4/6/2015. Agenda. VTE by the Numbers VTE. Pulmonary Embolism (PE)

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1 Generate Knowledge Agenda Anticoagulation Past and Present 2015 CLCC Meeting Denver, Colorado VTE Review of basic coagulation PT/INR and coumadin therapy Heparin monitoring past and present New anticoagulants Target points Measure or monitor? How do I get an answer? Claudia E. Escobar, MT(ASCP)SH Product Manager, Systems Diagnostica Stago Venous Thromboembolism (VTE) VTE by the Numbers VTE An estimated people are affected by VTE annually DVT Deep Vein Thrombosis PE Pulmonary Embolism Americans are estimated to die each year from VTE CDC Data and Statistics, DVT/PE Accessed 25 March Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Picture: Picture: 1

2 PTT BASED ASSAYS 4/6/2015 VTE Risk Factors The 3 steps of Hemostasis Primary Hemostasis Interaction between vessel walls, platelets and adhesive proteins Coagulation Consolidation of the platelet thrombus, an insoluble fibrin net Coagulation factors Fibrinolysis Clot lysis Picture: Coagulation Cascade PT BASED ASSAYS PT/INR AND COUMADIN THERAPY PT BASED ASSAYS Prothrombin Time (PT) Involves activation of FVII by tissue thromboplastin Reagent composition Thromboplastin (natural/recombinant) CaCl2 Heparin neutralizer Tests for factors II, V, VII and X Clinical uses for a PT OAC therapy monitoring Factor deficiency DIC Potential interference from DOAC/DTI Rivaroxaban (Xarelto) Apixaban (Eliquis) Dabigatran (Pradaxa) Monitoring VKA Therapy PT (1935): Wide range of reagents Lack of standardization Poor result correlation between labs INR (1984): Results standardization via a reagent assigned ISI value Improvement, but not great 2

3 PT result units - INR Why INR? Major differences are observed when PT are performed on the same patient with different PT reagents (different sensitivity) Different results are obtained when using seconds or ratio The solution: PT reagent dependent therapeutic range A mathematical correction (of the PT ratio) for differences in the sensitivity of thromboplastin reagents Relies upon "reference" thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants Allows for results comparison between labs and standardizes reporting of the prothrombin time Determination of the MNPT Each laboratory should determine their own Mean Normal PT MNPT = geometric mean* of at least 20 freshly prepared normal plasmas samples from healthy individuals, collected over a period no longer than 5 days A correct MNPT is of fundamental importance for accuracy of INR A control plasma or a pool of normal plasma cannot be used * Determination of the ISI ISI: slope of a regression line between a given thromboplastin and the Reference Thromboplastin VKA: Success and Pitfalls Oral - slow onset - multi-target (II, VII, IX, X) Chemically defined LOW cost Multiple interactions: genetic factors (CYP450 2C9 / VKORC1) Drugs (> 200 agents) nutritional supplements fluctuating levels of dietary vitamin K Routine monitoring: INR - multiple causes of errors frequent dose adjustments Half life: acenocoumarol 8 9 h warfarin h Reversal: vitamin K blood derivatives recombinant activated Factor VII Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e44S-88S. doi: /chest Recommended therapeutic ranges OAC monitoring: PT results in INR Heparin Monitoring in the Laboratory 17 3

4 Heparin Mechanism of action Widely used antithrombotic Naturally occurring glycosaminoglycan produced by mast cells Potentiates activity of Antithrombin Indications for use Prevention & treatment of thrombosis Drug of choice when rapid anticoagulant effect required Mechanism of action Heparin Comparison Unfractionated Primarily obtained from porcine intestine Varied molecular weight Binds to plasma proteins, PF4, macrophages & endothelial cells Limits bioavailability & accounts for varied response MONITORING NECESSARY Low Molecular Weight Derived from UFH by depolymerization Smaller molecules Lower affinity for binding proteins other than AT More predictable response Thrombosis Advisor Unfractionated and Low Molecular Weight Heparins. Accessed: 25 March Picture: Marmur et al. J Invasive Cardiol. 2009;21(12): Indications for LMWH Monitoring Impaired renal function UFH Pregnancy Extremes of body weight Newborns or young children Lack of response LMWH Picture: Weitz JI: Low-molecular-weight heparins. N Engl J Med 1997;337:

