Convegno regionale SIMI Lombardia 2013 Milano 6 aprile 2013 I NUOVI ANTICOAGULANTI ORALI Terapia del Tromboembolismo Venoso Cimminiello C. – Vimercate (MB) Terapia farmacologica del TEV Le LG ACCP 2012 TraBamento iniziale con terapia anDcoagulante parenterale EBPM (2B), Fondaparinux, ENF endovena (2C) Stabilizzazione del trombo e 0-‐7 giorni prevenzione delle recidive 7 giorni – 3 mesi Prevenzione delle recidive 3 mesi -‐ indefinitamente TraBamento a lungo temine con anD Vit K, EBPM, rivaroxaban, dabigatran ImpaFo della terapia standard del TEV sulla storia naturale della malaIa TEV acuto 1° mese) 50 TEV acuto (2-‐3° mese) TEV ricorrente RRR: 80% Rischio di recidiva 40 30 20 10 0 Kearon C et al NEJM 1997; 336:: 1507-‐11 Il traFamento del TEV: la sicurezza SICUREZZA Sanguinamento Maggiore 2.4% SICUREZZA Sanguinamento Maggiore > 6.5% EFFICACIA EFFICACIA Principali limiD degli anDcoagulanD in uso per il traBamento del TEV (in aggiunta ed oltre al sanguinamento) EBPM Eparina Non frazionata -‐ Somministrazione parenterale -‐ HIT (Heparin induced thrombocytopenia, alto rischio) -‐ Incapacità di ina]vare la trombina legata alla fibrina ed il faBore Xa legato alle piastrine -‐ Biodisponibilità del tuBo variabile -‐ Origine animale -‐ Richiesto monitoraggio di laboratorio -‐ Somministrazione parenterale -‐ HIT (Heparin induced thrombocytopenia, basso rischio) -‐ Incapacità di ina]vare la trombina legata alla fibrina ed il faBore Xa legato alle piastrine -‐ Rischio emorragico nei pazienD con Insuff. Renale -‐ Origine animale Fondaparinux -‐ Somministrazione parenterale -‐ Rischio emorragico nei pazienD con Insuff. Renale Dicumarolici -‐ Inizio e termine di effeBo lenD -‐ StreBa finestra terapeuDca -‐ Richiesto MONITORAGGIO di laboratorio -‐ Numerose interazioni con cibo e farmaci -‐ In grado di ridurre I livelli degli anDcoagulanD naturali, Proteina C ed S Nuovi anDcoagulanD e terapia del TEV Dabigatran Completato In corso Trattamento della RECOVER fase iniziale del RECOVER 2 TEV Prevenzione secondaria a lungo termine del TEV REMEDY RESONATE Rivaroxaban Apixaban Edoxaban Completato In corso Completato In corso EINSTEIN DVT EINSTEIN PE AMPLIFY* HOKUSAI EINSTEIN Ext AMPLIFY ext * I risultaD saranno presentaD al prossimo meeDng ESC 2013 Studies on iniDal treatment of VTE with novel anDcoagulants RE-‐COVER RE-‐COVER II * EINSTEIN DVT EINSTEIN PE Drug Dabigratan vs. warfarin Rivaroxaban vs. VKA Double blind Open label Study Design Dosing schedule Treament Period Pa]ent Number Recurrent VTE Major Bleeding Parenteral anDcoagulaDon followed by Dabigatran 150 mg bid 6 months 2564 2559 Rivaroxaban vs. VKA Open label Rivaroxaban 15 mg bid Rivaroxaban 15 mg bid for 3 weeks followed by for 3 weeks followed 20 mg od by 20 mg od 3-‐6 -‐12 months 3-‐6 -‐12 months 3449 4832 2.4% vs. 2.1% 2.4% vs. 2.1% 2.1% vs. 3.0% 2.1% vs. 1.8% 1.6% vs. 1.9% 1.1% vs. 1.7% 0.8% vs 1.2% 1.1% vs. 2.2% (P=0.003) P<0.001 (non-‐inferiority) P<0.001 (non-‐inferiority) P<0.0001 (non-‐inferiority) * Presented at XXIII ISTH Congress 2011, yet unpublished P<0.003 (non-‐inferiority) IniDal treatment of VTE with novel anDcoagulants: the safety issue Major and clinically relevant non major bleeding Standard therapy Dabigatran Rivaroxaban 10 11.4 P= 0.002 8 % 8.8 8.1 8.2 10.3 6 5.6 4 2 RECOVER EINSTEIN DVT EINSTEIN PE Le LG ACCP 2012 La terapia anDcoagulante prolungata (la prevenzione secondaria) Dopo i primi tre mesi di traBamento anDcoagulante dovrebbe essere riconsiderato il rapporto tra rischio di