Trattamento del tromboembolismo venoso: gestione della anticoagulazione.

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1 Trattamento del tromboembolismo venoso: gestione della anticoagulazione. Prof. Stefania Basili Centro Aterotrombosi Divisione di I Clinica Medica, (Direttore Prof. Francesco Violi)

2 VTE is the silent killer VTE is under recognized and goes undiagnosed When diagnosis is based on clinical signs and symptoms: <50% of all cases of fatal PE are detected prior to death 80% of cases of DVT are clinically silent No tests to predict who will have a VTE TERZA PIU COMUNE CAUSA DI MORTE CARDIOVASCO LARE PREVENTION IS KEY!!

3 Tromboembolia venosa Triade di Virchow Rudolf Virchow s Triad Ipercoagulabilità Ereditaria Acquisita Stasi Acquisita Trombosi venosa Lesione vascolare Acquisita Virchow R. In Gesammelte Abhandlugen zur Wissenschaftlichen Medizin, 1856; Frankfurt: Staatsdruckerei Rosendaal FR. Lancet 1999; 353:

4 Risk Factors CHF Malignancy Obesity Estrogen/OCP Pregnancy (esp post partum) Lower ext injury Coagulopathy Venous Stasis Prior DVT Age > 70 Prolonged Bed Rest Surgery requiring > 30 minutes general anesthesia Orthopedic Surgery

5 Definizione di Tromboembolismo Venoso EMBOLIA POLMONARE TROMBOSI VENOSA PROFONDA A. INFERIORI PROSSIMALE: vene iliache, vena femorale, vena poplitea DISTALE: vene profonde del polpaccio (peroniere e tibiali) TROMBOSI VENOSA PROFONDA A. SUPERIORI Arterioscler Thromb Vasc Biol 2009;29:

6 Interventi terapeutici sulla modulazione dell emostasi Attivazione piastrinica ATTIVAZIONE COAGULATORIA Wound aspirin antithrombins Wound platelet activation factor Xa release thrombin release of of ADP generation thromboxane A 2 ADP receptor antagonists Further activation of platelets Platelet aggregation GP IIb-IIIa receptor antagonists fibrinogen fibrin (monomers) fibrin (polymer) thrombin prothrombin vitamin K-dependent γ-carboxylation of Glu residues coumarins CLOT Taken from Desai UR (2004) Med. Res. Rev. 24,

7 Come agiscono le eparine? UFH LMWH

8 Fondaparinux: synthetic selective inhibitors of factor Xa Five saccharide units Synthetic Highly selective for AT3 Factor Xa inhibition No binding with plasma proteins No effect on platelet function No thrombocytopenia

9 Vitamin K antagonists 1941 First clinical use (short term) 1944 Use of dicumarol in long-term prophylaxis after MI 1948 Synthesis of warfarin as a rat poison 1954 Warfarin introduced in clinical practice Sweet clover Melilotus alba

10 VKA LMWH SC UFH IV UFH Fondaparinux MECCANISMO Antagonista vitamina K Inibitore fattore Xa e IIa Inibitore fattore Xa e IIa Inibitore fattore Xa e IIa Inibitore fattore Xa SOMMINISTRAZIONE OS 1/DIE SC 1-2/DIE SC 2/DIE IV SC 1/DIE POSOLOGIA Secondo INR Secondo Peso Embricatura iniziale con eparina Secondo PTT Secondo PTT 7.5 mg tra kg SI NO MONITORAGGIO SI (INR) NO SI (PTT) SI (PTT) NO FUNZIONE RENALE Attento monitoraggio Riduzione dose se GFR < 30 Attento monitoraggio Attento monitoraggio No con GFR < 30, cautela < 50 CONTRO Interazioni farmaco e dieta, monitoraggio Trombocito penia da eparina (HIT) HIT Osteoporosi monitoraggio stretto; ospedalizzazi one, HIT NO studi a lungo termine Antidoto Vitamina K No Protamina Protamina No