5 Heparin Use $4 billion estimated global annual sales 1 North America led the global market share of heparin in recent years 2 Potential Heparin Therapy Complications Bleeding complications Difficult to define risk because dependent on numerous parameters: indication, dosage, method, duration of therapy, patient characteristics, comedication 12% expected compound annual growth to Non-bleeding complications Caused by heparin binding to proteins other than AT and cells HIT is the most severe complication 1. Rensselaer Polytechnic Institute (RPI). "Synthetic version of heparin created for use in kidney patients." ScienceDaily. ScienceDaily, 23 February Heparin Market-Global Industry Size, Market Share Trends, Analysis and Forecast " Transparency Market Research, Accessed : 25 March Alban, S. (2012) Adverse Effects of Heparin In: Lever, R., Mulloy, B. and Page, C., eds. Heparin: a century of progress :. Handbook of experimental pharmacology (207). Springer, Berlin, pp ISBN High Alert Medications Drugs that bear risk of causing significant patient harm when used incorrectly Antithrombotic agents categorized as High- Alert Medications by the Institute for Safe Medication Practices (ISMP) Anticoagulants (e.g. warfarin, low-molecular-weight heparin, IV unfractionated heparin) Factor Xa inhibitors (e.g. Fondaparinux) Direct thrombin inhibitors (e.g. argatroban, bivalirudin, dabigatran etexilate, lepirudin) Thrombolytics (e.g. alteplase, reteplase, tenecteplase) Glycoprotein IIb/IIIa inhibitors (e.g. eptifibatide) Joint Commission National Patient Safety Goal Aims to reduce the likelihood of patient harm associated with the use of anticoagulant therapy Applies only to hospitals that provide anticoagulant therapy and/or long-term anticoagulation prophylaxis Rationale Anticoagulation medications are more likely to cause harm due to complex dosing, insufficient monitoring, and inconsistent patient compliance Accessed 15Jan2014, 15:50 EST accessed 10Jan2014, 11:24 EST Heparin Monitoring Assays Methods for Heparin Monitoring APTT Anti-Xa ACT 5

6 Activated Clotting Time (ACT) Point-of-care, whole blood clotting test to monitor high-dose heparin therapy 1 Often dose of heparin is beyond the range that can be measured with the aptt 2 Cardiopulmonary bypass graft surgery (CPBG) may exceed 400 to 500 seconds 3 Activated Partial Thromboplastin Time (aptt) A global test of the intrinsic coagulation pathway Indirect sensitivity to heparin through its anti-iia activity Subject to many interferences Patient variables: factor levels 13,16 (FVIII, fibrinogen, etc), presence of lupus anticoagulant or liver disease Pre-analytical variables: citrate concentration, sample storage, phlebotomy errors (short fill, wrong tube) etc. Analytical variables: reagent sensitivity, reagent/instrument system Blood Sampling (Pre-analytical) Tube fill Tube type Reasons for a Prolonged aptt UFH LMWH: no relation to aptt / drug dosage Congenital Deficiencies Mainly hemophilia (VIII, IX) vwf / VIII (von Willebrand s disease) II, V, X XI, XII Fibrinogen (hypo <0.8 g/l) Dysfibrinogenemia Acquired Deficiencies Liver disease DIC Vit K deficiency Warfarin Potential to Under-Anticoagulate Groce JB, Leumas J. Basic Skills in Interpreting Laboratory Data. 3 rd ed. Am Soc Health System Pharmacists. May Van Cott EM, Laposata M. Coagulation. In: Jacobs DS, Oxley DK, DeMott WR, eds. The Laboratory Test Handbook. 5th ed. Cleveland, Ohio: Lexi- Comp; 2001: Dougherty KG, Gaos CM, Bush HS, Leachman DR, Ferguson JJ. Activated clotting times and activated partial thromboplastin times in patients undergoing coronary angioplasty who receive bolus doses of heparin. Cathet Cardiovasc Diagn. 1992;26: Hirsh J, Raschke R. Heparin and low molecular- weight heparin: the Seventh ACCP Conference on Antithrombotic andthrombolytic Therapy. Chest. 2004;126: 188S 203S. Auto- Antibodies Specific (factors) Nonspecific (LA) How did the APTT become the standard? A 1972 landmark study concluded that a range APTT of x the baseline value is required (Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287: ) This range was determined in animal studies and had not been tested clinically in humans There was a question of whether you needed to monitor heparin or just use a standard dose They were prospectively looking for a relationship between the APTT and recurrent venous thromboembolism (VTE) or bleeding 5 patients being treated for VTE developed a new thrombosis and all 5 had lower APTT than patients without new thrombus development Later, it was determined that the x the baseline corresponded to U/mL Heparin by protamine sulfate titration CAP Guidelines for UFH Monitoring Since 1998, CAP has recommended calibrating aptt reagents used for UFH therapy against an anti-xa range of IU/mL Adjusted dose & therapeutic UFH requires monitoring using method with a defined range Test at 6 hour intervals until a stable response achieved, then daily, at same time of day, preferably prior to 10 am Specimens should be collected from different extremity Clinicians should be informed of method & its therapeutic range aptt reagents for UFH therapy should be calibrated against an anti-xa reagent corresponding to IU/mL Anti-Xa method is the preferred alternative method to the aptt for monitoring UFH Olson JD, Arkin CF, Brandt JT, Cunningham MT, Giles A, Koepke JA, Witte DL. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122: American College of Chest Physicians (ACCP) Guidelines for UFH Monitoring Since 2001, ACCP has recommended calibrating aptt reagents used for UFH therapy against an anti-xa range of IU/mL determine the appropriate therapeutic range based on the local laboratory reagent & adapt dosage adjustments accordingly..the targeted APTT should be equivalent to a heparin level of IU/mL by anti-factor Xa heparin levels. Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, et al. Heparin and Low-Molecular-Weight Heparin; Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. Chest 2001; 119: 64S 94S 6

