Charles E. Mahan

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.

Venous thromboembolism prevention: a systematic review of methods to improve prophylaxis and decrease events in the hospitalized patient.

Abstract Prevention of venous thromboembolism (VTE) is currently a key initiative internationally and in US hospitals, where there has been a recent focus on national quality initiatives to prevent hospital-acquired VTE. Multiple strategies exist to prevent VTE by increasing prophylaxis rates in the hospitalized setting. Active, multifaceted interventions, including provider education, an active reminder to the provider, and regular audit and feedback to medical and hospital staff, appear to be the most effective current interventions. Active intervention programs have been validated both as electronic alerts, with or without computerized clinical decision support software and, more recently, human alerts, many of which utilize in-hospital pharmacists. A passive strategy, such as guideline dissemination, should not be used as a lone method. Although inappropriate duration remains a key reason as to why at-risk patients do not receive appropriate thromboprophylaxis within the hospital (defined by type, dose, and duration of prophylaxis), few studies address duration compared with hospital length of stay. Preventable VTE is a new quality outcome measure for hospitals but is measured in few studies. Future studies should focus on comparing various multifaceted interventions to assess their effect over time, including endpoints of bleeding for safety, appropriate type, dose, and duration of prophylaxis, overall and preventable VTE, and the impact on unnecessary prophylaxis for patients not at risk.

New antithrombotics: The impact on global health care

New and generic forms of widely used medications introduced in the antiplatelet, anticoagulant and fibrinolytic therapeutic classes will have a world-wide impact on prescribing, practice guidelines, and routine patient care. However, several uncertainties regarding these agents will remain even after the publication of their respective pivotal trials or regulatory approval. These questions include dosing in the frail, the elderly, and in those with renal and/or hepatic dysfunction, timing of administration in the peri-operative period, efficacy and safety in subgroup populations such as patients with cancer, the interchangeability of biosimilar products, and outcome differences between new agents in the absence of head-to-head clinical trials. Additionally, new generic forms of widely used agents have recently impacted the United States (US) and Canadian market place and more are under development. Clinicians should be vigilant concerning these agents and be prepared to inform patients and make decisions with their use.

Venous thromboembolism prophylaxis in the medical patient: controversies and perspectives.

Despite the high morbidity and mortality associated with venous thromboembolism in hospitalized at-risk medical patients, the publication of large-scale studies showing that prophylaxis is effective in this patient group, and the presence of international guidelines, prophylaxis rates in medically ill patients remain suboptimal. Studies show that low-molecular-weight heparins, given once daily, are at least as effective as unfractionated heparin usually given thrice daily with equivalent or improved safety profiles, and that thrice-daily dosing of unfractionated heparin might be more effective than twice-daily dosing. However, the most recent American College of Chest Physicians guidelines do not distinguish between these regimens, and twice-daily unfractionated heparin is still commonly used in the United States. Furthermore, the optimal duration for out-of-hospital and extended prophylaxis for specific patient groups is not established. Finally, there are few data on the use of mechanical methods in this patient group and no established standard of care for prophylaxis of special patient populations, such as obese patients or those with renal insufficiency. Even though prophylaxis entails additional acquisition costs, it can reduce the incidence of venous thromboembolism, which can improve care and decrease overall costs.

Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population.

INTRODUCTION Medically ill, hospitalized patients are at increased risk for venous thromboembolism (VTE) after discharge. This study aimed to examine thromboprophylaxis patterns, risk factors, and post-discharge outcomes. METHODS This was a retrospective claims analysis involving administrative claims data and in-patient data abstracted from a sample of hospital charts. Patients aged ≥ 40 years hospitalized for ≥ 2 days for nonsurgical reasons between 2005 and 2009 were included. Hospital chart data were abstracted for a random sample of patients without evidence of anticoagulant use at 30 days post-discharge. The combined data determined whether in-patient thromboprophylaxis (anticoagulant or mechanical prophylaxis) reduces risk of VTE at 90 days post-discharge. Hazard ratios (HR) and odds ratios (OR) were calculated using Cox proportional hazard models and logistic regression. RESULTS Of 141,628 patients in the claims analysis, 3.9% received anticoagulants (3.6% warfarin). VTE, rehospitalization, and mortality rates were 1.9%, 17.2%, and 6.2%, respectively. The strongest predictors of post-discharge VTE were history of VTE (HR=4.0, 95% confidence interval [CI]: 3.3-4.8), and rehospitalization (HR=3.9, 95% CI: 3.6-4.3). Of 504 medical charts, 209 (41.5%) reported in-patient thromboprophylaxis. There was no statistically significant difference in post-discharge VTE rates between patients who did and did not receive in-patient thromboprophylaxis. All-cause mortality was greater among patients without use of VTE prophylaxis. CONCLUSION Utilization rates of in-hospital and post-discharge VTE prophylaxis were low. In-hospital VTE prophylaxis did not reduce the risk of post-discharge VTE in the absence of post-discharge anticoagulation. Combined in-patient and post-discharge thromboprophylaxis lowered the odds of short-term, all-cause post-discharge mortality.

Venous thromboembolism pharmacy intervention management program with an active, multifaceted approach reduces preventable venous thromboembolism and increases appropriate prophylaxis.

