La stratificazione del rischio tromboembolico venoso

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1 La stratificazione del rischio tromboembolico venoso Domenico Prisco Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze SOD Patologia Medica, AOU Careggi Palermo 7 giugno 2014

2 The iceberg model of VTE (after major ortopedic surgery) PE, fatal 0,2-0,5% PE, All 1-3% Symptomatic DVT, 2-4% Asymptomatic/ distal DVT 40-80% Diagnostic threshold Difficult diagnosis No predictive tests

3 Age-adjusted incidence rates of venous thromboembolism (per pt/yr) Worchester Olmsted Bretagne Nord- Trøndelag VTE Male Female

4 VTE burden in the Italian population Subjects > 70 years Half of the cases due to circumstantial risk factors Improve prophylaxis Risk-tailored prophylaxis? Half of the cases not avoidable (unprovoked) Improve treatment

5 VTE: A MULTIFACTORIAL DISEASE AT, PC, PS deficiency Factor V Leiden Prothrombin G20210A GENETIC ACQUIRED Cancer Autoimmune disease Antiphospsholipid antibodies MIXED TRANSIENT Hyperhomocysteinemia Oral contraceptive use Pregnancy/puerperium Surgery Trauma Prolonged immobilazation Long-haul flights Infectious

6 Relative Risk VTE is Multi-Causal Arising from Interacting Genetic and Acquired Risk Factors Transient acquired risk Trauma Pill Surgery Pregnancy Travel HRT Cumulative risk Thrombotic threshold Risk from ageing Genetic risk 2 Genetic risk 1 Age

7 FATTORI di RISCHIO PER TEV Alto grado (OR 2 9) Medio-basso grado (OR < 2) Storia personale di TEV Trombofilia congenita grave (deficit di Antitrombina, Proteina C, Proteina S, omozigosi per Fattore V Leiden o Protrombina G20210A, o doppia eterozigosi) Sindrome da anticorpi antifosfolipidi Emiplegia o paraplegia da danno neurologico Cancro in fase attiva Sindrome mieloproliferativa Chemioterapia o radioterapia Insufficienza respiratoria con NIV (Ventilazione Non Invasiva) Scompenso cardiaco classe NYHA III/IV Sepsi Gravidanza o puerperio (< 6 settimane dal parto) Storia familiare di TEV Obesità ( BMI > 30) Pillola contraccettiva (entro 1 mese) e terapia ormonale sostitutiva postmenopausa Trombofilia congenita eterozigote (eterozigosi per Fattore V Leiden o Protrombina G20210A) Varici importanti (insufficienza venosa cronica) Malattia infiammatoria cronica intestinale Insufficienza respiratoria o BPCO riacutizzata Presenza di CVC Sindrome nefrosica Recente ( < 1 mese) chirurgia e/o trauma Infarto miocardio acuto. Malattia infettiva acuta. Anderson 2003, Di Minno 2005, Samama 2006

8 AGENDA La stratificazione del rischio per la prevenzione primaria (e secondaria) in situazioni a rischio La stratificazione del rischio di recidiva dopo un primo episodio di TEV

10 VALUTAZIONE DEL RISCHIO TROMBOEMBOLICO INDIVIDUALE A RISCHIO DOVUTO ALL EVENTO B A+B RISCHIO DOVUTO A FATTORI PERSONALI PREDISPONENTI RISCHIO GLOBALE VALUTARE RISCHIO EMORRAGICO

11 Età L età superiore a 40 anni espone ad un rischio superiore che tende a raddoppiare per ogni successiva decade Anderson FA, Spencer FA. Risk factor for VTE. Circulation 2003; 107: 9-16

12 Il ruolo dell allettamento Immobilizzazione N pazienti (tot. 852) Odds Ratio p NO 141 (1,00) 1-29 gg ,17 (2,48-7,01) <0,01 30 gg ,19 (2,22-4,60) <0,01 Bosson JL et al. Arch Int Med 2004

13 Il rischio aumenta in relazione al numero dei fattori di rischio Anderson FA Circulation 2003; 107: I-9

14 Rischio di TEV in Medicina Interna L ospedalizzazione per patologia medica acuta determina un incremento del rischio trombotico di circa 8 volte ed è responsabile di circa il 25% di tutte le TEV. La stratificazione del rischio trombotico dei pazienti medici risulta spesso complessa a causa della polipatologia e della complessità della casistica

15 Complessità in Medicina Interna I pazienti ricoverati in Medina Interna presentano in funzione delle loro comorbosità un nuovo aspetto clinico, funzionale, assistenziale, organizzativo, ma che impone nuove riflessioni anche per gli aspetti formativi e di ricerca La cultura del malato internistico complesso

