D E A R. W Aspirin. AF New Anticoagulants: Todays Aims

Transcription

1 AF New Anticoagulants: Todays Aims 1. Characterize the new AC 2. Know critical differences 3. Know the latest study findings in AF 4. Ask critical questions on TTR, OAC naive pts Compliance and dosing intervals, future devel., CHADS2 scores, previous stroke, CCr, age, monitoring to Drs Conolly and Brunckhorst D E A R B W Aspirin

2 Stroke Prevention in AF New Anticoagulants D E A R B W Aspirin

3 Gebhard & Beer 2010 GP II b GP III a GP II b Endothelial Lesion GP III a GP II b GP III a GP II b GP III a Plasmatic LMWH/UFH Fondaparinux [Idraparinux] Idrabiotaparinux afxi IX Platelet vwf avwf aptamer XIa E5555 GP Ia/IIa GP Ib/IX/V Rivaroxaban* Apixaban* Otamixaban Edoxaban* Betrixa Eribaxa. LMWH/UFH II IIa VIIIa IXa Bivalirudin Lepirudin Dabigatran* [Ximelagatran] AZD0837 SCH afixa aptamer Aspirin Terutruban Platelet activation Secretion TxA 2 ADP Fibrin Fibrinogen Abxicimab Tirofiban Eptifibatide TxA 2 R TxA 2 ADP P2Y 12 R Platelet- Fibrinogen- Network Activation Cangrelor Ticagrelor Clopidogrel Prasugrel Elinogrel

4 Gebhard & Beer 2010 GP II b GP III a GP II b Endothelial Lesion GP III a GP II b GP III a GP II b GP III a Plasmatic LMWH/UFH Fondaparinux [Idraparinux] Idrabiotaparinux afxi IX Platelet vwf avwf aptamer XIa E5555 GP Ia/IIa GP Ib/IX/V Rivaroxaban* Apixaban* Otamixaban Edoxaban* Betrixa Eribaxa. LMWH/UFH II IIa VIIIa IXa Bivalirudin Lepirudin Dabigatran* [Ximelagatran] AZD0837 SCH afixa aptamer Aspirin Terutruban Platelet activation Secretion TxA 2 ADP Fibrin Fibrinogen Abxicimab Tirofiban Eptifibatide TxA 2 R TxA 2 ADP P2Y 12 R Platelet- Fibrinogen- Network Activation Cangrelor Ticagrelor Clopidogrel Prasugrel Elinogrel

5 The DEAR Trials in AF RE-LY ENGAGE AVERROES ARISTOTLE ROCKET- Dabigatran Edoxaban Apixaban Apixaban Rivaroxaban 110/150 bid 30/60mg od 5mg bid 5mg bid 20mg od INR 2-3 INR 2-3 ASA INR 2-3 INR ,000pts 20,500 5,600 18,000 14,000 1 RF moderate R >/= 1RF 1 RF moderate- CHADS 1: 32% CHADS >=2 unsuitable high risk CHADS 2: 35% intolerant CHADS 2: 10% CHADS 3: 33% CH >/=3: 90% 50% VK naive W:open label Stopped premat DD S-INR; Neur. DD; Sham INR S/SE S/SE S/SE S/SE S/SE Event d:450 Time 24m Event d 36m Event d 448 Event d 405 >12m >14m Published 3/2012 Published 4/2011 (Abstr)

6 Dabigatran etexilate Oral bioavailability ~6.5% Plasma concentrations with biexponential decline, mean terminal half-life 14 17h in healthy volunteers independent of dose O N N O N N CH 3 NH H 3 C O N H 2 N O O CH 3 Dabigatran etexilate Not metabolized by CYP450 enzymes, and does not affect the metabolism of other drugs that utilize this system 80% renal excretion Not affected by food No specific antidote available Contraindicated when creatinine clearance < 30 ml/min May cause dyspepsia No monitoring

7 110 Net difference -0.16% 150 Net difference -0.58% JACC 2010; 56:2067

8 -6* * * +5 more cases/1,000 pts/year compared with W * -5 less cases/1,000 pts/year Lancet 2010; 341:682

9 The FDAs View

10 Rivaroxaban (Xarelto) Oral and direct factor-xa-inhibitor High oral bioavailability (80-100%) Immediately effective: C max = 2-4 h (similar to NMH) Halflife: 5-9h (elderly pts.: h) Dual mode of elimination 1/3 renal elimination 2/3 metabolized in the liver Fixed dose independent of food, BMI, gender, age No monitoring O.D. O O N N O Cl H S N O O Rivaroxaban Perzborn E et al. J Thromb Haemost 2005;3: Kubitza D et al. Eur J Clin Pharmacol 2005;61: Kubitza D et al. J Clin Pharmacol 2006;46: Kubitza D et al. Br J Clin Pharmacol 2007;63: Kubitza D et al. J Clin Pharmacol 2007;47: Kubitza D et al. Blood 2006;108:Abstract 905.

11 Cumulative event rate (%) Rocket-AF: Primary Efficacy Outcome Stroke and non-cns Embolism (OT) Rivaroxaban Warfarin Event Rate Warfarin Net difference -0.45% Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization

12 Primary Efficacy Outcome: Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better 30 R / 7,000=0.42% Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

13 Apixaban: A Factor Xa Inhibitor Bicyclic pyrazole Highly selective for factor Xa inhibition: K i = 0.08 nm O Oral bioavailability: 50% N N NH 2 Rapid absorption (Tmax 3h to 4h) No food effect O O N Half-life: T 1/2 12 h Multiple elimination/excretion pathways: ~27% renal clearance N O No prodrug, no active metabolite No organ toxicity, LFT abnormalities, or QTc prolongation seen in studies B.I.D.

