THE NOVEL ORAL ANTICOAGULANTS

Transcription

1 IDEAL ANTITHROMBOTIC AGENT THE NOVEL ORAL ANTICOAGULANTS Kristin Jochmans MD, PhD Dienst Hematologie - Universitair Ziekenhuis Brussel Efficacious (in arterial and venous disease) Safe (no toxicity low bleeding risk) Promote thrombolysis and healing Wide therapeutic window Oral intake Rapid onset of action Gentse Apothekers & Artsen Biologen 11 september 2012 Fixed dose 2 GAB IDEAL ANTITHROMBOTIC AGENT Predictable pharmacokinetics and pharmacodynamics No food or drug interaction Novel anticoagulants No renal or hepatic clearance issues Rapidly and efficaciously reversible action (antidote) Anti Xa Low cost No need for routine monitoring Measurement possible in specific clinical conditions Anti IIa 3 GAB 4 GAB DIRECT ANTI IIa INHIBITORS Dabigatran etexilate Some pharmacological data DIRECT ANTI Xa INHIBITORS Rivaroxaban Apixaban Edoxaban LIXIANA edoxaban 5 GAB Weitz et al. Am J Hematol 2012; 87: S GAB

2 GAB RE-VOLUTION study program Treatment of acute VTE Prevention of stroke in patients with atrial fibrillation. Primary prevention of VTE in orthopedic surgery Secondary prevention of VTE Secondary prevention of cardiac incidents in patients with ACS patients > 34,000 patients 7 8 GAB Connolly SJ, et al. N Engl J Med 2009;361: Results - efficacy Results - efficacy/safety Efficacy Safety 9 GAB = 34% risk reduction 10 GAB Results - safety = 60% risk reduction Phase III, randomised, double blind, parallel-group study comparing efficacy and safety of dabigatran etexilate (150 mg bid) to warfarin (INR 2 3) for 6 month in treatment of acute symptomatic venous thrombo-embolism (DVT/PE) following initial treatment (5 10 days) with a parenteral anticoagulant 11 GAB 12 GAB

3 13 GAB Cumulative risk of VTE or related death Significant reduction in major or clinically relevant bleedings 2.4% vs 2.1% = non-inferiority Schulman S et al. N Engl J Med 2009;361: Percentage 9,0 8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0 5.6% HR 0.63 (95% CI: ) p=0.002 for superiority 37% RRR 8.8% Dabigatran etexilate 150 mg Warfarin bid 71 / / GAB Study program EINSTEIN DVT - efficacy Equivalent efficacy in preventing symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE) 2.1% (36/1731) for Xarelto 3.0% (51/1718) for LMWH/VKA (p<0.001 for non-inferiority) 15 GAB 16 GAB ROCKET AF - efficacy ARISTOTLE (AF)- efficacy 1,27% vs 1,6% superiority p=0,01 Equivalent efficacy for the prevention of stroke or systemic embolism 1.7%/year for Xarelto (188/6958) 2.2%/year for warfarin (241/7004; p < for non-inferiority) - median TTR of 55% in the warfarin arm 2,13% vs 3,09% p<0,001 N Engl J Med 2011; 365: GAB 18 GAB

4 GAB Primary efficacy results in AF for 3 NOACs NOAC Warfarin HR 95% CI No. of events (%/yr) CAVE: no head to head comparison!!! All-cause mortality in AF for 3 NOACs CAVE: no head to head comparison!!! NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 Dabi 150 Riva (safety AT) Apixaban 171 (1.44) 186 (1.58) 122 (1.01) 186 (1.58) 184 (1.65) 221 (1.96) 199 (1.19) 250 (1.51) Dabi 110 Dabi 150 Rivaroxaban Apixaban 446 (3.75) 487 (4.13) 438 (3.64) 487 (4.13) 603 (3.52) 669 (3.94) (4.5) 632 (4.9) Favors NOAC Favors warfarin Favors NOAC Favors warfarin 1. Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: GAB 3. Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: Potential reasons for monitoring activity of anticoagulant drugs Monitoring required? Monitoring measuring Monitoring = measuring in order to perform possible adaptation of dosage 21 GAB Bounameaux et al. J Thromb Haemost 2010; 8: GAB No routine monitoring required Highly predictable anticoagulant activity of fixed-dosed orally administered direct IIa or Xa inhibitors No evidence of correlation between: antithrombotic effect/bleeding risk and any biologic activity or drug concentration measured in plasma Demonstration of efficacy and safety of fixed doses in finalized clinical trials (thousands of patients) Measuring - Why/when should we be able to test? Thrombotic event on-treatment Therapeutic failure? Non-compliance? Effect of co-medication on efficacy? Hemorrhagic event on-treatment Overdosage? Drug accumulation? Effect of co-medication/organ impairment on safety? Emergency (trauma, surgery) Active anticoagulant present? Specific patient populations: low/high body weight, children, pregnant women, renal insufficiency 23 GAB 24 GAB

