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Anticoagulation Therapy: New Opportunities, New ChallengesSuraj Kapa, MD Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION © 2012 Direct One Communications, Inc. All rights reserved
Indications for Oral AnticoagulationMultiple clinical trials and guideline statements support the use of long-term oral anticoagulation for stroke prevention in high-risk patients with atrial fibrillation (AF).1–8 Long-term oral anticoagulation is also a mainstay in the management of patients with: Mechanical heart valves Deep venous thrombosis (DVT) Pulmonary embolism © 2012 Direct One Communications, Inc. All rights reserved
Shortcomings of WarfarinWarfarin therapy requires control of patients’ prothrombin time or international normalized ratio (INR) within a narrow therapeutic range. Warfarin levels above the therapeutic range lead to an increased risk of life-threatening bleeding, and levels below the therapeutic range obviate any potential benefits from the drug. Ensuring maintenance of therapeutic INRs requires frequent blood testing. Multiple dietary and pharmacologic interactions may complicate the maintenance of a therapeutic INR.9,10 © 2012 Direct One Communications, Inc. All rights reserved
Thrombus Formation In AF, the tissue factor pathway is the primary target for preventing thrombus formation and stroke.12–15 Thrombus formation involves tissue factor-bearing cells that come into contact with circulating coagulation factors. As factor VII comes into contact with tissue factor on these cells, an activated complex forms, which triggers factors IX and X. Factor Xa and factor Va then form prothrombinase complexes that activate prothrombin to thrombin, which, in turn, then stimulates factor VII and other components of the coagulation cascade. © 2012 Direct One Communications, Inc. All rights reserved
Coagulation Cascade Schematic diagram of the coagulation cascade along the tissue factor pathway and the targets of direct factor Xa and thrombin inhibitors. The vitamin K antagonist warfarin typically works on several calcium-dependent clotting factors, including factors II, VII, IX (not shown), and X. © 2012 Direct One Communications, Inc. All rights reserved
Targeting Specific Coagulation FactorsNewer oral anticoagulants target specific points in the coagulation cascade: Factor Xa inhibitors (eg, rivaroxaban, apixaban) target factor Xa, preventing the conversion of prothrombin to thrombin. Direct thrombin inhibitors (eg, dabigatran, ximelagatran) target thrombin (factor IIa), blocking the conversion of fibrinogen to fibrin. The goal of novel oral anticoagulants is, in part, to offer more specific targeting and to afford more predictable responses than current anticoagulant therapies, such as warfarin, can offer. © 2012 Direct One Communications, Inc. All rights reserved
The Ideal Oral AnticoagulantIdeally, an oral anticoagulant would: Require no remote monitoring Have little interaction with food or other drugs Offer a good safety profile with regard to bleeding risk Have similar efficacy to warfarin in reducing thromboembolic events Reach therapeutic levels within several hours © 2012 Direct One Communications, Inc. All rights reserved
Warfarin When warfarin therapy is started, its anticoagulant effects may not be apparent for several days. The duration of action of a single dose is 2–5 days. The therapeutic effect of warfarin exists within a narrow therapeutic window as dictated by the INR. Considerable inter- and intraindividual dose variability may be affected by a wide range of physiologic (liver and thyroid function), genetic, and environmental (eg, diet, other drugs) factors.9,10 Regular monitoring is required to avoid excessive or insufficient anticoagulation.16 © 2012 Direct One Communications, Inc. All rights reserved
Dabigatran Dabigatran etexilate is a direct thrombin inhibitor that is given at a fixed oral dose without the need for INR monitoring.17,18 Because of potential P-glycoprotein (P-gp) interactions, its absorption may be decreased if dabigatran is taken with a proton pump inhibitor.19 Excretion may be slowed in patients taking P-gp pump inhibitors such as quinidine, verapamil, or amiodarone, raising plasma levels of dabigatran.19 The drug has a relatively short half-life (12–17 hours). Patients with acute or chronic renal failure may require reduced doses.17,18 © 2012 Direct One Communications, Inc. All rights reserved