16 In-hospital symptomatic VTE and antithrombotic prophylaxis in Internal Medicine. 27 Unità di Medicina Interna 4846 pazienti(2006) Incidenza TEV sintomatico (3.65%) Profilassi sottoutilizzata 41.6% 58.4% Gussoni Thromb Haemost 2009; 101:

17 Quali pazienti devo trattare per prevenire le trombosi venose? Chi è il paziente ad alto rischio Come lo identifico?

18 Pazienti internistici a rischio Definizione basata sui criteri di inclusione degli studi Endorse 1 : 41.5% Gemini 2 : 40.9% Padua score 3 : 39.7% Circa il 40% dei pazienti internistici è a rischio aumentato 1 Cohen et al Lancet Gussoni et al Thromb Haemost Barbar et al J Thromb Haemost 2010

19 RISK ASSESSMENT MODELS : score dedicati E difficile individuare in maniera appropriata i soggetti ad alto rischio nei quali effettuare la profilassi Gli score dedicati pur presentando numerose limitazioni permettono di orientare la scelta con un comportamento omogeneo nei setting di assistenza.

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21 Fattori di rischio PADUA PREDICTION SCORE Punteggio Cancro in fase attiva 3 Pregresso TEV 3 Mobilità ridotta* 3 Conosciuta condizione trombofilica** 3 Recente ( 1 mese) trauma e/o chirurgia 2 Età 70 anni 1 Scompenso cardiaco NYHA III/IV e/o insufficienza respiratoria 1 IMA o ictus ischemico 1 Infezione acuta e/o malattia reumatica 1 Obesità (BMI 30) 1 Trattamento ormonale in corso 1 *Allettato, ma si reca autonomamente ai servizi igienici; **difetti di antitrombina, proteina C o S, fattore V di Leiden, mutazione G20210A della protrombina, sindrome da anticorpi antifosfolipidi La profilassi è indicata nei pazienti con punteggio pari o superiore a 4 Barbar S et al J Thromb Haemost 2012;8(11):

22 Padua Prediction score Studio di coorte su 1180 pazienti che furono seguiti con un follow-up di 90 giorni TEV Alto rischio Basso rischio 11% senza profilassi 0.3% senza profilassi Differenza > 30 volte (HR % CI ) Il rischio di TEV è maggiore nei pazienti ad alto rischio che ricevono profilassi rispetto a coloro che sono a basso rischio Barbar S et al J Thromb Haemost 2012;8(11):

23 Padua Prediction score 711 pazienti a basso rischio, 2 svilupparono TEV (0.3%) 1 embolia polmonare 1 embolia polmonare con TVP 283 pazienti ad alto rischio. TEV 6.7% EP 3.9% EP fatale 0 4% Il Padua Prediction Score costituisce il miglior modello per valutare il rischio trombotico nei pazienti medici ricoverati nonostante i suoi limiti. -Pochi eventi -Validazione sub-ottimale Barbar S et al J Thromb Haemost 2012;8(11):

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28 We designed a modified Khorana risk assessment score (the Protecht score) by adding platinum or gemcitabinebased chemotherapy to the predictive variables already taken into account in the Khorana score The aims were: (1) to evaluate the Protecht score, in comparison with the Khorana score, for identifying high risk cancer patients in a post hoc analysis of the placebo group of the Protecht study, and (2) to assess the effect of nadroparin for VTE prophylaxis according to the Khorana and Protecht scores.

29 Bleeding Risk Factors Points - Moderate renal failure (GFR vs 60 ml/min) 1 - Male vs Female 1 - Age y vs < 40 y Current cancer 2 - Rheumatic disease 2 - Central venous catheter 2 - ICU/CCU Severe renal failure (GFR <30 vs 60 ml/min) Hepatic failure (INR > 1.5) Age 85 y vs < 40 y Platelet count < 50 x 10 9 cells/l 4 - Bleeding in 3 mo before admission 4 - Active gastroduodenal ulcer 4.5 Decousus H et al. Chest 2011; 139: 69-79

30 Marcucci M, Intern Emerg Med 2013

31 Study population 15,2% 14,4% Marcucci M, Intern Emerg Med 2013

32 Predictors of thromboprophylaxis prescription (multivariate logistic regression) Marcucci M, Intern Emerg Med 2013

33 Conclusion Less than one-fifth of the more than 65 years old patients with multimorbidity and polipharmacy admitted to 70 internal medicine wards in Italy were prescribed TP in hospital. These findings point out the difficult application of prediction schemes, even when validated, in such a really complex and increasing patient population. An individualized patient management,. may be still the most recommendable in this setting, rather than a generalized MUST strategy Marcucci M, Intern Emerg Med 2013