5 25 GAB Ideal drugs in search of ideal laboratory assays Efficient, thus available at any time, in any laboratory Sensitive Standardized Well-established, commercially available Not expensive Specific for the direct anti-fiia or anti-fxa action Cover a broad range of plasma concentrations DIRECT ANTI Xa Indication Dose Prothrombin time regimen Cmax* Neoplastin Plasma Plasma Concentration Concentration Cmax * [µg/l] Ctrough * approx. 2 4 h after [µg/l] dose approx h after dose VTE prevention 1 10 mg od s N.a VTE treatment 15 mg bid s (first 3 weeks)** 2 VTE treatment 2 20 mg od s Stroke prevention in AF 2 20 mg od s Stroke prevention in AF 2 (with impaired renal function) 15 mg od s * 5 th 95 th percentiles 26 GAB Pharmakokinetic profile: interpretation in relation to timing and administered dose Rivaroxaban plasma concentration (µg/l) Single dose Healthy volunteers 1.25 rivaroxaban mg (n = 8) 5 mg rivaroxaban (n = 6) 10 mg rivaroxaban (n = 8) 20 mg rivaroxaban (n = 7) 40 mg rivaroxaban (n = 8) 80 mg rivaroxaban (n = 6) 1. The only validated quantification method = High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) 2. Potential assays Prothrombin Time (PT) Anti-Factor Xa chromogenic assays Modified HepTest? Modified Prothrombinase-induced Clotting Time (PiCT)? Thrombin Generation? Time (hours) Kubitza D et al, GAB 27 GAB Not recommended assays Activated Partial Thromboplastin Time (aptt) Dilute PT dilute Russel Viper Venom Time (drvvt) Thromboelastogram = assays affected by rivaroxaban, but not suitable for quantification of broad range of plasma concentrations or not routinely available Prothrombin Time (PT) Dose-dependent prolongation, linear correlation with plasma concentrations Large variations with different thromboplastins, not corrected by INR! Not sensitive at lower concentrations 29 GAB 30 GAB

6 GAB Normal plasma pool spiked with increasing concentrations of rivaroxaban PT with same analyzer, different thromboplastins PT in seconds Prothrombin Time (PT) Transient effect on PT, time after intake -dependent No correlation between PT and bleeding events in studies Bad performance at low concentrations Useful for peak levels or overdose PT ratio (PT with drug/pt baseline) Need for calibrators and controls: expression in rivaroxaban concentrations Samama et al. Thromb Haemost 2010; 103: GAB Anti-factor Xa chromogenic assays Specific Sensitive for assessing a broad range of plasma concentrations Validated calibrators and controls required CAVE: interpretation in relation to time of drug intake Recently on the market: specific assays for Direct Factor Xa Inhibitors with calibrators and controls (and with CE conformity certification) Overall Interference with all common clot-based assays in which Xa activity has impact on the results Interference with Xa-based chromogenic assays No interference with immunologic assays 33 GAB 34 GAB Ex vivo Ex vivo STA-R STA-R CA7000 CA7000 CA1500 CA1500 STA-R STA-R ACL Top 700 ACL Top 700 BCS BCS Influence on Prothrombin Time (PT): 20 healthy volunteers before and 2-3 h after 10 mg rivaroxaban; mean of 9 labs, testing in own anlyzer/reagent setting Influence on Activated Partial Thromboplastin Time (aptt): 20 healthy volunteers before and 2-3 h after 10 mg rivaroxaban; mean of 9 labs, testing in own anlyzer/reagent setting Asmis et al. Thromb Res 2012; 129: GAB Asmis et al. Thromb Res 2012; 129: GAB

