quid novi? en pathologie vasculaire dominique farge, service de médecine interne et pathologie...
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QUID NOVI? EN PATHOLOGIE VASCULAIRE
Dominique FARGE, Service de Médecine Interne et Pathologie Vasculaire,
INSERM U697, Hôpital St Louis, Université P7 Denis Diderot
LA MTEV : POURQUOI CETTE SELECTION? 14 / 725 Articles dans Pub Med en 2008
• Evolution des connaissances MTEV en cancérologie et son impact– PB thérapeutiques quotidiens :↑ accidents hémorragiques graves + récidive– Modification des pratiques sans recommandations nationales (US et Italie)– ↑ prévisible des thromboses sur cathéter: ↑ cancers + KTVC
= > RECOMMANDATIONS FRANCAISES SOR AVRIL 2008 www.sor.fr1. Akl EA Anticoagulation for the long term treatment of VTE in cancer patients.
Cochrane data base Syst Rev 2008 2. Noble SI: Management of VTE in patients with advanced cancer Lancet. oncology
20083. Prandoni P: Risk stratification and VTE in hospitalized medical and cancer
patients. BJH 20084. Palumbo A : Prevention of thalidomide and lenalidomide-associated thrombosis
in myeloma Leukemia 20085. Gerber DE: The incidence and risk factors for VTE and bleeding among 1514
pateinst undergoing HSCT: implications for VTE prevention Blood 20086. Bennett CL VTE and mortality associated with recombinant EPO and darbepoietin
administration for treatment of cancer-associated anemia. JAMA 2008
QUID NOVI en dehors du cancer ?
• Mise en application des recommandations...!1. Cohen TA VTE and prophylaxis in the acute hospital care setting (ENDORSE study): a
mutinational cross-sectionnal study. Lancet 2008
• Modalités diagnostiques ?1. Righini M. Diagnosis of PE by multidetector CT alone or combined with venous US
of the leg: a randomized, open-label, non inferiority trial Lancet 2008
• Progrès thérapeutiques ? Idraparinux1. The Amadeus Investigators. Comparison of Idraparinux with Vitamins K antagonists
in patients with atrila fibrillation. Lancet 2008
• Devenir des patients : TVP Mb Sup /EP 1. Munoz FJ Clinical outcome of patients with upper-extremity DVT: results from the
RIETE registry Chest 20082. Laporte S Clinical predictors for fatal PE in 15 520 patients with VTE Circulation 2008
Thrombose et Cancer Recommandations pour la pratique clinique (RPC)
SOR: Production de documents pour aide décision médicale Promoteur: FNCLCC
Partenaires: INCa, La ligue, CLCC, FHF, FNCHRU, FFCCHG, UNHPCCoordination Scientifique : Pr D. Farge – Dr P. DebourdeauGroupe de travail multi-disciplinaire (25 experts)
Oncologie : F. Cajfinger, H. Hocini, M. PavicMedecine interne: H. Desmurs-Clavel, C. Grange, G. Le Gal, H. Lévesque, I. MahéMédecine Vasculaire : A. Elias, I. Quéré, J-M. RenaudinAnesthesie: E. Desruennes, M-C. Douard, I. KriegelBiologie, Pneumologie I. Elalamy, M-L. Scrobohaci, P. Mismetti, G. Meyer
Parteneriat Scientifique: SFMV, SNFMI
www.sor.fr
Ia Meta-analysis of randomised clinical trials Ib At least 1 randomised controlled trialIIa At least 1 well-designed controlled study without randomisationIIb At least 1 other type of well-designed quasi-experimental studyIII Well-designed descriptive (comparative / correlation / case)
studiesIV Expert committee reports or opinions A Level I studies B Level II studies or extrapolations from level I studies
C Level III studies or extrapolations from level I or II studies
D Level IV studies or extrapolations from level I, II, or III studies
1996- 20073986 références8 RCT
TT Curatif de la MTEV chez cancéreux
Etudes rétrospectives:
Tt classique HNF / HBPM - AVK
=>Récidive MTEV 11 - 34% Hémorragies Majeures 8-36%
Essais randomisés prospectifs:
2 / 4
HBPM 3-6 mois vs tt classique
HBPM pendant 3 à 6 mois vs HBPM - AVK
Risque RECIDIVE METV
Risque Hémorragique
RECOMMENDATIONS pour MTEV chez pts atteints de CANCER (stade avancé)
1 Long-term full-dose LMWH: the drug of choice in the secondary prophylaxis of VTE in patients with cancer of any stage, performance status, or prognosis (grade A, level Ib)
2 For at least 6 mths after a 1st episode of VTE. Because of ongoing prothrombotic tendency in pts with incurable cancer, indefinite anticoagulation should be considered (grade B, level Ib)
3 Warfarin not recommended for pts with extensive / metastatic disease or poor performance status or prognosis (grade B, level Ib)
4 For pts at high risk of bleeding: full-dose LMWH for 7 days + long-term decreased fixed dose (dalteparin 10 000 IU daily) should be considered (grade B, level IIb)
5 For pts with contraindications to anticoagulation, an inferior-vena-caval filter should be considered (grade C, level III)
Noble Lancet Oncology 2008
EFFET DES HBPM AU LONG COURS SUR LA SURVIE DES PATIENTS ATTEINTS DE CANCER ? NS..mais
Risk stratification and VTE thromboprophylaxisin hospitalized medical and cancer pts Prandoni P BJH 141; 587
Genetic Acquired MixedAT deficiency
Protein C deficiency
Protein S deficiency
F5 Leiden
F2 G20210A
Dysfibrinogenaemia
Plasminogen deficiency?