Two concepts relating to venous thromboembolism (VTE) prevention have recently emerged—“appropriate” prophylaxis and “preventable” VTE. We evaluated whether a human alert, as part of a pharmacy intervention program, can increase appropriate prophylaxis and decrease preventable symptomatic VTE in hospitalized patients. This prospective study with retrospective data collection was conducted utilizing data from 1879 patients in 2006 as a control cohort. The intervention cohort data were from 1646 patients during 2007, after program implementation. The rate of appropriate prophylaxis increased from 23.8% in 2006 to 37.9% in 2007 (odds ratio 1.8; 95% confidence interval [CI] = 1.6-2.1; P < .0001). Preventable VTE incidence was reduced by 74% (95% CI = 44%-88%) from 18.6 to 4.9 per 1000 patient discharges in 2006 and 2007, respectively (P = .0006). In conclusion, a pharmacy-led multifaceted intervention can significantly increase the rates of appropriate prophylaxis and significantly reduce the incidence of preventable VTE in hospitalized patients.

European Union-28: An annualised cost-of-illness model for venous thromboembolism

Annual costs for venous thromboembolism (VTE) have been defined within the United States (US) demonstrating a large opportunity for cost savings. Costs for the European Union-28 (EU-28) have never been defined. A literature search was conducted to evaluate EU-28 cost sources. Median costs were defined for each cost input and costs were inflated to 2014 Euros (€) in the study country and adjusted for Purchasing Power Parity between EU countries. Adjusted costs were used to populate previously published cost-models based on adult incidence-based events. In the base model, annual expenditures for total, hospital-associated, preventable, and indirect costs were €1.5-2.2 billion, €1.0-1.5 billion, €0.5-1.1 billion and €0.2-0.3 billion, respectively (indirect costs: 12 % of expenditures). In the long-term attack rate model, total, hospital-associated, preventable, and indirect costs were €1.8-3.3 billion, €1.2-2.4 billion, €0.6-1.8 billion and €0.2-0.7 billion (indirect costs: 13 % of expenditures). In the multiway sensitivity analysis, annual expenditures for total, hospital-associated, preventable, and indirect costs were €3.0-8.5 billion, €2.2-6.2 billion, €1.1-4.6 billion and €0.5-1.4 billion (indirect costs: 22 % of expenditures). When the value of a premature life-lost increased slightly, aggregate costs rose considerably since these costs are higher than the direct medical costs. When evaluating the models aggregately for costs, the results suggests total, hospital-associated, preventable, and indirect costs ranging from €1.5-13.2 billion, €1.0-9.7 billion, €0.5-7.3 billion and €0.2-6.1 billion, respectively. Our study demonstrates that VTE costs have a large financial impact upon the EU-28s healthcare systems and that significant savings could be realised if better preventive measures are applied.

Reversing factor Xa inhibitors – clinical utility of andexanet alfa

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies.

Stroke Prevention in Patients With Atrial Fibrillation and Renal Dysfunction

The overall prevalence of atrial fibrillation (AF) is 1% of the US population. However, diagnosis of AF is increasingly common with age, and prevalence rises to ≈10% in Americans aged >80 years. As the population ages, the estimated prevalence of AF may nearly triple from 2.3 million to 5.6 million US adults by 2050, with more than half of the patients aged ≥80 years.1 The prevalence of renal dysfunction also increases with age.2 More than 10% of the US population or >20 million people aged ≥20 years have chronic kidney disease (CKD).3 The definition of CKD is glomerular filtration rate (GFR) 70 years.8 AF, older age, and CKD are independent risk factors for stroke, which indicates an intensified need for stroke prophylaxis.8–10 Warfarin use is associated with a reduction in risk for stroke or thromboembolism in patients with AF with CKD (hazard ratio, 0.76), whereas acetylsalicylic acid is associated with increased risk (hazard ratio, 1.17).10 Current national and international guidelines for the care of patients with AF recommend stroke prophylaxis.11–15 Many patients with AF and coexisting CKD do not receive adequate anticoagulation; as many as 50% of eligible patients are not receiving anticoagulant therapy.16–21 However, the benefit of warfarin and the newer anticoagulants in patients receiving dialysis is undetermined.22 CKD is associated with an increased risk of bleeding, particularly in patients with end-stage renal disease, which may increase physicians’ apprehension of prescribing …

Renal Function Considerations for Stroke Prevention in Atrial Fibrillation

Renal impairment increases risk of stroke and systemic embolic events and bleeding in patients with atrial fibrillation. Direct oral anticoagulants (DOACs) have varied dependence on renal elimination, magnifying the importance of appropriate patient selection, dosing, and periodic kidney function monitoring. In randomized controlled trials of nonvalvular atrial fibrillation, DOACs were at least as effective and associated with less bleeding compared with warfarin. Each direct oral anticoagulant was associated with reduced risk of stroke and systemic embolic events and major bleeding compared with warfarin in nonvalvular atrial fibrillation patients with mild or moderate renal impairment. Renal function decrease appears less impacted by DOACs, which are associated with a better risk-benefit profile than warfarin in patients with decreasing renal function over time. Limited data address the risk-benefit profile of DOACs in patients with severe impairment or on dialysis.