Lynn B. Oertel

Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment

Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.

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.

Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation. BAATAF Investigators.

BACKGROUND AND PURPOSE The Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) demonstrated that low-intensity warfarin anticoagulation can, with safety, sharply reduce the rate of stroke in patients with nonvalvular atrial fibrillation. The beneficial effect of warfarin was presumably related to a decrease in clot formation in the cardiac atria and subsequent embolization. METHODS To assess the effect of warfarin therapy on in vivo clotting in patients in the BAATAF, we measured the plasma level of prothrombin activation fragment F1+2. One sample was obtained from 125 patients from the BAATAF; 62 were taking warfarin and 63 were not taking warfarin (control group). RESULTS The warfarin group had a 71% lower mean F1+2 level than the control group (mean F1+2 of 1.57 nmol/L in the control group compared with a mean of 0.46 nmol/L in the warfarin group; P < .001). F1+2 levels were higher in older subjects but were consistently lower in the warfarin group at all ages. Fifty-two percent of patients in the control group were taking chronic aspirin therapy at the time their F1+2 level was measured. Control patients taking aspirin had F1+2 levels very similar to control patients not taking aspirin (mean of 1.52 nmol/L for control patients on aspirin compared with 1.64 nmol/L for control patients off aspirin; P > .1). CONCLUSIONS We conclude that prothrombin activation was significantly suppressed in vivo by warfarin but not aspirin among patients in the BAATAF. These findings correlate with the marked reduction in ischemic stroke noted among patients in the warfarin treatment group observed in the BAATAF.

Unfractionated heparin: focus on a high-alert drug.

Unfractionated heparin (UFH) is associated with a high rate of drug‐related problems due to either its inherent pharmacologic properties or an extension of these properties often caused by medication errors. The drug‐related problems associated with UFH can significantly hinder the success of therapy and negatively affect the overall cost of care. Unfractionated heparin has been classified as a high‐alert drug by the Institute for Safe Medication Practices. Approximately 2.1% of the total records submitted to the MedMARx national error database were related to UFH; 4.5–5.5% of these errors reported were harmful. With this high potential for error, it is essential that all health care providers adopt a collaborative or systems approach to identify solutions to reduce the occurrence of these medication errors. The Joint Commission on Accreditation of Healthcare Organizations has published national patient safety goals for improving the safety of patient care, many of which are applicable to UFH therapy. Unfractionated heparin drug‐related problems not necessarily related to medication errors include heparin‐induced thrombocytopenia, bleeding events, and osteopenia. Heparin‐induced thrombocytopenia is a serious complication of heparin therapy and remains seriously undiagnosed. Bleeding events often occur with therapeutic as well as prophylactic UFH administration even when monitoring indexes are within the therapeutic range. However, due to the variability associated with UFH monitoring methods, definitive guidelines are lacking to assist in avoiding such serious events. Osteopenia has been associated with long‐term UFH therapy; one third of patients experience reductions in bone density, potentially leading to fractures. Today, safer alternative anticoagulation therapies are available, such as the low‐molecular‐weight heparins. When compared with UFH, these alternative therapies provide equivalent or superior efficacy for numerous indications.

Limited English Proficient Patients and Time Spent in Therapeutic Range in a Warfarin Anticoagulation Clinic

Background While anticoagulation clinics have been shown to deliver tailored, high‐quality care to patients receiving warfarin therapy, communication barriers with limited English proficient (LEP) patients may lead to disparities in anticoagulation outcomes. Methods and Results We analyzed data on 3770 patients receiving care from the Massachusetts General Hospital Anticoagulation Management Service (AMS) from 2009 to 2010. This included data on international normalized ratio (INR) tests and patient characteristics, including language and whether AMS used a surrogate for primary communication. We calculated percent time in therapeutic range (TTR for INR between 2.0 and 3.0) and time in danger range (TDR for INR <1.8 or >3.5) using the standard Rosendaal interpolation method. There were 241 LEP patients; LEP patients, compared with non‐LEP patients, had a higher number of comorbidities (3.2 versus 2.9 comorbidities, P=0.004), were more frequently uninsured (17.0% versus 4.3%, P<0.001), and less educated (47.7% versus 6.0% ≤high school education, P<0.001). LEP patients compared with non‐LEP patients spent less TTR (71.6% versus 74.0%, P=0.007) and more TDR (12.9% versus 11.3%, P=0.018). In adjusted analyses, LEP patients had lower TTR as compared with non‐LEP patients (OR 1.5, 95% CI [1.1, 2.2]). LEP patients who used a communication surrogate spent less TTR and more TDR. Conclusion Even within a large anticoagulation clinic with a high average TTR, a small but significant decrease in TTR was observed for LEP patients compared with English speakers. Future studies are warranted to explore how the use of professional interpreters impact TTR for LEP patients.