7 Additional ACCP Guidelines for UFH Monitoring Examples of heparin dose adjustment nomograms are provided for aptt based UFH monitoring, but these nomograms have the shortcoming of being reagentdependent Monitoring is required except for patients receiving low dosages Doses for intravenous (IV) and subcutaneous UFH therapy are described along with weight-based dosing strategies Clinical factors for increased bleeding risk are described, along with reversal by protamine sulfate to avoid bleeding Monitoring with anti-xa may be useful for patients at high risk of bleeding Target ranges for LMWH therapy by anti-xa are also described aptt monitoring of Heparin (UFH Only) Historical method: x the baseline (Not Recommended) Based on a retrospective study in the 1970 s Not confirmed by randomized trials in humans In Vitro Heparin Curve 12 (Not Recommended) Uses normal pool spiked with heparin to determine the aptt values correlating to IU/mL anti-xa range Increases upper & lower aptt range compared to Ex Vivo method Ex Vivo Heparin Curve 13 Uses samples from patients receiving UFH to determine the aptt values correlating to IU/mL anti-xa range Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, et al. Heparin and Low-Molecular-Weight Heparin; Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. Chest 2001; 119: 64S 94S Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral Anticoagulants. American College of Chest Physicians. Evidence-based Clinical Practice Guidelines (9th Edition). Chest 2012; 141 (2 Suppl): e24s-e43s APTT Reagent Variability aptt monitoring of Heparin (UFH Only) Reagent APTT Range Corresponding to U/mL Corresponding Ratio (mean control) Actin IL Test Thrombosil Actin FSL Actin FS Historical method: x the baseline 11 (Not Recommended) Based on a retrospective study in the 1970 s Not confirmed by randomized trials in humans In Vitro Heparin Curve (Not Recommended) Uses normal pool spiked with heparin to determine the aptt values correlating to IU/mL anti-xa range Increases upper & lower aptt range compared to Ex Vivo method Ex Vivo Heparin Curve 13 Uses samples from patients receiving UFH to determine the aptt values correlating to IU/mL anti-xa range Bates SM, Weitz JI, Johnston M, Hirsh J, Ginsberg JS. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001; 161: Comparison of In Vitro & Ex Vivo Curves aptt monitoring of Heparin (UFH Only) Historical method: x the baseline 11 (Not Recommended) Based on a retrospective study in the 1970 s Not confirmed by randomized trials in humans In Vitro Heparin Curve 12 (Not Recommended) Uses normal pool spiked with heparin to determine the aptt values correlating to IU/mL anti-xa range Increases upper & lower aptt range compared to Ex Vivo method In Vitro Range: seconds Ex Vivo Range: seconds Ex Vivo Heparin Curve Uses samples from patients receiving UFH to determine the aptt values correlating to IU/mL anti-xa range Gausman JN, Marlar RA. Inaccuracy of a Spiked Curve for Monitoring Unfractioned Heparin Therapy Am J Clin Pathol. 2011; 135: Graph from: Gausman JN, Marlar RA. Inaccuracy of a Spiked Curve for Monitoring Unfractioned Heparin Therapy Am J Clin Pathol. 2011; 135:

8 Anti-Xa Assay Anti-Xa Methodology Quantitative determination of the plasma levels of both UFH and LWMH Direct sensitivity to heparin through measurement of anti- Xa activity on antithrombin Few interferences Patient variables: not susceptible to interference from elevated factor VIII or fibrinogen and not influenced by factor deficiencies Pre-analytical variables: not affected by under-filled collection tubes Analytical variables: reagents are calibrated to international standards for UFH and LMWH =Reagent 1 =Reagent 2 Anti-Xa Methodology Reagent Formulation Differences: Antithrombin There is an inverse relationship between chromogenic readout and drug levels Heparin concentration Inhibition of F.Xa Hydrolysis of the chromogenic substrate Color development Containing Exogenous AT Standard AT concentration in the reaction Measuring a standardized heparin inhibitory activity in the sample Possibility for overestimation of heparin levels 19 Drug unbound to AT in vitro (inactive) to bind exogenous AT an have an anticoagulant effect in vitro Without Exogenous AT AT-Heparin complex is already formed in the sample Heparin activity depends on the sample concentration of AT Reaction of the AT- Heparin complex inhibiting FXa happens all in one step Measures the true heparin inhibitory activity in the sample In vitro effect closely emulates in vivo effect 19 8

9 Reagent Formulation Differences: Dextran Sulfate (DS) Dextran sulfate releases UFH bound nonspecifically to off-target proteins Reagents containing dextran sulfate measure all UFH present in plasma and may overestimate heparin levels 19 Anti-Xa Assays With/Without Dextran Sulfate 21 Reagent (+) DS Reagent (+) DS after neutralizing UFH by protamine sulfate Reagent (-) DS Reagent (-) DS after neutralizing UFH by protamine sulfate Reagents without DS measure only that portion of UFH participating in the anticoagulant effect (ie not bound to off-target proteins) The (+) DS assay continued to demonstrate activity after samples were neutralized to baseline APTT and TT where as the (-) DS assay gave baseline results Picture: Wikipedia Graph adapted from Mouton C, Calderon J, Janvier G, Vergnes MC. Dextran Sulfate included in factor Xa assay reagent over estimates heparin activity in patients after heparin reversal by protamine. Thrombosis Research 2003; 111: : Assay Discordance Discordance between the aptt and anti-xa assays is a well documented problem aptt and Anti-Xa Discordance Preanalytic variables Biologic factors aptt reagent/instrument combination variability Differences in testing targets Final Heparin Therapeutic Range Graph Case #1: - APTT: 75.4 seconds - Anti-Xa: 0.12 IU/mL APTT=Therapeutic Anti-Xa=Sub therapeutic Concordant therapeutic results APTT is prolonged in relation to anti-xa level Patients are dosed based on the graph constructed from these samples n = 60 9

10 Case #2: - APTT: seconds - Anti-Xa: 0.38 IU/mL APTT=Super therapeutic Anti-Xa=Therapeutic APTT is prolonged In relation to anti-xa level Discordance Case Study Presentation Treatment 41-yr old patient, 25 weeks gestation, twin pregnancy Left lower extremity pain & swelling Ultrasound showed occlusive clots UFH with an Initial bolus of 6,300 units and infusion of 1,400 u/hour Dose was adjusted & monitored using aptt The aptt range was correlated to anti-xa Patient required 48,000 units UFH/day to achieve therapeutic APTT levels Raschke RA, Guidry JR, Foley MR. Apparent heparin resistance from elevated factor VIII during pregnancy. Obstet Gynecol 2000; 96: Laboratory Results Anti-Xa levels performed in addition to aptt Follow Up FVIII level 566% (normal range %) UFH monitored with anti-xa and dose reduced Subsequent lab tests: All anti-xa values were therapeutic 10/11 aptt were sub-therapeutic Symptoms resolved and patient was discharged APTT results significantly depressed compared to anti-xa 10

