ARE THE NOVEL ORAL ANTICOAGULANTS POSING A CHALLENGE TO WARFARIN?

Transcription

1 ARE THE NOVEL ORAL ANTICOAGULANTS POSING A CHALLENGE TO WARFARIN? Moosa Patel Clinical Haematology Unit, Department of Medicine, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

2 INTRODUCTION DRUGS USED IN THE TREATMENT OF THROMBOTIC DISORDERS 1. Antiplatelet agents 2. Thrombolytics / fibrinolytics 3. Anticoagulants Vitamin K antagonists Indanediones and Coumarins (Warfarin) Heparins IVI or sc Direct thrombin inhibitors oral and parenteral Factor Xa inhibitors oral and sc

3 HISTORY OF THE ANTICOAGULANTS 1. Heparin Warfarin 1954 (1920 s) 3. LMWH 1990 s 4. New/novel/direct oral Anticoagulants 2000 s

4 INTRODUCTION For more than half a century, Vitamin K antagonists (such as warfarin) were the only class of oral anticoagulants (1950 s to early 2000 s) However, despite warfarin being effective, it has a number of shortcomings and is not the ideal oral anticoagulant In the last 1-2 decades, new/novel oral anticoagulants (NOACs) have been developed and are approved and available for clinical use The NOACs are able to overcome a number of the shortcomings of warfarin, and in the studies in which they have been tested, demonstrate a non-inferior or superior efficacy and safety profile This has led to their increasing use in clinical practice With time, it is possible that the NOACs will provide a significant challenge to, or may even displace warfarin as the gold standard oral anticoagulant

5 PRESENTATION 1. Introduction 2. Warfarin 3. New/novel/direct oral anticoagulants A. Direct thrombin inhibitors B. Factor Xa inhibitors 4. Conclusion 5. References

6 CHARACTERISTICS OF AN `IDEAL ORAL ANTICOAGULANT Efficacy and safety at least equivalent to Warfarin Good bioavailability No or minimal food or drug interactions Wide therapeutic window Predictable AC response (no monitoring required) Availability of an antidote No unexpected toxicities Reasonable cost Mechanisms to ensure compliance with treatment Bauer KA. New Anticoagulants. ASH Handbook, 2006,

7 WARFARIN Most widely used oral anticoagulant for the prophylaxis and treatment of venous thrombosis and embolism History 1920 s Haemorrhagic disease in cattle in USA and Canada 1940 s Karl Paul Link and Harold Campbell, chemists at Wisconsin WARF ARIN 1948 Warfarin developed 1952 Registered as a rodenticide 1954 Registered for clinical use in man (RS)-4hydroxy-3-(3oxo-1 phenylbutyl)-2h-chromen-2-one

8 MECHANISM OF ACTION OF WARFARIN Adapted from Nash et al Postgraduate Haematology 2005, p869

9 WARFARIN Indications DVT, PE, recurrence of VTE, Inherited thrombophilia, atrial fibrillation, cardioversion, CMO/mural thrombosis, APLS, mechanical prosthetic heart valves, coronary artery graft thrombosis etc. Contraindications Pre-existing haemostatic defects, severe uncontrolled HPT, PUD, severe renal and liver disease, non-thromboembolic strokes, non compliance, pregnancy (1 st trimester,?all trimesters) etc. Slow onset of action (half life 20 to 60 hours), prolonged effect and requires monitoring Activity monitored by the INR (target INR; target range). Meta-analysis by Oake N et al, CMAJ, 2007: 44% of bleeding complications and 48% of thromboembolic events occurred with supratherapeutic or subtherapeutic doses of warfarin

10 WARFARIN Side-effects Bleeding mild ±5%, severe 1-2% annually; risk increases significantly with INR >5. Annual risk of bleeding is 0.3% - INR=2, 1% - INR=3, 3% - INR=4. Fatal 0.1-1%; Major 2-5% Drug and food interactions Pregnancy related complications (warfarin embryopathy) Skin skin necrosis, purple toe syndrome, allergic and other rashes Resistance primary (genetic polymorphisms) - secondary (drug interactions) Other alopecia, agranulocytosis, anorexia, hepatitis, other

