Thrombosis management: A time for change practical management with NOACs Dr Wala Elizabeth Medical Director, Bayer Healthcare

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1 Thrombosis management: A time for change practical management with NOACs Dr Wala Elizabeth Medical Director, Bayer Healthcare Kenya Association of Physicians Conference 10 th May 2013

2 New anticoagulants: Practical issues to be discussed Pharmacology and summary of platform of evidence for NOACs Handling of NOACs in daily practice Dosing Switching strategies Interactions with other drugs Monitoring or measuring feasible and helpful? Management of bleeding Pausing for surgery Conclusion: Individualized therapeutic approach 2

3 Venous Arterial (VAT) Space for NOACs VTE PE DVT Pulmonary embolism 500,000 deaths per year in Europe - 1 in 10 hospital deaths Deep vein thrombosis 1 event every 12 seconds Ischaemic stroke 15 20% caused by atrial fibrillation Unstable angina and myocardial infarction 1 death every 17 seconds SPAF ACS VTEp OS Elective hip replacement surgery DVT risk: 42 57% Elective knee replacement surgery DVT risk: 41 85% 3

4 Traditional anticoagulants: drawbacks UFH 1 Parenteral administration Monitoring and dose adjustment required Risk of HIT Oral VKAs 2 Narrow therapeutic window Interaction with food and drugs Frequent monitoring and dose adjustment required LMWH 1 Parenteral administration Weight-adjusted dosing 1. Hirsh J et al. Chest 2008;133;141S 159S; 2. Ansell J et al. Chest 2008;133;160S 198S 4

5 Properties of an ideal anticoagulant versus currently available agents Oral No significant food/drug interactions Predictable response No routine coagulation monitoring Fixed dosing No risk of HIT IDEAL LMWH UFH Fondaparinux VKAs Rivaroxaban Dabigatran Apixaban 5

6 The promise of novel OACs Simplified dosing regimen, no dietary restrictions, predictable anticoagulation and no need for routine coagulation monitoring. Can be given at fixed doses Reduced potential for food and drug interactions Less labourintensive Less impact on patient s daily life Improved compliance Reduced administrative costs Improved QoL Improved efficacy and safety 1. Ansell J et al, 2004; 2. Mueck W et al, 2007; 3. Mueck W et al, 2008; 4. Mueck W et al, 2008; 5. Raghavan N et al, 2009; 6. Shantsila E, Lip GY

7 Anticoagulants in development have single targets Initiation TF VIIa Indirect Fondaparinux AT X IX Propagation Xa IXa Inactive factor Active factor Transformation Catalysis Direct Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban IIa II Thrombin Prothrombin Direct Lepirudin Bivalirudin Argatroban Dabigatran TGN-167 Clot formation Fibrinogen Fibrin Adapted from Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:

8 Comparison of the pharmacological characteristics of newer OACs Parameter Dabigatran Rivaroxaban Apixaban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Oral bioavailability 6.5% %* ~66% 50% Plasma protein binding 34 35% 92 95% 87% 40 59% Dosing (for SPAF indication) Fixed, twice daily Fixed, once daily Fixed, twice daily Fixed, once daily Prodrug Yes No No No Half-life (h) (young healthy) (elderly) T max (h) ~ Routine coagulation monitoring *After oral ingestion *15 20 mg to be taken with food No No No No Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; Xarelto SmPC 2011; Xarelto PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al,

9 Comparison of the pharmacological characteristics of new OACs Parameter Dabigatran Rivaroxaban Apixaban Edoxaban Renal clearance 80% 33%; additional 33% cleared after metabolic degradation to inactive drug Potential drug interactions Rifampicin, quinidine, amiodarone, potent P-gp inhibitors Potent inhibitors of both CYP3A4 and P-gp*, strong inducers of CYP3A4 ~25% 35% Potent CYP3A4 inhibitors* Potent inhibitors of both CYP3A4 and P-gp *CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and Pgp include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Eriksson BI et al, 2011; Xarelto Summary of Product Characteristics

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13 Dosing in Stroke Prevention in Atrial Fibrillation (SPAF) 13

14 ESC 2012 guidelines: selection of patients for OACs Non-valvular atrial fibrillation Valvular atrial fibrillation Yes < 65 years and lone AF including women Stroke risk assessment using CHA 2 DS 2 -VASc Oral anticoagulant Assess bleeding risk (HAS-BLED score); consider patient values/preferences No antithrombotic therapy New oral anticoagulant; rivaroxaban, dabigatran apixaban Vitamin K antagonist Camm AJ et al. Eur Heart J 2012 Slide line preferred; dotted line alternative

15 ESC 2012 guidelines: recommendations for new OACS All NOACs are recommended for SPAF in patients at risk of stroke (CHA 2 DS 2 - VASc 2) in preference over a VKA Rivaroxaban 20 mg od Rivaroxaban 15 mg od with: HAS-BLED 3 CrCl ml/min No recommendation in severe renal impairment CrCl < 30 ml/min No recommendation for cardioversion* Dabigatran 150 mg bid Dabigatran 110 mg bid in: 80 years Concomitant use of interacting drugs HAS-BLED 3 CrCl ml/min Peri-cardioversion No recommendation in severe renal impairment CrCl < 30 ml/min Apixaban No recommendation in severe renal impairment CrCl <30 ml/min No recommendation for cardioversion * No specific recommendations due to regulatory approval status Camm AJ et al. Eur Heart J 2012; od=once daily; bid=twice daily*based on lack of published data