11 Conclusions Apparent heparin resistance due to elevated FVIII Decreased aptt response despite adequate anti-xa activity and antithrombotic effect Likely due to pregnancy-related elevation of factor VIII Sub-therapeutic aptt results led to increased UFH dosing Testing with anti-xa allowed for reduction in heparin dose and a good clinical outcome aptt to Anti-Xa for Heparin Monitoring Experience at Exempla St. Joseph s 24 Switching to anti-xa requires lab and pharmacy to work together to improve patient care while accepting higher reagent costs Electronic Medical Record (EMR) conversion and healthcare provider education are critical Hospital-wide results Widespread satisfaction among nursing and lab staff with the switch Some resistance from clinicians, especially surgeons who worry about excessive bleeding post-surgery Practitioners are discouraged from requesting both an APTT and anti-xa Baseline aptts are collected to screen for coagulopathies Exempla St. Joseph s Institutional Impact Anti-Xa APTT Mean number tests /patient / day Mean number UFH dosage adjustments /patient / day Reagent cost Lab tech and phlebotomy labor Nurse labor $2.55 / test $5.30 / patient / day $3.08 / test $6.40 / patient / day $2.58 / dosage adjustment $1.60 / patient / day $0.65 / test $1.77 / patient / day $3.08 / test $8.41 / patient / day $2.58 / dosage adjustment $2.58 / patient / day Total cost / patient / day $13.30 $13.97 Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy 2012; 32: Data from: Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy 2012; 32: Dosing Efficacy: APTT vs. Anti-Xa PTT Trends Across Doses Heparin Level Trends Across Doses Hour PTT Level Heparin Level DIRECT ORAL ANTICOAGULANTS Dose Number Dose Number Courtesy of Boulder Community Hospital Dept of Pharmacy (personal communication) 11

12 The new anticoagulant Holy Grail What is (are) the best target(s)? Oral administration Rapid onset of action A single dose regimen Factor Xa Strategically located at junction of extrinsic and intrinsic pathway Thrombin Final effecter in coagulation Predictable onset of effect, maximum plasma concentration and half-life, all unaffected by age, renal disease or liver disease No routine lab monitoring Safe (low risk of bleeding) Reversible Gatekeeper of thrombin generation No effect on thrombin-mediated hemostatic mechanisms Few functions outside of the coagulation cascade Directly drives fibrin formation Induces feedback amplification of coagulation Induces initiation and amplification of coagulation inhibition and fibrinolysis pathways Potent platelet agonist Weitz JI, Eikelboom JW, Samama MM. New Antithrombotic Drugs. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based clinical practice guidelines. Chest 2012; 141: e120s-e151s 5 New DOACs: Target a Single Coag Factor Reasons Customers Perform DOAC Tests rivaroxaban (XARELTO ) apixaban (ELIQUIS ) edoxaban (SAVAYSA ) X TF/VIIa IX IXa VIIIa Va Xa II Before surgery or invasive procedure, or emergency/trauma screening Identification of sub- and supratherapeutic levels Drug-drug interactions At extremes of body weight Deteriorating renal function Monitoring anticoagulation reversal Test for overdose, compliance IIa dabigatran (PRADAXA ) Fibrinogen Fibrin PT & APTT Pros/Cons Anti-Xa and Anti-IIa assays for NOACs PT and APTT were designed for historical compounds (VKA, UFH) PROS Widely available Cost effective Could be a screen test CONS A more specific tool is required Non specific Poor sensitivity Platform and batch dependent Inter and intra-individual variability NOACs are chemically defined compounds with a different mechanisms of action compared to VKA or UFH Activity of NOACs are much higher than existing anticoagulants Dedicated test set-ups are necessary to measure anticoagulant activity IU based on UFH or LMWH cannot be used Results expressed in specific gravimetric units (ng/ml) for interpretation 12

