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

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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