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) 0-7 giorni Stabilizzazione del trombo e prevenzione delle recidive Prevenzione delle recidive 7 giorni 3 mesi 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 50 40 TEV acuto 1 mese) TEV acuto (2-3 mese) RRR: 80% TEV ricorrente Rischio di recidiva 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 EFFICACIA EFFICACIA Sanguinamento Maggiore > 6.5%
Principali limid degli andcoaguland in uso per il trabamento del TEV 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 (in aggiunta ed oltre al sanguinamento) EBPM - 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 Rivaroxaban Apixaban Edoxaban Completato In corso Completato In corso Completato In corso Trattamento della fase iniziale del TEV RECOVER RECOVER 2 EINSTEIN DVT EINSTEIN PE AMPLIFY* HOKUSAI Prevenzione secondaria a lungo termine del TEV REMEDY RESONATE 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 Rivaroxaban vs. VKA Study Design Double blind Open label Open label Dosing schedule Treament Period Pa]ent Number Recurrent VTE Major Bleeding Parenteral andcoaguladon followed by Dabigatran 150 mg bid 6 months 2564 2559 2.4% vs. 2.1% P<0.001 (non- inferiority) P<0.001 (non- inferiority) 1.6% vs. 1.9% 2.4% vs. 2.1% 1.1% vs. 1.7% Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg od 3-6 - 12 months Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg od 3-6 - 12 months 3449 4832 2.1% vs. 3.0% P<0.0001 (non- inferiority) 0.8% vs 1.2% 2.1% vs. 1.8% P<0.003 (non- inferiority) 1.1% vs. 2.2% (P=0.003) * Presented at XXIII ISTH Congress 2011, yet unpublished
IniDal treatment of VTE with novel andcoagulants: the safety issue Major and clinically relevant non major bleeding Standard therapy Dabigatran Rivaroxaban 10 P= 0.002 11.4 % 8 6 8.8 8.1 8.2 10.3 4 5.6 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 16 12 8 4 TVP distale vs prossimale Sesso e progredire dell età Eleva] valori di D- Dimero Residuo trombo]co 15 8.8 EP 27 vs TVP Trombofilie TEV Post- chirurgia TEV e fabori 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 Risk Factor Recent major bleeding CreaDnine levels >1.2 mg/dl RIETE Risk Score Score 2 1.5 Anemia 1.5 Cancer 1 Clinically overt PE 1 Age >75 years 1 Maximum Score 8 Low risk: 0; Intermediate risk: 1-4; High risk :>4 ACCP Risk Score 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 Dabigratan vs warfarin Dabigatran vs placebo Rivaroxaban vs. placebo Apixaban vs placebo Study Design Double blind Double blind Double blind Dosing schedule Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Apixaban 2.5 mg bid Treament Period 6-36 months 18 months 6-12 months 12 months Pa]ent Number Unprovoked VTE Completed An]coagula]on Period 2866 1353 1196 2482 NR* NR 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 Any bleeding 36/684 (5.3%) 12/659 (1.8%) 2.92 =0.0013 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 (n=1430), n (%) Warfarin (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) Placebo (n=594) n (%) n (%) Symptoma]c recurrent VTE* 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 (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) Placebo (n=590) n (%) n (%) Major bleeding 4 (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) Placebo (n=590) n (%) n (%) Non- major clinically relevant bleeding 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 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 2.5 mg N=840 Apixaban 5 mg N=813 Placebo N=820 Apixaban 2.5 mg vs placebo Apixaban 5 mg vs placebo 2.5 mg vs 5 mg Recurrent VTE or death From any cause (%) Recurrent VTE or VTE- related death (%) Non VTE- related CV death, MI, or stroke (%) Recurrent VTE, VTE- related death, MI, stroke, or CVD- related death (%) 3.8 4.2 11.6 1.7 1.7 8.8 0.5 0.6 1.3 2.1 2.3 10 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 Apixaban 2.5 mg N=840 Apixaban 5 mg N=813 Placebo N=820 Apixaban 2.5 mg vs placebo Apixaban 5 mg vs placebo 2.5 mg vs 5 mg Major bleeding(%) 0.2 0.1 0.5 CRNM (%) 3.0 4.2 2.3 0.49 0.25 1.93 (0.09-2.64) (0.03-2.24) (0.18-21.25) 1.29 1.82 0.71 (0.72-2.33) (1.05-3.18) (0.43-1.18) Major or CRNM bleeding (%) 3.2 4.3 2.7 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 AnDcoagulant Therapy 6-18 months WARFASA 6-24 months ASPIRE RAND Double blind treatment for 23.9 months (median, WARFASA) Double blind treatment for 37.2 months (median, ASPIRE) Placebo once daily Recurrent SymptomaDc confirmed VTE BecaBni C et al NEJM 2012 Brighton TA et al NEJM 2012
ASPIRIN HR Recurrent VTE Aspirin Placebo (95% CI) p WARFASA N= 402 6.6% 11.2 0,58.02 (0,36-0.93) ASPIRE N= 822 4.8% 6.5 0,74.09 (0,52-1.05) Pooled 0,68.007 (0,51-0.90) Major vascular Events (VTE, MI, Stroke, CV death) WARFASA ASPIRE Pooled HR (95% CI) 0,67 (0,43-0103) 0,66 (0,48-0.92) 0,66 (0,51-0.86).06.01.002 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 - vasdssima esperienza di impiego di warfarin - costo/beneficio (rispebo a warfarin) - assenza di anddoto - difficile valutazione della compliance - Assenza di confrond dire] tra le varie molecole - Limitata aderenza alle due somministrazioni /die PRO - no necessità monitoraggio di laboratorio - pari efficacia rispebo a warfarin - possibile minore impabo sul rischio emorragico complessivo - possibile unico trabamento per la fase iniziale del TEV e per quella successiva (rivaroxaban e apixaban) - Possibile nuovo standard di sicurezza (emorragie) per I trabamend prolungad