new antithrombotic agents in the treatment of vte; a ... · new antithrombotic agents in the...
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New antithrombotic agents in the
treatment of VTE; a subgroup
analysis of the Phase III
randomized clinical trials.
Interactions cellulaires tumorales et
leur environnement et réponses
aux agents anticancéreux.
Grigoris T Gerotziafas, Michel M Samama, Ismail
Elalamy
Disclosures for G. T. Gerotziafas
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)]
In compliance with CME policies, 6th ICTHIC requires the following disclosures, related to the speaker’s presentation, to the session audience :
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: 761-768
Blom et al, JAMA. 2005;293:715-22
Cronin et al, Am J Roentgenol. 2007;189:162-70
Cancer and VTE
a reciprocal interaction
decrease morbidity
improve the quality of life
contribute to the decrease of mortality
Cancer and VTE
Aims of the antithrombotic treatment
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.
LMWH treated patients VKA treated patients
Recurrent VTE rates of 9-17% occur despite the
use of therapeutic anticoagulation
9% 20%
Lee AY. Hematology Am Soc Hematol Educ Program;2010:144-9 (2010).
Prandoni P et al Ann Intern Med;137:955-60 (2002).
Kearon C Circulation;107(23 Suppl 1):I22-30 (2003)
Failure of VTE treatment in cancer patients
Recurrent VTE
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
Challenges of VTE treatment in cancer
patients
20th century
Discovery by serendipity of
heparin in Baltimore and anti-
vitamin K in Wisconsin
21st century Programmed and designed new antithrombotics aiming at specific targets
1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
1914 Discovery of Heparin
1980 : LMWHs
1966 : s.c. administration of UFH
1924 -1930 Clinical studies with UFH
1950 : Clinical use of vitamin K antagonists
1940 Discovery of dicoumarol
2002 Fondaparinux 1983 synthesis of pentasaccharide
2003 specific anti-IIa
2004 : Orally active FXa inhibitors
History of antithrombotic agents
HCII-dependent inhibitors
Factor Xa
Direct inhibitors:
Rivaroxaban, apixaban,
edoxaban …
AT-dependent inhibitors:
Pentasaccharide,
heparins, ULMWHs
(semuloparin)
Direct inhibitors:
Dabigatran, lepirudin,
bivalirudin…
AT-dependent inhibitors:
Heparins, danaparoid,
ULMWHs (semuloparin)
Thrombin
Parenteral Oral Gerotziafas GT, Samama MM. Current
Pharmaceutical Design, 2005,
Simple classification of
anticoagulants
Origin and mode of preparation Synthetic or hemi-synthetic
Specific target Specific inhibition of single clotting factor resulting in inhibition of thrombin generation
Mechanism of action Indirect inhibition: antithrombin dependent Direct inhibition : high affinity and specificity for the active center of the target serine protease
Potential antigenicity No
Administration route Oral, intravenous, subcutaneous
Pharmacokinetic characteristics Rapid onset and offset of the anticoagulant activity after treatment initiation and discontinuation
Effect on blood coagulation tests (i.e. thrombin generation test, prothrombin time, aPTTT etc)
Potential development of assays for laboratory monitoring and dose adjustment, if needed in some patient groups.
Efficacy and safety of for the treatment of venous and arterial thrombosis
Improvement of the management of thrombosis at the acute phase and during the long term treatment
Main characteristics of the New
Antithrombotic Agents
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) 24 – 36 hours
30% renal
50% intestinal.
Dabigatran 2 h within 30 min after 3
days
9 - 13 hours
after a single
dose
12–17 h after
multiple doses
12 hours
80% renal (40% in
active form and 40%
in form of
metabolites)
20% biliary
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.
Aim of the study
Methodology
Research in www.clinicaltrials.gov 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
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.
Efficacy and safety of NATA in VTE prophylaxis
RCT Total studied population Patients with cancer
MAGELLAN Rivaroxaban = 3977 Enox/placebo = 4001
rivaroxaban = 7% enox/placebo = 7%
ADOPT Apixaban = 2211 Enoxaparin = 2211
History of cancer apixaban = 9.6% enoxaparin = 9.8% Active cancer apixaban = 3.5% enoxaparin = 3 % Remote cancer apixaban = 6.1% enxaparin = 6.8%
SAVEONCO Semuloparin = 1608 Placebo = 1604
patients with metastatic (70%) or locally advanced cancer of lung (37%), colon-rectum (29%), stomach, ovary, pancreas, or bladder
Efficacy of NATA in VTE prophylaxis
0,00%
0,50%
1,00%
1,50%
2,00%
2,50%
3,00%
3,50%
MANGELLAN ADOPT SAVEONCO
0,00%
0,50%
1,00%
1,50%
2,00%
2,50%
3,00%
3,50%
MANGELLAN ADOPT SAVEONCO
NATA
comparator
Total studied population Cancer patients
Fre
quency o
f V
TE
Safety* of NATA in VTE prophylaxis
0,00%
1,00%
2,00%
3,00%
4,00%
MANGELLAN ADOPT SAVEONCO 0
0,01
0,02
0,03
0,04
MANGELLAN ADOPT SAVEONCO
NATA
comparator
Descriptive values for the incidence
of clinically relevant bleeding
consistently favored enoxaparin over
rivaroxaban in patients with active
cancer *Major and clinically relevant bleeding
Total studied population Cancer patients
Fre
quency o
f ble
edin
g
Randomized Controlled Trials
with NATA in VTE treatment
RCT Studied populations Experimental design
EINSTEIN Acute DVT
treatment of sympromatic DVT for 3, 6 or 12 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 for 6 months
EINSTEIN DVT extension
Duration more 6 months after completing the first phase of treatment.
