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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.

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Présentation au sujet: "QUID NOVI? EN PATHOLOGIE VASCULAIRE Dominique FARGE, Service de Médecine Interne et Pathologie Vasculaire, INSERM U697, Hôpital St Louis, Université P7."— Transcription de la présentation:

1 QUID NOVI? EN PATHOLOGIE VASCULAIRE Dominique FARGE, Service de Médecine Interne et Pathologie Vasculaire, INSERM U697, Hôpital St Louis, Université P7 Denis Diderot

2 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 Akl EA Anticoagulation for the long term treatment of VTE in cancer patients. Cochrane data base Syst Rev Noble SI: Management of VTE in patients with advanced cancer Lancet. oncology Prandoni P: Risk stratification and VTE in hospitalized medical and cancer patients. BJH Palumbo A : Prevention of thalidomide and lenalidomide-associated thrombosis in myeloma Leukemia Gerber DE: The incidence and risk factors for VTE and bleeding among 1514 pateinst undergoing HSCT: implications for VTE prevention Blood Bennett CL VTE and mortality associated with recombinant EPO and darbepoietin administration for treatment of cancer-associated anemia. JAMA 2008

3 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 ? Idraparinux 1.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 Laporte S Clinical predictors for fatal PE in patients with VTE Circulation 2008

4 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, UNHPC Coordination Scientifique : Pr D. Farge – Dr P. Debourdeau Groupe de travail multi-disciplinaire (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 Parteneriat Scientifique: SFMV, SNFMI

5 Ia Meta-analysis of randomised clinical trials Ib At least 1 randomised controlled trial IIa At least 1 well-designed controlled study without randomisation IIb At least 1 other type of well-designed quasi-experimental study III Well-designed descriptive (comparative / correlation / case) studies IV 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 références 8 RCT

6 TT Curatif de la MTEV chez cancéreux Etudes rétrospectives: Tt classique HNF / HBPM - AVK =>Récidive MTEV % Hémorragies Majeures 8-36% Essais randomisés prospectifs: 2 / 4 HBPM 3-6 mois vs tt classique

7 HBPM pendant 3 à 6 mois vs HBPM - AVK Risque RECIDIVE METV Risque Hémorragique

8 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 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

9 EFFET DES HBPM AU LONG COURS SUR LA SURVIE DES PATIENTS ATTEINTS DE CANCER ? NS..mais

10 Risk stratification and VTE thromboprophylaxis in hospitalized medical and cancer pts Prandoni P BJH 141; 587 GeneticAcquiredMixed AT 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….? / 1000 habitants/an, très bas 75 ans HOSPITALISATION EN MILIEU MEDICAL( = ¼ MTEV): RR x 8

11 RISK STRATIFICATION OR of independent VTE risk factors in medical pts 95% CI Old age1·171·11–1·24 Hosp/nursing home8·0 4·5–14·2 Increased BMI1·241·04–1·5 Cancer + chemotherapy4·24 2·6–6·9 - chemotherapy2·2 1·6–3·06 Neurologic disease + extremity paresis 3·3 1·3–7·4 Trauma12·7 4·1–39·7 Varicose veins At 45 yrs4·2 1·6–11·3 At 60 yrs1·9 1·0–3·6 Superficial VTE4·3 1·8–10·6 OR > 10 risque ELEVE, 0R, 2-9: risque MODERE, OR < 2 risque FAIBLE Pooled data from Heit et al (2000 and 2006) Prandoni P BJH 141; 587

12 Risk stratification and VTE thromboprophylaxis in hospitalized medical and cancer pts Prandoni P BJH 141; 587 connaissance des FDR + nbreux algorythmes proposés : aucun validé

13 Score d alerte électronique (Kucher NEJM 2005): Risque TVP et EP à 90 jours FeatureScore Cancer3 Previous VTE3 Hypercoagulability3 Recent major surgery2 Advanced age1 Obesity1 Bed rest1 Hormonal treatment1 Risk of VTE and need for thromboprophylaxis: score 4. Prandoni P BJH 141; 587

