Direct oral anticoagulants: A new chapter in anticoagulation therapy

Thromboembolic events are the leading cause of morbidity and mortality worldwide. From the second half of the 20th century, vitamin K antagonists (VKAs), warfarin and acenocoumarol, were the only anticoagulants taken orally. The major reform in anticoagulation therapy was made by the advent of direct oral anticoagulants (DOACs), about 10 years ago. Direct thrombin inhibitor (dabigatran) and direct inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban, and betrixaban) have demonstrated favorable risk/benefit ratio. Compared to warfarin, DOACs are associated with a predictable pharmacokinetic profile, lower severe bleeding complications, particularly intracranial hemorrhages, and minimal drug interactions. Moreover, DOACs achieve a rapid onset of action and have shown comparable efficacy with warfarin and low molecular weight heparin (LMWH) in clinical trials. As a result, DOACs are now replacing VKAs and LMWH for many indications including stroke and systemic embolism prevention in nonvalvular atrial fibrillation, prevention, and treatment of venous thromboembolism and thromboprophylaxis following total knee/hip replacement surgery. In addition, rivaroxaban (in combination with aspirin alone or aspirin and clopidogrel) is used in the prevention of atherothrombotic events following acute coronary syndrome with elevated cardiac biomarkers. In case of severe bleeding complications under DOACs treatment, antidotes are available; idarucizumab for dabigatran reversal and andexanet alfa for rivaroxaban and apixaban.

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Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing

Cardiology ◽

10.1159/000489922 ◽

2018 ◽

Vol 140 (2) ◽

pp. 126-132 ◽

Cited By ~ 9

Author(s):

Dimitrios Farmakis ◽

Periklis Davlouros ◽

Gregory Giamouzis ◽

George Giannakoulas ◽

Athanasios Pipilis ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Comparable Efficacy ◽

Thrombin Inhibitor ◽

Systemic Embolism ◽

Nonvalvular Atrial Fibrillation ◽

Clinical Scenarios

Direct or new oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have recently revolutionized the field of antithrombotic therapy for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (NVAF). Randomized controlled trials have shown that these agents have at least comparable efficacy with vitamin K antagonists along with superior safety, at least in what concerns intracranial hemorrhage. As a result, NOACs are indicated as first-line anticoagulation therapy for NVAF patients with at least one risk factor for stroke or systemic embolism. The rapid introduction, however, of NOACs in a field dominated for decades by vitamin antagonists and the variety of agents and dosing schemes may create difficulties in decision making. In the present article, we attempt to determine a practical approach to the choice of agent and dose in different clinical scenarios by considering not only the results of seminal randomized trials and post hoc analyses but also data from real-world patient populations as well as the recently available possibility of rapid NOAC reversal.

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New Oral Anticoagulants: An Update

Journal of Bangladesh College of Physicians and Surgeons ◽

10.3329/jbcps.v37i3.41736 ◽

2019 ◽

Vol 37 (3) ◽

pp. 135-150

Author(s):

Quamruddin Ahmad ◽

Md Mahin Reza ◽

Md Ahosan Habib ◽

Syed Faravee Masud ◽

Nasiruddin ◽

...

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Mechanical Heart Valve ◽

The United States ◽

Medical Intervention ◽

New Drugs ◽

Thrombin Inhibitor ◽

Valve Prosthesis ◽

Coronary Syndrome

One of the most common and useful forms of medical intervention is anticoagulant therapy and it is the mainstay of treatment and prevention of thrombosis in different clinical settings, like atrial fibrillation (AF), acute coronary syndrome (ACS), acute venous thromboembolism (VTE), and in patients undergoing invasive cardiac procedures. More than 6 million patients in the United States receive long-term anticoagulation therapy for the prevention of thromboembolism due to AF, placement of a mechanical heart-valve prosthesis, or VTE.1 For more than 60 years, until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants (OAC) available. Although these drugs are highly effective in prevention of TE, their use is limited by a narrow therapeutic index that necessitates frequent monitoring and dose adjustments. This results in substantial risk and inconvenience, leading to inadequate anticoagulant prophylaxis. Recently some new OAC have been marketed which are effective, easier to use and has less side effects. Dabigatran is a new oral thrombin inhibitor and Rivaroxaban, Apixaban and Edoxaban are oral factor Xa inhibitors. This review outlines why these new OACs were essential and describes in detail about these new drugs. J Bangladesh Coll Phys Surg 2019; 37(3): 135-150