16 Dosing in Venous Thromboembolism Treatment

17 Summary of ACCP guidelines: initial treatment of acute VTE Initial anticoagulation Acute DVT or PE PE with hypotension Long-term therapy ACCP recommendation Parenteral anticoagulation (overlapping with a VKA) or rivaroxaban LMWH or fondaparinux suggested over: i.v. UFH s.c. UFH Thrombolytic therapy (for patients who do not have high bleeding risk) Grade of recommendation 1B 2C 2B 2C DVT or PE without cancer VKA suggested over LMWH 2C LMWH suggested over dabigatran or rivaroxaban 2C DVT or PE with cancer LMWH suggested over VKA 2B VKA suggested over dabigatran or rivaroxaban 2B Kearon C et al. Chest 2012;141:419S 494S

18 VTE: disease phases and approved treatment options Types and intensity of conventional anticoagulation treatment UFH, LMWH, fondaparinux Initial, parenteral therapeutic dose At least 5 days VKA INR Early maintenance/secondary prevention At least 3 months VKA INR or Extended maintenance anticoagulation/ secondary prevention >3 months/years/indefinite* Rivaroxaban treatment for VTE 15 mg twice daily for the initial treatment of acute DVT for the first 3 weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE *With re-assessment of the individual benefit risk at periodic intervals

19 Summary of ESC recommendations for anticoagulant treatment of PE Treatment recommendations Class* Level # PE secondary to a transient (reversible) risk factor: treatment with a VKA recommended for 3 months Unprovoked PE: treatment with a VKA recommended for at least 3 months I A I A First episode of unprovoked PE and low risk of bleeding: consider long-term oral anticoagulation Second episode of unprovoked PE: long-term treatment recommended I A IIb B In patients with PE, the dose of VKA should be adjusted to maintain a target INR of 2.5 (range ) regardless of treatment duration Benefit risk ratio of continuing long-term anticoagulation treatment should be reassessed at regular intervals I I A C *Class of recommendation; # level of evidence The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:

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26 Need for monitoring according to guidelines VKAs Unpredictable anticoagulation response that necessitates regular monitoring 1,2 PT/INR testing to ensure patients are within INR range 2,3 LMWHs Routine coagulation monitoring not normally needed, except for patients with severe renal failure and pregnant women 2 Anti-Factor Xa assay can be used 2 UFH Anticoagulant response varies among patients; UFH (intravenous and subcutaneous) requires monitoring (weight-based subcutaneous UFH does not) 2,4 aptt test to be used to maintain doses that correspond to therapeutic heparin levels 2 1. Merli G et al. Ann Surg 2009;250: ; 2. Kearon C et al. Chest 2008;133:454S 545S; 3. Ansell J et al. Chest 2008;133:160S 198S; 4. Hirsh J et al. Chest 2008;133:141S 159S

27 Measuring NOACs If you seek to measure drug activity in cases of overdosing or bleeding: Anti Xa chromogenic assay for Rivaroxaban Anti IIa chromogenic assay or dtt for Dabigatran In our experience rarely necessary INR, PTT, and other coagulation tests will be altered by treatment but cannot be relied on

29 ESC 2012 guidelines: management of bleeding with NOACs Patient on a NOAC presenting with bleeding Check haemodynamic status, basic coagulation tests to assess anticoagulation effect Minor Delay next dose or discontinue treatment Moderate Symptomatic/supportive treatment Mechanical compression Fluid replacement Blood transfusion Oral charcoal if recently ingested Very severe Consider rfviia or PCC Charcoal filtration Dabigatran only: haemodialysis Camm AJ et al. Eur Heart J 2012

30 Patients receiving Rivaroxaban and experiencing bleeding complications Mild / local bleeding Severe bleeding Life threatening bleeding Stop rivaroxaban Local compression Stop rivaroxaban Local compression Assess surgery Assess support measures (Fluid therapy, haemodynamic support, transfusion) Assess other measures (charcoal, haemostatic measures, e.g. PCC, apcc, rfviia Stop rivaroxaban Surgery if possible Aggressive support measures (Fluid therapy, haemodynamic support, transfusion, haemostatic measures, e.g. PCC, apcc, rfviia Thromb Haemost. 2012;108:876-86

31 New anticoagulants: Practical issues to be discussed Pharmacology and summary of platform of evidence for NOACs Handling of NOACs in daily practice Dosing Switching strategies Interactions with other drugs Monitoring or measuring feasible and helpful? Management of bleeding Pausing for surgery Conclusion: Individualized therapeutic approach

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34 Responsible use of anticoagulant therapy New oral anticoagulants are effective and safe and more convenient than existing agents However, all anticoagulants carry the risk of bleeding Before initiating anticoagulant therapy, the benefit risk balance needs to be carefully assessed