Actualités AOD et Cancer

Dr H Desmurs Clavel

Service de médecine interne – médecine vasculaire

Hopital E Herriot Hospices Civils de Lyon France

LIENS D’ INTERET

Participation à des boards et oratrice :

ASPEN, BAYER, BMS-PFIZER, LEO PHARMA, MERCK

ETAT DES LIEUX

Risque MTEV chez le patient avec cancer Particularités du patient avec cancer

MTEV ET CANCER

• Incidence ETE : 1 patient sur 200 patients avec cancer (1)

• Risque X 7 de MTEV et X 3 d’ EP fatale

• 10 % de patients avec cancer décèdent d’ ETE (2)

• 1ere cause de décès chez le patient ambulatoire sous chimiothérapie (3)

20,7% de récidive sous traitement anticoagulant

dans les 12 mois suivant le 1er ETE

1 Lee AY et al Circulation 2003 ; 107 : 117-21 2 Khorana AA et al JTH 2007 ; 5 : 632-634 3 Kucher N et al, Ann Oncol 2010, 21 : 931-935

MTEV : marqueur et facteur de mauvais pronostic

chez le patient cancereux

Risque de MTEV varie avec l’histoire naturelle du cancer

8

Chemotherapy

Risk of VTE in the cancer population

Remission

Risk of VTE in the general population

Time

Diagnosis

End of life Hospitalization

Ris

k (o

dd

s ra

tio

) Metastasis

Adapted from Lyman GH, Cancer 2010;7:1334–1349

7

6

5

4

3

2

1

0

MTEV : tous les cancers concernés, survenue précoce de l’ événement thrombotiques

Pancréas Poumon Estomac

Moins de 100 jours

Particularités du patient avec cancer : risque de récidive et risque hémorragique

Particularités du patient avec cancer : atteinte rénale

MOINS DE 40 % DES PATIENTS

ONT UNE FONCTION RENALE NORMALE

Patient avec cancer : polymédicamenté donc à risque d’interactions

5 à 9 MEDICAMENTS

PAR PATIENT

COMPLEMENTS ALICAMENT

TRAITEMENT CURATIF D’UN EVENEMENT THROMBOTIQUE CHEZ

UN PATIENT AVEC UN CANCER

ETUDE CLOT Lee AY et al NEJM 2003

REDUCTION DU RR DE 50 % PAS DE SURRISQUE HM

PAS DE MODIFICATION

DE LA SURVIE

META ANALYSE 2009

LMWH in Cancer Associated Thrombosis Treatment:

Efficacy and Safety Observed in the CLOT and CATCH Trial

LMWH monotherapy LMWH overlapping

with VKA

HR (95% CI)

n/N (%) n/N (%)

Recurrent VTE

CLOT study*1 27/336 8.0 53/336 15.8

CATCH study#2 31/449 6.9 45/451 10.0

Meta-analysis‡3 42/591 7.1 82/571 14.4

Major bleeding

CLOT study*1 19/338 5.6 12/335 3.6 Not reported

CATCH study#2 12/449 2.9 11/451 2.4

Meta-analysis§3 37/556 6.7 32/536 6.0

*Dalteparin versus VKA; in the VKA arm the estimated time in therapeutic range was 46% (30% below and 24% above); #tinzaparin versus warfarin; in the warfarin arm the time in

therapeutic range was 47% (26% below and 27% above); ‡meta-analysis included four other small studies in addition to the CLOT study; §meta-analysis included three other small

studies in addition to the CLOT study

1. Lee AYY et al, New Engl J Med 2003;349:146–153; 2. Lee AYY et al, JAMA 2015;314:677–686; 3. Akl EA et al, Cochrane Database Rev 2014;7:CD006650

0,1 1 10

Favours LMWH Favours VKA

Not reported

HBPM : TRAITEMENT DE REFERENCE

ACCP 2016 Guidelines: traitement de la phase aigue et durée de traitement

ACCP recommendation Grade of recommendation

Initial anticoagulation

Acute DVT or haemodynamically stable PE and no cancer

NOAC preferred to LMWH/VKA 2B

LMWH/VKA preferred to LMWH alone 2C

PE with hypotension Thrombolytic therapy (systemic rather than catheter-directed unless bleeding risk is high)

2B (2C)

