Nouveaux antithrombotiques Charles Marc SAMAMA Service d Anesthésie-Réanimation Hôtel-Dieu de Paris

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1 Nouveaux antithrombotiques 2009 Charles Marc SAMAMA Service d Anesthésie-Réanimation Hôtel-Dieu de Paris

2 Conflits d intérêts Firmes pharmaceutiques et produits (DCI) : AstraZeneca (ximelagatran) Bayer (rivaroxaban) BMS (apixaban) Boehringer-Ingelheim (dabigatran) - CSL Behring (PCC) - Curacyte (antiplasmine) GSK (fondaparinux - nadroparine) - LFB (PPSB - fibrinogène) - Leo (tinzaparine) - Lilly (prasugrel) - Mitsubishi (argatroban) Octapharma (PCC) Organon (danaparoïde) - Pfizer (daltéparine, apixaban) Sanofi-Aventis (enoxaparine, idraparinux, aspirine, clopidogrel) Agences, sociétés savantes et EPST : AFSSaPS : groupe cardio-thrombose de la Comm. AMM (expert titulaire) ACCP : application for the 9th guidelines SFAR : recos 2010 EMEA : efficacy working party (expert consultant) INSERM : laboratoire de thrombose expérimentale (U765)

3 Taux d hospitalisation pour effet indésirable médicamenteux en France : 3,2 % Médicaments en cause 13 % Anticoagulants 46 % 13 % AINS Anticancéreux Psychotropes 5 % 7 % 8 % 8 % Antiarythmiques Antibiotiques Divers Incidence des hospitalisations liées à un accident des AVK : / an 4000 à 5000 morts

4 World LMWH Treatment Days by Country

5 Remaining issues with LMWHs Efficacy - Post-operative VTE rate still between 1 and 2% (orthopaedic surgery, abdominal surgery for cancer) - Questions in thoracic or bariatric surgery patients (doses?, treatment duration?) - Indirect effect (LMWHs bind to Antithrombin) Safety - Heparin-induced thrombocytopenia (HIT, 1/1000) - Renal elimination (potential accumulation) - Non-synthetic compounds ( )

6 Problèmes avec les HNF Depuis décembre 2007, des effets indésirables associés aux HNF de Baxter aux EU Surtout réactions allergiques nausées, vomissements, tr. respiratoires, hypotension, urticaire 81 décès aux EU au 13 Avril 2008 Centres d hémodialyse (injection en bolus) Retrait des héparines de Baxter fin février 2008

7 Héparine Baxter aux USA Provient de «heparin active pharmaceutical ingredient API» de Scientific Protein Laboratory (Wisconsin) Construction manufacture héparine API à Changzhou en 2000 Approbation de la manufacture par la FDA en 2004

8 Matière première This family-owned workshop in Xinwangzhuang, a village in Juangsu Province, China, processes pig intestines. Mucous membranes from the intestines are used to make heparin (The New York Times, March 30, 2008)

9 Workers sort pig intestines at a plant in China, the first step in producing the blood thinner heparin. (Qilai Shen/Bloomberg News)

10 Causes de la contamination? Contaminant : chondroïtine hypersulfatée (OSCS) Quantité présente = 5-20% Dans la matrice du cartilage Contamination Accidentelle? Négligence? Intentionnelle? - épidémie ayant décimé les porcs en Chine - adjonction d un «contaminant» pour maintenir la production et diminuer les coûts? Différence de coût entre l OSCS ($9/livre) et l héparine ($900/livre).

11 Blood born TF Vascular lesion Atherosclerotic plaque Tissue Factor VII VIIa // FXIa FXI NAPC2 ASIS-rTFPI X Xa IX IXa // Anti-IXa amplification Platelets Activation Prothrombinase Va - Xa Phospholipids Thrombin Va VIII Intrinsic Tenase Fibrinogen Fibrin V VIIIa // // Anti-Xa Pentasaccharide+AT Heparins + AT + F VIIIa + Phospholipids DX-9065a Rivaroxaban Apixaban Anti-IIa Heparins+AT Hirudin Argatroban Xi/Melagatran Dabigatran

12 History of antithrombotic agents 21 st century Programmed and designed new antithrombotics aiming at specific targets 2004 : Orally active FIIa and FXa inhibitors 2003 Ximelagatran 2002 Fondaparinux 1983 synthesis of pentasaccharide 20 th century Discovery by serendipity of heparin in Baltimore and vitamin K antagonists in Wisconsin Clinical studies with UFH 1914 Discovery of Heparin 1980 : LMWHs 1966 : s.c. administration of UFH 1950 : Clinical use of vitamin K antagonists 1940 Discovery of dicoumarol

