JOURNAL ARTICLES ABOUT ANTICOAGULATION AND LIXIANA® (EDOXABAN) FROM PUBMED

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The ENGAGE AF-TIMI 48 Trial: Edoxaban versus warfarin in patients with atrial fibrillation.

Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.

A randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years).

The Hokusai-VTE Trial: Edoxaban versus warfarin for the treatment of symptomatic recurrent venous thromboembolism.

Bϋller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med.2013;369(15):1406-1415.

A randomized, double-blind, noninferiority study that randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin.

Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors

Andersen KK, Olsen TS, Dehlendorff C, Kammersgaard LP. Hemorrhagic and ischemic strokes compared stroke severity, mortality, and risk factors. Stroke. 2009;40(6):2068-2072.

Stroke patients with hemorrhagic (HS) and ischemic strokes were compared with regard to stroke severity, mortality, and cardiovascular risk factors.

Venous thromboembolism

Blann AD, Lip GYH. Venous thromboembolism. BMJ. 2006;332(7535):215-219.

Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, are common and treatable in hospital and the community

The hemostatic system as a modulator of atherosclerosis.

Borissof JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. NEJM. 2011;364:1746-1760

Medication adherence: WHO cares?

Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304-314.

The treatment of chronic illnesses commonly includes the long-term use of pharmacotherapy. Although these medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed.

2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association.

Camm JA, Lip G, De Caterina R. et al. 2012 focused update of the ESC guidlines for the management of atrial fibrillation. Eur Heart J. (2012);33(21):2719–2747.

Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).

Camm AJ, Kirchhof P, Lip GYH, et al.. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369-2429.

New Oral Anticoagulants in Atrial Fibrillation and Acute Coronary Syndromes ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease Position Paper

De Caterina R, Husted S, Wallentin L, et al; Coordinating Committee. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol. 2012;59(16):1413-1425.

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.

National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation

Dlott JS, George RA, Huang X, et al. National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation. Circulation. 2014;129(13):1407-1414. 5. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005; 3: 692-694.

Anticoagulation control with warfarin, as assessed by the international normalized ratio (INR), is challenging. Time in the therapeutic range has been inversely correlated with major hemorrhage, thrombosis, and mortality. Quest Diagnostics offers standardized INR laboratory testing services to approximately half of US physician practices. To inform national stroke prevention strategies, we evaluated anticoagulation control in office-based community practices.

ABC of arterial and venous disease. Swollen lower limb-1: general assessment and deep vein thrombosis.

Gorman WP, Davis KR, Donnelly R. ABC of arterial and venous disease: swollen lower limb–l: General assessment and deep venous thrombosis. BMJ. 2000;320:1453-1456.

Importance of dose selection in novel oral anticoagulants for atrial fibrillation.

Grip LT, Giugliano RP. Importance of dose selection in novel oral anticoagulants for atrial fibrillation. Arch Cardiol Mex. 2012;82(4):308-311.

There are several excellent alternatives to warfarin on the horizon for atrial fibrillation. Results from the trials, as well as pharmacokinetic data from the edoxaban studies, suggest that dose selection, based on pharmacokinetic and pharmacodynamic properties, is a critical component in the development of novel anticoagulants. Greater flexibility in dosing with edoxaban and the opportunity for dose adjustment throughout the ENGAGE AF-TIMI 48 trial may be advantageous in the competitive field of novel oral anticoagulants.

European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation.

Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625-651

New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients will have to learn how to use these drugs effectively and safely in clinical practice. Many unresolved questions on how to optimally use these drugs in specific clinical situations remain. The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs.

New oral anticoagulants: good but not good enough!

Kaluski E, Maher J, Gerula CM. New oral anticoagulants: good but not good enough! J Am Coll Cardiol. 2012;60(15):1434.

Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.

Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res. 2014;133(6):1145-1151.

Numerous new oral anticoagulants (NOACs) have been compared to a parenteral anticoagulant/oral vitamin K antagonist (VKA) for the treatment of acute venous thromboembolism (VTE). We aimed to conduct a systematic review and adjusted indirect comparison meta-analysis to compare the efficacy and safety of NOACs for this indication.

Natural history of venous thromboembolism.

Kearon C. Natural History of Venous Thromboembolism. Circulation. 2003;107(23 suppl 1): I-23-I-30.

Most deep vein thromboses (DVTs) start in the calf; however, thrombi that remain confined to the calf rarely cause leg symptoms or are associated with symptomatic pulmonary embolism (PE). The probability that calf DVT will extend to involve the proximal veins, and subsequently cause PE, increases with the severity of the initiating prothrombotic stimulus and if this stimulus persists. Although acute venous thromboembolism (VTE) usually presents with either leg or pulmonary symptoms, most patients have thrombosis at both sites at the time of diagnosis. Treated proximal DVTs resolve slowly, and half of patients still have detectable thrombi after a year.