DVT or PE with cancer LMWH suggested over NOAC or VKA 2C

Duration of anticoagulant therapy

Proximal DVT or PE 3 months recommended over shorter duration 1B

First proximal DVT or PE provoked by surgery or other transient risk factor

3 months 1B (2B if low/moderate

bleeding risk; 1B if high)

Unprovoked DVT or PE Extended therapy if bleeding risk is low/moderate 2B

3 months if bleeding risk is high 1B

DVT or PE associated with active cancer Extended therapy recommended over 3 months’ therapy 1B (2B if high bleeding risk)

Kearon C et al, Chest 2016;149:315–352

NOUVELLES ETUDES avec impact éventuel *

• HOKUSAI CANCER 2018 Raskob et al NEJM 2108

• SELECT D 2019 Young et al J Clin Oncol 2019

• CARAVAGIO en cours

• APICAT en cours

5 NOUVELLES RECOMMANDATIONS

2018 SCC/ISTH ; ASH 2019 ESC/ERS ; ASCO . Recos francaises multi sociétés

Khorana et al JTH 2018; Witt et al Blood avances 2018

Konstantidines et al Eur Heart J 2019; Key et al J Clin Oncl 2019 Sanchez et al Rev Mal Resp 2019

*Etudes de sous groupes de patients a posterio dans les etudes pivotales Ne sont pas recevables scientifiquement

HOKUSAI CANCER ETUDE OUVERTE NON INFERIORITE

ÉTÉ SYMPTOMATIQUE ET ASYMTOMATIQUE

Ins renale 7% Thrombopénie 7 %

HOKUSAI CANCER STUDY

Pas de difference Moins de thrombose Plus de saignement

*For patients with CrCl 30–49 ml/min dosing recommendations as in rivaroxaban SmPC; #The second randomization phase for extended treatment of VTE from 6 to 12 months for

patients with PE as an index event or patients with Residual DVT at 5 month assessment was closed due to low recruitment. Sample size reduced from 530 to 400 patients for

main trial comparison (95% CI for VTE recurrence +/-4.5%)

Young A et al, Thromb Res 2016;140:S172–S173; EudraCT number: 2012-005589-37; Bach M et al, Thromb Haemost 2016;116:S24–S32; Data on File

Study design: Prospective, randomized, open-label, multicentre pilot phase III study

Rivaroxaban* 15 mg BID for 21 days followed by 20 mg OD

Study population: Active cancer with symptomatic DVT

and/or any PE ECOG PS ≤ 2

Dalteparin 200 IU/kg OD for the first 30 days followed by 150 IU/kg OD

R

6 months#

N 530

Open-label

select-d: Phase III Pilot Study Comparing Rivaroxaban versus

Dalteparin for the Treatment of Cancer Associated Thrombosis

Stratification variables: • Stage of disease • Baseline platelet count • Type of VTE • Risk of clotting by tumour type

Rivaroxaban

(n=203)

Dalteparin

(n=203)

Age, years, median

(range)

67 (22–87) 67 (34–87)

Gender male, % 54 48

Metastatic cancer, % 59 59

ECOG performance

status, %

0 or 1

2

72

26

76

21

Qualifying VTE, %

Symptomatic VTE

Incidental PE

46

54

48

52

Tumour type, % Rivaroxaban

(n=203)

Dalteparin

(n=203)

Colorectal 27 23

Lung 11 12

Breast 9 10

Ovarian 5 9

Pancreatic 9 5

Lymphoma 5 6

Oesophageal/

gastro-oesophageal 5 9

Prostate 6 3

Bladder 5 2

Other 18 21

select-d: Patients Baseline Characteristics

Baseline characteristics Primary tumour type

Young A et al, ASH 2017: Abstract 625; Available at: http://www.clinicaltrialresults.org/

Young A et al, ASH 2017: Abstract 625; Available at: http://www.clinicaltrialresults.org/

select-d Primary Outcome: Lower Incidence of VTE

Recurrence Events with Rivaroxaban Versus Dalteparin

Dalteparin

Rivaroxaban

Number at risk

Dalteparin 203 171 139 115

Rivaroxaban 203 174 149 134

40

35

30

25

20

15

10

5

0

0 1 2 3 4 5 6

Time from trial entry (months)

VT

E r

ecu

rre

nce (

%)

Outcome at 6 months Rivaroxaban

(n=203)

Dalteparin

(n=203)

VTE recurrence,

% (95% CI) 4 (2–9) 11 (7–16)

Lower limb DVT/PE

recurrence,

% (95% CI)

3 (1-7) 9 (6-15)

select-d Secondary Outcome: Incidence of Major, Fatal and

Clinically Relevant Non-Major Bleedings

2,9

0,5

2,9

5,4

0,5

12,3

0

5

10

15

20

Major bleeding Fatal Bleeding CRNMB

Pa

tie

nts

(%

)

Dalteparin Rivaroxaban

* All bleedings events were adjudicated .Overall survival at 6 months was 70%(63-76%) in the rivaroxaban group and 75%(69-81%) in the dalteparin group.

