4/7/2014 Lab Results • PT: 18.5 seconds (12.0 – 14.5) • PTT: 80.2 seconds (24 – 39) • Platelet count: 265 K/uL (160 – 400 K) New Anticoagulants Are we going in a new direction? Karen Levisen MT(ASCP)SH Financial disclosure Follow Up Lab Tests • Karen Levisen is employed by Diagnostica Stago, Inc. • Mixing study - No correction with addition of NPP • Factor VIII Activity - Shows a non-parallel increase of activity as the dilution increases o 1:20 = 25% o 1:40 = 50% o 1:80 = 80% Scenario What Is The Answer? • 87 yr old female presents to Hematologist for evaluation of new bruising • Lab work ordered includes PT, PTT and platelet count • • • • Inhibitor? Factor deficiency? Platelet dysfunction? What additional information do we need? 1 4/7/2014 Question: What is the drug history? New Anticoagulants • Patient is taking Pradaxa (Dabigatran) • Dabigatran etexilate - Oral medication, absorbed in GI, becomes the active form dabigatran. - Bioavailability is 6.5% Maximum concentrations achieved in 1.5 – 3 hrs Half life is 14 – 17 hrs About 80% excreted in the active form by the kidneys Drug interaction minimal Food interaction not significant Traditional Anticoagulant Therapy New Anticoagulants • LMWH is widely used in both outpatient and inpatient settings for DVT and PE • When UFH is used, it is started at or near the same time as Coumadin - Achieves a therapeutic INR as quickly as possible - Heparin is maintained until a therapeutic INR is reached and stabilized New Anticoagulants • Rivaroxaban (Xarelto) - Oral Anti-Xa inhibitor Inhibits free and clot-bound Anti-Xa by 20 – 61% Peak levels 1 – 4 hrs post administration Half life about 12 hrs Metabolized in liver, kidneys and some excreted as active drug New Anticoagulants • Dabigatran (Pradaxa®) Indications1: - Reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation • Rivaroxaban (Xarelto®) Indications2: - Reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation - Treatment of DVT/PE - Reduction in the risk of recurrence of DVT/PE - Prophylaxis of DVT following hip or knee replacement surgery • Apixaban (Eliquis®) Indications3: - Reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation - Prophylaxis of DVT following hip or knee replacement surgery • Apixaban (Eliquis) - Selective inhibitor of FXa - Decreases thrombin generation and prevents clot formation - Bioavailability is approximately 50%, maximum concentration 3-4 hours after ingestion - Half life is approximately 12 hours - No known antidote • More in the queue (Betrixaban) 1 2 3 Pradaxa® Package Insert (12/2012), Boehringer-Ingelheim Xarelto® Package Insert (3/2013), Janssen Pharmaceuticals Eliquis® Package Insert (12/2012), Bristol-Myers Squibb 2 4/7/2014 Current Trends In Anticoagulation What Is The Excitement? • Oral doses - Outpatient status - Easy to administer • Per manufacturers, no need to monitor - Follow-up is minimal - Patients are happier What Is The Difference? Safety and Efficacy Studies Enoxaparin Dabigatran Etexilate 150 mg Dabigatran Etexilate 220 mg DVT, PE, and all-cause mortality (%) • New anticoagulants have different targets - Dabigatran o Direct thrombin inhibitor - Rivaroxaban and Apixaban o Direct Factor Xa inhibitor P P RE-NOVATE (THR) 6.7 8.6 <.0001* 6.0 <.0001* RE-MOBILIZE (TKR) 25.3 33.7 .0009† 31.1 .02† RE-MODEL (TKR) 37.7 40.5 .003* 36.4 .017* Major Bleeding (%) RE-NOVATE (THR) 1.6 1.3 2.0 RE-MOBILIZE (TKR) 1.4 0.6 0.6 RE-MODEL (TKR) 1.3 1.3 1.5 THR = total hip replacement; TKR = total knee replacement *Noninferior to enoxaparin. †Inferior to enoxaparin. Sites of Action Safety and Efficacy studies Application AF Major/CRNM HR/TKR Major/CRNM Warfarin Enoxaprin 3.09/3.00 Apixaban 0.82/5.0 0.68/4.8 2.13/2.08 3 4/7/2014 How Do These Drugs Affect Testing? References for Studies: •Eriksson BI, Dahl OE, Rosencher N, , et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: A randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. •The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9. • Studies published in Europe • Numerous analyzers and reagents • Includes POC •Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: The Re-model randomized trial. J Thromb Haemost. 