Rivaroxaban and ApixabanRivaroxaban and apixaban are direct factor Xa inhibitors.20–23 The two drugs interact slightly differently with the S4 region of factor X. Both rivaroxaban and apixaban bind to the catalytic/active site of factor X and directly interfere with the coagulation cascade. They have predictable pharmacokinetics and allow for fixed oral dosing without the need for INR monitoring. Similar to dabigatran, the half-lives of rivaroxaban and apixaban are under 12 hours. © 2012 Direct One Communications, Inc. All rights reserved
Models of Care: Warfarin TherapyRoutine medical care, wherein a physician or office staff manage warfarin dosing based on INRs obtained from blood draws in a laboratory or via a point-of-care device in the clinic. Anticoagulation clinics managed by dedicated healthcare professionals that have systematic policies to manage and dose patients, using either point-of-care or laboratory-based INRs.25–27 Patients using a point-of-care monitor at home to measure their INRs and then reporting back to the personnel in a clinic to alter the dose.28,29 © 2012 Direct One Communications, Inc. All rights reserved
Switching to Newer Oral AnticoagulantsAdvantages: Fixed oral dosing No need to monitor prothrombin time or INR Fewer drug interactions No dietary restrictions Disadvantages: Lack of validated tests to assay their anticoagulant effect30 No antidote readily available to halt bleeding More difficult to assess patient compliance Lack of data on long-term adverse effects beyond bleeding Absence of head-to-head comparisons between novel oral anticoagulants © 2012 Direct One Communications, Inc. All rights reserved
Other Issues with Newer AnticoagulantsPeaks and troughs in anticoagulation levels may result from their relatively shorter half-lives, compared with warfarin. The dosing of these drugs is fixed, so there is no easy way to measure their therapeutic effects using specific blood tests. Additional monitoring of liver and renal function may be needed to ensure that dose adjustments or switching of agents is not required. There is little to educate patients about beyond compliance. © 2012 Direct One Communications, Inc. All rights reserved
Comparison of Oral Anticoagulants© 2012 Direct One Communications, Inc. All rights reserved
Anticoagulant Therapy and StrokePatients with AF-related stroke have a 1.8-fold increase in mortality when compared with those who experience a stroke unrelated to AF, possibly because AF-related strokes tend to be larger in size and more often lead to hemorrhagic transformation.2,31,32 Although patients with AF and at least two additional risk factors for stroke benefit from warfarin therapy, many patients and their physicians resist using warfarin because of concerns related to INR monitoring, the risk of falls, and the potential for bleeding and intracranial hemorrhage. © 2012 Direct One Communications, Inc. All rights reserved
INR Variability in AF PatientsRandomized clinical trials comparing dabigatran, apixaban, and rivaroxaban with warfarin have shown a strong trend toward the superiority of these novel oral anticoagulants in preventing stroke and in reducing the rate of intracranial hemorrhage.33–36 However, data from systematic overviews suggest that patients on warfarin maintain a therapeutic INR only 63% of the time at best, with even worse results being observed in community practices.37 The importance of maintaining a minimum INR of 2.0 to obtain effective stroke prevention during warfarin therapy has been well documented.38–41 © 2012 Direct One Communications, Inc. All rights reserved
INR Variability in AF PatientsAnalyses of data from the ROCKET AF, RE-LY, and ARISTOTLE studies have shown no significant difference in stroke outcomes between patients given a novel oral anticoagulant and those using warfarin.33–36,42 However, RE-LY data showed that 50% of patients using warfarin who had a therapeutic INR at least 67% of the time had a composite event rate of 5.48, which was lower than the event rates among patients using dabigatran, whereas patients who were in the therapeutic range less than 54% of the time had an event rate of 12.32, which was much worse than the event rate in patients taking dabigatran.42 © 2012 Direct One Communications, Inc. All rights reserved
INR Variability in AF PatientsIn the SPORTIF trial, 25% of patients who had the greatest percentage of time in the therapeutic INR range had the lowest event rates; however, patients who were in the therapeutic range less than 60% of the time had much higher event rates.43,44 In the ATRIA study, there was an 8-fold increase in ischemic events with any reduction in the INR < 1.3; if the INR was > 4.0, there was a 12-fold increase in intracranial hemorrhage.45 © 2012 Direct One Communications, Inc. All rights reserved