11 New Oral anticoagulants and their targets in the coagulation pathways

12 Nuovi farmaci introdotti nelle ultime linee guida CHEST 2012: Indicazioni scheda tecnica italiana: Rivaroxaban (Xarelto) 10 mg/die Rivaroxaban e Dabigatran: Prevenzione TEV in chirurgia Rivaroxaban sostitutiva elettiva dell anca Dabigatrano del XIa VIIa ginocchio XIIa Posologia 10 mg o.d. (no peso) 220 mg o.d. (no peso) 150 mg bid se FA IXa Dabigatran: Monitoraggio No No Xa Prevenzione Antidotodi ictus e embolia No sistemica in FA non No valvolare ad alto rischio Funzione renale No in GFR < 15 (cautela < 30) Interazioni Fibrinogen Factor II (prothrombin) Antimicotici (no fluconazolo) e antiretrovirali Fibrin clot No in GFR < 30 No Ketoconazolo, itraconazolo, tacrolimus, ciclosporina, cautela amiodarone, chinidina 220 mg/die o verapamil Tissue factor Dabigatran (Pradaxa)

13 TREATMENT of VENOUS THROMBOEMBOLISM Both Pulmonary embolism and DVT are treated the same An adequate level of anticoagulation is essential Patients will have variable effect of anticoagulants Treatment requires monitoring

14 Obiettivi della terapia prevenire l estensione locale della trombosi venosa e l embolizzazione rimuovere l ostruzione al flusso ematico polmonare e migliorare l emodinamica prevenire le complicanze a distanza (sindrome post-trombotica-ipertensione polmonare )

15 Flow chart trattamento embolia polmonare 2008;358:

16 ANTICOAGULAZIONE Controindicazioni Controidicazioni assolute 1. grave emorragia in atto, 2. recente intervento neurochirurgico o emorragia SNC, 3. grave diatesi emorragica Controidicazioni relative 1. ipertensione arteriosa di grado severo non controllata, 2. trauma cranico recente, 3. sanguinamento gastrointestinale recente, 4. retinopatia proliferativa diabetica, 5. piastrinopenia < /mm3 Heparin and Low-Molecolar-Weight Heparin. Chest 2004;126:188S-203S203S

17 General Recommendations ACCP Conference on Antithrombotic and Thrombolytic Therapy (2008) We recommend that renal function be considered when making decisions about the use and/or the dose of LMWH, fondaparinux, and other antithrombotic drugs that are cleared by the kidneys, particularly in the elderly patients, patients with diabetes mellitus, and those at high risk for bleeding (Grade 1A). Depending on the circumstances, we recommend one of the following options in this situation: avoiding the use of an anticoagulant that bioaccumulates in the presence of renal impairment, using a lower dose of the agent, or monitoring the drug level or its anticoagulant effect (Grade 1B). (The DIRECT Study (n=138) Arch Intern Med. 2008;168(16): ) 1812)

18 Antithrombotic Therapy for Venous Thromboembolic Diseases Antithrombotic Therapy and Prevention of Thrombosis: ACCP Evidence-Based Clinical Practice Guidelines, 9th ed Copyright: American College of Chest Physicians 2012

19 1. Come impostare la terapia iniziale? Tp parenterale Sospensione Terapia eparinica 5-7 gg Terapia anticoagulante orale 4-7 gg Warfarin 5 mg INR > 2.0 (per 24 h)

20 Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT /PE In patients with ACUTE DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux).. In patients with ACUTE PE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux).

21 Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy In patients with ACUTE DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B). In patients with ACUTE PE, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B).