2007;5:2178-2185. •Apixaban Medication Guide and Package Insert, March 2014. What is the problem? Dabigatran’s effects: • No established FDA-approved test to directly measure any of these drug levels • PT: Elevated values, varying sensitivities depending upon which reagents were used - No assay to monitor these drugs • No specific reversal agents • Levels can become dangerous in certain populations - Kidney function important (GFI< 30 = contraindicated) • PTT: Elevated values with a steep increase at low values of drug and leveling off • FIB: Could falsely underestimate levels in certain reagent/analyzer platforms • ATIII: Falsely high results with clotting assays, but chromogenic assays essentially not affected • APCR: Normalizing of ratio, potentially causing some heterozygotes to be seen as normal Lindahl, T.L., et.al. Thrombosis and Haemostasis, 105.2, 2011. The Ideal Anticoagulant Rivaroxaban and Apixaban effects: Source: Schulman, Majeed; Sem Thromb/Hemost 2012; 38 Characteristic Advantage Dabigatran VKA LMWH Oral Easy to take ++ ++ - Predictable Fixed dose + - + Rapid onset No need for bridging + - + Little interaction Easy to use + - + Few adverse events Safety + - + Combined elimination route Useful in renal impairment - + - Availability of effective antidote Easy to manage bleeding - ++ + • PT: dose dependent increase in seconds - INR conversion did not reduce the variability of results with different reagents and platforms • aPTT: less affected compared to PT • TEG: wide variability • dRVV, HepTest and PICT show non-linear increases in clotting times – Samana, M.M. et al, Thrombo Haemost, 2010. 4 4/7/2014 Measurement of Dabigatran vanRyn, et al; Thromb and Haemost; 2010;103; 1116-1127 • PT and PTT limited to a qualitative type of analysis • ECT specifically designed to measure DTI’s but no calibrators approved for Dabigatran • Dilute TT shows a linear response curve over therapeutic range, but not specific to Dabigatran Why is This Good News? • Per 2013 ISTH recommendations, there are clinical circumstances in specific patients when measurement of the anticoagulant effect will be required such as: - Bleeding - Before surgery or invasive procedure when patient has taken drug in previous 24 hours, or longer if creatinine clearance (CrCl) is < 50ml/min - Identification of sub- or supra-therapeutic levels in patients taking other drugs that are known to significantly affect pharmacokinetics - Identification of sub- or supra-therapeutic levels in patients at extremes of body weight - Patients with deteriorating renal function - Peri-operative management - Reversal of anticoagulation - Suspicion of overdose - Assessment of compliance in patients suffering thrombotic events while on treatment (although this application may be limited by the short half life) Baglin, T. 2013 Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. International Society on Thrombosis and Haemostasis (Accepted Article). doi: 10.1111/jth.12149 What are the consequences? “If a patient on dabigatran has a prolonged APTT over 90 seconds and a PT/INR greater than 2.0, overdosing or accumulation of dabigatran should be considered.” Lindahl, T. L. et. al. Anti-Xa assay for Rivaroxaban and Apixaban • Chromogenic test based upon a competition principle - Hydrolysis of the substrate by Anti-Xa - Inhibition of the Factor-Xa by Rivaroxaban or Apixaban • Results in ng/ml from a standard curve established using specific standards What is the Good News? More good news: • Direct factor Xa inhibitors appear to be favored in the most recent studies 1 • Phase 2 study of a recombinant protein (PRT4445) developed by Portola Pharmaceuticals, Inc. which will potentially reverse the two anti-Xa inhibitors • FDA recognized the lack of an effective reversal agent as a significant unmet clinical need when the two drugs were approved • Mechanism of action based upon the similar molecular structure of the drug to Factor Xa - Dabigatran getting mixed reviews 1 - Emphasis on targeting farther up in cascade • Anti-Xa assays are already cleared for heparin monitoring - Specific calibrators and controls are available for Rivaroxaban and Apixaban (Currently RUO status) - Development for additional direct factor Xa inhibitors is underway o 1 The heart.org/heartwire 3/18/2013 5 4/7/2014 What is the Role of The Lab? • Offer meaningful tests to reflect the clinical status of our patients • Consult with clinicians when questions appear concerning these new drugs • Stay up to date by reading journals, subscribing to medical education services • Ask your hemostasis vendor for assistance Questions? 6