Self-Monitoring of INR LevelsSelf-testing may provide a better way to maintain INR levels within a narrow therapeutic window. Results from the THINRS trial suggested beneficial trends in mortality, major bleeding, and stroke when patients performed self-testing, rather than relying on specific clinics for monitoring and managing their anticoagulation therapy.46–48 Similarly, in the STOARM2 trial, INR management improved with automated self-monitoring, with INR values < 1.5 or > 5 seen in only 0.47% of patients.49 © 2012 Direct One Communications, Inc. All rights reserved
Self-Monitoring of INR LevelsOther studies have suggested that anticoagulation clinics run by clinical pharmacists may reduce major events, hospitalizations, and emergency visits by 60%–80%, when compared with usual clinic-based management of warfarin, and that weekly INR self-testing and self-management may reduce major events by as much as 70% and mortality by as much as 61%.28,29,46–51 Thus, some contend that the primary issue is to fix how we are managing patients using warfarin rather than to switch patients to another agent. © 2012 Direct One Communications, Inc. All rights reserved
Cost-Effectiveness Cost-effectiveness analyses of newer anticoagulants in preventing stroke in patients with AF are limited. At a cost of $7–$9/day (two capsules), dabigatran use may cost an estimated $10,000 per year of life saved.52–54 However, this analysis does not consider direct comparisons against the cost of maintaining patients on warfarin under current models of care. Further studies are needed to better analyze the relative cost-effectiveness of warfarin versus that of any of the newer oral anticoagulants and also to consider the cost of improving INR management. © 2012 Direct One Communications, Inc. All rights reserved
Potential of Newer Oral AnticoagulantsNewer anticoagulant agents have issues55 not shared with warfarin, including: A shorter half-life with rapid offset and potential attendant clotting risk The need for a reversal agent in cases of acute bleeding or at the time of emergent procedures The lack of laboratory monitoring to evaluate patient adherence These newer agents are easy to use, and AF patients can benefit from lower stroke risk without needing repeated blood tests for INR monitoring, so the potential benefits are obvious. © 2012 Direct One Communications, Inc. All rights reserved
Anticoagulant Therapy and DVTThe same concerns related to INR monitoring, the narrow therapeutic window of warfarin, and the wide variety of dietary and pharmacologic interactions with warfarin still exist in treating patients with DVT. One key difference in these patients is that the goal is treating an existing problem rather than preventing a potential one.56,57 However, the decision to treat as an outpatient versus as an inpatient is more difficult, because the time to reach an effective therapeutic range on warfarin varies from 2 to 5 days. © 2012 Direct One Communications, Inc. All rights reserved
Rivaroxaban vs Warfarin in DVTIn both the EINSTEIN DVT trial, which compared rivaroxaban with warfarin, and in an extension of the EINSTEIN trial, which examined the prevention of recurrent venous thromboembolism with rivaroxaban, a nonsignificant decrease in mortality was noted with rivaroxaban therapy.58,59 The study population excluded use of interacting medications (strong CYP3A4 inhibitors and inducers) and patients with significantly elevated liver function tests or renal impairment. Warfarin-treated patients were within the therapeutic INR range less than 60% of the time. © 2012 Direct One Communications, Inc. All rights reserved
Dabigatran vs Warfarin in DVTIn the RE-COVER trial, dabigatran was noninferior to warfarin in treating acute DVT.60 The study population excluded patients if they had recent unstable cardiovascular disease, baseline liver function test results that were more than twice the upper limit of normal, or significant renal impairment. As in the EINSTEIN DVT trial and similar clinical trials in AF, warfarin-treated patients were within the therapeutic INR range less than 60% of the time. © 2012 Direct One Communications, Inc. All rights reserved
Choosing an Oral Anticoagulant for DVTConsiderations related to the choice of an initial oral anticoagulant for patients with acute DVT are similar to those used for patients with AF, namely, the: Ability to keep the patient on warfarin within therapeutic INR levels Costs of individual agents Unknown long-term risks related to novel anticoagulants Lack of clarity regarding efficacy in patients with significant liver or renal impairment © 2012 Direct One Communications, Inc. All rights reserved