Young A et al, ASH 2017: Abstract 625; Available at: http://www.clinicaltrialresults.org/

Most Major Bleedings events were Gastrointestinal Bleedings*. No Central Nervous System

Bleeding was observed in rivaroxaban and dalteparin groups.

Select D study

Moins de thrombose Plus de saignement

LES RECOMMANDATIONS DES SOCIETES SAVANTES

2018 SCC/ISTH ; ASH 2019 ESC/ERS ; ASCO . Recos francaises multi sociétés

ISTH Guidelines

Clinical Discussion: What CAT Patient Would Benefit Most From NOACs?

Anticoagulant therapy* Suggested use

Specific NOACs (edoxaban or rivaroxaban)†

First option in cancer patients with acute VTE with low risk of bleeding and no drug–drug interactions with current systemic therapy

LMWH

In cancer patients with acute VTE with high risk of bleeding, including:‡

Patients with luminal GI cancers with an intact primary

Patients with cancers at risk of bleeding from the genitourinary tract, bladder or nephrostomy tubes

Patients with active GI mucosal abnormalities (such as duodenal ulcers, gastritis, esophagitis or colitis)

*Shared decision making with patient regarding potential reduced recurrence but greater bleeding rates with NOACs, incorporating patient preferences and values; †Only edoxaban and rivaroxaban have been compared with LMWH in RCTs in cancer patients; ‡Specific NOACs are an acceptable alternative if no drug–drug interactions exist with current systemic therapy.

Khorana AA et al. J Thromb Haemost 2018;16:1891–1894.

AOD 1ere choix si faible risque hm et pas d’interaction

REPONSES A 23 QUESTIONS PRATIQUES 4 CONCERNAIENT LES AOD INTERACTIONS MEDICAMENTEUSES GESTION HEMORRAGIQUE ET DOSAGE SANGUIN GESTION INSUFFISANCE RENALE MODEREE ET AOD GESTION INSUFFISANCE RENALE SEVERE ET AOD

Si traitement par des molécules Inhibitrices ou inductrices De la P- gp ou du CYP P 450 AVK ou HBPM plutôt que AOD Tres peu de preuve……

HBPM EDOXABAN /RIVAROXABAN

Plutôt que AVK

Attention pour les AOD Tumeurs gastro intestinales

Tumeurs génito urinaires Interaction médicamenteuses

34

RECOMMANDATIONS FRANCAISES 2019

Sanchez, Rev Mal Respir 2019

HBPM

Si intolérance aux HBPM AOD plutôt que AVK

Sauf si risque hémorragique élevé Tumeur intestinale ou urologique

RECOMMANDATIONS FRANCAISES 2019

Sanchez, Rev Mal Respir 2019

Après 6 mois, si maintien d’un traitement Poursuivre HBPM si possible

( surtout si poursuite traitement anticancéreux) Sinon AOD ou AVK

SYNTHESE

SOCIETES Traitement initial LONG TERME Niveau de preuve

ISTH EDOXABAN/RIVAXOBAN* HBPM

suggestion

ESC HBPM, Edoxaban rivaroxaban

Traitement qui peut etre consideré

ASCO HBPM fondaparinux, rivaroxaban HNF

HBPM, rivaroxaban, edoxaban (AVK)

Recos francaises multicsocietes

Hbpm AOD

HBPM AOD AVK

TOUS METTENT UNE RESTRICTION SUR LES CANCERS GASTRO INTESTINAUX LES PATIENTS A HAUT RISQUE HEMORRAGIQUE ET LES INTERACTIONS

MEDICAMENTEUSES POTENTIELLES

AOD : OUI MAIS……

Patients à risque hémorragique quelque soit l’anticoagulant utilisé

• Insuffisant rénale sévère ( clairance inf à 30 ml/min Cockroft)