13 Evaluation d un nouvel anticoagulant Prophylaxie PTH PTG Traitement TVP EP FA sélection des patients Syndromes coronaires aiguës Prophylaxie en milieu médical Etudes des influences médicamenteuses et alimentaires

14 Anti-Xa only Parenteral: fondaparinux (GSK), idraparinux (Sanofi-Aventis), DX-9065A (Daiichi), otamixaban (Sanofi-Aventis), Oral: rivaroxaban (Xarelto - Bayer), apixaban (BMS- Pfizer), (Lilly), YM-150 Yamanouchi, PD (Pfizer)

15 Heparin and its derivatives UFH LMWHs Pentasaccharide New antithrombotics fondaparinux Antithrombin binding site

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17 Pharmacokinetics of Fondaparinux After one subcutaneous injection of 2,5 mg concentration (µg/ml) Bioavailability = 100% Cmax = 0.34 µg/ml Tmax = 1.7 h Cmax/2 = 25 mn A.U.C. = 6,65 mgh/l Clearance = 5,6 ml/mn T1/2 = 17 h Vol. dist. = 8,2 l Equilibrium = 0,32-0,47 mg/l time (h) Boneu et al, Thromb Haemost 1995;74:

18 dose choisie 2,5mg

19 2002; 359: Day 49 - venous thromboembolism 12/1129 F vs 9/1123 E : NS Major bleeding : 42F vs 29E : p=0.11

20 % patients Résultats sur le critère principal d efficacité : PTH (US) ETE TVP proximale RRR = 25 % p = 0,12 p = 0,42 Arixtra 2,5 mg x 1/j n = 787 énoxaparine 30 mg x 2/j n = 797 Arixtra 2,5 mg x 1/j n = 816 énoxaparine 30 mg x 2/j n = 830

21 2002; 359: Day 49 - venous thromboembolism : 29/1126 (3%) Fonda vs 13/1128 (1%) Enox - p = Major bleeding : 18F vs 8E : p=0.11

22 Turpie AGG et al. Fondaparinux versus Enoxaparin For the prevention of Venous Thrombo-embolism in Major Orthopedic Surgery A Meta-analysis of 4 randomized double-blind studies Arch Int Med 2002; 162: Major bleeding events : Fondaparinux 96 (2.7%)* Enoxaparin 63 (1.7%) P=0.008 excès de transfusion dans le groupe fondaparinux : 1950 versus 1864 (p=0,04)

23 A T I S S..... E M.. Matisse Study Designs patients with PE + DVT R 5 days IV UFH (aptt ) +VKA (INR 2-3) Open-Label 5 days 7.5 mg fondaparinux * sc + VKA (INR 2-3) patients with DVT R Double-blind * 5 mg if body weight < 50 kg 10 mg if body weight > 100 kg 5 days SC enoxaparin (1 mg/kg, bid) + VKA (INR 2-3) 90 ± 7 Days Primary Efficacy Outcome (3 months) Fatal PE / unexplained death Recurrent symptomatic non-fatal PE or DVT Principal Safety Outcome (initial treatment) Major bleed Clinically relevant non-major bleed

24 A T I S S..... E. M. Matisse PE Primary Efficacy Outcome Fondaparinux (N=1103) UFH (N=1110) Fatal PE 16 (1.5 %) 15 (1.4 %) Non-fatal PE or DVT 26 (2.4 %) 41 (3.6 %) Total symptomatic recurrent VTE 42 (3.8 %) 56 (5.0 %) -3.0% -1.2% 0 0.5% Fondaparinux - UFH (95% CI ) = 3.5% Matisse DVT Fondaparinux (N=1098) LMWH (N=1107) Fatal PE 5 (0.5 %) 5 (0.5 %) Non-fatal PE or DVT 38 (3.5 %) 40 (3.6 %) Total symptomatic recurrent VTE 43 (3.9 %) 45 (4.1 %) -1.8% % 0 1.5% Fondaparinux - LMWH (95% CI ) = 3.5%

25 A T I S S..... E. M. Principal Safety Outcome - initial treatment - Matisse PE Fondaparinux 1.3% 3.2% 4.5 % UFH 1.1% 5.2% 6.3 % 0% 2% 4% 6% 8% Major bleed Clinically relevant non-major bleed Matisse DVT Fondaparinux 1.1% 2.6% 3.7 % LMWH 1.2% 3.0% 0% 2% 4% 6% 8%