14 AVERROES 2x5mg Apixaban vs Aspirin 3.7%/y -2.1% 1.6%/y NEJM 2011; Febr 10

15 1.4%/y 1.2%/y NEJM 2011; Febr 10

16 Half dose, if CCr 30-50ml, <60kg, Medi Verapamil or Quinidine ASA<100 Stop, if TRIPLE Edoxaban and atrial fibrillation AHJ 2010; 160: 637 Individualized design; O.D.

17 The Forbidden Table: Summary of Outcomes in %/year D110 D150 Riva OT Riva ITT Apix War(-D) War(-R) ASA(-A) RE-LY RE-LY ROCKET-AF AVER Dabigatran Rivaroxaban Apixaban Warfarin S/SE / ICB Death M Bleed

18 4 Runner-ups? 1) Otamixaban is an iv applicable substance after MI 2) Betrixaban is excreted unchanged in the bile and only minimal renal excretion (<5%), will be suitable for pts with renal failure 3) YM150 Phase II in AF AZD 0837 (anti-iia) favorable in Phase II in AF 4) LY

19 Anti-Thrombin-Effects Beyond Anticoagulation? 1) Antiinflammatory and anti-atherosclerotic effects of thrombin-inhibition 2) Thrombin activates protease activated receptors (PAR 1-4) on plts and Lc 3) Thrombin activates thrombomodulin 4) Thrombin reduces endothelial NO 5) Thrombin stimulates smooths mm cell proliferation (yet stabilizes the plaque) JACC 2010; 56:2067

20 Country Distribution of cttr CH:68% 72% (Marko et al) Lancet 2010; 367:976

21 Cumulative hazard ratio Cumulative hazard ratio TTR subgroup analysis: time to primary outcome: D150 more effective if TTR is bad cttr <57.1% Warfarin Dabigatran 110 mg Dabigatran 150 mg D cttr % Number at risk Dabigatran 110 mg Dabigatran 150 mg Warfarin cttr % 0.06 cttr >72.6% Number at risk Dabigatran 110 mg Dabigatran 150 mg Warfarin Follow-up (yrs) Follow-up (yrs) TTR = time in therapeutic range; cttr = centre mean TTR Wallentin L et al. Lancet 2010;376: Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only. 21

22 Cumulative hazard ratio Cumulative hazard ratio TTR subgroup analysis: time to major bleeding: More Bleeds in W if TTR is bad cttr <57.1% Warfarin Dabigatran 110 mg Dabigatran 150 mg W cttr % Number at risk Dabigatran 110 mg Dabigatran 150 mg Warfarin cttr % cttr >72.6% Number at risk Dabigatran 110 mg Dabigatran 150 mg Warfarin Follow-up (yrs) Follow-up (yrs) TTR = time in therapeutic range; cttr = centre mean TTR Wallentin L et al. Lancet 2010;376: Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only. 22

23 NEJM 2003; 349:1019 Why not compare INRs when things happen

24 Ann Int Med 2011;154:1

25 Monitoring Thrombos Haemost 2010: 103:1116 ECT PT Relevance of plasma concentrations? No bleeding =baseline conc Any bleeds (=major +minor): +20% Major: +50% TT aptt

26 and if it is bleeding Thrombos Haemost 2010: 103:1116

27 Summary 1) New anticoagulants targeting factor Xa and IIa have been shown to be at least as effective and in some instances superior in efficacy and side effects compared to warfarin. 2) Individualized treatment options have emerged and will further open new perspectives in the choice of dose and substance according to the clinical situations.

28 Individualized Scenarios for the Future 1) Pts > 75-80y: Lower dose of D 2) Renal insufficiency: Choose agent with hepatic clearance or lower the dose. 3) High GI bleed risk: R? 4) Difficult compliance: O.D.? 5) Excellent TTR: W? 6) CHADS>3: lower ds D, R, E? 7) Unsuitable for Warfarin: At lower CHADS Scores: A

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30 TTR in the Warfarin ctr Group ROCKET-AF (Rivaroxaban in AF): 58% RE-LY (Dabigatran in AF): 68% Recover (Dabigatran in DVT): 60%

31 Individualized dose recommendation based on RE-LY and the new data analyses Pradaxa in AF: mg bid life-long - pts > 80 yrs should be treated with 110 mg bid due to the increased bleeding risk mg bid can be individually considered at discretion of physician when: Thromboembolic risk is low AND bleeding risk is high e.g. age 75 yrs CHADS2 score 3 moderate renal impairment concomitant treatment with a strong P-gp inhibitor GI bleed history

32 Safe(r) Anticoagulation? Targeting FXI with Anti-Sense Oligonucleotides results abolishes pathological thrombosis but has minor effects on haemostasis BLOOD 2010; 116:4390

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34 Taiwan Mexico Peru Romania India Colombia Russia Brazil China Korea Greece Thailand Malaysia Poland South Africa Japan France Slovakia Portugal Czech Republic Israel Philippines Bulgaria Hungary Hong Kong Turkey Belgium United States Austria Spain Germany Switzerland Singapore Argentina Netherlands Norway Canada United Kingdom Italy Ukraine Denmark Australia Finland Sweden Mean TTR (%) TTR subgroup analysis: mean 80 TTR by country TTR = time in therapeutic range Wallentin L et al. Lancet 2010;376: Country Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only. 34

35 Monitoring Thrombos Haemost 2010: 103:1116 ECT PT TT aptt