The new oral anticoagulant will replace LMWHs? No?

Transcription

1 Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux. The new oral anticoagulant will replace LMWHs? No? Grigoris T Gerotziafas

2 Disclosures for G. T. Gerotziafas In compliance with CME policies, 6 th ICTHIC requires the following disclosures, related to the speaker s presentation, to the session audience : Research Support/P.I. Sanofi aventis, Bayer HealthCare, Bristol Myers Squibb, GlaxoSmithKline, Leo Pharma, Diagnostca Stago, Dynabate Employee Consultant Major Stockholder Scientific Advisory Board Honoraria Other (Specify) No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Sanofi aventis, Bayer HealthCare, Bristol Myers Squibb, GlaxoSmithKline, Leo Pharma, Diagnostca Stago Sanofi aventis, Bayer HealthCare, Bristol Myers Squibb, GlaxoSmithKline, Leo Pharma, Diagnostca Stago [No relevant conflicts of interest to declare or Company Name(s)]

3 FDA and EMA approved indications of LMWHs Indication enoxaparin nadroparin tinzaparin dalteparin bemiparin reviparin General surgery VTE prophylaxis Major orthopedic surgery Medical patients ACS treatment Unstable angina, Non Q AMI VTE treatment Treatment of VTE Hemofiltration

4 Simple classification of anticoagulants Factor Xa Thrombin AT-dependent inhibitors: Pentasaccharide, heparins, ULMWHs (semuloparin) AT-dependent inhibitors: Heparins, danaparoid, ULMWHs (semuloparin) HCII-dependent inhibitors Direct inhibitors: Rivaroxaban, apixaban, edoxaban Direct inhibitors: Dabigatran, lepirudin, bivalirudin Parenteral Oral Gerotziafas GT, Samama MM. Current Pharmaceutical Design, 2005,

5 Molecular weight distribution and mechanism of action of heparins Pentasaccharide : PM = 1700 D AT Xa AT IIa LMWH UFH % anti- Xa activity Molecular weight (daltons) 5

6 Heparin Macrophage Endothelial cells Fondaparinux Idraparinux antithrombin fondaparinux other plasma proteins Heparin

7 Kinetics of anti-xa activity and TFPI release in patients with unstable angina treated with enoxaparin 140 enoxaparin 100 mg/kg s.c. enoxaparin 100 mg/kg s.c. 1 Free TFPI (ng/ml) ,8 0,6 0,4 0,2 0 pre time from start (hours) Free TFPI anti- Xa activity anti-xa IU/ml Gerotziafas et al BJH 2002

8 Effect of treatment with a LMWH on FVIIa levels in plasma from patients with unstable angina 7 enoxaparin 100 mg/kg s.c. enoxaparin 100 mg/kg s.c. 1 FVIIa (ng/ml) P<0.05 0,8 0,6 0,4 0,2 0 anti-xa IU/ml pre time from start (hours) FVIIa anti-xa activity Gerotziafas et al BJH 2002

9 Enoxaparin-derived oligosaccharides and inhibition of TF/FVIIa

10 inhibition of FVIIa generation (%) P<0,05 n=5 experiments Gerotziafas et al poster 1106, 52nd ASH meeting Orlando 2010

11 Effect of FXa inhibitors on free and prothrombinase bound FXa Direct inhibitors of FXa (rivaroxaban, DX9065a, ) Fluide phase FXa AT/pentasaccharide AT/Heparins (UFH and LMWHs) FXa FVa Phospholipids Ca ++ prothrombinase Barrowcliffe et al Biochem J 1987; 243: Pieters et al, J Biol Chem 1988; 263: Hemker et al, Biochim Biophys Acta 1989; 992: Herault et al J Pharmacol Exp Ther 1997; 283:16 22 Rezaie AR. Blood 2001; 97: Herault et al J Thromb Haemost 2003;1: Perzborn et al J Thromb Haemost 2005; 3:

12 Role of free FXa in early amplification of blood coagulation FV?? FVII LMWHs VIIa/TF FIXa FVa FIX Prothrombinase Va - Xa Phospholipids The amplification of blood coagulation is driven not only by thrombin but also by free FXa specially in the initiation phase of coagulation before the initial generation of thrombin G.T. Gerotziafas Service d Hématologie Biologique, Hôpital Tenon. EUROPACE, Lisbon June 2007

13 Pharmacokinetic properties of LMWHs Cmax (anti-xa IU/ml) Tmax (hours) AUC (anti-xa IU/hr/ml) AUC (anti-iia IU/hr/ml) Enoxaparin 4000 anti-xa IU/sc 0, ,47 0,25 Nadroparin 3075 anti-xa IU/sc 0,32 3,62 2,35 - Dalteparin 5000 anti-xa IU/sc 0,49 3 3,2 0,56 Tinzaparin 4500 anti-xa IU/sc 0, Reviparin 4250 anti-xa IU/sc 0,72 3,1 2,44 Samama MM, Gerotziafas GT, Seminars Thromb Haemostasis 2000

14 Pharmacokinetics of direct NATA ttpeak Onset of anticoagulatio n after the first dose Steady state levels Elimination 1/2 life Duration of anticoagulatio n after the last dose exertion Rivaroxaban 2 4 h within 30 min after the first dose 7 11 hours 24 hours 66% renal 28% intestinal/fecal hepatic Apixaban 1 3 h within 30 min after the first dose 8 12 hours (twice daily) hours 30% renal 50% intestinal hours 80% renal (40% in Dabigatran 2 h within 30 min after 3 days after a single dose h after 12 hours active forme and 40% in forme of metabolites) multiple doses 20% biliary

15 Main characteristics of the New Antithrombotic Agents Origin and mode of preparation Specific target Mechanism of action Potential antigenicity Administration route Pharmacokinetic characteristics Effect on blood coagulation tests (i.e. thrombin generation test, prothrombin time, apttt etc) Efficacy and safety of for the treatment of venous and arterial thrombosis Synthetic or hemi synthetic Specific inhibition of single clotting factor resulting in inhibition of thrombin generation Indirect inhibition: antithrombin dependent Direct inhibition : high affinity and specificity for the active center of the target serine protease No Oral, intravenous, subcutaneous Rapid onset and offset of the anticoagulant activity after treatment initiation and discontinuation Potential development of assays for laboratory monitoring and dose adjustment, if needed in some patient groups. Improvement of the management of thrombosis at the acute phase and during the long term treatment

16 Aim of the study We analyzed the results of the phase III clinical trials which assessed the efficacy and safety of NATA in the treatment of VTE focusing on the subgroups of patients with cancer.

17 Methodology Research in published in pub-med Rivaroxaban : EINSTEIN-DVT, EINSTEIN-PE, MANGELLAN Apixaban : ADOPT Dabigatran : RE-COVER Fondaparinux : MATISS-DVT and PE, ARTEMIS Idra(biota)parinux : Van Gogh DVT, DVT extension and PE, EQUINOX Semuloparin : SAVEONCO efficacy and safety of studied treatments vs the comparator in the subgroups of patients with cancer

18 RCT of NATA in VTE prophylaxis in medical and oncological patients RCT Studied populations Experimental design MAGELLAN Acutely ill medical patients Rivaroxaban 10 mg vs enoxaparin 40 mg for 10 d and Rivaroxaban 10 mg vs placebo until the day 35. ADOPT Acutely ill medical patients Apixaban 2.5 mg b.o.d vs enoxaparin 40 mg for 6 14 d and Apixaban 2.5 mg b.o.d vs placebo until the day 35 SAVEONCO Oncological patients on chemotherapy Semuloparin 20 mg o.d vs placebo for 3.5 months.