26 2.5 mg Oasis 5

27 Oasis 5

28

29 Fondaparinux Produit synthétique, large développement Anticoagulant injectable très puissant, demi-vie longue Efficacité démontrée pour le traitement de la thrombose veineuse et de l embolie pulmonaire Attention à la tolérance chez les sujets «fragiles»: insuffisants rénaux, age>75ans, poids<50kg Pas d antidote. NovoSeven en cas de catastrophe? Thrombopénies induites peu probables, mais numération des plaquettes quand même

30 Idraparinux Pentasaccharide hyperméthylé Bloque le facteur Xa (indirectement) Par voie s-cut, biodisponibilité complète Métabolisme rénal Résultats prometteurs en phase 2, marge thérapeutique large, pas de monitoring Très longue demi-vie ( heures, ou plus?)

31 Randomized, open-label, noninferiority trials 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism SC idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. Primary efficacy outcome: 3-month incidence of symptomatic recurrent VTE. In patients with DVT, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. In patients with PE, t he incidence of recurrence at day 92 was 3.4% in t he idraparinux group and 1.6% in t he st andard-t herapy group (odds rat io, 2.1) ; idraparinux was less efficacious than standard therapy.

32 The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P = 0.004). At 6 months, bleeding rates were similar.

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34 Trial stopped after randomisation of 4576 patients (2283 idraparinux, 2293 vitamin K antagonists) and a mean follow-up period of 10.7±5.4 months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). 21 instances of intracranial bleeding with idraparinux and 9 with vitamin K antagonists (1 1 vs 0.4 per 100 patient-years; p=0.014); Elderly patients and those with renal impairment were at greater risk of such complications.

35 Concept of biotinylated long-acting pentasaccharide as a neutralizable anticoagulant drug idraparinux biotin Xa Xa AT AT AT ELIMINATION Avidine From Dr Bouthier et al, Sanofi Aventis

36 Quel avenir pour l idraparinux? CASSIOPEA : traitement de l EP EQUINOX : traitement de la TVP BOREALIS : fibrillation auriculaire

37 «The terminal half-life was 66.3 days and time to steady-state was 35 weeks»

38 Selective and direct Xa inhibitors Indirect Xa Inhibitor AT Xa Direct Xa Inhibitor Xa gla domain gla domain

39 Rivaroxaban (Xarelto ) oxazolidone derivative, oral bioavailability > 70%, inhibits factor Xa with a Ki of 0.4 nm reversibly inhibits free and clot-associated factor Xa activity, prothrombinase activity and thrombin generation Tmax 2-4h half-life: 9-13 hours cleared by the kidneys (2/3) and the gut (1/3)

40 Lassen M et al. RECORD 3 (knee) 20 Total VTE Rivaroxaban has: 15 RRR 49% Superior efficacy for the primary endpoint (total VTE) Superior efficacy major VTE and symptomatic VTE A good safety profile Incidence (%) 10 Low and similar incidence of major bleeding 5 Major VTE RRR 62% Symptomatic VTE RRR 66% Major bleeding % 9.6% 2.6% 1.0% 2.0% 0.7% 0.5% 0.6% Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily

41 mitt population valid for major VTE, n=3364, and symptomatic VTE in safety population who underwent surgery, n=4399 Eriksson BI et al. RECORD 1 THR prolonged prophylaxis secondary endpoints Incidence (%) Major VTE RRR = 88% ARD = 1.7% ( 2.5, 1.0 ) p< % 0.2% Incidence (%) Symptomatic VTE 0.5% RRR = 45% ARD = 0.2% ( 0.6, 0.1) p= % 0 Enoxaparin 40 mg once daily 33/1678 Rivaroxaban 10 mg once daily 4/ Enoxaparin 40 mg once daily 11/2206 Rivaroxaban 10 mg once daily 6/2193

42 5 Secondary efficacy endpoints Major VTE 5 Symptomatic VTE Incidence (%) ARD = 0.80% ( 1.82, 0.22) p= ARD = 0.47% ( 1.16, 0.23) Incidence (%) 4 p= % 1.2% Enoxaparin 30 mg twice daily 22/1112 Rivaroxaban 10 mg once daily 13/ % 0.7% Enoxaparin 30 mg twice daily 18/1508 Rivaroxaban 10 mg once daily 11/1526 ARD, absolute weighted risk difference (with 95% CI)

43 Major bleeding 5 4 Incidence (%) p= % 0.7% 0 Enoxaparin 30 mg twice daily 4/1508 Rivaroxaban 10 mg once daily 10/1526 On-treatment major bleeding; safety population, n=3034