Is patient self-testing a good thing?

The ability to produce an accurate and reliable INR from a fingerstick drop of blood has opened the doors for patients to take ownership and active participation in their day-today chronic management of oral anticoagulation therapy. Small, hand-held devices offer patients the option to selftest their INR (international normalized ratio) value at home on a regular and frequent testing schedule as opposed to going to a traditional, central laboratory. In most cases, the INR values are reported into their warfarin managing physician or anticoagulation management service for updated instructions regarding their dose. There is little, but growing, experience in the United States for patients to take this one step beyond and self manage their warfarin dose using prescribed parameters defined by their prescribing physician or managing clinic. Patient self testing (PST) or self management in the United States has yet attained the acceptance and utilization as has been witnessed in other countries. For example, in Germany there are over 130,000 patients who self-test (reflecting approximately 16% of the warfarin patient population in that country) [1]. Yet, in the United States, less than 1% of the warfarin patient population, or 20–30,000, patients self-test [2, 3]. Evidence is emerging, primarily outside the United States, on the success of self management. Benefits of PST

Prediction Score for Anticoagulation Control Quality Among Older Adults

Background Time in the therapeutic range (TTR) is associated with the effectiveness and safety of vitamin K antagonist (VKA) therapy. To optimize prescribing of VKA, we aimed to develop and validate a prediction model for TTR in older adults taking VKA for nonvalvular atrial fibrillation and venous thromboembolism. Methods and Results The study cohort comprised patients aged ≥65 years who were taking VKA for atrial fibrillation or venous thromboembolism and who were identified in the 2 US electronic health record databases linked with Medicare claims data from 2007 through 2014. With the predictors identified from a systematic review and clinical knowledge, we built a prediction model for TTR, using one electronic health record system as the training set and the other as the validation set. We compared the performance of the new models to that of a published prediction score for TTR, SAMe‐TT 2R2. Based on 1663 patients in the training set and 1181 in the validation set, our optimized score included 42 variables and the simplified model included 7 variables, abbreviated as PROSPER (Pneumonia, Renal dysfunction, Oozing blood [prior bleeding], Staying in hospital ≥7 days, Pain medication use, no Enhanced [structured] anticoagulation services, Rx for antibiotics). The PROSPER score outperformed SAMe‐TT 2R2 when predicting both TTR ≥70% (area under the receiver operating characteristic curve 0.67 versus 0.55) and the thromboembolic and bleeding outcomes (area under the receiver operating characteristic curve 0.62 versus 0.52). Conclusions Our geriatric TTR score can be used as a clinical decision aid to select appropriate candidates to receive VKA therapy and as a research tool to address confounding and treatment effect heterogeneity by anticoagulation quality.