34 Violi F, Intern Emerg Med 2013

35 DVT in the REPOSI STUDY TEV rate in pts TP+= 1.6% TEV rate in pts TP-= 1.1% Violi F, Intern Emerg Med 2013

36 Major and minor bleeding in the REPOSI STUDY Bleeding rate in pts TP+= 3.5% Bleeding rate in pts TP-= 2.7% Violi F, Intern Emerg Med 2013

37 Conclusion During the hospital stay the rate of symptomatic DVT was a little bit less (0.5 %) compared with the rate observed in the interventional trials. In the real world of acutely ill medical patients the rate of symptomatic DVT is relatively low even in case of very old people. Should clinicians treat patients hospitalized for acutely ill medical or use TP only in patients who are at higher risk of venous thrombosis? Violi F, Intern Emerg Med 2013

38 Conclusion The analysis of these findings leads us to suggest that a more appropriate methodological approach should be followed to investigate the occurrence of venous thrombosis and eventually PE in acutely ill medical patients. The first objective would be to clearly define the rate of DVT and PE in a unselected population hospitalized in internal medicine departments The second objective would be the identification of clinical settings which are candidates to TP Violi F, Intern Emerg Med 2013

40 Cumulative incidence of recurrent DVT and/or PE Recurrence rates in patients with unprovoked vs secondary VTE Prandoni et al, Haematologica 2007

41 Risk categorization of patients with VTE UNPROVOKED PROVOKED by a permanent risk factor e.g. cancer PROVOKED by a transient, surgical risk factor PROVOKED by a transient, non-surgical factor immobilization >4 days acute medical illness pregnancy/puerperium hormonal therapy

42 Prevalence of risk factors for VTE: Cancer % Ageno et al Intern Emerg Med 2011 MASTER registry Surgical risk factor % Non surgical risk factors Immobilization % Trauma /fracture % Severe medical diseases % Oral contraceptives % Pregnancy/puerperium % Central venous catheter 5 0.5% Unprovoked %

43 Annualized recurrence rates after a first episode of venous thromboembolism Transient risk factor: 3.3% per patient-year 0.7% with a surgical risk factor (95% CI 0-1.5%) 4.2% with a non-surgical risk factor (95% CI %) Unprovoked VTE: 7.4% per patient-year (95% CI %) Iorio et al Arch Intern Med 2010

44 Boutitie F et al. BMJ 2011

45 VTE recurrences during follow-up (Palareti et al. T&H 2002) Type of index VTE Rate % pts % pt-y Idiopathic Permanent risk factor (cancer) Transient risk factor

46 Possible strategies in pts with a previous unprovoked VTE Prolonged OAT in all (many pts treated unnecessarily; complications) Prolonged, low intensity OAT in all pts (less effective, complications non completely avoided) Prolonged treatment with new, low risk drugs (for the future?) Identify those pts who are at higher/lower risk Thrombophilia D-dimer test Persistence of residual vein thrombosis

47 La trombofilia congenita

48 Ho et al, Arch Intern Med 2006 Risk of recurrence in common thrombophilia

49 Il residuo venoso

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51 Association between residual vein obstruction (RVO) and VTE JTH, 2011

52 Association between residual vein obstruction (RVO) and VTE in patients with a first episode of unprovoked deep vein thrombosis JTH, 2011

53 After multivariate Cox analysis, RVO was independently associated with recurrent VTE (HR =1.32, 95% CI: ). The association was stronger if RVO was detected early, i.e. at three months after DVT (HR = 2.17; 95% CI: ), but non-significant if detected later, i.e. >6 months (HR = 1.19; 95% CI: ). In conclusion, after a first unprovoked DVT, RVO is a weak overall predictor of recurrent VTE. The association is stronger if RVO is detected at an earlier time (3 months) after thrombosis. JTH, 2014

54 Il Ddimero

55 Risk of Recurrence n=222 (> 500) (< 500; n=377) Palareti et al, Circulation 2003

56 (Palareti et al., NEJM 2006;335:1780-9)

57 Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, Poli D, Lim W. Author, reference Palareti, 2003 Eichinger, 2003 Palareti, 2006 Shrivastava, 2006 positive D-dimer post-anticoagulation Vs negative D-dimer post-anticoagulation Patients, n Recurrent VTE Annualized risk (95%CI) (4.3,10.3) (3.4,5.6) (5.9,15.9) (0.0,24.1) Tait, (7.7, 21.1) Baglin, (5.2,12.2) Poli, (5.6,15.9) Pooled (5.8,11.9)* Patients, n Recurrent VTE N (%) Annualized risk (95%CI) (1.0,4.5) (1.5,4.4) (2.6,6.1) (0.0,8.7) (0.1,7.6) (1.5,8.1) (1.4,6.1) (2.7,4.3)** Ann Intern Med 2008