recidiva e rischio emorragico Si riDene ragionevole considerare un traBamento anDcoagulante prolungato quando la frequenza aBesa di recidive supera il 5% Frequenza aBesa di recidiva/anno in varie categorie di pazienD con TEV (traBaD) 20 Eleva] valori di D-‐ Dimero 16 % 15 Residuo trombo]co 12 8 4 EP 27 vs TVP TVP distale vs prossimale Sesso e progredire dell’età Trombofilie 8.8 TEV TEV e faBori Post-‐chirurgia non chirurgici TEV idiopaDco TEV in oncologia Risk Assessment of Recurrence in Pa]ents With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism : The Vienna Predic]on Model Eichinger S et al CirculaDon 2010; 121: 1610 DASH predicDon score ToseBo A et al JTH 2012 Assessing the risk of bleeding RIETE Risk Score Risk Factor 2 Clinically overt PE Age >75 years ACCP Risk Score Score Recent major bleeding CreaDnine levels >1.2 mg/dL Anemia Cancer Maximum Score 1.5 1.5 1 1 8 1 Low risk: 0; Intermediate risk: 1-‐4; High risk :>4 Age . 65 y Age . 75 y Previous bleeding Cancer MetastaDc cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anemia AnDplatelet therapy Poor anDcoagulant control Comorbidity and reduced funcDonal capacity Recent surgery Frequent falls Alcohol abuse Low risk: 0 RF; moderate risk: 1 RF; High risk :>1 RF Studies on extended treatment of VTE with novel anDcoagulants RE MEDY RE SONATE EINSTEIN EXTENSION AMPLIFY EXTENSION Drug Study Design Dosing schedule Dabigratan vs warfarin Dabigatran vs placebo Rivaroxaban vs. placebo Double blind Double blind Treament Period 6 -‐36 months 18 months 2866 1353 Unprovoked VTE Completed An]coagula]on Period NR* Double blind Rivaroxaban 20 mg od Apixaban 5 mg bid Apixaban 2.5 mg bid Dabigatran 150 mg bid Pa]ent Number Apixaban vs placebo NR 6 -‐12 months 12 months 1196 2482 74% 92% 3 to 12 months 6 to 18 months 6-‐12 months 6-‐12 months * At increased risk for recurrent venous thromboembolism on the basis of the site invesDgator’s assessment RESONATE 1343 paDents with VTE who received 6 to 18 months of anDcoagulaDon randomized, to dabigatran 150 mg twice daily or placebo for an addiDonal six months. Outcome Dabigatran (n=681), n (%) Placebo (n=662), n (%) HR p Recurrent VTE 23(0.4) 37(5.6) 0.08 <0.0001 Major bleeds 2 0 NS 2.92 =0.0013 Any bleeding 36/684 (5.3%) 12/659 (1.8%) Schulman S et al N Engl J Med 2013;368:709-‐18 RE MEDY 2856 paDents with VTE who received three to 12 months of anDcoagulaDon randomized, to dabigatran 150 mg twice daily or warfarin for an addiDonal six to 36 months. Outcome Dabigatran Warfarin (n=1430), n (%) (n=1426), n (%) HR p Recurrent VTE 26 (1.8) 18 (1.3) 1.44 0.03 * Deaths 17 19 0.90 NS Major bleeds 13 (0.9) 25 (1.8) 0.52 0.058 Any bleeding 277 (19) 373 (26) 0.71 <0.0001 ACS 13 (0.9) 3 (0.2) 0.02 * non-‐inferiority Schulman S et al N Engl J Med 2013;368:709-‐18 EINSTEIN Extension: primary efficacy outcome and individual components Rivaroxaban (n=602) n Placebo (n=594) (%) n (%) 8 (1.3)# 42 (7.1) Recurrent DVT 5 (0.8) 31 (5.2) Non-‐fatal PE 2 (0.3) 13 (2.2) Fatal PE 0 1 (0.2) Unexplained death (where PE cannot be excluded) 1 Symptoma]c recurrent VTE* (0.2) 0 ITT populaDon; *Some paDents experienced more than one event; #p<0.001 The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510 EINSTEIN Extension: major bleeding Rivaroxaban (n=598) n Major bleeding 4 Placebo (n=590) (%) n (%) (0.7)* 0 Bleeding contribuDng to death 0 0 Bleeding in a criDcal site 0 0 Associated with fall in haemoglobin ≥2 g/dl and/or transfusion of ≥2 units 4 0 GastrointesDnal bleeding 3 (0.5) 