19 Efficacy and safety of NATA in VTE prophylaxis RCT Total studied population Patients with cancer MAGELLAN Rivaroxaban = 3977 Enox/placebo = 4001 ADOPT Apixaban = 2211 Enoxaparin = 2211 SAVEONCO Semuloparin = 1608 Placebo = 1604 rivaroxaban = 7% enox/placebo = 7% History of cancer apixaban = 9.6% enoxaparin = 9.8% Active cancer apixaban = 3.5% enoxaparin = 3 % Remote cancer apixaban = 6.1% enxaparin = 6.8% patients with metastatic (70%) or locally advanced cancer of lung (37%), colon rectum (29%), stomach, ovary, pancreas, or bladder

20 Efficacy of NATA in VTE prophylaxis Total studied population Cancer patients Frequency of VTE 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% MANGELLAN ADOPT SAVEONCO 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% MANGELLAN ADOPT SAVEONCO NATA comparator

21 Safety* of NATA in VTE prophylaxis Total studied population Cancer patients Frequency of bleeding 4.00% 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% MANGELLAN ADOPT SAVEONCO 4.00% 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% MANGELLAN ADOPT SAVEONCO NATA comparator *Major and clinically relevant bleeding Descriptive values for the incidence of clinically relevant bleeding consistently favored enoxaparin over rivaroxaban in patients with active cancer

22 Randomized Controlled Trials with NATA in VTE treatment

23 RCT Studied populations Experimental design EINSTEIN Acute DVT EINSTEIN DVT extension treatment of sympromatic DVT for 3, 6 or 12 months Duration more 6 months after completing the first phase of treatment. Rivaroxaban 15 mg b.i.d x 3 weeks and then 20 mg o.d versus Enoxaparin 1 mg/kg bid s.c./vka for 6 months Rivaroxaban 20 mg o.c versus placebo EINSTEIN PE RECOVER treatment of sympromatic PE for 3, 6 or 12 month Treatment of sympromatic acute proxymal DVT orpe who were initially given parenteral anticoagulant therapy Duration of treatment 6 months Rivaroxaban 15 mg b.i.d x 3 weeks and then 20 mg o.d versus Enoxaparin 1 mg/kg bid s.c./vka Dabigatran 150 mg b.i.d versus dose adjusted warfarin INR 2 3

24 Cancer patients in the RCT with direct NATA in VTE treatment RCT Total studied population Patients with cancer EINSTEIN Acute DVT Rivaroxaban = 1731 Rivaroxaban = 6.8% EINSTEIN DVT extension Enox/VKA= 1718 Rivaroxaban= 602 placebo= 594 Enox/VKA = 5.2% Rivaroxaban = 4.5% Placebo = 4.4% EINSTEIN PE Rivaroxaban= 2419 Enox/VKA= 2413 RECOVER Dabigatran = 1274 VKA = 1265 Rivaroxaban = 4.7% Enox/VKA= 4.5% Dabigatran = 5% VKA = 4.5%

25 Efficacy of direct NATA in VTE treatment Total studied population Cancer patients 8.00% 8.00% Frequency of VTE 7.00% 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% EINSTEIN DVT EINSTEIN DVT extenion EINSTEIN PE RECOVER 7.00% 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% EINSTEIN DVT EINSTEIN DVT extenion EINSTEIN PE RECOVER NATA comparator

26 Safety* of direct NATA in VTE treatment Total studied population Cancer patients Frequency of bleeding 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% EINSTEIN DVT EINSTEIN DVT extenion EINSTEIN PE RECOVER 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% EINSTEIN DVT EINSTEIN DVT extenion EINSTEIN PE RECOVER NATA comparator *Major and clinically relevant bleeding

27 RCT with antithrombin-dependent NATA in VTE treatment

28 RCT Studied populations Experimental design MATISSE PE Treatment of sympromatic PE Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus MATISSE DVT Treatment of sympromatic acute DVT UFH i.v./vka for 6 months Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus Enoxaparin 1 mg/kg bid s.c./vka EQUINOX Van Gogh Treatment of sympromatic acute DVT Treatment of sympromatic acute Idrabiotapariux 3 mg s.c./week Versus Idraparinux 2.5 mg s.c./ week Idraparinux 2.5 mg s.c. once weekly versus LMWH s.c./vka total duration of treatment 3 months (22% of patients) or 6 months (78%)