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Safety and Feasibility of Treatment with Rivaroxaban in Children for Non-Routine Indications: A Case Series Analysis

Blood ◽

10.1182/blood.v128.22.5014.5014 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5014-5014 ◽

Cited By ~ 1

Author(s):

Kathryn E. Dickerson ◽

Ravi Sarode ◽

Ayesha Zia

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Case Series ◽

Bleeding Complications ◽

Fixed Dose ◽

The Mean ◽

Recurrent Vte

Background. Anticoagulation therapy is the cornerstone of acute treatment of venous thromboembolism (VTE) and for prevention of recurrent VTE. The need for anticoagulation is increasing in children, largely in part due to increasing VTE rates. Conventional anticoagulants, including heparin, low-molecular weight heparins (LMWH), Fondaparinux, and vitamin K antagonists (VKA) are widely used in children but have limitations. Standard of care management with these agents is plagued with the trade-off between daily or twice daily injections or frequent monitoring of therapeutic effect. The advent of direct oral anticoagulants (DOACs) have catalyzed significant changes in the therapeutic landscape of VTE management. DOACs have been evaluated for safety and efficacy in large, randomized controlled trials in the treatment and prevention of VTE in adults, with results that are comparable to conventional therapy. None of the current DOACs have FDA-approved indications and dosing in children yet. Off-label use of these agents is largely based on adult data and doses, and is increasing at many Children's Hospitals across US. Rivaroxaban, a DOAC, is a factor Xa inhibitor with predictable pharmacokinetic and pharmacodynamics properties. Methods. We describe a case series of 8 unique pediatric cases, treated with Rivaroxaban, for a variety of non-routine indications, due either to adverse effects, intolerability of LMWH or VKA or the need for ongoing, long term anticoagulation. Rivaroxaban was started after informed consent and assent from parents or patients respectively, and was initiated at a fixed dose but titrated to a final dose after monitoring of trough and peak Rivaroxaban levels (Aniara, West Chester,OH, USA). Results. The mean age of patients in this case series is 14 years (median: 16, range 3-17) (see Table). The most common indication to use Rivaroxaban was the need for long term anticoagulation after having completed therapeutic anticoagulation, except in two patients, one of whom developed warfarin skin necrosis due to protein C deficiency and another with heparin induced thrombocytopenia. Only two patients needed dose adjustments to achieve target trough and peak drug levels. The mean duration of follow-up is 9 months (median= 5.5; range 3-24) (see Table) at this time. None of the patients developed recurrent VTE while on Rivaroxaban. A soft tissue traumatic bleed occurred in one patient which was treated with holding off the drug for 48 hours. No other bleeding complications were observed. Conclusions. Clinical application of DOACs in a real world clinical setting, including strong thrombophilia and malignancy, results in treatment profile of high efficacy and safety in children; however, larger studies are needed to validate these findings. Disclosures Sarode: CSL Behring: Consultancy, Honoraria.

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The current place of direct oral anticoagulants in the prevention/treatment of venous thromboembolism

Arhiv za farmaciju ◽

10.5937/arhfarm2005284t ◽

2020 ◽

Vol 70 (5) ◽

pp. 284-296

Author(s):

Maja Tomić

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Secondary Prevention ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Comparable Efficacy ◽