Laboratory MonitoringAlthough dabigatran can raise the INR, activated partial thromboplastin time (aPTT), and thrombin time, the degree of elevation has not been clearly associated with its therapeutic effect.61 The ecarin clotting time (ECT)—in which a known quantity of ecarin is added to the patient’s plasma and the time to clotting is evaluated—has been suggested for monitoring the anticoagulant activity of dabigatran.61 ECT is notably unaffected by heparin or warfarin.61 Recently developed chromogenic dabigatran assays may permit monitoring serum dabigatran levels.61 © 2012 Direct One Communications, Inc. All rights reserved
Laboratory MonitoringSimilarly, an anti-factor Xa level may be used to evaluate the therapeutic effects of rivaroxaban or apixaban.61 These assays are not as quickly obtained or as widely available as is the INR. Furthermore, therapeutic ranges for these laboratory tests remain to be determined. © 2012 Direct One Communications, Inc. All rights reserved
Managing Bleeding ComplicationsThere is some evidence that the anticoagulant actions of dabigatran and rivaroxaban may be reversible.62–65 Preclinical studies suggest that both recombinant factor VIIa and prothrombin complex concentrate (PCC) can reverse the effects of dabigatran and rivaroxaban on bleeding time and aPTT. Injection of PCC immediately reversed the anticoagulant activity of rivaroxaban in 12 healthy human volunteers but had no effect on dabigatran-induced increases in aPTT, ECT, or thrombin time.62 How these blood products might function in actual emergent clinical situations is unknown. © 2012 Direct One Communications, Inc. All rights reserved
Conclusions Although the introduction of rivaroxaban, apixaban, and dabigatran has the potential to revolutionize the day-to-day care of patients who require oral anticoagulation therapy, the best use of these drugs ultimately may need to be determined on a patient-by-patient and center-by-center basis. The efficacy of individual centers in managing INRs, the ability to safely maintain a therapeutic INR range in individual patients on warfarin, and the current lack of a clear methodology for monitoring or reversing the anticoagulant effects of these new agents all must be taken into account when a patient is switched from warfarin to them. © 2012 Direct One Communications, Inc. All rights reserved
Conclusions The new era of anticoagulant therapy has resulted in a milieu of studies and evolving guidelines to help refine the optimum use of these novel agents as more convenient and possibly safer therapeutic alternatives to warfarin. Future studies to examine the cost-effectiveness of these agents and their impact on individual patients and systems-based care, as well as head-to-head comparisons of novel oral anticoagulants, will be the key to understanding how these novel agents may enter the current lexicon of anticoagulation. © 2012 Direct One Communications, Inc. All rights reserved
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JOURNAL REVIEW Newer Antithrombotics in AF 1 Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode.
Date of download: 7/1/2016 Copyright © The American College of Cardiology. All rights reserved. From: ACC/AHA/ESC 2006 Guidelines for the Management of.
A Randomized Trial of Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism Schulman S et al. Proc ASH 2011;Abstract 205.
Study by: Granger et al. NEJM, September 2011,Vol No. 11 Presented by: Amelia Crawford PA-S2 Apixaban versus Warfarin in Patients with Atrial Fibrillation.
NEW ORAL ANTICOAGULANTS
Patients Are Undertreated NABOR Warfarin/Warfarin + Aspirin No Treatment Patients, % Waldo AL, et al. J Am Coll Cardiol. 2005;46:  Retrospective.
Oral Rivaroxaban for Symptomatic Venous Thrombroenbolism Group /06/11.
Net clinical benefit of OAC Net clinical benefit - stroke, systemic embolism, ICH – events prevented per 100 person years Singer 2009.
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Target
Apixaban versus Aspirin in Atrial Fibrillation Patients ≥ 75 years old: An Analysis from the AVERROES Trial Kuan H Ng, Olga O Shestakovska, John W. Eikelboom,
The GARFIELD Registry is funded by an unrestricted research grant from Bayer Pharma AG The Role of Anticoagulants Keith A A Fox Edinburgh.
Date of download: 6/26/2016 Copyright © The American College of Cardiology. All rights reserved. From: 2014 AHA/ACC/HRS Guideline for the Management of.
The NEW ENGLAND JOURNAL of MEDICINE Idarucizumab for Dabigatran Reversal R3 김동연 / F. 김선혜.