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23 Determine Recurrence Risk of VTE Clinical scenario/patient risk factors Thrombophilia work up Residual vein thrombosis on Ultrasound D-dimer testing

24 Risk of VTE After Cessation of Therapy

25 Risk of VTE Recurrence After Cessation of VTE Risk factor 1 st yr Next 5 yrs Distal DVT 3% <10% Minor Transient Major Transient 3% 10% 5-6% 15% Unprovoked At least 10% 30% Recurrent >10% >30% Provoked Major risk factors: major surgery, major trauma, cancer Minor risk factors: OCP, HRT, pregnancy, airline travel, non-major surgery, minor trauma Associated medical diseases- IBD, nephrotic syndrome, cancer, sickle cell, multiple myeloma, Waldentrom s, MGUS, Bechets, P.Vera, APLS

26 TERAPIA 3 MESI SEMPRE (indipendentemente dal rischio emorragico) TEV provocata TEV NON provocata STOP Terapia a lungo termine

27 Duration of Anticoagulation 1)Transient risk (e.g., surgery, immobilization, estrogen use, trauma): 3 months. Shorter treatment periods are associated with a higher rate of recurrence and are not recommended. 2) Idiopathic or medical risk: 6-12 months. - Patients with documented antiphospholipid antibodies or two or more thrombophilic conditions should be treated for 12 months and considered for indefinite anticoagulation therapy. -Patients with documented deficiency of antithrombin, protein C or S, factor V Leiden, prothrombin mutation, homocysteinemia, or high factor VIII conditions should be treated for 6-12 months and considered for indefinite anticoagulation therapy. 3) Recurrent disease or continued risk factors: indefinite. - Patients with cancer should be initially treated for three to six months with LWMH and anticoagulation therapy should be indefinitely or until the cancer is resolved. - Patients with two or more episodes of documented DVT should receive anticoagulation therapyindefinitely. 7th American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy

28 PROLONG Study Optimal duration of TAO The optimal duration of oral anticoagulation in patients with idiopathic venous thromboembolism is uncertain. Testing of D-dimer levels may play a role in the assessment of the need for prolonged anticoagulation Palareti G et al. N Engl J Med 2006;355: Cumulative Incidence of and Hazard Ratios (HRs) for Main Outcomes

29 F.C.S.A TVP/EP idiopatica o fattori di rischio persistenti (trombofilia): 3-6 mesi Se trombofilia grave o multipla: 1 anno/indefinitamente Se D-DIMERO +++ dopo 1 mese: ripresa trattamento Se recidive: indefinitamente Neoplastici: lungo termine fino alla remissione della neoplasia. Valutare utilizzo LMWH a dosi terapeutiche per almeno 6 mesi.

30 Choice of Anticoagulant Regimen for Long-term Therapy In patients with DVT of the leg/pe and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C). For patients with DVT/PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).

31 Choice of Anticoagulant Regimen for Long-term Therapy In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy(grade 2B). Remarks ( ):Choice of treatment in patients with and without cancer is sensitive to the individual patient's tolerance for daily injections, need for laboratory monitoring, and treatment costs. LMWH, rivaroxaban, and dabigatranare retained in patients with renal impairment, whereas this is not a concern with VKA. Treatment of VTE with dabigatranor rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatranand rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the other.

32 Long-term Treatment of Patients With PE In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C). Remarks ( ): Choice of treatment in patients with and without cancer is sensitive to the individual patient's tolerance for daily injections, need for laboratory monitoring, and treatment costs. Treatment of VTE with dabigatranor rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketingstudies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatranand rivaroxaban, and we have not made any recommendation in favor of one of the new agents over the other.

33 Why are heparins the preferred treatment in Trousseau s syndrome? Heparin has several antithrombotic mechanisms that warfarin lacks Copyright 2007 American Society of Hematology. Copyright restrictions may apply. Varki, A. Blood 2007;110:

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35 Embolizzazione rara (estensione nel 15-25%) N.B. Unico caso da non trattare subito! Fattori di rischio per estensione: - D-dimero positivo - sede limitrofa a vena prossimale -estensione del trombo >5 mm -storia di TEV Ecodoppler a 2 - fattore provocativo non reversibile settimane o neoplasia - ospedalizzazione SI: terapia per 3 mesi Estensione? NO: no terapia

36 Centro Aterotrombosi Divisione di Prima Clinica Medica Direttore: Prof. Francesco Violi Sapienza- Università di Roma Azienda Policlinico Umberto I Centro Aterotrombosi Telefoni: Call center Centro TAO senza appuntamento Piano Terra