• Cancer avec Métastases

• Tumeur gastrointestinale

• Thrombopénie inférieur à 100 G/L

Traitement prophylactique

Recommandations pour la Thromboprophylaxie chez les

Patients cancéreux ambulatoires

Guideline Recommendations

ASCO 2013, 20151,2 Thromboprophylaxis is not routinely recommended

LMWH may be considered in highly selected outpatients with solid tumours receiving chemotherapy

Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone

should receive prophylaxis with either low-dose ASA or LMWH (for lower-risk patents) or LMWH (for higher-risk patients)

The Khorana score recommended to assess VTE risk

ITAC-CME 20163 Thromboprophylaxis is not routinely recommended

LMWH may be used in patients with locally advanced or metastatic pancreatic or lung cancer treated with systemic anticancer

therapy and who have a low bleeding risk

VKA, LMWH or low-dose ASA therapy in patients treated with thalidomide and lenalidomide combined with steroids and/or other

systemic anticancer therapies

NCCN 20184 VTE prophylaxis not recommended outside of clinical trial settings

For patients with myeloma, ASA (low-risk patients) and LMWH or warfarin (high-risk patients) in patients receiving

thalidomide, lenalidomide or pomalidomide

The Khorana score recommended to assess VTE risk

La Thromboprophylaxie n’est pas recommandée en systématique

1. Lyman GH et al, J Clin Oncol 2013;31:2189–2204; 2. Lyman GH et al, J Clin Oncol 2015; 33: 654–656;

3. Farge D et al, Lancet Oncol 2016;17:e452–e466;

4. National Comprehensive Cancer Network, Inc. 2018. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf [accessed Nov 2018]

Patients ambulatoire avec cancer sous thromboprophylaxie parenterale. Mortalité à 1 an

Pas de modification

HOSPITALISATION CANCER DU PANCREAS CANCER DU POUMON

HBPM

IMIBS + steroides HBPM

ou aspirine Ou AVK faible dose

CASSINI : Rivaroxaban10 mg vs pcb en Prophylaxie chez

les patients à haut risqué thrombotique ( Khorana > ou =2)

30-day

follow-up

Rivaroxaban 10 mg od

Placebo

180 days

N=841 Population:

Ambulatory patients with various cancer

types initiating systemic cancer therapy and at

high risk of VTE*1

R

Day 180

Primary efficacy: composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death2,3 Primary safety: Time to a major bleeding event (ISTH)2,3

Short design:2

• Randomized, double-blind, placebo-controlled, parallel-group, multicentre

2-week screening

period

Bilateral, lower-extremity, venous duplex CUS performed at screening visit, week 8, week 16 and day 180

*As indicated by a Khorana risk score ≥2

1. Khorana AA et al, Blood 2008;111:4902–4907; 2. Khorana AA et al, Thromb Haemost 2017;117:2135–2145;

3. Khorana AA et al, ASH 2018. https://ash.confex.com/ash/2018/webprogram/start.html [accessed Nov 2018]

Day 210

CUS CUS CUS CUS

Caractériques de la population

Rivaroxaban

(n=420)

Placebo

(n=421)

Age, years

Median

Range

63

23–87

62

28–88

Male 222 (52.9) 206 (48.9)

Khorana score

2

3

4

281 (66.9)

106 (25.2)

26 (6.2)

295 (70.1)

96 (22.8)

25 (5.9)

Prior VTE

DVT

PE

11 (2.6)

2 (0.5)

2 (0.5)

0 (0)

Primary tumor site, n(%) Rivaroxaban

(n=420)

Placebo

(n=421)

Pancreatic 136 (32.4) 138 (32.8)

Breast 9 (2.1) 9 (2.1)

Gastric/gastro-

oesophageal junction 89 (21.2) 87 (20.7)

Genitourinary 15 (3.6) 17 (4.0)

Lung 62 (14.8) 72 (17.1)

Lymphoma 33 (7.9) 26 (6.2)

Ovarian 24 (5.7) 30 (7.1)

Other gastrointestinal 16 (3.8) 10 (2.4)

Other gynecological 24 (5.7) 21 (5.0)

Others 12 (2.9) 11 (2.6)

RESULTATS : Rivaroxaban réduit les ETE symptomatiques

et asymtomatiques sur la période de prise de traitement

Study Period On-Treatment Period

*Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients). The primary analysis considered the study period (up-to-day 180

observation period) and the supportive analysis the on-treatment period. #Considering the primary efficacy outcome was not significantly reduced, all subsequent efficacy

analyses are exploratory.

