Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
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……