11 WARFARIN LIMITATION Slow onset of action (Prolonged effect) Genetic variation in metabolism Multiple food and drug interactions Narrow therapeutic index CONSEQUENCES Overlap with a parenteral anticoagulant Variable (inter-individual) dose requirements Frequent coagulation monitoring (INR) Frequent coagulation monitoring (INR)

12 ORAL ANTICOAGULANTS Although warfarin is a very effective oral anticoagulant, it is not the ideal oral anticoagulant 2 approaches to optimise oral anticoagulation: - Improve the efficacy of the VKAs - Develop new/novel oral anticoagulants

13 IMPROVING THE EFFICACY OF VKA S Support compliance education, systematic INR testing, tracking & follow up Availability of a broader dose range Avoid concurrent foods or drugs with potential interactions or drugs that increase bleeding In selected patients, use of self testing or self dosing after careful teaching Avoid large loading doses. Initiate doses likely to be close to the maintenance dose Genetic testing and dosing based on PG genotype dominant predictor of warfarin dose (maintenance dose) Low intensity anticoagulation Novel approaches use of algorithms, combined pill etc.

14 MANAGEMENT OF EXCESSIVE ANTICOAGULANT EFFECT Non bleeding patient 1. Withold VKA alone 2. Withold VKA and administer Vitamin K 3. Transfusion therapy generally not used Bleeding patient or requiring urgent reversal of anticoagulant 1. Withold VKA 2. Vitamin K 3. Coagulation factor replacement PCC s (ideally 4 factor), FFP only if PCC not available 4. Recombinant FVIIa generally not recommended

15 NEW/NOVEL/DIRECT ORAL ANTICOAGULANTS New/novel AC - target a single coagulation factor and have a predictable dose-response relationship. Include A. Direct thrombin inhibitors B. Factor Xa Inhibitors Mechanism of action of NOACs Role of thrombin

16 COAGULATION CASCADE - THROMBIN GENERATION Adapted from DI Nisio et al NEJM 2005;353(10);

17 COAGULATION CASCADE

18 NOVEL ORAL ANTICOAGULANTS Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Approved by EU and US US and Japan only Approved Indications NOAC compared with warfarin in respect to major bleeding Increased risk of MI in comparison with warfarin Increased risk of GI bleed compared with warfarin Lower risk of stroke and major bleeding a) Stroke/systemic embolism prevention in NVAF b) Prevention of recurrent VTE in patients who have previously been treated c) DVT and PE treatment following 5 10 days of initial therapy with a parenteral anticoagulant d) VTE prevention in elective hip or knee replacement surgery a) Stroke/systemic embolism prevention in NVAF b) Treatment of DVT and PE c) Prevention of recurrent DVT and PE in adults d) VTE prevention in elective hip or knee replacement surgery a) Stroke/systemic embolism prevention in NVAF b) VTE prevention in elective hip or knee replacement surgery Target Thrombin Factor Xa Factor Xa Factor Xa Dyspepsia Similar Similar/better Better Better Dosing Twice daily (150mg) (110mg, 220mg) Once daily (20mg) (5mg, 10mg) Twice daily (2.5 10mg) (5mg) Peak 2-3 hr 3 hr 3 hr Half-life hr 5 9 hr (young) hr (elderly) 12 hr Renal clearance 80% 35% 27% 35 50% Liver metabolism: CYP3A4 X (minimal) a) Stroke/systemic embolism prevention in NVAF b) DVT and PE treatment following 5 10 days of initial therapy with a parenteral anticoagulant Once daily (60mg) Unplanned surgery Stop for at least 12 h Stop for at least 24 h Minor bleed: stop for at least 24 h; major bleed: stop for at least 48 h