58 Cumulative hazard of recurrence combining Ddimer with sex and hormone therapy Douketis et al, Ann Int Med 2010

59 Gli algoritmi

60 Clinical decision rule to identify patients at low risk(*) of recurrent venous thromboembolism after 5 7 months of oral anticoagulant therapy Men Women Predictive values always long-term anticoagulation score Post-thrombotic signs (hyperpigmentation, edema or redness in either leg) 1 D-Dimer level 250 μg/l 1 Body mass index 30 kg/m2 1 Age 65 yr 1 (*)Low-risk 1 Rodger M et al. CMAJ, 2008

61 Predictive values Points (according to nomogram) sex males 60 females 0 Localization of distal 0 VTE Proximal DVT 70 PE 90 D-dimer levels continous Low-risk 180 points (according to nomogram) 4.4% (95% CI 2.7%-6.2%) Circulation, 2010

62 Predictive values Elevated D-dimer levels 1 months after stopping VKA score 2 Age < 50 years 1 Male sex 1 Women assuming oral contraceptives -2 The DASH score varies between -2 to 4, identifying patients at low risk of recurrence when the score is 1. Tosetto A et al. JTH, 2012

63 Gli studi di management

64 PERCORSO DIAGNOSTICO-TERAPEUTICO DEI SOGGETTI ARRUOLATI: VALUTAZIONE SU BASE CLINICA- STRUMENTALE (CUS E/O ECOCARDIOGRAMMA) Tutti i pazienti inclusi (con TVP e/o EP) CUS bilaterale degli arti inferiori (V. femorale comune all inguine, la femorale superficiale a metà coscia e la poplitea nel cavo popliteo fino alla triforcazione) Se in almeno uno dei punti suddetti dell arto sintomatico permane un residuo trombotico (> 4 mm): proseguire TAO per un totale di almeno 12 mesi Al termine di almeno 12 mesi di TAO CUS ripetuta; qualsiasi siano i risultati i paz avviati alla fase successiva

65 Prevalence of first-time ever D-dimer above the predefined cut-off levels after VKA withdrawal Blood, in press

66 Total screened patients n = 2458 Excluded for pre-specified criteria n = 442 DD neg 52,3% DD pos reassume VKA 36,9% DD pos refuse VKA 10,8% Candidate to extended VKA treatment n = 606 Candidate to short VKA treatment n = 353 Eligible for the study n = 1057 Excluded for various reasons # n = 47 Patients included in the analysis n = 1010 Patients with always negative DD (no VKAs) n = 528 (52.3%) (VTE idiopathic = 377) (Associated with WRF = 151) Patients with positive DD - resumed VKAs n = 373 (36.9%) (VTE idiopathic = 311) (Associated with WRF = 62) - refused VKAs n = 109 (10.8%) (VTE idiopathic = 83) (Associated with WRF = 26) Blood, in press

67 Kaplan Meier Cumulative Event Rates for recurrent VTE in patients with persistently negative D-dimer results in whom anticoagulation was definitively stopped (dotted line) and in those with positive D-dimer results who refused to resume anticoagulation (continuous line) Blood, in press

68 D-DIMER TO GUIDE THE DURATION OF ANTICOAGULATION IN PATIENTS WITH VENOUS THROMBOEMBOLISM; A MANAGEMENT STUDY Gualtiero Palareti, M.D.(1), Benilde Cosmi, M.D., Ph.D.(1), Cristina Legnani, D.Sci., Ph.D.(1), Emilia Antonucci, Clinical Researcher (2), Valeria De Micheli M.D.(3), Angelo Ghirarduzzi, M.D.(4), Daniela Poli M.D. (2), Sophie Testa M.D.(5), Alberto Tosetto, M.D.(6), Vittorio Pengo, M.D.(7), Paolo Prandoni M.D.(8), for the DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators Conclusions: Serial D-dimer measurement in combination with the assessment of residual thrombosis is suitable in clinical practice for the identification of VTE patients for the identification of VTE patients in whom anticoagulation can be safely discontinued. Blood, in press

69 SOD Patologia Medica Prof. Domenico Prisco Regional reference center for Autoimmune Disease Lupus Clinic Behcet Center Dr. Lorenzo Emmi Dr.Danilo Squatrito Dr. Lucia Ciucciarelli Dr. Vanina Scarpelli Dr. Amedeo Amedei Dr. Mario Milco D Elios Dr. Lorenzo Emmi Dr. Carlo Tamburini Dr. Elena Silvestri Dr. Giacomo Emmi Dr. Caterina Cenci Dr. Benedetta Tomberli Dr. Marisa Benagiano Dr. Chiara Della Bella Dr. Elena Niccolai Dr. Alessia Grassi