29 Cancer patients in RCT of Antithrombindependent NATA in VTE treatment RCT Total studied population Patients with cancer MATISSE PE Fondaparinux = 1103 UFH/VKA= 1110 MATISSE DVT Fondaparinux = 1098 Enoxaparin/VKA= 1107 Fondaparinux = 10% UFH/VKA= 10% Fondaparinux = 11% UFH/VKA = 11% EQUINOX idrabiotaparinux= 386 idraparinux= 371 Van Gogh Idraparinux = 1452 LMWH/VKA = 1452 Idrabiotaparinux = 4.7% Idraparinux = 5.7% Idraparinux = 15% LMWH/VKA =14.5%

30 Efficacy of AT-dependent NATA in VTE treatment Total studied population Cancer patients Frequency of VTE 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% MATISSE PE MATISSE DVT EQUINOX Van Gogh 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% MATISSE PE MATISSE DVT EQUINOX Van Gogh NATA comparator

31 Influence of cancer stage on the efficacy of fondaparinux 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% NATA MATISSE PE advanced cancer MATISSE PE cancer comparator

32 Safety* of AT-dependent NATA in VTE treatment Total studied population Cancer patients Frequency of bleeding 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% MATISSE PE MATISSE DVT EQUINOX Van Gogh 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% MATISSE PE MATISSE DVT EQUINOX Van Gogh NATA comparator *Major and clinically relevant bleeding

33 Main drug interactions and contraindications of the NATA Rivaroxaban Apixaban Dabigatran drug interactions Potentiators inhibitors of CYP3A4 azole drugs : i.e antimycotics like ketokonazol traconazole, voriconazole, posaconazole, except fluconazole, selective serotonin reuptake inhibitors, diltiazem, and cimetidine HIV protease inhibitors (i.e ritonavir) Inhibitors of P glycoprotein rifampycine amiodaron, quinidin, clarithromicine, verapamil, macrolides (clarithromycine), phenytoine, phenobarbital, St. John s wort Inhibitors of P glycoprotein Minor interactions with atorvastatin contraindications creatinin clearance < 30 ml/min or liver impairment ketokonazol co administration creatinin clearance < 30 ml/min in liver impairement : Possibly safe as no hepatic metabolism but caution advised ketokonazol co administration Lower dose if creatinin clearance is ml/min Contraindication if creatinin clearance < 30 ml/min

34 Antithrombin and Anti-Xa Drugs Will they replace heparins? No. These drugs may be useful in specific indications. However none of these agents exhibit the polytherapeutic spectrum and modulate endogenous processes (TFPI release).

35 Will Oral Anti-Xa and Antithrombin Agents Replace Pentasaccharide? Maybe Pentasaccharides is an indirect sole inhibitor of factor Xa which is totally dependent on antithrombin. Because of the indirect anti Xa actions, pentasaccharide has certain limitations.

36 LMWH vs Direct FXaIs The parenteral D XaIs exhibit short half life and require continuous infusion for their pharmacologic effects. LMWH produces lasting effect after SC and IV administration. LMWH has multiple sites of action and is capable of releasing TFPI and other mediators from the vascular endothelium. D XaIs do not produce this effect. Oral D XaIs exhibit wide population based PK/PD differences, whereas such differences are not observed with LMWH. Because of the peptidomimetic (organic) structure, D XaIs may exhibit similar toxicology profile as reported oral DTIs. Oral D XaIs due to their smaller structure pass through placental and blood brain barriers. Thus, their use in pregnancy is not recommended, moreover, these agents may have increased hemorrhagic potential.