19 MONITORING ASSAYS There is no need for routine monitoring of the NOACs: Stable pharmacokinetic properties; rapid onset of action; lack of significant drug interactions. However, monitoring is useful in the following situations: - Severe bleeding and thrombotic complications - Urgent/emergent invasive procedure or surgery - Overdose - Special situations elderly, renal/liver dysfunction, extremes of body weight In general, the available laboratory tests measure the global status of the coagulation system in a patient, and not the precise plasma concentrations. They provide an indication of the anticoagulant effect rather than the anticoagulant intensity

20 RECOMMENDATIONS FOR MONITORING - ASSAYS Dabigatran Rivaroxaban Apixaban Edoxaban Summary of potential laboratory tests aptt TT dtt ECT* Anti-FXa PT Anti-FXa mpt Anti-FXa (few firm data) Recommended 1. dtt 2. ECT* Anti-FXa Anti-FXa Anti-FXa (few firm data) In an emergency aptt PT (Sensitivity depends on reagent used) mpt* Quantitative tests dtt Interpretation: At trough, higher risk of bleeding if >65 s or 200 ng/ml ECT* Interpretation: At trough, higher risk of bleeding if level >3x ULN (directly measures the activity of dabigatran) Anti-FXa Anti-FXa (few firm data) Qualitative tests aptt Interpretation: At trough, higher risk of bleeding if level >2x ULN TT Interpretation: At trough, no bleeding risk if normal level PT Interpretation: Prolonged indicates excess bleeding risk Not recommended PT INR TT aptt ECT INR TT aptt ECT PT INR TT ECT

21 MANAGEMENT OF NOAC-RELATED BLEEDING Severity / Other General measures Bleeding management Resuscitation Investigations: FBC, group and screen, renal and liver function, PT, aptt, TT/dTT; anti-fxa level if rivaroxaban/apixaban Enquire about dose and timing of NOAC Drug interactions Identify bleeding source. Consider other aetiologies for bleeding DIC, thrombocytopenia Maintain diuresis to aid drug clearance Other antifibinolytics; desmopressin Mild Moderate/major Severe/Lifethreatening Supportive measures Mechanical compression Discontinuation of NOAC if bleeding risk outweighs thrombotic risk Supportive measures Blood product replacement where indicated: Red blood cells/platelet transfusion Stop NOAC Treat bleeding source (surgical or radiological intervention) Dialysis for dabigatran-associated bleeding (especially with renal impairment and overdose) Activated charcoal within 6 hours for dabigatran and apixaban General and supportive measures as above. Stop NOAC. Resuscitation and blood products as indicated PCC (4-factor: Haemosolvex or prothromplex -50 IU/kg) or apcc (FEIBA) IU/kg - more useful for rivaroxab. Recombinant VIIa consider in case of emergency and no response to other agents Treat bleeding source Antidote if available

22 POTENTIAL ADVANTAGES AND DISADVANTAGES OF NAOCS COMPARED TO WARFARIN ADVANTAGES No routine monitoring Improved safety profile Rapid onset (may preclude need for induction or bridging therapy) Short half life Fixed dosing Greater convenience, patient satisfaction and QOL? Potentially more cost effective from health system perspective Fewer drug, disease and diet interactions DISADVANTAGES Available assays generally a measure of anticoagulant effect rather than intensity Dose reduction or avoidance in severe renal impairment and avoidance in moderate or severe hepatic impairment. Care in elderly. Increase in GIT bleeding Antidotes evolving. Approved for DTIs. Short half life (mandates strict adherence) Less flexibility in dosing Fewer approved indications Potentially higher drug acquisition costs for patients Drug interactions may preclude use

23 CONCLUSION Warfarin has a demonstrable and proven safety and efficacy profile long track record Warfarin has a very broad range of indications and is arguably still the most widely used oral anticoagulant Warfarin has a number of limitations narrow therapeutic index, marked variation in dosing requirements, need for regular monitoring Introduction of new/novel oral anticoagulants to improve and optimise anticoagulation management