Thrombin Inhibitor ◽

Medical Patients ◽

Vte Prophylaxis

Venous thromboembolism (VTE; includes deep venous thrombosis, DVT, and pulmonary embolism, PE) represents the third most common acute cardiovascular syndrome. Contemporary VTE management comprises primary prevention in high-risk patients, treatment of established VTE, and prevention of its recurrence (secondary prevention). Anticoagulants are the basis of VTE pharmacological prophylaxis and treatment. For several decades, parenteral (heparin and low-molecular-weight heparins, LMWHs) and oral anticoagulants (vitamin K antagonists, VKAs) have been the cornerstone of VTE prevention/treatment. The introduction of direct oral anticoagulants (DOACs: thrombin inhibitor dabigatran and Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban) markedly improved the management of VTE by overcoming many disadvantages of conventional anticoagulants. For primary VTE prevention in patients after total hip/knee arthroplasty, rivaroxaban, apixaban, and dabigatran are preferred over LMWHs, due to comparable efficacy and safety, but favourable acceptability (avoided everyday injections). In other high-risk populations (other surgical patients, acutely ill medical patients), LMWHs are still the recommended option. Betrixaban is currently the only DOAC approved for VTE prophylaxis in medically ill patients during and after hospitalization. For acute VTE treatment and secondary prevention, DOACs (rivaroxaban, apixaban, edoxaban, and dabigatran) are recommended as the first-line therapy in the general population. DOACs proved to be similarly effective but safer than VKAs. In some specific populations, DOACs also seem to be advantageous over conventional treatment (patients with renal impairment, elderly, long-term secondary prevention in cancer patients). Currently, there is no data from randomized head-to-head comparative studies between the DOAC classes or representatives so the choice is made mainly according to patient characteristics and pharmacokinetic properties of the drug.

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Direct oral anticoagulants (DOAC) – Management of emergency situations

Hämostaseologie ◽

10.5482/hamo-16-11-0043 ◽

2017 ◽

Vol 37 (04) ◽

pp. 257-266 ◽

Cited By ~ 3

Author(s):

Edelgard Lindhoff-Last

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Real Life ◽

Bleeding Complications ◽

Severe Bleeding ◽

Emergency Operations ◽

Reversal Agents ◽

Life Threatening

SummaryThe worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in “real-life” conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.

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Impaired kidney function at ED admission: a comparison of bleeding complications of patients with different oral anticoagulants

BMC Emergency Medicine ◽

10.1186/s12873-021-00497-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Martin Müller ◽

Michaela Traschitzger ◽

Michael Nagler ◽

Spyridon Arampatzis ◽

Aristomenis K. Exadaktylos ◽

...

Keyword(s):

Renal Function ◽

Kidney Function ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Patient Treatment ◽

Bleeding Complications ◽

Study Patient ◽

Bleeding Events

Abstract Background Up to a fourth of patients at emergency department (ED) presentation suffer from acute deterioration of renal function, which is an important risk factor for bleeding events in patients on oral anticoagulation therapy. We hypothesized that outcomes of patients, bleeding characteristics, therapy, and outcome differ between direct oral anticoagulants (DOACs) and vitamin-K antagonists (VKAs). Methods All anticoagulated patients older than 17 years with an impaired kidney function treated for an acute haemorrhage in a large Swiss university ED from 01.06.2012 to 01.07.2017 were included in this retrospective cohort study. Patient, treatment, and bleeding characteristics as well as outcomes (length of stay ED, intensive care unit and in-hospital admission, ED resource consumption, in-hospital mortality) were compared between patients on DOAC or VKA anticoagulant. Results In total, 158 patients on DOAC and 419 patients on VKA with acute bleeding and impaired renal function were included. The renal function in patients on VKA was significantly worse compared to patients on DOAC (VKA: median 141 μmol/L vs. DOAC 132 μmol/L, p = 0.002). Patients on DOAC presented with a smaller number of intracranial bleeding compared to VKA (14.6% DOAC vs. 22.4% VKA, p = 0.036). DOAC patients needed more emergency endoscopies (15.8% DOAC vs, 9.1% VKA, p = 0.020) but less interventional emergency therapies to stop the bleeding (13.9% DOAC vs. 22.2% VKA, p = 0.027). Investigated outcomes did not differ significantly between the two groups. Conclusions DOAC patients were found to have a smaller proportional incidence of intracranial bleedings, needed more emergency endoscopies but less often interventional therapy compared to patients on VKA. Adapted treatment algorithms are a potential target to improve care in patients with DOAC.

