic and renal), and is a substrate for P-glycoprotein. Rivaroxaban has a lower potential for drug interactions compared with warfarin. Despite the advantages of a once/day fixed-dose oral agent, in many clinical situations limited evidence is available to guide optimal management of rivaroxaban therapy. In this article, we review the available evidence and provide recommendations where possible for such situations including the desire to monitor the anticoagulation intensity, use in special patient populations, managing drug interactions, and transitioning across anticoagulant agents. Potential strategies for reversing rivaroxaban's anticoagulant effect are reviewed. Health systems will need to perform a systematic safety evaluation and ensure that numerous hospital policies related to anticoagulation are updated to include rivaroxaban. A comprehensive approach to education is needed for clinicians, patients, and technical support personnel involved in patient interactions to ensure safe use.

Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum.

OBJECTIVE: To provide recommendations for optimized anticoagulant therapy in the inpatient setting and outline broad elements that need to be in place for effective management of anticoagulant therapy in hospitalized patients; the guidelines are designed to promote optimization of patient clinical outcomes while minimizing the risks for potential anticoagulation-related errors and adverse events. DATA SOURCES: The medical literature was reviewed using MEDLINE (1946-January 2013), EMBASE (1980-January 2013), and PubMed (1947-January 2013) for topics and key words including, but not limited to, standards of practice, national guidelines, patient safety initiatives, and regulatory requirements pertaining to anticoagulant use in the inpatient setting. Non-English-language publications were excluded. Specific MeSH terms used include algorithms, anticoagulants/administration and dosage/adverse effects/therapeutic use, clinical protocols/standards, decision support systems, drug monitoring/methods, humans, inpatients, efficiency/ organizational, outcome and process assessment (health care), patient care team/organization and administration, program development/standards, quality improvement/organization and administration, thrombosis/ drug therapy, thrombosis/prevention and control, risk assessment/standards, patient safety/standards, and risk management/methods. STUDY SELECTION AND DATA EXTRACTION: Because of this document's 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 and are endorsed by 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 experience in the management of patients receiving anticoagulation therapy. DATA SYNTHESIS: Recommendations for delivering optimized inpatient anticoagulation therapy were developed collaboratively by the authors and are summarized in 8 key areas: (1) process, (2) accountability, (3) integration, (4) standards of practice, (5) provider education and competency, (6) patient education, (7) care transitions, and (8) outcomes. Recommendations are intended to inform the development of coordinated care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized inpatient anticoagulation therapy are intended to apply to all clinicians involved in the care of hospitalized patients receiving anticoagulation therapy. CONCLUSIONS: Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients. Several national organizations have introduced initiatives to reduce the likelihood of patient harm associated with the use of anticoagulants. Health care organizations are under increasing pressure to develop systems to ensure the safe and effective use of anticoagulants in the inpatient setting. This document provides consensus guidelines for anticoagulant therapy in the inpatient setting and serves as a companion document to prior guidelines relevant for outpatients.

Impact of target-specific oral anticoagulants on transitions of care and outpatient care models.

Patients with acute or chronic illness experience transitions of care when they leave one healthcare setting and move to another. Care transitions are points of increased patient risk. Numerous care transition models have been developed that focus on improving the hospital discharge process to prevent adverse events after hospital discharge and to reduce readmission rates. Anticoagulants are a common cause of adverse drug events in hospitals, and of adverse events that lead to patient harm and hospital readmission. Anticoagulation management services improve the outcomes of anticoagulant therapy in both hospitalized and ambulatory patients. The services they provide, including improved communication, medication management, and patient education, are also central tenets of care transition models. These services have traditionally been focused around warfarin and heparin. Recently, new target specific oral anticoagulants have been approved in the US for various indications that traditionally have been treated with warfarin. These new agents are administered in fixed doses without the need for routine laboratory monitoring or frequent dosing adjustments. Yet as high risk drugs, they will require systematic efforts to assure their safety and minimize potential adverse events. These concerns are of particular importance during transitions of care. Anticoagulation management services, must be prepared to establish practices that improve patient outcomes regardless of the anticoagulant prescribed, using the established principals of care transition models.

Novel oral anticoagulants and their role in clinical practice.

The complexities of oral anticoagulation with warfarin have led to the search for more practical alternative agents. Novel direct factor IIa inhibitors and direct factor Xa inhibitors currently in development can be administered at a fixed dose and do not require routine coagulation monitoring and ongoing dosage adjustment to ensure their effectiveness and safety. A number of phase III trials of these agents for the prevention of venous thromboembolism associated with orthopedic surgery and acute medical illness, for the treatment of venous thromboembolism, and for stroke prevention in patients with atrial fibrillation have been completed, with almost universally positive results. If these novel agents are approved for use in the United States, the future of oral anticoagulant therapy will allow a more nuanced approach to drug selection than has been available in the past. Attention to drug interactions and renal function will be required, as methods to measure the presence of these agents are not precise, cannot quantify the degree of anticoagulant present, and are influenced by the changes in serum drug concentrations during the dosing interval. In the future, patient preferences and the pharmacokinetic and pharmacodynamic characteristics of individual drugs will be able to be matched to optimize therapy. These new agents represent a new paradigm for anticoagulation that promises to improve patient care in the long term.

Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

A number of novel anticoagulants are moving through various stages of drug development. Recently, the United States Food and Drug Administration approved the oral direct thrombin inhibitor dabigatran etexilate to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Although dabigatran offers a number of advantages over existing oral and parenteral anticoagulants, challenges exist for clinicians who must ensure its safe and effective use. Limited data are available on dabigatran use in patients with renal dysfunction and in obese patients, or in combination with other drugs. Clinical experience is lacking in populations for whom anticoagulants are routinely used, such as patients with a previous stroke, acute coronary syndromes, or pregnancy-associated thrombosis, or those requiring ablation therapy. More important, clinicians will be faced with incorporating dabigatran into hospital guidelines for transitioning between oral and parenteral anticoagulants, measuring anticoagulant intensity, managing anticoagulant-related hemorrhage, ensuring safe use around neuraxial anesthesia, and implementing computer-based alert or warning systems. Since anticoagulants are ubiquitously used in the prevention or treatment of venous and arterial thrombosis, both clinicians and patients must be provided structured education on dabigatran's benefits and limitations. In this article, our goal was to provide practical advice to enhance clinician understanding of dabigatran, identify clinical and operational challenges to its use, and offer system improvements that can ensure safe and effective use of dabigatran.

Evaluation of online training on the prevention of venous thromboembolism.

INTRODUCTION: The integration of new evidence into clinical practice can be a prolonged process, with delays of years or even decades. One approach to speed this integration is through the use of online provider education. PROBLEM: Venous thromboembolism (VTE) is a serious patient safety issue. Prevention requires coordinated care and adherence to evidence-based guidelines, supported by provider education. PURPOSE: This study reports how an interdisciplinary team developed and piloted an online provider training program for the prevention of VTE. HYPOTHESIS: If providers use the online educational training, they will demonstrate increased mastery of key content areas related to VTE prophylaxis. METHODS: We used a prospective test-retest study design in which medical residents and fellows served as their own controls. All participants were given a pretest followed by educational content and then a posttest. We also assessed 2 different types of learning content (ie, with and without case studies/questions) and randomized participants to each type prior to assessment. RESULTS: Using the McNemar test we found a trend for knowledge gains related to VTE guidelines on the posttest for clinicians (n = 67) with a 14.5% improvement in content mastery (P = .05, 2-tailed). We did not find any significant differences between training modalities. Clinicians overall reported high levels of satisfaction with the application. CONCLUSION: Our online education efforts indicate the potential for increasing mastery of VTE prophylaxis concepts. If resources are limited, we suggest a static approach to content delivery and an exploration of standardized methods for portability of online curriculums across learning management systems.

New oral anticoagulants: a practical guide for clinicians.

The search for an oral anticoagulant with acceptable efficacy and safety in the treatment and prevention of venous and arterial thromboembolism, but with practical advantages over warfarin, has been a focus of drug development for many years. Three oral agents, dabigatran, rivaroxaban, and apixaban, are nearing approval in the US. Their use in practice will be guided by the clinical trials available, as well as their pharmacokinetic and pharmacodynamic properties. Practitioners need to be fully aware of these characteristics in order to use these agents appropriately in clinical practice. This review compares the results of the phase 3 trials investigating these agents in the prevention of venous thromboembolism in patients undergoing orthopedic surgery, examines the reporting of bleeding complications in the trials, and highlights various practical considerations regarding their use in clinical practice.

Pharmacogenomic trial design: use of a PK/PD model to explore warfarin dosing interventions through clinical trial simulation.

OBJECTIVE: Variants of two genes, CYP2C9 and VKORC1, explain approximately one third of variability in warfarin maintenance dose requirements. However, the clinical utility of using this information in addition to clinical and demographic data ('pharmacogenomic-guidance') is unclear, as few comparative clinical trials have been conducted to date. The objective of this study was to explore the incremental effect of pharmacogenomic-guided warfarin dosing under various conditions using clinical trial simulation. METHODS: We used an existing pharmacokinetic/pharmacodynamic model to perform clinical trial simulations of pharmacogenomic-guided versus standard of care warfarin therapy. The primary outcome was the percentage of patient time spent in therapeutic range over the first month of therapy. We assessed the influence of the frequency of INR monitoring, and the use of a loading dose and dose increase delay in patients with CYP2C9 variants. RESULTS: Pharmacogenomic guidance resulted in a 3-4 percentage point absolute increase in time spent in therapeutic range over the first month of therapy compared with standard of care. The improvement in time in range was greater when the frequency of INR monitoring in both arms was assumed to be lower. The absolute difference increased to 6-8 percentage points with the use of a loading dose and dose increase delay in patients with a CYP2C9 variant. CONCLUSION: Our initial results imply that pharmacogenomic-guided warfarin dosing may be more useful in settings with less intensive patient follow-up, and when adjustments are made for slower therapeutic response in patients with a CYP2C9 variant. Further pharmacokinetic/pharmacodynamic model development may be useful for warfarin pharmacogenomic trial design.

