New drugs for anticoagulation so much choice, how do they compare? Dr Patrick Kesteven Newcastle

Transcription

1 New drugs for anticoagulation so much choice, how do they compare? Dr Patrick Kesteven Newcastle

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4 CONCLUSIONS 1. Arrival of new anticoagulants is a Good Thing.

5 CONCLUSIONS 1. Arrival of new anticoagulants is a Good Thing. 2. Groups of anticoagulants differ: mode of administration mode of elimination half-life ability to reverse interaction with diet/alcohol/medications side-effects allergic potential

6 Targets of New Anticoagulant Agents ORAL PARENTERAL TF/VIIa TTP889 TFPI (tifacogin) X IX Xa Inhibitors: Rivaroxaban Apixaban Edoxaban LY YM150 PRT IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Indirect Xa inhibitors Fondaparinux Idraparinux SSR IIa Inhibitors Ximelagatran Dabigatran IIa Direct Xa Inhibitors DX-9065a Otamixaban Fibrinogen TF=tissue factor Adapted from Weitz JI et al. J Thromb Haemost. 2005;3: Fibrin

7 Evolution of Anticoagulant Therapy 1993 First commercially available LMWH 1998 First commercially available DTI 2001 First commercially available synthetic Xa inhibitor 1940s UFH commercially available Warfarin commercially available ~50 years 2003 FDA rejects ximelagatran 2009 Rivaroxaban AC=anticoagulant; DTI=direct thrombin inhibitor; FDA=Food and Drug Administration; LMWH=low molecular weight heparin; UFH=unfractionated heparin 2008 Dabigatran approved for clinical use NICEN approves bothice

8 ANTICOAGULANT = DOSE + POTENCY EFFECT

9 WARFARIN ANTICOAGULANT = DOSE + POTENCY EFFECT INR mgs/day constant

10 Odds ratio Warfarin and its challenging therapeutic window Stroke Therapeutic range 10 Intracranial bleed International normalized ratio (INR) 8

11 SAFETY AND EFFICACY Therapeutic Window THROMBOSIS BLEEDING Target INR

12 SAFETY AND EFFICACY THROMBOSIS BLEEDING Anticoagulant dose

13 SAFETY AND EFFICACY THERAPEUTIC WINDOW THROMBOSIS BLEEDING?

14 SAFETY AND EFFICACY THERAPEUTIC WINDOW

15 POPULATION SPREAD Recent trauma gastritis Recent surgery Long-haul flight Thrombophilia Platelet function defect Bed-bound

16 HEPARIN AND WARFARIN BOTH HEPARIN AND VIT-K ANTAGONISTS INHIBIT THE WHOLE COAGULATION CASCADE ACTION OF BOTH CAN BE REVERSED BOTH REQUIRE FREQUENT LABORATORY MONITORING

17 Cumulative survival Why time in therapeutic range (TTR) matters Warfarin group % 61 70% 51 60% 41 50% 31 40% <30% Non warfarin Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124: DBG2919 September 2011

18 CHARACTERISTICS OF THE IDEAL ANTICOAGULANT OOF THE IDEALF THE IDEAL Wide therapeutic window No food or drug interactions Predictable response no monitoring required Rapid onset of action Antidote readily available Cheap

19 NEW ANTICOAGULANT ANTICOAGULANT = DOSE + POTENCY EFFECT?? fixed??

20 WARFARIN DOSE INR

21 Dabigatran plasma concentration aptt (s) Dabigatran plasma concentration (ng/ml) Br J Clin Pharmacol 2006;62(5):

22 Clotting time (sec) Hemoclot thrombin time assay Dabigatran (nmol/l) Linear fit ( X) 95% CI 95% Prediction interval Stangier J. Blood Coagul Fibrinolysis 2012; 23:

23 Samama et al

24 Overview over the most important Phase III randomized controlled trials involving the novel anti coagulants DBG2919 September 2011

25 Pradaxa : evolution or revolution? Warfarin vs.: Meta-analysis of ischaemic stroke or systemic embolism Favours warfarin Favours other treatment Placebo Low-dose warfarin Aspirin Aspirin + clopidogrel Ximelagatran Dabigatran 110 mg BID Dabigatran 150 mg BID 0.0 Error bars = 95% CI; BID = twice daily Hazard ratio Adapted from Camm J. ESC 2009; oral presentation # Lip GYH & Edwards SJ. Thromb Res 2006;118: DBG2919 September 2011

26 DBG2919 September 2011

27 DBG2919 September 2011

28 STROKE AND SYSTEMIC EMBOLISM

29 INTRACRANIAL BLEEDING

30 HAEMORRHAGIC STROKE

31 ALL CAUSE MORTALITY MAJOR BLEEDING

32 GI BLEEDING MYOCARDIAL INFARCTION

33 Major bleeding and components D D Characteristic Warfarin 110 mg 150 mg Number of patients (n) P-value 110 vs. W P-value 150 vs. W Major bleeding Life threatening < Non-life threatening Gastrointestinal <0.001 Data represents %/year Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

34 Net clinical benefit and components Characteristic Dabi Dabi P-value P-value Warfarin 110 mg 150 mg 110 vs. W 150 vs. W Number of patients (n) Net clinical benefit Stroke / SSE <0.001 (NI) <0.001 (NI) 0.34 (sup) <0.001 (sup) - Death MBE PE MI All data represents %/year Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

35 Seconds PT BL T=0 15 min 30 min 1 hr 2 hr 4 hr 6 hr 24 hr Time Rivaroxaban 20 mg BID for two and a half days PCC or placebo infusion Placebo PCC

36 Seconds aptt BL T=0 15 min 30 min 1 hr 2 hr 4 hr 6 hr 24 hr Time Dabigatran 150 mg BID for two and a half days PCC or placebo infusion Placebo PCC

37 CONCLUSIONS 1. Introduction of new anticoagulants is a Good Thing. 2. Groups of anticoagulants differ: mode of administration mode of elimination half-life ability to reverse interaction with diet/alcohol/medications side-effects allergic potential

38 Some characteristics of available anticoagulants UFH LMW H Warfari n Inj. Anti- Xa administration IV SC Oral IV or SC Oral Anti-XA Oral Inj. DTI IV or SC monitoring Yes No Yes No No No No Risk of HIT Yes Yes No No No No No Antidote Yes Some Yes Yes No No No Half-life (hrs) Rapid onset Yes Yes No Yes Yes Yes Yes CYP450 interact. Oral DTI Oral No No Yes No No No No Drug interaction No No Yes No Some No Some

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