24 CONCLUSION New/novel anticoagulants target a single coagulation factor (more selective) and have a more predictable dose-response. For most patients, there is no need for monitoring. They have the potential to be more effective, safer and more convenient/easier to use. However, the NOACs face several challenges: The need for reliable laboratory assays to assess their anticoagulation effect and intensity; perioperative management; management of bleeding; availability and use of specific antidotes

25 CONCLUSION Currently, the indications are limited to: i) Prevention (elective hip and knee surgery) and treatment of VTED, ii) Stroke prevention in non-valvular AF iii) Other emerging indications such as cancer associated thrombosis Caution needs to be exercised in elderly patients and those with renal impairment Are they posing a challenge to warfarin? Yes, they are being used increasingly in the developed world and private sector in SA (16% of patients). No, they pose less/no real challenge in developing countries and the public sector in SA (84% of patients) The use is likely to increase as the indications for their use broaden to incorporate more entities or where warfarin is unsuitable or C/I

26 REFERENCES 1. Di Nisio M et al. Direct Thrombin Inhibitors. NEJM 2005;353: Francis CW and Kaplan KL. Principles of antithrombotic therapy. In Wiliams Hematology. 7 th Ed. 2006, Nash MJ et al. Acquired coagulation disorders and vascular bleeding. In Postgraduate Haematology. 5 th Ed. 2005, Bauer KA. New anticoagulants. ASH Handbook, 2006, Gage BF. Pharmacogenetics-Based Coumarin therapy. ASH Handbook, 2006, Francis CW. A Historical Perspective. ASH Handbook, 2008, Francis CW. New issues in Oral Anticoagulation. ASH Handbook, 2008,

27 REFERENCES 8. Dentali F and Crowther MA. Management of excessive anticoagulant effect due to Vitamin K antagonists. ASH Handbook, 2008, Millican EA et al. Genetic based dosing in orthopaedic patients beginning warfarin therapy. Blood 2007;110: Burnett AE et al. Guidance for practical management of the DOACs in VTE treatment. J Thromb Thrombolysis 2016;41: Rahmat NA and Yip GYH. Montoring the effects and antidotes of the Non-vitamin K Oral Anticoagulants. Arrhythmia and Electrophysiology Review 2015;4(1); Keeling D et al. Guidelines on oral anticoagulation with warfarin fourth edition. Br J Haematol 2011;154(3):

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30 PCCs PCCs products Derived from human plasma Contain factors II, IX and X with or without significant levels of factor VII Also contains varying amounts of protein C and S Three-factor PCC: contain factors II, IX, X and low levels of factor VII Four-factor PCC: contain factors II, IX, X and higher levels of factor VII Activated PCC: contains four coagulation factors (in inactive and activated forms, e.g. factor VIII inhibitor bypassing activity)

31 GENETIC INFLUENCES Polymorphisms in CYP2C9, a critical cytochrome p-450 enzyme in the metaboloism of warfarin, alters its clearance and affects dosing. CYP*1 has higher activity than either the *2 or *3 variants, and patients with the *2 or *3 variants require a lower dose VKORC1 is the enzyme inhibited by warfarin. Its levels are affected by several polymorphisms that can be divided into high and low level haplotypes, which correlate with warfarin resistance and sensitivity. Patients with high level haplotypes require higher warfarin doses.

32 MECHANISM OF ACTION OF DIRECT THROMBIN INHIBITORS AS COMPARED WITH HEPARIN Adapted from DI Nisio et al NEJM 2005;353(10);

33 SIDE EFFECTS CONTINUED Resistance 1. Primary - Hereditary/Genetic e.g. VKORC1 Asp36Tyr polymorphism - 7/15 Loebstein et al, Blood 2007;109: Secondary - Drug interactions, impaired absorption, rapid clearance, decreased affinity of the receptor, excessive intake of vitamin K or use of large doses of vitamin K to reverse overdose, compliance etc.