0 Menorrhagia 1 (0.2) 0 Safety populaDon; *p=0.11 The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510 EINSTEIN Extension: non-‐major clinically relevant bleeding Rivaroxaban (n=598) n Placebo (n=590) (%) n (%) 32 (5.4) 7 (1.2) Urogenital/uterus 12 (2.0) 2 (0.3) Nasal 8 (1.3) 1 (0.2) Rectal/anal 6 (1.0) 2 (0.3) Skin 4 (0.7) 2 (0.3) Ear 1 (0.2) 0 GastrointesDnal 1 (0.2) 0 Surgical site 1 (0.2) 0 Non-‐major clinically relevant bleeding Safety populaDon; some paDents experienced more than one event The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510 AMPLIFY-‐EXT Clinical diagnosis of DVT or PE, an]coagula]on treatment 6-‐12 months, completed with no recurrence N= 2482 Apixaban 2,5 mg BID 12 months Apixaban 5 mg BID 12 months Placebo 12 months Primary end point: Venous Thromboembolic recurrence or death Secondary outcome measures: Bleeding Agnelli G et al N Engl J Med 2013;368:699-‐708 AMPLIFY-‐EXT: efficacy RR (95% CI) End point Apixaban Apixaban Placebo 5 mg 2.5 mg N=813 N=820 N=840 Recurrent VTE or death From any cause (%) 3.8 4.2 11.6 Recurrent VTE or VTE-‐ related death (%) 1.7 1.7 8.8 Non VTE-‐related CV death, MI, or stroke (%) 0.5 0.6 1.3 Recurrent VTE, VTE-‐ related death, MI, stroke, or CVD-‐related death (%) 2.1 2.3 10 Apixaban 2.5 mg vs placebo Apixaban 5 mg vs placebo 2.5 mg vs 5 mg 0.33 0.36 NA (0.22-‐0.48) (0.25-‐0.53) 0.19 0.20 0.77 (0.11-‐0.33) (0.11-‐0.34) (0.21-‐2.88) 0.36 0.47 0.77 (0.11-‐1.12) (0.16-‐1.33) (0.21-‐2.88) 0.21 0.23 0.92 (0.13-‐0.35) (0.14-‐0.38) (0.48-‐1.74) Agnelli G et al N Engl J Med 2013;368:699-‐708 AMPLIFY-‐EXT: safety RR (95% CI) End point Major bleeding(%) Apixaban Apixaban Placebo 5 mg 2.5 mg N=813 N=820 N=840 0.2 0.1 0.5 Apixaban 2.5 mg vs placebo Apixaban 5 mg vs placebo 2.5 mg vs 5 mg 0.49 0.25 1.93 (0.09-‐2.64) (0.03-‐2.24) (0.18-‐21.25) CRNM (%) Major or CRNM bleeding (%) 3.0 4.2 2.3 3.2 4.3 2.7 1.29 1.82 0.71 (0.72-‐2.33) (1.05-‐3.18) (0.43-‐1.18) 1.20 1.62 0.74 (0.69-‐2.10) (0.96-‐2.73) (0.46-‐1.22) Agnelli G et al N Engl J Med 2013;368:699-‐708 ASPIRIN and prevenDon of VTE ASPIRE and WARFASA trial design Aspirin 100 mg daily First unprovoked proximal DVT or PE RAND AnDcoagulant Therapy 6-‐18 months WARFASA 6-‐24 months ASPIRE Double blind treatment for 23.9 months (median, WARFASA) Recurrent SymptomaDc confirmed Double blind treatment for 37.2 VTE months (median, ASPIRE) Placebo once daily BecaBni C et al NEJM 2012 Brighton TA et al NEJM 2012 ASPIRIN Recurrent VTE Aspirin Placebo HR (95% CI) p WARFASA N= 402 6.6% 11.2 0,58 (0,36-‐0.93) .02 ASPIRE N= 822 4.8% 6.5 0,74 (0,52-‐1.05) .09 0,68 (0,51-‐0.90) Pooled Major vascular Events (VTE, MI, Stroke, CV death) .007 HR (95% CI) WARFASA 0,67 (0,43-‐0103) .06 ASPIRE 0,66 (0,48-‐0.92) .01 Pooled 0,66 (0,51-‐0.86) .002 BecaBni C et al NEJM 2012 Brighton TA et al NEJM 2012 I nuovi anDcoagulanD orali per il traBamento del tromboembolismo venoso: pro e contro CONTRO PRO -‐ vasDssima esperienza di impiego di -‐ no necessità monitoraggio di laboratorio warfarin -‐ pari efficacia rispeBo a warfarin -‐ costo/beneficio (rispeBo a warfarin) -‐ possibile minore impaBo sul rischio -‐ assenza di anDdoto emorragico complessivo -‐ difficile valutazione della compliance -‐possibile unico traBamento per la fase -‐ Assenza di confronD dire] tra le varie iniziale del TEV e per quella successiva molecole (rivaroxaban e apixaban) -‐Limitata aderenza alle due -‐ Possibile nuovo standard di sicurezza somministrazioni /die (emorragie) per I traBamenD prolungaD
Scarica