The Influence of Patient Adherence on Anticoagulation Control With Warfarin Results From the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study

Kimmel SE, Chen Z, Price M, et al. The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med. 2007;167(3):229-235.

Warfarin sodium is a highly efficacious drug, but proper levels of anticoagulation are difficult to maintain. Conflicting data exist on the influence of patient adherence on anticoagulation control.

Burden of comorbidities among patients with atrial fibrillation.

LaMori JC, Mody SH, Gross HJ, et al. Burden of comorbidities among patients with atrial fibrillation. Ther Adv Cardiovasc Dis. 2013;7(2):53-62.

This study examined comorbidity prevalence and general medication use among individuals with atrial fibrillation in the United States to convey a more comprehensive picture of their total disease burden.

Deep vein thrombosis of the axillary-subclavian veins: epidemiologic data, effects of different types of treatment and late sequelae.

Lindblad B, Tengborn L, Bergqvist D. Deep vein thrombosis of the axillary-subclavian veins: epidemiologic data, effects of different types of treatment and late sequelae. Eur J Vasc Surg. 1988; 2: 161–165.

Upper extremity deep venous thrombosis (DVT) is uncommon. In the city of Malmö, Sweden (240,000 inhabitants), 296 cases undergoing phlebography due to a suspicion of upper extremity DVT, during 1971-1986 were analysed. 165 arm phlebograms did not reveal any thrombi (56%). In 11 cases (4%) external compression of the vein was found. Thrombi in the axillary or subclavian vein were found in 120 cases (40%) and were classified as primary in 73 cases and secondary in 47 cases. Only seven cases of effort thrombosis were found. Four cases had neurovascular symptoms mimicking thoracic outlet syndrome and underwent elective first rib resection.

Bleeding risk assessment and management in atrial fibrillation patients. Executive Summary of a Position Document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis.

Lip GY, Andreotti F, Fauchier L, et al; European Heart Rhythm Association. Bleeding risk assessment and management in atrial fibrillation patients. Executive Summary of a Position Document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Thromb Haemost. 2011;106(6):997-1011.

In this executive summary of a Consensus Document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in atrial fibrillation (AF) patients. The main aim of the document was to summarise 'best practice' in dealing with bleeding risk in AF patients when approaching antithrombotic therapy, by addressing the epidemiology and size of the problem, and review established bleeding risk factors. We also summarise definitions of bleeding in the published literature. Patient values and preferences balancing the risk of bleeding against thromboembolism as well as the prognostic implications of bleeding are reviewed. We also provide an overview of published bleeding risk stratification and bleeding risk schema. Brief discussion of special situations (e.g. periablation, peri-devices such as implantable cardioverter defibrillators [ICD] or pacemakers, presentation with acute coronary syndromes and/or requiring percutanous coronary interventions/stents and bridging therapy) is made, as well as a discussion of the prevention of bleeds and managing bleeding complications. Finally, this document puts forwards consensus statements that may help to define evidence gaps and assist in everyday clinical practice.

Symptoms in atrial fibrillation: why keep score?

McRae CA, et al. Symptoms in atrial fibrillation: why keep score? Circ Arrhythm Electrophysiol. 2009;2(3):215-217.

Underuse of oral anticoagulants in atrial fibrillation: a systematic review.

Ogilvie IM, Newton N, Weiner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7):638-645.

Atrial fibrillation is associated with substantial mortality and morbidity from stroke and thromboembolism. Despite an efficacious oral anticoagulation therapy (warfarin), atrial fibrillation patients at high risk for stroke are often under-treated. This systematic review compares current treatment practices for stroke prevention in atrial fibrillation with published guidelines.

Stroke and bleeding in atrial fibrillation with chronic kidney disease.

Olesen JB, Lip GYH, Kamper A-L, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635.

Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions.

Asymptomatic atrial fibrillation.

Rho RW, Page RL. Asymptomatic atrial fibrillation. Prog Cardiovasc Dis. 2005;48(2):79–87.

Atrial fibrillation (AF) is a significant cause of morbidity and health care expenditures. Patients with AF suffer a variety of symptoms including chest pain, palpitations, shortness of breath, and fatigue. Some patients have no symptoms, a condition referred to as asymptomatic or "silent" AF. Asymptomatic AF has significant clinical implications. Patients with unrecognized AF may present with devastating thromboembolic consequences or a tachycardia-mediated cardiomyopathy. The incidence of asymptomatic AF is greater than previously perceived. This manuscript provides an overview of the clinical entity of asymptomatic AF including the epidemiology, clinical significance, and the implications it has on the daily management of patients suffering from AF.

Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial.

Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial [published online ahead of print March 11, 2015]. Lancet. doi:10.1016/S0140-6736(14)61943-7.

In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. This study assessed whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.

Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of inimized trials. Lancet. 2014;383(9921):955-962.

Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.

Systemic thrombolysis in the upper extremity deep vein thrombosis

Sadeghi R, Safi M. Systemic thrombolysis in the upper extremity deep vein thrombosis. ARYA Atheroscler. 2011;7(1):40-46.

Almost 4% of all patients with venous thrombosis have upper extremity deep vein thrombosis (UEDVT) and the incidence of UEDVT increases over time. The frequency of post-thrombotic syndrome (PTS) after UEDVT is not low and upper extremity PTS is a potentially major morbidity that adversely affects quality of life, particularly if the dominant arm is involved. We discuss briefly the role of thrombolytic therapy in the treatment of upper extremity deep vein thrombosis and also the role of systemic thrombolysis in selected patients.

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.

Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005; 3: 692-694.

A variety of definitions of major bleeding have been used in published clinical studies, and this diversity adds to the difficulty in comparing data between trials and in performing meta-analyses. In the first step towards unified definitions of bleeding complications, the definition of major bleeding in non-surgical patients was discussed at the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Arising from that discussion, a definition was developed that should be applicable to studies with all agents that interfere with hemostasis, including anticoagulants, platelet function inhibitors and fibrinolytic drugs. The definition and the text that follows have been reviewed and approved by the cochairs of the subcommittee and the revised version is published here. The intention is to also seek approval of this definition from the regulatory authorities.

The net clinical benefit of warfarin anticoagulation in atrial fibrillation.

Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151(5):297-305.

Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage.

Plenty of pills: polypharmacy prevails in patients of a Danish anticoagulant clinic

Skov J, Bladbjerg EM, Sidelmann J, Vamosi M, Jespersen J. Plenty of pills: polypharmacy prevails in patients of a Danish anticoagulant clinic. Eur J Clin Pharmacol. 2011;67(11):1169-1174.

Vitamin K antagonist (VKA) treatment can successfully prevent thromboembolic complications, but the modality has a narrow therapeutic window and numerous interactions with other pharmaceuticals. The aim of the study reported here was to describe the use of co-medications and the prevalence of polypharmacy among patients treated with VKA.

Diagnosis, investigation, and management of deep vein thrombosis.

Tovey C, Wyatt S. Diagnosis, investigation, and management of deep vein thrombosis. BMJ. 2003;326 (7400):1180-1184.

New anticoagulants for treatment of venous thromboembolism

Weitz, New Anticoagulants for Treatment of Venous Thromboembolism. Circulation. 2004;110:I-19-I26.

Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin.

Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux.

Wolzt M, Samama MM, Kapiotis S, Ogata K, Mendell J, Kunitada S. Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thromb Haemost. 2011;105(6):1080-1090.

Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in phase III clinical development for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The shed blood model allows for study of activated coagulation at a site of standardised tissue injury due to local release of tissue factor. The objective of this study was to evaluate the effect of three doses of edoxaban on markers of coagulation in shed and venous blood versus placebo and a standard prophylactic dose of fondaparinux. A total of 100 healthy male subjects were randomised to receive single doses of one of five treatments: subcutaneously administered fondaparinux 2.5 mg; orally administered edoxaban 30, 60, or 120 mg; or placebo. The primary objective was measurement of blood coagulation markers prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) complex, and platelet activation marker β-thromboglobulin (β-TG), in venous and shed blood.

Edoxaban administration following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects.

Zahir H, Matsushima N, Halim AB, et al. Edoxaban administration following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost. 2012;108(1):166-175.

Edoxaban is an oral direct factor (F)Xa inhibitor in advanced stages of clinical development. The primary objective of the present study was to assess the pharmacodynamics (PD) and safety of enoxaparin 1 mg/kg followed 12 hours (h) post-dose by edoxaban 60 mg, which is the regimen being used in the phase III study of edoxaban for the treatment of venous thromboembolism (Hokusai-VTE). This was a phase I, open-label, randomised, four-period, four-treatment cross-over study. Treatments were edoxaban alone (EDOX), enoxaparin alone (ENOX), edoxaban plus enoxaparin (EDOX+ENOX), and enoxaparin followed by edoxaban 12 h later (ENOX12-EDOX). Serial blood samples were collected for PD (thrombin generation, anti-FXa) and pharmacokinetic (PK) variables (edoxaban and its principal metabolite M4 by LC-MS/MS, and anti-FIIa as a surrogate of enoxaparin). The highest effect on thrombin AUC (endogenous thrombin potential, or ETP), thrombin (peak), thrombin generation lag time, and velocity index was observed for EDOX+ENOX, followed by ENOX, ENOX12-EDOX, and EDOX.