34 COAGULATION CASCADE

35 RECOMMENDATIONS ON THE MANAGEMENT OF BLEEDING AND EXCESSIVE ANTICOAGULATION BY THE BRITISH COMMITTEE FOR STANDARDS IN HAEMATOLOGY (Third ed. 1998; Update 2005) INR 3 6 (target INR 2.5) reduce warfarin dose or stop INR 4 6 (target INR 3.5) reduce warfarin when INR < 5 INR 6 8 No or minor bleeding stop warfarin. Small dose (1mg vitamin k if needed) Restart when INR < 5 INR >8 stop warfarin No or minor bleeding restart warfarin when INR < 5 If other risk factors for bleeding, give mg vitamin k orally Major bleeding stop warfarin. Give PCC or FFP. Give 5 mg vitamin k (IVI or oral)

36 A. DIRECT THROMBIN INHIBITORS DTI s inhibit thrombin by directly binding to exosite 1 and / or the active site of thrombin Parenteral 1. Lepirudin (Refludin) HIT (higher risk of bleeding and immunogenicity compared to argatroban). PTT 2. Desirudin (Iprivask) VTE prophylaxis hip replacement 3. Argatroban (Novastan) HIT (drug of choice in renal impairment). PTT 4. Bivalirudin (Hirulog/Angiomax) PCI. CT

37 DIRECT THROMBIN INHIBITORS Oral a. Ximelagatran (Exanta) Prodrug of melagatran. Predictable AC response. Fixed dose. Little drug and food interactions. Rapid onset of action. No monitoring. Efficacy in: Prevention and treatment of VTE and stroke prevention in AF FDA approval denied in 2004 non-haematologic toxicity (hepatic). Long term treatment ALT elevated after 1-6m in 6-10% - usually asymptomatic and reversible. Europe approved for short term prophylaxis of DVT following major ortho. surgery (about 12 days). Removed from market in 2006 Proof of principle high oral bioavailability, wide therapeutic window

38 DIRECT THROMBIN INHIBITORS b. Dabigatran Etixilate 2 nd new oral drug, April 2008 approved in Europe for prophylaxis of DVT (ortho surgery) and continues in phase three studies. A reversible high affinity thrombin inhibitor. Plasma ½ life is hrs daily dosing RE-MOBILIZE, RE-MODEL, RE-NOVATE, RE-COVER, RE-MEDY, RE-LY Non inferiority with other comparator drugs. Well tolerated. No increase in bleeding. No increase in other toxicities

39 FACTOR XA INHIBITORS Synthetic pentasaccharides 1. Fondaparinux (Arixtra) Selective Xa inhibitor. FDA approval for the prevention and treatment of VTE following hip fracture surgery, hip and knee replacement and abdominal surgery, as well as for treatment of patients with DVT and PE. 2.5mg dly subcutaneously, 6hrs post-op. surgical patients. ½ life 17hrs. High bioavailability no monitoring 2. Idraparinux Hypermethylated derivative of Fondaparinux. ½ life 80 hrs. Administered weekly sc 2.5mg in thetreatment of VTE and long term prevention of stroke in patients with AF

40 GENETIC INFLUENCES The use of algorithms that incorporate pharmacogenetic information perform better than those using clinical information alone fewer and smaller dose changes.. FDA modified the labelling for warfarin and highlighted these findings. The new labelling indicates that certain genetic variations in CYP2C9 and VKORC1 in a patient may increase the need for frequent INR monitoring and use of lower warfarin doses. It also states that the lower initiation doses should be considered for patients with certain variations in CYP2C9 and VKORC1 enzymes FDA approved tests are now available Unclear: Widespread testing, cost of testing, need for rapid test results No studies have demonstrated improved clinical outcomes Additional studies required

41 COMMON VARIATIONS IN CYP2C9 AND VKORC1 THAT AFFECT WARFARIN DOSE NAME VARIATION CAUCASIAN AFRICAN ASIAN CYP2C9 *1 Wild type *2 R144c *3 1359l VKORC1 GROUP A Haplotypes GROUP B Haplotypes

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