Old age
Immobilization
Surgery
Cancer
Pregnancy/post-partum
Oral contraception
Hormonal therapy
APL syndrome
Myeloproliferative disorders
Paroxysmal nocturnal Hbnuria
↑ homocysteinaemia
↑ level of:
Factor VIII
Fibrinogen
Factor XI
Factor IX
Une meilleure connaissance des Facteurs de Risque en milieu médical….?
1.6- 1.8 / 1000 habitants/an, très bas < 40-60 ans, ↑1% > 75 ans
HOSPITALISATION EN MILIEU MEDICAL( = ¼ MTEV): RR x 8
RISK STRATIFICATIONOR of independent VTE
risk factors in medical pts95% CI
Old age 1·17 1·11–1·24
Hosp/nursing home 8·0 4·5–14·2
Increased BMI 1·24 1·04–1·5
Cancer
+ chemotherapy 4·24 2·6–6·9
- chemotherapy 2·2 1·6–3·06
Neurologic disease + extremity paresis
3·3 1·3–7·4
Trauma 12·7 4·1–39·7
Varicose veins
At 45 yrs 4·2 1·6–11·3
At 60 yrs 1·9 1·0–3·6
Superficial VTE 4·3 1·8–10·6OR > 10 risque ELEVE, 0R, 2-9: risque MODERE, OR < 2 risque FAIBLEPooled data from Heit et al (2000 and 2006) Prandoni P BJH 141; 587
Risk stratification and VTE thromboprophylaxisin hospitalized medical and cancer pts Prandoni P BJH 141; 587
↑ connaissance des FDR + nbreux algorythmes proposés : aucun validé
Score d’ alerte électronique (Kucher NEJM 2005):
↓ Risque TVP et EP à 90 jours Feature Score
Cancer 3
Previous VTE 3
Hypercoagulability 3
Recent major surgery 2
Advanced age 1
Obesity 1
Bed rest 1
Hormonal treatment 1
Risk of VTE and need for thromboprophylaxis: score ≥ 4.
Prandoni P BJH 141; 587
Main results from MEDENOX, PREVENT and ARTEMIS studies at the end of treatment.PROPHYLAXIE MILIEU MEDICAL
TT actif (%) Placebo (%) P-value
MTEV globale (↓50%) MEDENOX (1102) 5·5 14·9 <0·001
PREVENT (3706) 2·8 5·0 0·0015
ARTEMIS (849) 5·6 10·5 0·029
MTEV Symptomatique MEDENOX 0·3 1·7 NS
PREVENT 0·7 1·1 NS
ARTEMIS 0·0 1·2 0·029
Saignement Majeur MEDENOX 1·7 1·1 NS
PREVENT 0·5 0·2 NS
ARTEMIS 0·2 0·2 NS
MEDENOX, MEDical patients with ENOXaparin (40mg); PREVENT, Preventionof Recurrent VTE with Dalteparine (5000UI); ARTEMIS, ARixtra (Fondaparinux,
2.5 mg) for VTE prevention in a Medical Indications Study.
Prandoni P BJH 141; 587
Score prédictif survenue MTEV chez pt cancereux sous chimiothérapie (Khorana Blood 2008)
Patient characteristicRisk score
Site of cancer: stomach, pancreas 2
Site of cancer: lung, lymphoma, gynaecologic, bladder, testicular
1
Platelet count ≥350 × 109/l 1
Haemoglobin <100 g/l or use of erythropoietin 1
Leucocyte count >11 × 109/l 1
Body mass index ≥35 1
0 risque MTEV faible1-2 risque MTEV intermédiaire3 risque MTEV élevé
VTE incidence in trials of thalidomide or lenalidomide without thromboprophylaxis Palumbo Leukemia 2008; 22:414
Treatment regimen Newly diagnosed pts Relapsed/refractory pts
VTE incidence (%) VTE incidence (%)
Thalidomide
Alone 3–4a 2–4
+ dexamethasone 14–26 2–8
+ melphalan 10–20 11
+ doxorubicin 10–27 58b
+ cyclophosphamide 3b–11 4–8
+ multiagent chemotherapies
16–34 15
Lenalidomide
Alone — 0–33
+ dexamethasone 8–75 8–16
+ cyclophosphamide — 14
+ bortezomib — 0
All newly diagnosed => prophylaxis recommended In relapsed pts? those at high risk should receive prophylaxis
VTE incidence in trials of thalidomide or lenalidomide with thromboprophylaxis in newly diagnosed pts
Palumbo Leukemia 2008; 22:414
Treatment regimen VTE incidence (%)
LMWH Low-fixed-dose
warfarin Full-dose
warfarin Aspirin
Thalidomide
Plus dexamethasone — 13–25 8 —
Plus melphalan 3 — — —
Plus doxorubicin 9 14 — 18
Plus multiagent chemotherapies
15–24 31 —
Lenalidomide
Alone — — — —
Plus dexamethasone — — — 3–14
Plus melphalan — — — 5
Plus doxorubicin — — — 9
◙ 0 prophylaxis at induction
Risk assessmentfor managementof VTE in multiple Myeloma treated with thalidomideor lenalidomideLeukemia 2008;22:414
1
2
3
4
5
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Bennett, C. L. JAMA 2008;299:914-924.