13 Recommended Tests for DOACs The debate about lab monitoring 13 Rivaroxaban Apixaban Edoxaban Dabigatran PT Screening only No No aptt No No Screening only TT No No No Screening only Dilute TT No No No Screening/Measurement ECA No No No Measurement Anti-Xa Measurement Measurement Measurement No Lab monitoring or no lab monitoring Rivaroxaban (Xarelto ) Is an oral, factor Xa inhibitor No need for monitoring, but there is a desire and need for tests to measure anticoagulant activity in special populations: fragile patients, elderly, renal impairment, obese patients, etc. in life-threatening situations such as active bleeding or an overdose In emergency cases when information is not available Inhibits free and clot-bound factor Xa Was developed by and marketed by Has been FDA approved for AF, VTE prevention THR and TKR, and for VTE treatment Target values - Rivaroxaban For rivaroxaban no therapeutic range has been established. Observed peak and trough concentrations in patients exposed to therapeutic dosing are outlined below 1,2 Apixaban/Eliquis Is an oral, factor Xa inhibitor Stroke Prevention in AF (20mg daily) VTE Treatment (20mg daily) VTE Prevention (10mg daily) Peak values ng/ml ng/ml ng/ml Trough values 4 96 ng/ml ng/ml ng/ml 1. Mueck W et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in aptients undergoing total hip replacement. Thromb Haemost 2008; 100: Buller HR et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The Einstein DVT Dose Ranging Study. Blood 2008; 112: Inhibits free and clot-bound factor Xa Was developed by and marketed by Has been approved by the FDA for stroke prevention in atrial fibrillation (SPAF). 13

14 Target values - Apixaban Apixaban dose VTE Prophylaxis 2.5mg bid Observed Peak Concentration Observed Trough Concentration ng/ml ng/ml Edoxaban/Savaysa Is an oral, factor Xa inhibitor VTE Treatment 2.5mg bid ng/ml ng/ml Was developed by currently marketed in the US and is not 5mg bid 10mg bid ng/ml ng/ml ng/ml ng/ml January 2015 approved for Atrial Fibrillation and VTE prevention in THR and TKR Stroke Prevention in AF 2.5mg bid ng/ml ng/ml Is currently in trials for VTE treatment and SPAF 5mg bid ng/ml ng/ml * from Dabigatran/Pradaxa Target values - Dabigatran Is an oral pro-drug, factor IIa inhibitor In patients receiving dabigatran 150mg bid Observed Serum concentrations 1 Peak values ng/ml Inhibits unbound and fibrin-bound thrombin Was developed by and marketed by Trough values ng/m Has been approved by the FDA for stroke prevention in atrial fibrillation (SPAF). 1 van Ryn J, et al. Dabigatran etexilate a novel reversible oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: Measuring dabigatran/pradaxa Useful for monitoring Not recommended aptt TT Hemoclot Thrombin Inhibitor PT ECA PiCT ECT ACT TGA dpt Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-xa assay is preferable to prothrombin time assay. Thromb Haemost Dec;104(6): ECT Clotting Time (ECT) and Ecarin Chromogenic Assay (ECA) 28 ECT Clotting assay Sensitive to plasma levels of prothrombin and fibrinogen Principle: cleavage of prothrombin to meizothrombin which cleaves fibrinogen to fibrin Lack of standardization Not FDA cleared ECA Chromogenic assay Insensitive to plasma factor levels Principle: cleavage of prothrombin to meizothrombin which cleaves bound PNA resulting in color production Standardized Clemens A; Haertter S; Friedman J; Brueckmann M; Stangier J; van Ryn J; Lehr T. Twice daly dosing of dabigatran for stroke prevention in atrial fibrillation: A pharmacokinetic justification. Curr Med Res Opin 28 (2), (2012) Boehringer Ingelheim, Pradaxa Patient Alert Brochure Not FDA cleared 14

15 Take home messages PT/INR remains the Gold Standard for monitoring VKA anticoagulant therapy Anti-Xa testing is the preferred method for monitoring UFH therapy Certain patients require monitoring for LMWH therapy using the Anti-Xa Heparin reagents containing AT or dextran sulfate may lead to incorrect anticoagulant values DOAC anticoagulants target specific areas of the coagulation cascade Although claiming to not need monitoring, clinicians are requesting plasma levels in patients The Anti-Xa or ECA assays are the recommended assay methods for measurement of DOAC s 15