Comment on: Editorial by Husted et al. “Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel”: (Thromb Haemost 2014; 111: 781–782)

Comment on: Editorial by Husted et al. “Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel” - (Thromb Haemost 2014; 111: 781–782)

Workshop: Internet Delivery of an Anticoagulation Therapy Management Certificate Program

Nurses, advanced practice nurses, clinical pharmacists, and physician assistants work closely with physicians to provide quality care for patients receiving anticoagulation therapy. With the increased use of anticoagulant drugs, there is a growing need for educational programs designed for these health care providers to develop their patient assessment and management skills, and to deepen their understanding of the pharmacokinetics and pharmacodynamics of anticoagulants and related drugs. In an attempt to meet the growing demand for this advanced level of knowledge, a limited number of university and hospital-sponsored anticoagulation-speci®c educational programs have been developed. These programs vary in length from 2 to 5 days. The constraints of work schedules, geography, and costs prevent many health care providers from attending such training programs. Internet-based instruction offers an attractive solution to this problem of access, and capitalizes on the technology and resources available in the homes and practice settings of most health care providers. During the past several years, there has been an explosion of Internet-based educational programs for degree credit and professional development. Continuing education, credit courses, and degree programs are offered by an increasing number of public and proprietary academic institutions. (1) Industry and health care organizations have found the Internet to be an effective approach to delivering in-service and professional education programs for their employees. (2) Internet delivery of nursing and health professions instruction began at the University of Southern Indiana (USI) in 1996 and has proven to be an effective approach for health care professionals who must maintain their fulltime employment while advancing their professional education. (3) Success with such programming has provided a strong base of experience and technical expertise that has been applied to the development of the Anticoagulation Therapy Management Certi®cate Program. The development, delivery, and evaluation of the interactive Internet-delivered Anticoagulation Therapy Management Certi®cate Program was a collaborative effort among regional health care providers, members of the National Certi®cation Board for Anticoagulation Providers (NCBAP), the University of Southern Indiana School of Nursing and Health Professions, and DuPont Pharma, Inc.

Anticoagulation Services: Quality Improvement Direction Pursuing a Certification Process

There is still in a certification process for anticoagulant therapy providers. The primary, and certainly most important, goal is to improve patient care. Defining measurable competencies to which the anticoagulation provider is made accountable is but one mechanism to help improve quality in patient care. Great improvements have been achieved in the field of anticoagulation. For example, determining optimum intensity levels, for the traditional as well as the newer indications for treatment, have yielded greater efficacy and safety. Additionally, the acceptance of the INR reporting system has greatly reduced hemorrhagic and thromboembolic complications. However, the process of care, that is, how patients are managed and by whom, remains a variable that is difficult to quantify and measure. Anticoagulation providers are comprised of professionals from three major disciplines, namely, medicine, nursing, and pharmacy. This multidisciplinary approach enriches the quality of care for patients. However, this very fact presents a dilemma when seeking an appropriate certifying body. Nevertheless, keeping quality patient care as the primary focus, a multidisciplinary group has developed a body of knowledge that is unique to anticoagulant and antithrombotic therapies. The foundation of this project stems from the Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy and the recently published paper by Ansell et al. on consensus guidelines for coordinated outpatient oral anticoagulation therapy management. This work in progress includes a mission statement and outlines five major knowledge domains along with measurable competencies for each section. This effort will help standardized the process of care across the country.There is still in a certification process for anticoagulant therapy providers. The primary, and certainly most important, goal is to improve patient care. Defining measurable competencies to which the anticoagulation provider is made accountable is but one mechanism to help improve quality in patient care. Great improvements have been achieved in the field of anticoagulation. For example, determining optimum intensity levels, for the traditional as well as the newer indications for treatment, have yielded greater efficacy and safety. Additionally, the acceptance of the INR reporting system has greatly reduced hemorrhagic and thromboembolic complications. However, the process of care, that is, how patients are managed and by whom, remains a variable that is difficult to quantify and measure. Anticoagulation providers are comprised of professionals from three major disciplines, namely, medicine, nursing, and pharmacy. This multidisciplinary approach enriches the quality of care for patients. However, this very fact presents a dilemma when seeking an appropriate certifying body. Nevertheless, keeping quality patient care as the primary focus, a multidisciplinary group has developed a body of knowledge that is unique to anticoagulant and antithrombotic therapies. The foundation of this project stems from the Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy and the recently published paper by Ansell et al. on consensus guidelines for coordinated outpatient oral anticoagulation therapy management. This work in progress includes a mission statement and outlines five major knowledge domains along with measurable competencies for each section. This effort will help standardized the process of care across the country.