Key articles and guidelines in the treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a significant medical diagnosis that affects millions of patients each year. Appropriate management of VTE can help treat the initial event as well as reduce the frequency of complications such as postthrombotic syndrome, pulmonary hypertension, and death. Due to increasing regulatory requirements, hospitals nationwide are developing necessary documentation of appropriate and safe use of anticoagulants for the management of VTE. It is essential that a wide range of clinicians have an understanding of what constitutes appropriate VTE treatment in various patient populations. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE treatment can be difficult for clinicians. Therefore we have provided bibliographies of key articles and guidelines related to the treatment of VTE with a number of different strategies in a variety of special patient populations. It is our hope that this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with VTE.

Key articles and guidelines for the prevention of venous thromboembolism.

Venous thromboembolism (VTE) is an important medical problem that affects millions of patients each year. With appropriate prophylaxis, many of these thromboembolic events can be prevented. Although strong evidence supporting VTE prophylaxis spans several decades, several large American and global registries have documented very poor use of appropriate prophylaxis. Because of increasing regulatory requirements, hospitals nationwide are in the process of developing documentation of appropriate VTE prophylaxis programs for both surgical and medical patients. A wide range of clinicians must understand what constitutes appropriate VTE prophylaxis in various patient populations. With the existence of numerous pharmacologic agents, abundance of data from major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE prophylaxis can be difficult for clinicians. Therefore, we provide a bibliography of key articles and guidelines related to the prevention of VTE in various patient groups. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients who may be at risk for VTE.

Adherence to guidelines for the management of excessive warfarin anticoagulation.

OBJECTIVES: The American College of Chest Physicians (ACCP) provides guidelines for the management of excessive anticoagulation in patients receiving warfarin. This multi-site prospective cohort study evaluated patient-level practice patterns and adherence to ACCP guidelines. METHODS: Patients presenting with an INR > or = 4.5 between January 3 and April 29, 2005 were observed and therapeutic management documented. Adherence was assessed retrospectively. RESULTS: Four hundred and seventeen patients from 22 centers were observed. The mean, initial INR was 7.7. At enrollment, 85% of the patients had an INR < 9 or were not bleeding; 15% were seriously bleeding. Treatment for 170 patients (41%) did not adhere to guidelines. Among those, 15% were undertreated, 48% overtreated. Lack of adherence was attributed primarily to excessive doses (mean initial dose = 6.9 mg) and inappropriate routes of administration (subcutaneous or intramuscular) of vitamin K1. CONCLUSION: Adherence to the ACCP guidelines is low. Inappropriate use of vitamin K1 is the primary reason.

Discrepancies in identification of major bleeding events in patients taking warfarin.

STUDY OBJECTIVE: To assess the level of agreement between one subjective definition of major bleeding (criteria A) and two objective definitions: the International Society on Thrombosis and Haemostasis ([ISTH] criteria B) and the Italian Study of Complications of Anticoagulant Therapy ([ISCOAT] criteria C). DESIGN: Retrospective cohort study. SETTING: Four anticoagulation clinics at a university-affiliated medical center. PATIENTS: One hundred twenty patients aged 21-96 years who were taking long-term warfarin therapy and experienced a nonminor bleeding event between July 1, 2001, and June 30, 2006. MEASUREMENTS AND MAIN RESULTS: Bleeding events were evaluated using three definitions of major bleeding: criteria A-event was fatal or required hospitalization; criteria B-event was fatal, was symptomatic in a critical area or organ, caused a decrease in hemoglobin level of 2 g/dl or more, and/or led to transfusion of 2 or more units of whole blood or red blood cells; and criteria C-event met criteria B definition (but less inclusively identifies critical areas or organs) and/or necessitated surgical or angiographic intervention. One hundred thirty-eight bleeding events in the 120 patients met at least one of the definitions of major bleeding and thus were included in the analysis. Level of agreement among the definitions was determined by the kappa statistic. The level of agreement between criteria B and C was excellent; no discrepancies were found; however, the level of agreement between criteria A and criteria B or C was poor, with a kappa statistic value of -0.134 (95% confidence interval -0.196 to -0.071). Use of criteria A resulted in underreporting of 31 major bleeding events by excluding events that were managed on an outpatient basis. CONCLUSION: The discrepant event rates determined by using three different definitions of major bleeding underscore the need for implementation of a standardized objective definition. Use of a standardized definition in clinical trials to accurately predict and compare patient outcomes and in clinical practice as a marker for patient safety will increase quality of care and decrease total costs of care in patients treated with warfarin. We suggest implementation of the ISTH criteria in clinical practice as a method to standardize the reporting of major bleeding events.

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

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.