Rivaroxaban 20 mg o.c versus placebo
EINSTEIN-PE treatment of sympromatic PE for 3, 6 or 12 month
Rivaroxaban 15 mg b.i.d x 3 weeks and then 20 mg o.d versus Enoxaparin 1 mg/kg bid s.c./VKA
RECOVER Treatment of sympromatic acute proxymal DVT orPE who were initially given parenteral anticoagulant therapy Duration of treatment 6 months
Dabigatran 150 mg b.i.d versus dose adjusted warfarin INR 2-3
Cancer patients
in the RCT with direct NATA in VTE treatment
RCT Total studied population Patients with cancer
EINSTEIN Acute DVT Rivaroxaban = 1731 Enox/VKA= 1718
Rivaroxaban = 6.8% Enox/VKA = 5.2%
EINSTEIN DVT extension
Rivaroxaban= 602 placebo= 594
Rivaroxaban = 4.5% Placebo = 4.4%
EINSTEIN-PE Rivaroxaban= 2419 Enox/VKA= 2413
Rivaroxaban = 4.7% Enox/VKA= 4.5%
RECOVER Dabigatran = 1274 VKA = 1265
Dabigatran = 5% VKA = 4.5%
Efficacy of direct NATA in VTE treatment
Total studied population Cancer patients
0,00%
1,00%
2,00%
3,00%
4,00%
5,00%
6,00%
7,00%
8,00%
EINSTEIN-DVT EINSTEIN-DVT extenion
EINSTEIN-PE RECOVER 0,00%
1,00%
2,00%
3,00%
4,00%
5,00%
6,00%
7,00%
8,00%
EINSTEIN-DVT EINSTEIN-DVT extenion
EINSTEIN-PE RECOVER
NATA
comparator
Fre
quency o
f V
TE
Safety* of direct NATA in VTE treatment
NATA
comparator
*Major and clinically relevant bleeding
Total studied population Cancer patients
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
EINSTEIN-DVT EINSTEIN-DVT extenion
EINSTEIN-PE RECOVER
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
EINSTEIN-DVT EINSTEIN-DVT extenion
EINSTEIN-PE RECOVER
Fre
quency o
f ble
edin
g
RCT with antithrombin-dependent NATA in VTE
treatment
RCT Studied populations Experimental design
MATISSE-PE Treatment of sympromatic PE Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus UFH i.v./VKA for 6 months
MATISSE-DVT Treatment of sympromatic acute DVT
Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus Enoxaparin 1 mg/kg bid s.c./VKA
EQUINOX Treatment of sympromatic acute DVT
Idrabiotapariux 3 mg s.c./week Versus Idraparinux 2.5 mg s.c./ week
Van-Gogh Treatment of sympromatic acute
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%)
Cancer patients in RCT of Antithrombin-
dependent NATA in VTE treatment
RCT Total studied population Patients with cancer
MATISSE-PE Fondaparinux = 1103 UFH/VKA= 1110
Fondaparinux = 10% UFH/VKA= 10%
MATISSE-DVT Fondaparinux = 1098 Enoxaparin/VKA= 1107
Fondaparinux = 11% UFH/VKA = 11%
EQUINOX idrabiotaparinux= 386 idraparinux= 371
Idrabiotaparinux = 4.7% Idraparinux = 5.7%
Van-Gogh Idraparinux = 1452 LMWH/VKA = 1452
Idraparinux = 15% LMWH/VKA =14.5%
Efficacy of AT-dependent NATA in VTE
treatment
Total studied population Cancer patients
NATA
comparator
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
14,00%
16,00%
18,00%
20,00%
MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
14,00%
16,00%
18,00%
20,00%
MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh
Fre
quency o
f V
TE
Influence of cancer stage on the efficacy of
fondaparinux
NATA
comparator
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
14,00%
16,00%
18,00%
20,00%
MATISSE-PE advanced cancer
MATISSE-PE cancer
Safety* of AT-dependent NATA in VTE
treatment
NATA
comparator
*Major and clinically relevant bleeding
Total studied population Cancer patients
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
14,00%
16,00%
18,00%
20,00%
MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh
0,00%
2,00%
4,00%
6,00%
8,00%
10,00%
12,00%
14,00%
16,00%
18,00%
20,00%
MATISSE-PE MATISSE-DVT EQUINOX Van-Gogh
Fre
quency o
f ble
edin
g
Main drug interactions and contraindications of
the NATA drug interactions contraindications
Rivaroxaban 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
creatinin clearance < 30 ml/min
or liver impairment ketokonazol co-administration
Apixaban creatinin clearance < 30 ml/min
in liver impairement : Possibly safe as no hepatic metabolism but caution advised
ketokonazol co-administration
Dabigatran Inhibitors of P-glycoprotein
Minor interactions with atorvastatin
Lower dose if creatinin clearance is 15 – 30 ml/min
Contraindication if creatinin clearance < 30 ml/min
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
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.
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.