Meta-analysis Overall Mortality Rates
for phase 3 trials with ESAs vs placebo / C,
comparing anemia of cancer
andTt-Related Anemia Trials
ESA associated mortalityP = 0.03
HR 1.29
HR 1.09
HR 1.10
◙
◙
◙
◙
By day 180: VTE 4.6% (95% CI: 3.6-5.8)Significant bleeding:15.2% (95% CI: 13.4-17.5)
Lancet 2008; 371:387
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Application RECO: 58.5 % en chirurgie et 39.5% en médecine
Lancet 2008; 371; 1342
Score prédictif de Genève révisé
Sensibilité globale MSCT 83% (PIOPED II) Valeur Prédictive N 95% si faible proba clinValeur Prédictive N 89% si proba clin interméd
PIOPED II valeur ajoutée phlébographie + CT?VPN 97% vs 95%.....
STRATEGIE D-DIMERES ELISA + MSCT = D-DIMERES ELISA + US + MSCT (Intention treat) => US utile si MSCT contreindiquée Righini Lancet 2008
Comparison of IDRAPARINUX with VKA for prevention of VTE in pts with atrial fibrilllation: a randomized, open-label, non-inferioritytrialThe AMADEUS investigatorsLancet 2008
4576 pts en AC/FA : - Idraparinux 2.5 Mg / semaine SC- AVK adjusted INR 2-3
Comparison of IDRAPARINUXwith VKA for prevention of VTE in pts with atrial fibrilllation: a randomized, open-label, non-inferiority trial The Amadeus investigators
Lancet 2008
ESSAI INTERROMPU après suivi moyen 10.4 (SD 5.4) moisExcès de saignement sous Idraparinux: 19.3 % vs 11.3 %
**
Comparison of IDRAPARINUX with VKA for prevention of VTE in pts with atrial fibrilllation: a randomized, open-label, non-inferiority trial The Amadeus investigators Lancet 2008
1 épisode confirme AVC recidivant ou embolie non SNC
1 épisode saignement significatif
CLINICAL OUTCOME OF P with UPPER EXTREMITY DVT Munoz et al Chest 2008
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3 MTHS OUTCOMES in 512 PTS WITH ARM DVT according to the existence of cancer and/or KT Munoz et al Chest 2008
Analyse Univariée Risque Récidive ou Saignement Majeur: Age > 55 ans, Cancer, EP symptomatique
CLINICAL PREDICTORS for FATAL PE in 15 520 pts with VTE (RIETE registry 2001-2006) Laporte et al Circulation 2008
CLINICAL PREDICTORS for FATAL PE in 15 520 pts with VTE (RIETE registry) Laporte et al Circulation 2008
Analyse multivariée
*
CLINICAL PREDICTORS for FATAL PE in 15 520 pts with VTE (RIETE registry) Laporte et al Circulation 2008
CONCLUSIONS
• La MTEV chez le cancéreux: fréquente et grave…..l’interniste doit la saisir
• TT curatif acquis … encore dix ans pour démontrer éventuels bénéfices des nouveaux antithrombotiques
• Mise en application des Recommandations…• TT préventif à affiner…..selon FDR
REMERCIEMENTS• Dr P. Debourdeau (H Degennettes, Lyon) et équipe des SOR : D
Kassab et L Bosquet + INCA
• Groupe de travail multi-disciplinaire nationnal (25 experts)• Oncologie : F. Cajfinger, H. Hocini, M. Pavic• Medecine interne: H. Desmurs-Clavel, C. Grange, G. Le Gal,
H. Lévesque, I. Mahé• Médecine Vasculaire : A. Elias, I. Quéré, J-M. Renaudin• Anesthesie: E. Desruennes, M-C. Douard, I. Kriegel• Biologie, Pneumologie I. Elalamy, M-L. Scrobohaci, P.
Mismetti, G. Meyer
• Groupe de RCP Thrombose Hôpital ST Louis: A De Raignac, H Kehmandht, N Boumadhi, S Villiers, M Marty et équipes du cancéropole