7 GAB DIRECT ANTI IIa dabigatran etexilate PT, aptt: time prolongs PT-based coagulation factors II, V, VII, X: decrease Pharmacokinetics aptt-based coagulation factors VIII, IX, XI: decrease Antithrombin anti-xa based assay: increases with ~10%/100µg/L rivaroxaban Antithrombin anti-iia based assay : not affected APC-R aptt-based method: ratio increases slightly No influence on fibrinogen (Clauss method), D-dimer, Thrombin Time Asmis et al. Thromb Res 2012; 129: Hillarp et al. JTH 2011; 9: Van Ryn et al. Thromb Haemost 2010, 103: GAB Dabigatran quantification - dabigatran Dabigatran quantification -dabigatran 1. Recommended assays Hemoclot Thrombin inhibitor assay = Sensitive diluted Thrombin Time Dilution with normal pooled human plasma Clotting assay based on inhibition of a constant, defined concentration of purified human α-thrombin Quantitative measurement of DTI, broad range Calibrators and controls HemosIL DTI : coming [ Chromogenic anti IIa in development (?) ] 39 GAB Stangier et al. JTH 2009; 7 (suppl 2): GAB Dabigatran quantification - dabigatran Dabigatran quantification -dabigatran 2. Less suitable assays (currently) 3. Less or not recommended assays Ecarin Clotting Time Ecarin (snake venom) converts prothrombin to (the intermediate) meisothrombin that is inhibited by DTI Linear correlation with plasma concentrations of DTI Sensitive but Limited access in our routine labs, mainly research tool Not (yet?) standardized for dabigatran aptt: limited sensitivity; curvilinear concentration-response curve, flattening at higher concentrations (> 200µg/L) Thrombin Time (TT): very (too) sensitive PT (and INR): relatively insensitive Activated Clotting Time (ACT): limited data; rather flat dose-response curve Thrombin Generation? 41 GAB 42 GAB

8 43 GAB - dabigatran -dabigatran Overall Dabigatran acts on thrombin-mediated conversion of Plasma from 10 healthy donors spiked aptt with dabigatran in wide concentration range fibrinogen to fibrin effect on all routine coagulation assays Interference with IIa-based chromogenic assays No interference with immunologic assays Lindahl et al. Thromb Haemost 2011; 105: GAB - dabigatran -dabigatran Plasma from 10 healthy donors spikedpt/inr with dabigatran in wide concentration range PT: modest elevations of INR at therapeutic dose aptt: prolongs Antithrombin anti-iia based: increases (~10%/200 µg/l) Antithrombin anti-xa based: not affected APC-R aptt-based method: ratio increases Fibrinogen (Clauss method): marked decrease with some reagents Lindahl et al. Thromb Haemost 2011; 105: GAB Lindahl et al. Thromb Haemost 2011; 105: Samama et al Clin Chem Lab Med 2011; 49: GAB Monitor? NO Measure/quantify? YES, in particular clinical situations HOW? Screening test in any lab? (case of bleeding or emergency intervention) Sensitive/specific test Interference with routine coagulation assays? YES, beware! experience required The new oral anticoagulants (NOACs) Study results Step forward in stroke prevention in atrial fibrillation Step forward in prevention and treatment of VTE Alternative to vitamin K antagonists without the burden of laboratory control, with no food and limited drug interaction but New drugs = questions, doubts, learning-how-to-use process 47 GAB 48 GAB

9 49 GAB Correct use Sources Summary of product characteristics (SPC) from the companies Practical national and international guidance/guidelines Recent reports/reviews in literature Correct and complete information to the patient Mode of action, duration of effect, timing of intake, possible interactions and side effects Follow-up (compliance!) in order to improve medication adherence and persistence No routine monitoring Booklet 50 GAB The new oral anticoagulants (NOACs) Correct indication and dose selection Check indications/contraindications of the prescribed NOAC Check renal function (CrCL) at start and periodically Check concomitant medication (inhibitors or inducers of P-glycoprotein or CYP3A4) Check bleeding risk 51 GAB Huisman et al. Thromb Haemost 2012; 107: GAB Potential factors for increased bleeding risk in the clinical trials Conversion from VKA to NOACs or reverse Periprocedural management Important to remember: Short half-life of the NOACs Rapid onset of action (~2h) Huisman et al. Thromb Haemost 2012; 107: GAB 54 GAB

10 55 GAB Practical guide dabigatran Guidance for use in particular situations Low bleeding risk: continue drug If discontinuation: Schulman and Crowter. Blood 2012; 119: GAB Managing overdose and bleeding complications No antidote available! Minor and moderate bleeding Stop medication for 1 or more days Search and eventually treat bleeding source Major and life-threatening bleeding Monitoring, lifesaving therapies, transfusion PC, Managing overdose and major bleeding Dabigatran Gastric lavage and/or activated charcoal Prothrombin Complex Concentrate (FII, VII, IX, X)? Acute hemodialysis Rivaroxaban Prothrombin Complex Concentrate (FII, VII, IX, X)? 57 GAB 58 GAB Practical guide dabigatran Guidance for use in particular situations Table Of Contents Preamble 1. Measuring the anticoagulant effect of dabigatran 2. Measures to take in case of an overdose without bleeding, or a clotting test indicating risk of bleeding 3. Management of bleeding complications 4. Patients undergoing a surgical intervention 5. Patient presenting with an acute coronary syndrome (ACS) 6. Cardioversion in a dabigatran treated patient 7. Patient presenting with a stroke 8. Initiation of dabigatran following an ischaemic stroke or TIA 9. Ischaemic stroke on dabigatran: management post acute phase References similar document for other NOACs 59 GAB 60 GAB