44 Once-daily, oral rivaroxaban for the prevention of venous thromboembolism after major orthopaedic surgery A pooled analysis of the RECORD1, 2, 3, and 4 studies Alexander GG Turpie On behalf of Michael R Lassen, Ajay K Kakkar, Bengt I Eriksson, Frank Misselwitz, Tiemo Bandel, Martin Homering, Torsten Westermeier, Michael Gent and the RECORD1 4 Study Investigators

45 Primary efficacy outcome Total treatment duration pool Symptomatic VTE + all-cause mortality 58% reduction HR=0.42 (95% CI: ) p<0.001 Incidence (%) % Primary population for analysis % 0 Enoxaparin regimens 82/6,200 Rivaroxaban regimens 35/6,183 Homogeneity test, p=0.313; safety population, n=12,383

46 Treatment-emergent bleeding Total treatment duration pool n (%) Enoxaparin regimens (n=6,200) Rivaroxaban regimens (n=6,183) p-value # Major bleeding 13 (0.21) 24 (0.39) Major bleeding including surgical site Any clinically relevant non-major bleeding Major + clinically relevant non-major bleeding 85 (1.37) 111 (1.80) (2.34) 177 (2.86) (2.55) 197 (3.19) Any bleeding 401 (6.47) 434 (7.02) Treatment duration Rivaroxaban Enoxaparin Active treatment Placebo Follow-up Follow-up Follow-up # Analyzed using a Cox regression model Patients may have had more than one type of event; safety population, n=12,383

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48 Rivaroxaban : Programme de développement clinique de plus de 50,000 patients Phase II (terminées) Phase III Prévention MTEV après chirurgie orthopédique majeure Prévention MTEV chez les patients alités Traitement de la MTEV Prévention de l AVC dans le cadre de la fibrillation auriculaire Prévention Secondaire dans le cadre des syndrômes coronariens aigüs ODIXa-HIP1 ODIXa-HIP2 ODIXa-KNEE ODIXa-OD-HIP ODIXa-DVT EINSTEIN-DVT RECORD1 RECORD2 RECORD3 RECORD4 Terminé p. En cours 8000 p. En cours EINSTEIN-DVT 2900 p. EINSTEIN-PE 3300 p. EINSTEIN-EXT 1300 p. En cours p. + Etude de Phase III au Japon ATLAS ACS TIMI 51 Début fin 2008

49 Apixaban (BMS - Pfizer) direct reversible anti-xa inhibitor oral bioavailability of 51-85%, inhibits FXa with a Ki of 0.08 nm half-life of about hours elimination: renal 25% non renal 75% (hepatic metabolism, biliary and intestinal excretion)

50 Ongoing phase III studies DVT-PE: apixaban 10 mg twice daily for one week and then 5 mg twice daily (4800 patients) Extended (vs placebo): 2.5 mg twice daily Atrial Fibrilation: two studies (15,000 and 5600 patients) Prevention in medicine: 2 x 2.5 mg (6500 patients)

51 Direct Thrombin Inhibitors (Anti IIa) Parenteral Lepirudin Bivalirudin Desirudin Argatroban Oral Xi/Melagatran (AstraZeneca) Dabigatran (Boehringer Ingelheim).

52 Dabigatran etexilate (Pradaxa ) Oral Direct Thrombin Inhibitor Pharmacokinetic Profile Oral Bioavailability 6.5% Peak plasma concentrations within 2 hours 1 Post-operative peak concentrations are later and lower Terminal half-life of hours with multiple doses 2 Once or twice daily dosing 1 No interactions with food Excreted unchanged via the kidney 1. Eriksson BI, et al. J Thromb Haemost 2005; 3: ; 2. Stangier J, et al. Thromb Haemost 2001; 86: [Abstract].

53 Eriksson et al Multicenter, double-blind, 1973 patients, 6 10 days dabigatran starting 1 4 h after surgery, or SC enoxaparin (40 mg) 12 h prior to surgery. Incidence of VTE (bilateral venography or symptomatic events) Treatment Dabigatran 50mg b.i.d (n = 302) Dabigatran 150mg b.i.d (n = 282) Dabigatran 300mg o.d (n = 283) Dabigatran 225mg b.i.d (n = 297) Enoxaparin 40mg SC (n = 300) VTE 28.5% 17.4%* 16.6%* 13.1%* 24% VTE Hip 23.6% 13.4% 13.1% 8.3% 14.9% VTE knee 39,4% 27.2% 23.9% 23.4% 44.6% Treatment period and follow-up : 10 symptomatic VTE (9D(3PE)vs1E) Major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%) but elevated with higher doses (2-fold increase)

