New antithrombotic agents in the treatment of VTE; a subgroup analysis of the Phase III randomized clinical trials.

Transcription

1 Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux. New antithrombotic agents in the treatment of VTE; a subgroup analysis of the Phase III randomized clinical trials. Grigoris T Gerotziafas, Michel M Samama, Ismail Elalamy

2 Disclosures for G. T. Gerotziafas In compliance with CME policies, 6th 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 No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Scientific Advisory Board Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, GlaxoSmithKline, Leo-Pharma, Diagnostca Stago Honoraria Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, GlaxoSmithKline, Leo-Pharma, Diagnostca Stago Other (Specify) [No relevant conflicts of interest to declare or Company Name(s)]

3 Cancer and VTE a reciprocal interaction x7 the relative risk of VTE in patients with active cancer 20% of all new cases of VTE are associated with underlying cancer 7% of cancer patients undergoning staging CT scan for cancer are diagnosed with asymptomatic VTE 5% - 60% of cancer patients present VTE 15% of patients hospitalized for cancer with limited metastases of without metastases die from PE 50% of cancer patients who die have DVT and/or PE (autopsie studies) Shen et al South Med J. 1980;73:841-3 Heit et al, Arch Intern Med. 2000;160: Blom et al, JAMA. 2005;293: Cronin et al, Am J Roentgenol. 2007;189:162-70

4 Cancer and VTE Aims of the antithrombotic treatment decrease morbidity improve the quality of life contribute to the decrease of mortality

5 Failure of VTE treatment in cancer patients Recurrent VTE rates of 9-17% occur despite the use of therapeutic anticoagulation LMWH treated patients VKA treated patients Recurrent VTE 9% 20% Complete resolution and partial resolution of DVT occur in up to 38% and 54%, respectively, after 6 months of anticoagulant treatment. Thrombi remain detectable in half of cancer patients after a year. Lee AY. Hematology Am Soc Hematol Educ Program;2010:144-9 (2010). Prandoni P et al Ann Intern Med;137: (2002). Kearon C Circulation;107(23 Suppl 1):I22-30 (2003)

6 Challenges of VTE treatment in cancer patients VTE risk in prophylaxis risk of recurrence in secondary prevention Bleeding risk Compromised by chemotherapy-induced thrombocytopenia DIC renal or liver impairment Quality of life, compliance and adherence to the treatment Compromised by the daily subcutaneous injections HIT skin hematoma frequent dose adjustment of VKA regular INR measurement dietary restrictions interactions with many other drugs frequently used in cancer patients

7 History of antithrombotic agents 21 st century Programmed and designed new antithrombotics aiming at specific targets 1966 : s.c. administration of UFH 20 th 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 2004 : Orally active FXa inhibitors 2003 specific anti-iia 2002 Fondaparinux 1983 synthesis of pentasaccharide 1980 : LMWHs

8 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,

9 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

10 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 form and 40% in form of metabolites) multiple doses 20% biliary

11 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.

12 Methodology Research in published in pub-med Rivaroxaban : EINSTEIN-DVT, EINSTEIN-PE, MANGELLAN Apixaban : ADOPT Dabigatran : RE-COVER Semuloparin : SAVEONCO efficacy and safety of studied treatments vs the comparator in the subgroups of patients with cancer

13 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.

14 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

15 Frequency of VTE Efficacy of NATA in VTE prophylaxis Total studied population Cancer patients 3,50% 3,50% 3,00% 3,00% 2,50% 2,50% 2,00% 2,00% 1,50% 1,50% 1,00% 1,00% 0,50% 0,50% 0,00% MANGELLAN ADOPT SAVEONCO 0,00% MANGELLAN ADOPT SAVEONCO NATA comparator

16 Frequency of bleeding Safety* of NATA in VTE prophylaxis Total studied population Cancer patients 4,00% 0,04 3,00% 0,03 2,00% 0,02 1,00% 0,01 0,00% MANGELLAN ADOPT SAVEONCO 0 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

17 Randomized Controlled Trials with NATA in VTE treatment

18 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

19 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%

20 Frequency of VTE Efficacy of direct NATA in VTE treatment Total studied population Cancer patients 8,00% 8,00% 7,00% 7,00% 6,00% 6,00% 5,00% 5,00% 4,00% 4,00% 3,00% 3,00% 2,00% 2,00% 1,00% 1,00% 0,00% EINSTEIN-DVT EINSTEIN-DVT extenion EINSTEIN-PE RECOVER 0,00% EINSTEIN-DVT EINSTEIN-DVT extenion EINSTEIN-PE RECOVER NATA comparator

21 Frequency of bleeding Safety* of direct NATA in VTE treatment Total studied population Cancer patients 12,00% 10,00% 8,00% 6,00% 4,00% 2,00% 12,00% 10,00% 8,00% 6,00% 4,00% 2,00% 0,00% EINSTEIN-DVT EINSTEIN-DVT extenion EINSTEIN-PE RECOVER 0,00% EINSTEIN-DVT EINSTEIN-DVT extenion EINSTEIN-PE RECOVER NATA comparator *Major and clinically relevant bleeding

22 RCT with antithrombin-dependent NATA in VTE treatment

23 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%)

24 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%

25 Frequency of VTE Efficacy of AT-dependent NATA in VTE treatment Total studied population Cancer patients 20,00% 18,00% 20,00% 18,00% 16,00% 16,00% 14,00% 14,00% 12,00% 12,00% 10,00% 10,00% 8,00% 6,00% 4,00% 2,00% 0,00% MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh 8,00% 6,00% 4,00% 2,00% 0,00% MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh NATA comparator

26 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

27 Frequency of bleeding Safety* of AT-dependent NATA in VTE treatment Total studied population Cancer patients 20,00% 20,00% 18,00% 18,00% 16,00% 16,00% 14,00% 14,00% 12,00% 12,00% 10,00% 10,00% 8,00% 8,00% 6,00% 6,00% 4,00% 4,00% 2,00% 2,00% 0,00% MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh 0,00% MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh NATA comparator *Major and clinically relevant bleeding

28 Rivaroxaban Apixaban Dabigatran Main drug interactions and contraindications of the NATA drug interactions Inhibitors of CYP3A4 : imatinib -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) of P-glycoprotein Cyclosporine, lapatinib, nilotinib, sunitinib, tamoxifen rifampycine amiodaron, quinidin, clarithromicine, verapamil, macrolides (clarithromycine), phenytoine, phenobarbital, St. John s wort Inducers of CYP3A4 dexamethasone of P-glycoprotein dexamethasone, doxorubicin, vinblastin 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

29 Conclusions: NATA in VTE prophylaxis 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 efficacy and safety profile of the specific direct FXa inhibitors in VTE prophylaxis in patients with cancer does not seem to be optimal Semuloparin is the only NATA studied in specific cancer population of patients and shows promising efficacy and safety profile when compared versus placebo

30 Conclusions: NATA in VTE treatment The NATA are Simple and Specific drugs for Selected and risk stratified patients with VTE Rivaroxaban brings a different concept in the management of VTE as compared to that of dabigatran. 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.

31 Conclusions: NATA in cancer patients 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.