37 LMWHs vs Parenteral DTIs LMWHs has multiple sites of action, whereas P DTIs inhibit thrombin only. LMWHs has longer duration of action, whereas P DTIs are shorter duration of action and require continuous infusion. LMWHs releases endogenous mediators such as TFPI, whereas P DTIs do not. LMWHs inhibits both the pre formed thrombin and FXa and their generation, whereas P DTIs mainly inhibit formed thrombin. P DTIs compromise the regulatory functions of thrombin (Protein C/TAFI), whereas LMWH does not. LMWHs is poly therapeutic and can be used in multiple indications, whereas the P DTIs have limited and qualified indications.

38 Will Oral Anti Xa and Antithrombin No. Agents Replace Heparin? Heparin is used as a universal anticoagulant with prophylactic, therapeutic and surgical/interventional indications. At this time only limited data in DVT prophylaxis is available. There is no dose response. Long term toxicity is not known. No antagonist is available.

39 Current Perspectives and Future Trends Heparins and related drugs will continue to be developed in expanded indications. The newer synthetic anti Xa and anti IIa drugs will only be useful in qualified indications. Moreover the safety issues will be under strong regulatory scrutiny. A total conversion from the current standard of care to use the anti Xa and anti IIa agents in thrombotic and cardiovascular indications is not projectable at this time.

40 RCT of NATA in VTE treatment The NATA even if they belong in the same class most probably have variable clinical efficacy and safety profile. Cancer patients are heterogenous regarding the risk of VTE and bleeding The limited though promising clinical data on the efficacy and safety of NATA in cancer patients with VTE stress out the urgent need for conducting clinical trials. The revision of the inclusion criteria and the methodology of the future RCT aiming specific cancer population regarding the type and the stage of canceris un urgent need in order to reveal the benefit of the NATA. The NATA are Simple and Specific drugs for Selected and risk stratified patients

41 Discussion Rivaroxaban bring a different concept in the management of VTE as compared to that of fondaparinux and dabigatran. Semuloparin is the only NATA studied in specific cancer population of patients With these NATA, VTE can be efficienlty managed using a single antithrombotic agent which opposes to the standard dual treatment with heparins (or fondaparinux) and VKA. This new concept in the management of VTE could substantially improve the quality of life of cancer patients with VTE.

42 RCT of NATA in VTE treatment

43 RCT of NATA in VTE treatment

44 RCT of NATA in VTE treatment

45 RCT of NATA in VTE treatment

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

47 Thromboprophylaxis with NATA major abdominal surgery RCT Experimental design n primary efficacy endpoint in total population PEGASUS fondaparinux 2.5 mg x 10 d versus dalteparin 2500 anti Xa IU pre op and 5000 anti Xa IU post operatively routine venography on day 10 fondaparinux = 1027 dalteparin = 1021 fondaparinux = 4.6% dalteparin = 6.1% 24.6% RRR (p=0.144) Apollo fondaparinux 2.5 mg x 10 days +mechanical prophylaxis versus placebo + mechanical prophylaxis routine venography on day 10 fondaparinux = 635 placebo = 650 fondaparinux = 1.7% placebo = 5.3% 70% RRR In both studies safety was similar in the two studied groups

48 Prophylaxis with NATA major abdominal surgery for cancer RCT Experimental design n subgroup of cancer patients primary efficacy end point in cancer subgroup primary end point cancer safety in PEGASUS fondaparinux 2.5 mg x 10 d versus dalteparin 2500 anti Xa IU pre op and 5000 anti Xa IU post operatively routine venography on day 10 Fondaparinux 1027 dalteparin = 1021 Fondaparinux 954 (66.6%) dalteparin = 987 (69.3%) fondaparinux 4.7% Dalteparin 7.7% 38.6% RRR fondaparinux 3.4% dalteparin 2.4% Apollo fondaparinux 2.5 mg x 10 d +mechanical prophylaxis versus placebo + mechanical prophylaxis routine venography on day 10 fondaparinux = 635 placebo = 650 fondaparinux = 246 placebo = 262 fondaparinux = 2.5% placebo = 6.7% 64% RRR in the cancer subgroup safety was the same as in total population in total population fondaparinux = 1.6% placebo = 0.2%