54 Randomised Total Knee Arthroplasty Patients; 670 per group R Start 12 hours pre-operatively* Start 1-4 hours post-operatively Enoxaparin 40 mg qd Dabigatran etexilate 75 / 150 mg qd 110 / 220 mg qd Randomisation Venography Day 6-10 Follow-up weeks Central Adjudication Committee for all Efficacy and Safety Outcomes *The evening before surgery; qd, once daily

55 Total VTE and All-Cause Mortality Dabigatran better Enoxaparin better 220 mg -9.2% % 150 mg +2.8 Equivalence -10% -7.5% -5% -2.5% 0 2.5% Difference in Absolute Event Rates (Dabigatran Enoxaparin) 5% 7.5% Major VTE and VTE related mortality: 3,8%, 2.6% vs 3.5% (NS) 10%

56 There was no significant difference in major bleeding rates with either dose of dabigatran compared with enoxaparin. No increases in liver enzyme concentrations and in acute coronary events.

57 Pooled Analysis Major VTE and VTE-Related Death Study Dabigatran 150 mg Dabigatran 220 mg Enoxaparin RE-NOVATE* (THR) 4.3% 3.1% 3.9% RE-MODEL (TKR) 3.8% 2.6% 3.5% RE-MOBILIZE (TKR) 3.0% 3.4% 2.2% Pooled 3.8% 3.0% 3.3% Absolute risk difference (Dabigatran Enoxaparin) [95% CI] [-0.6 to 1.6] [-1.3 to 0.9] * Eriksson et al. Lancet 2007;370:949

58 Pooled Analysis Bleeding Events Dabigatran etexilate 150 mg N= mg N=2682 Enoxaparin N=2716 Major Bleeding Event 1.1% 1.4% 1.4% 95% CI (0.7, 1.4) (1.0, 1.9) (1.0, 2.0)

59 Patients > 75 ans Etudes schéma Européen, PTH + PTG (883 patients / 5539 patients) Analyse post-hoc en sous-groupe Événements TVP totales + Décès +EP Dabigatran 150mg/jour 22.6% (49/217) (CI 17.2%-28.7%) p=0.32 Enoxaparine 40mg/j 27.2% (58/213) (CI 21.4%-33.7%) TVP majeures 4.5% (10/221) (CI 2.2%-8.2%) p=0.53 Saignements majeurs 1.4% (4/282) (CI 0.4%-3.6%) p= % (13/218) (CI 3.2%-10.0%) 2.9% (9/306) (CI 1.4%-5.5%) * 2 patients ont eu 1 saignement majeur en perop, avant la première dose de dabigatran Dahl Oet all : Blood 2008;Dec (supp ASH).

60 Insuffisants rénaux modérés, clairance 20-50ml/min Etudes schéma Européen, PTH + PTG (337 patients / 5539 patients) Analyse post-hoc en sous-groupe Événements TVP totales + Décès +EP Dabigatran 150mg/jour 23.5% (16/68) (CI 14.1%-35.4%) p=0.59 Enoxaparine 40mg/j 27.8% (25/90) (CI 18.9%-38.2%) TVP majeures 4.3% (3/70) (CI 0.9%-12.0%) 9.0% (8/89) (CI 4.0%-16.9%) p=0.35 Saignements majeurs 0.0% (0/96) (CI %) P= % (6/128) (CI 1.7%-9.9%)

61 Dabigatran etexilate Clinical Program Overview: Re-volution Primary DVT prevention VTE secondary prevention Europe US VTE treatment SPAF

62 Comparison of three upcoming novel specific oral anticoagulants Drug Class Compa ny Half-life Bioavailability Elimination Dosage (oral) Apixaban antixa BMS/ Pfizer % 25% renal 75% liver b.i.d. Rivaroxaban antixa Dabigatran DTI Bayer/ J&J 7-13 >80% 33% renal (unchanged) 33% renal (inactive metabolites) 33% biliary B-I % 80% renal 20% biliary o.d. o.d./b.i.d.

63 En pratique En règle générale prudence si atteinte de la fonction rénale ou âge avancé Tenir compte de la demi-vie Arrivée du dabigatran-pradaxa (anti-iia) depuis deux mois, et du rivaroxaban-xarelto (anti-xa) en mai, puis de l apixaban (anti-xa) Antidote uniquement pour l idraparinux rviia (NovoSeven )???? Meilleure expérience quand études cardio disponibles (angor, arythmie) En attendant, patience