Khorana AA et al, NEJM 2019

38.7% VTE events

in subjects who had

discontinued drug

Arret de traitement

chez 43 % des patients

dans les deux bras

Phase II randomized, double-blind study1,2

Primary Study Outcome: lower extremity symptomatic or incidental DVT, upper limbs symptomatic or incidental DVT,

non-fatal symptomatic or incidental PE, and VTE-related deaths (fatal PE or unexplained death)

Secondary Safety Outcomes: Major Bleeding, CRNMB, Overall Survival

Apixaban vs pcb en prophylaxie chez les patients cancéreux

ambulatoire (AVERT)

1. Ottawa Hospital Research Institute. https://clinicaltrials.gov/ct2/show/NCT02048865. 2. Kimpton M, et al. Thromb Res. 2018 Apr;164 Suppl 1:S124-S129

N=563

Placebo

End of study

period: 7 months

R

Apixaban 2.5 mg bid

Estimated

Newly diagnosed cancer site or progression after complete or

partial remission

Initiating new course of chemotherapy for a minimum of

3 months

VTE risk stratification score of ≥2

1:1

Apixaban : prévention de la MTEV chez le patient cancéreux

(AVERT Study) versus placebo

4,2 3,5

12,2

10,2

1,8

9,8

0

2

4

6

8

10

12

14

VTE Major Bleeding Death

Apixaban (n=288) Placebo (n=275)

1

2,1

7,3

1,1

0

2

4

6

8

10

12

14

VTE Major Bleeding

Apixaban (n=288) Placebo (n=275)

Study Period (mITT)# On-treatment*

p<0.001 p=0.046 HR 1.29

(0.98-1.71)

HR 0.14

(0.05-0.42)

HR 1.89

(0.39-9.24)

#mITT: modified intention-to-treat population, which included all the patients who had undergone randomization and received at least one dose of apixaban or placebo on or

before day 180 (±3 days). *On-treatment: while the patient took the active drug or placebo plus 2 days after their last dose.

Carrier M, et al. NEJM, 2018.

Primary Analysis

Résultats

CASSINI placebo rivaroxaban HR p

Efficacité primaire J180

8.8 % 6.0 % 0.66 [0.4 6 1.09]

Efficacité primaire période de TT

6.4 % 2.6 % 0.4 [0.2 – 0.8]

Saignements 1 % 2 % 1.96 [0.59 – 6.49] 0.26

Khorana et al NEJM 2019

ADVERT PLACEBO apixaban HR p

ÉTÉ J180 10.2 % 4.3 % P< 0.01

HM J 180 1.8 % 3.5 % P = 0.046

ÉTÉ sous TT 7.3 % 1 0.14 [0.05 – 0.42]

Hm sous TT 1] % 2.1 % 1.89 [0.39 – 9.21]

Carrier et al NEJM 2018

• Suggestion d’utilisation des AOD en prophylaxie primaire chez les patients à haut risque thrombotique, avec un risque hémorragique faible et en dehors des cancers gastro intestinaux

• Si haut risque thrombotique et tumeur intestinale : HBPM

Mais comment vraiment identifier les patients à haut risque ????

Comparaison des scores

En pratique

La thromboprophylaxie est suggérée …..

mais elle ne modifie pas la survie des patients.

La réduction relative du risque est de 50 à 60 % ….

mais seulement de 2 % en risque absolue.

Utilisation dans le cancer du pancréas ???

Le risque hémorragique augmente relativement de 50 à 100 %

mais cela correspond à une augmentation du risque absolue …

de 0.5 à 1 %

PAS DE CONCLUSION HATIVE ET DE CHANGEMENT DE PRATIQUE immédiat Nouvelles études nécessaires . Score performant

les AOD dans le cancer : conclusion

• Alternative possible à discuter chez certains patients en curatif

• Nécessité de mieux connaitre • les interactions médicamenteuses, • La gestion du risque hémorragique ( thrombopénie…)

• Pas de précipitation en préventif…

• Nécessité d’identifier le sous groupe à haut risque

PAS DE MODIFICATION DE LA SURVIE……