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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

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Page 1: New antithrombotic agents in the treatment of VTE; a ... · New antithrombotic agents in the treatment of VTE; a subgroup analysis of the Phase III randomized clinical trials. Interactions

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

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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 :

Page 3: New antithrombotic agents in the treatment of VTE; a ... · New antithrombotic agents in the treatment of VTE; a subgroup analysis of the Phase III randomized clinical trials. Interactions

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

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decrease morbidity

improve the quality of life

contribute to the decrease of mortality

Cancer and VTE

Aims of the antithrombotic treatment

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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Randomized Controlled Trials

with NATA in VTE treatment

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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

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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%

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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

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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

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RCT with antithrombin-dependent NATA in VTE

treatment

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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%)

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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%

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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

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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

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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

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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

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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

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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.

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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.