14 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)5·514·9<0·001 PREVENT (3706)2·85·00·0015 ARTEMIS (849)5·610·50·029 MTEV Symptomatique MEDENOX0·31·7NS PREVENT0·71·1NS ARTEMIS0·01·20·029 Saignement Majeur MEDENOX1·71·1NS PREVENT0·50·2NS ARTEMIS0·2 NS MEDENOX, MEDical patients with ENOXaparin (40mg); PREVENT, Prevention of Recurrent VTE with Dalteparine (5000UI); ARTEMIS, ARixtra (Fondaparinux, 2.5 mg) for VTE prevention in a Medical Indications Study. Prandoni P BJH 141; 587

15 Score prédictif survenue MTEV chez pt cancereux sous chimiothérapie (Khorana Blood 2008) Patient characteristic Risk score Site of cancer: stomach, pancreas2 Site of cancer: lung, lymphoma, gynaecologic, bladder, testicular 1 Platelet count 350 × 10 9 /l1 Haemoglobin <100 g/l or use of erythropoietin1 Leucocyte count >11 × 10 9 /l1 Body mass index risque MTEV faible 1-2 risque MTEV intermédiaire 3 risque MTEV élevé

16 VTE incidence in trials of thalidomide or lenalidomide without thromboprophylaxis Palumbo Leukemia 2008; 22:414 Treatment regimenNewly diagnosed ptsRelapsed/refractory pts VTE incidence (%) Thalidomide Alone3–4 a 2–4 + dexamethasone14–262–8 + melphalan10– doxorubicin10–2758 b + cyclophosphamide3 b –114–8 + multiagent chemotherapies 16–3415 Lenalidomide Alone0–33 + dexamethasone8–758–16 + cyclophosphamide14 + bortezomib0 All newly diagnosed => prophylaxis recommended In relapsed pts? those at high risk should receive prophylaxis

17 VTE incidence in trials of thalidomide or lenalidomide with thromboprophylaxis in newly diagnosed pts Palumbo Leukemia 2008; 22:414 Treatment regimenVTE incidence (%) LMWH Low-fixed-dose warfarin Full-dose warfarin Aspirin Thalidomide Plus dexamethasone13–258 Plus melphalan3 Plus doxorubicin91418 Plus multiagent chemotherapies 15–2431 Lenalidomide Alone Plus dexamethasone3–14 Plus melphalan5 Plus doxorubicin9 0 prophylaxis at induction

18 Risk assessment for management of VTE in multiple Myeloma treated with thalidomide or lenalidomide Leukemia 2008;22:

19

20 * *

21 Bennett, C. L. JAMA 2008;299: Meta-analysis Overall Mortality Rates for phase 3 trials with ESAs vs placebo / C, comparing anemia of cancer and Tt-Related Anemia Trials ESA associated mortality P = 0.03 HR 1.29 HR 1.09 HR 1.10

22 By day 180: VTE 4.6% ( 95% CI: ) Significant bleeding:15.2% ( 95% CI: )

23 Lancet 2008; 371:387

24 * *

25 Application RECO: 58.5 % en chirurgie et 39.5% en médecine

26 Lancet 2008; 371; 1342 Score prédictif de Genève révisé Sensibilité globale MSCT 83% (PIOPED II) Valeur Prédictive N 95% si faible proba clin Valeur Prédictive N 89% si proba clin interméd PIOPED II valeur ajoutée phlébographie + CT? VPN 97% vs 95%.....

27 STRATEGIE D-DIMERES ELISA + MSCT = D-DIMERES ELISA + US + MSCT (Intention treat) => US utile si MSCT contreindiquée Righini Lancet 2008

28 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 pts en AC/FA : - Idraparinux 2.5 Mg / semaine SC - AVK adjusted INR 2-3

29 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) mois Excès de saignement sous Idraparinux: 19.3 % vs 11.3 % * *

30 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 épisode confirme AVC recidivant ou embolie non SNC 1 épisode saignement significatif

31 CLINICAL OUTCOME OF P with UPPER EXTREMITY DVT Munoz et al Chest 2008 * *

32 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

33 CLINICAL PREDICTORS for FATAL PE in pts with VTE (RIETE registry ) Laporte et al Circulation 2008

34 CLINICAL PREDICTORS for FATAL PE in pts with VTE (RIETE registry) Laporte et al Circulation 2008 Analyse multivariée *

35 CLINICAL PREDICTORS for FATAL PE in pts with VTE (RIETE registry) Laporte et al Circulation 2008

36 CONCLUSIONS La MTEV chez le cancéreux: fréquente et grave…..linterniste 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

37 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


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