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Falls in ED patients: do elderly patients on direct oral anticoagulants bleed less than those on vitamin K antagonists?

Scandinavian Journal of Trauma Resuscitation and Emergency Medicine ◽

10.1186/s13049-021-00866-6 ◽

2021 ◽

Vol 29 (1) ◽

Author(s):

Martin Müller ◽

Ioannis Chanias ◽

Michael Nagler ◽

Aristomenis K. Exadaktylos ◽

Thomas C. Sauter

Keyword(s):

Elderly Patients ◽

Vitamin K ◽

Intracranial Haemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Complications ◽

Lower Odds ◽

Anticoagulated Patients ◽

Proportional Incidence

Abstract Background Falls from standing are common in the elderly and are associated with a significant risk of bleeding. We have compared the proportional incidence of bleeding complications in patients on either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA). Methods Our retrospective cohort study compared elderly patients (≥65 years) on DOAC or VKA oral anticoagulation who presented at the study site – a Swiss university emergency department (ED) – between 01.06.2012 and 01.07.2017 after a fall. The outcomes were the proportional incidence of any bleeding complication and its components (e.g. intracranial haemorrhage), as well as procedural and clinical parameters (length of hospital stay, admission to intensive care unit, in-hospital-mortality). Uni- and multivariable analyses were used to compare the studied outcomes. Results In total, 1447 anticoagulated patients were included – on either VKA (n = 1021) or DOAC (n = 426). There were relatively more bleeding complications in the VKA group (n = 237, 23.2%) than in the DOAC group (n = 69, 16.2%, p = 0.003). The difference persisted in multivariable analysis with 0.7-fold (95% CI: 0.5–0.9, p = 0.014) lower odds for patients under DOAC than under VKA for presenting with any bleeding complications, and 0.6-fold (95% 0.4–0.9, p = 0.013) lower odds for presenting with intracranial haemorrhage. There were no significant differences in the other studied outcomes. Conclusions Among elderly, anticoagulated patients who had fallen from standing, those under DOACs had a lower proportional incidence of bleeding complications in general and an even lower incidence of intracranial haemorrhage than in patients under VKAs.

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Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation

Arrhythmia & Electrophysiology Review ◽

10.15420/aer.2015.4.1.44 ◽

2015 ◽

Vol 4 (1) ◽

pp. 44 ◽

Cited By ~ 2

Author(s):

Philipp Bushoven ◽

Sven Linzbach ◽

Mate Vamos ◽

Stefan H Hohnloser ◽

◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Stroke Prevention ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Prospective Trial ◽

Bleeding Complications ◽

Order Of Magnitude ◽

Pharmacological Cardioversion

For many patients with symptomatic atrial fibrillation, cardioversion is performed to restore sinus rhythm and relieve symptoms. Cardioversion carries a distinct risk for thromboembolism which has been described to be in the order of magnitude of 1 to 3 %. For almost five decades, vitamin K antagonist therapy has been the mainstay of therapy to prevent thromboembolism around the time of cardioversion although not a single prospective trial has formally established its efficacy and safety. Currently, three new direct oral anticoagulants are approved for stroke prevention in patients with non-valvular atrial fibrillation. For all three, there are data regarding its usefulness during the time of electrical or pharmacological cardioversion. Due to the ease of handling, their efficacy regarding stroke prevention, and their safety with respect to bleeding complications, the new direct oral anticoagulants are endorsed as the preferred therapy over vitamin K antagonists for stroke prevention in non-valvular atrial fibrillation including the clinical setting of elective cardioversion.

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The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

Stroke Research and Treatment ◽

10.1155/2017/6516401 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Kyle M. Ware ◽

Douglas L. Feinstein ◽

Israel Rubinstein ◽

Prudhvi Battula ◽

Jose Otero ◽

...

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemoglobin Concentration ◽

Thrombin Inhibitor ◽

Free Hemoglobin ◽

Intracranial Hemorrhages ◽

The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

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Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

Author(s):

Ali Zalpour ◽

Thein Hlaing Oo

Keyword(s):

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factors ◽

Current Evidence ◽

Thrombin Inhibitor ◽

Prevention And Treatment ◽

Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

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