Review on NOACs Studies DR. KOUROSH SADEGHI TEHRAN UNIVERSITY OF MEDICAL SCIENCES.
Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D.,
Date of download: 7/10/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Choice of Antithrombotic Therapy for Stroke Prevention.
ARISTOTLE TRIAL Dr R Nyabadza GPST1 Ward 32. Structure AF, stroke and CHA 2 -DS 2 VASC Anticoagulant choices ARISTOTLE trial Cost NICE guidance and the.
Gli anticoagulanti diretti nel mondo reale Il neurologo: Efficacia e sicurezza Antonio Carolei* e Cindy Tiseo Clinica Neurologica e Stroke Unit Avezzano.
Spotlight Case Watch the Warfarin!. 2 Source and Credits This presentation is based on the July 2011 AHRQ WebM&M Spotlight Case –See the full article.
The Efficacy of Dabigatran versus Warfarin for Stroke Prevention in Patients With Atrial Fibrillation: Systematic Review Karim Bouferrache Pacific University.
Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D., Werner Hacke, M.D., Ph.D., Gunter Breithardt,
N Engl J Med 2009;361: Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf, F.R.C.P.C., D.Phil., John Eikelboom,
Prof. Alberto Corsini Università degli Studi di Milano
Presented by Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, Duke University, USA for the ARISTOTLE investigators. Efficacy and Safety of Apixaban.
Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart DiseaseClinical Perspective by Michael D. Ezekowitz, Rangadham.
The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism.
How to Navigate the New Oral Anticoagulants and Deal With Triple Therapy Dr. Morteza Safi Professor of interventional cardiology Cardiovascular Research.
The EINSTEIN DVT Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Deep Vein Thrombosis.
Care of the Anti-coagulated Trauma Patient Julie Mayglothling, MD, FACEP Emergencies in Medicine March 8 th, 2012.
The Changing Landscape of Anticoagulation William D. Cahoon, Jr., PharmD, BCPS Cardiology Clinical Pharmacist VCU Health System April 12, 2012.
Atrial Fibrillation Warfarin and its newer alternatives
UK/CVS (1) | February 2013 Emerging technologies for stroke prevention in atrial fibrillation UK/CVS (1) | Date of preparation: February 2013.
New Oral Anticoagulant R2 Patcharee Seesongsom R2 Sirada Phojai Advisor AJ Tachawan Jiratiwanon.
A Screening Test for Xa based DOACs Uzma Ahmad BMS Haematology at The Mid Yorkshire Hospitals NHS Trust Introduction A study was undertaken to investigatie.
R4 문정락 / IC prof. 김진배 Lancet Haematol 2015;2: e150–59.
Venous thromboembolism: how long to treat?
Anti-thrombotic agents. New and Emerging Anticoagulants Anti – Xa : direct Rivaroxaban (oral) Apixaban (oral) Betrixiban (oral) Edoxaban (oral)
Pulmonary Embolism Treatment in Cancer - Is It Different 34th Brazilian Thoracic Conference 6th ALAT Congress 5th Brazil-Portugal Congress Brazilia/DF.
Supervisor: Vs 余垣斌 Presenter: CR 周益聖. INTRODUCTION.
Rohan Subasinghe. Non valvular aF increases with age from 0.5 % at age to 9 % at age AF is an independent Risk factor for CVA Patients.
New Oral Anticoagulants (NOACs) Dabigatran and Rivaroxaban for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation Dr Dipti.
The EINSTEIN EXT Study 'Xarelto' for the Long-Term Prevention of Recurrent Venous Thromboembolism.
Praxbind ® - Idarucizumab Manufacturer: Boehringer Ingelheim Pharmaceuticals, Inc. FDA Approval Date: 10/16/2015.
Dr. MUHAMMAD SYUKRI, Sp JP
WARFARIN AN OVERVIEW.
Bleeding complications and management in patients treated with NOACs Nico De Crem ASO Interne Geneeskunde.
Impact of New Anticoagulants on the Blood Bank
Clinical Pharmacy Part 2
The New Oral Anticoagulants: Handle with Care Philip C. Comp, M.D., Ph.D. October 18, 2013.
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