Capri Conference 2.0 Capri 28/29 Marzo 2014 nella trombosi venosa profonda e nell embolia polmonare il single drug approach Claudio Ferri Università dell Aquila Cattedra e Scuola di Medicina Interna Dipartimento MeSVA UOC di Medicina Interna e Nefrologia Ospedale San Salvatore
DVT and pulmonary embolism 1. Vascular damage (Endothelial) 2. Abnormal blood flow (Stasis) 3. Hypercoagulability (Trombophilia) Rudolph Carl Virchow (1821-1902)
DVT and pulmonary embolism Pulmonary Embolism Migration Embolization Thrombus DVT
DVT and pulmonary embolism: Meta-analysis (8 studies, 2.994 patients), modified DVT incidence = 1-2 cases per 1.000 persons per year VKA 3-folds increment bleedings -85% recurrence 5-folds reduction PE Intracranial bleedings about 8% of major bleedings (mortality about 46%)
Direct Thrombin inhibition XIIa XIa VIIa Tissue factor IXa Xa II Factor IIa (thrombin) Dabigatran
Direct Thrombin inhibition Major bleeding (HR 0.52; 95% CI, 0.27 to 1.02; p<0.001) Recurrent venous thromboembolism (HR 1.44; 95% CI, 0.78 to 2.64; P=0.01 for noninferiority). Major or clinically relevant bleeding (HR 0.54) Schulman S et al. N Engl J Med. 2013 Feb 21;368(8):709-18.
Direct Factor Xa inhibition XIIa XIa IXa Xa Factor II (prothrombin) VIIa Apixaban Edoxaban Betrixaban.. Tissue factor Fibrinogen Fibrin clot
Agnelli G et al (Amplify Investigators). N Engl J Med. 2013;369(9):799-808. doi: 10.1056/NEJMoa1302507. Efficacy Outcomes Direct Factor Xa inhibition - Apixaban Apixaban n=2609 Enoxaparin/ Warfarin n=2635 First recurrent VTE or VTErelated death, n (%) 59 (2.3) 71 (2.7) 0.84 (0.60 1.18) <0.0001 Noninferiority Index event: DVT 38/1698 (2.2) 47/1736 (2.7) 0.83 (0.54 1.26) Index event: PE DVT 21/900 (2.3) 23/886 (2.6) 0.90 (0.50 1.61) VTE or CV-related death, n (%) VTE or all-cause death, n (%) 61 (2.3) 77 (2.9) 0.80 (0.57 1.11) 84 (3.2) 104 (4.0) 0.82 (0.61 1.08)
Direct Factor Xa inhibition - Apixaban Agnelli G et al (Amplify Investigators). N Engl J Med. 2013;369(9):799-808. doi: 10.1056/NEJMoa1302507.
Direct Factor Xa inhibition - Edoxaban Edoxaban Warfarin (HR 0.89; 95% CI, 0.70 to 1.13; P<0.001 for noninferiority) Overall On-Rx TTR : 63.5% Number at Risk: Edoxaban Overall 4118 4050 4024 4002 3985 3974 3959 3885 3692 3524 3358 3190 2918 Warfarin Overall 4122 4055 4023 4001 3992 3975 3962 3864 3683 3519 3367 3184 2936 Edoxaban On-tx 4118 3892 3793 3724 3539 3478 3200 2320 2169 2029 1890 1769 1308 Warfarin On-tx 4122 3893 3791 3703 3499 3423 3170 2305 2140 2015 1880 1740 1306 The Hokusai-VTE Investigators. N Engl J Med 2013
Direct Factor Xa inhibition - Edoxaban Outcome First major or clinically relevant non-major bleeding, n (%) Major bleeding, n (%) Fatal Non-fatal in critical sites Non-fatal in non-critical sites Edoxaban (N=4118) Warfarin (N=4122) Relative risk (95% CI) 349 (8.5) 423 (10.3) 0.81 (0.71 0.94) * 56 (1.4) 2 (<0.1) 13 (0.3) 41 (1.0) 66 (1.6) 10 (0.2) 25 (0.6) 33 (0.8) 0.84 (0.59 1.21) # Clinically relevant non-major bleeding, n (%) 298 (7.2) 368 (8.9) 0.80 (0.68 0.93) * Any bleeding, n (%) 895 (21.7) 1056 (25.6) 0.82 (0.75 0.90) * P=0.004, # P=0.35, P<0.001 for superiority The Hokusai-VTE Investigators. N Engl J Med 2013
Reimbursement Apixaban Dabigatran - Conditio sine qua non: Any NV-AF Apixaban and Dabigatran - Only permanent NV-AF Conditio sine qua non: >65 years Apixaban Any age Dabigatran and Group 1. Eligibility: CHA 2 DS 2 -VASC >1 Dabigatran, > 3 Apixaban, >3 HAS Bled > 3 Apixaban, Dabigatran, Group 2. Eligibility : TTR last 6 months < 70% Apixaban and Dabigatran, < 60% Group 3. Eligibility: VKA treatment is not feasible due to any problem related to INR blood sampling-control : DVT treatment and prevention of DVT recurrence and PE after DVT (adults)
Record 2: Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with low molecular weight heparin after total hip arthroplasty Double blind R S U R G E R Y Evening before surgery 10 mg od 6 8 hours post-surgery 6 8 hours post-surgery Enoxaparin 40 mg od Oral placebo Mandatory bilateral venography F O L L O W U P Day 1 Day 36±4 Day 65+5 Inclusion criteria Patients aged 18 years, scheduled to undergo elective THR Major exclusion criteria Active bleeding or high risk of bleeding Significant liver disease Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors
Incidence (%) Record 2 - Results 10 8 Total VTE 10 mg once daily Enoxaparin 40 mg once daily 6 Major VTE 4 2 0 9.3% Symptomatic VTE RRR 78.9% RRR 87.8% RRR 80.1% 2.0% 5.1% 0.6% 1.2% 0.2% 0.1% 0.1% Major bleeding
Record 1: Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty Double blind R S U R 6 8 hours post-surgery G E 6 8 hours post-surgery R Y Evening before surgery 10 mg od Enoxaparin 40 mg od Mandatory bilateral venography Day 1 Day 36±4 F O L L O W U P Up to Day 65 Inclusion criteria Patients aged 18 years, scheduled to undergo elective THR Major exclusion criteria Last dose, day before venography Active bleeding or high risk of bleeding Significant liver disease Anticoagulant therapy that could not be stopped Use of HIV-protease inhibitors
Incidence (%) Record 1 - Results 5 4 Total VTE RRR 70% 10 mg once daily Enoxaparin 40 mg once daily 3 2 1 Major VTE RRR 88% Symptomatic VTE Major bleeding 0 3.7% 1.1% 2.0% 0.2% 0.5% 0.3% 0.1% 0.3%
Clinical programme overview: 50,000 patients to be enrolled VTE prevention after major orthopaedic surgery VTE prevention in hospitalized medically ill patients Phase II ODIXa-HIP1 ODIXa-HIP2 ODIXa-KNEE ODIXa-OD-HIP Phase III RECORD1 RECORD2 RECORD3 RECORD4 VTE treatment Stroke prevention in atrial fibrillation Secondary prevention of acute coronary syndromes ODIXa-DVT EINSTEIN-DVT EINSTEIN-DVT EINSTEIN-PE EINSTEIN-EXT Japanese Phase III study
EINSTEIN DVT: Primary outcome by subgroups No. events (n/n) Enox/V KA (n/n) 36/1,731 51/1,718 HR (95% CI) 0.68 (0.44 to 1.04) Outcome Enoxaparin/VKA HR Net clinical benefit: primary efficacy outcome + major bleeding EINSTEIN DVT: Net clinical benefit and total mortality n/n (%) n/n (%) (95% CI) 51/1,731 (2.9) 73/1,718 (4.2) 0.67 (0.47 0.95) Total mortality 38/1,731 (2.2) 49/1,718 (2.9) 0.67 (0.44 1.02) Cardiovascular events 12/1,718 (0.7) 14/1,711 (0.8) 0.79 (0.36 1.71) EINSTEIN Investigators. N Engl J Med 2010 363(26):2499-25100
EINSTEIN PE: study design Randomized, open-label, event-driven, non-inferiority study Up to 48 hours heparins/fondaparinux treatment permitted before study entry 88 primary efficacy outcomes needed Non-inferiority margin: 2.0 Predefined treatment period of 3, 6, or 12 months Day 1 Day 21 Objectively confirmed PE ± DVT N=4833 R 15 mg bid 20 mg od Enoxaparin bid for at least 5 days, 30-day poststudy treatment period plus VKA INR 2.5 (range 2.0 3.0) Primary efficacy outcome: first recurrent VTE Principal safety outcome: first major or nonmajor clinically relevant bleeding
EINSTEIN PE: Primary efficacy (N=2419) Enoxaparin/VKA (N=2413) n (%) n (%) First symptomatic recurrent VTE 50 (2.1) 44 (1.8) Recurrent DVT 18 (0.7) 17 (0.7) Recurrent DVT + PE 0 2 (<0.1) Non-fatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.2) HR 0.75 1.12 1.68* 0 1.00 2.00 superior p=0.57 for superiority (two-sided) non-inferior p=0.0026 for non-inferiority (one-sided) inferior *Potential relative risk increase <68.4%; absolute risk difference 0.24% ( 0.5 to 1.02)
Cumulative event rate (%) EINSTEIN PE: principal safety outcome major or non-major clinically relevant bleeding 15 Enoxaparin/VKA 14 N=2405 13 12 11 10 EINSTEIN PE: 9 8 N=2412 7 6 Enoxaparin/VKA HR (95% CI) 5 n/n (%) n/n (%) p-value 4 3 249/2412 274/2405 0.90 (0.76 1.07) 2 (10.3) (11.4) p=0.23 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313 Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251 Safety population
Cumulative event rate (%) EINSTEIN PE: major bleeding 3.0 n/n (%) Enoxaparin/VKA n/n (%) HR (95% CI) p-value 2.5 2.0 26/2412 (1.1) 52/2405 (2.2) 0.49 (0.31 0.79) p=0.0032 Enoxaparin/VKA N=2405 1.5 1.0 0.5 N=2412 Safety population 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350 Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278
Percentage Compliance/adherence rates in mixed therapeutic areas P < 0.001 among dose schedules Claxton AJ, Clin Ther 2001,23,8: 1296-1310
DVT costs - ITALY DVT treatment Drugs (7 months) INR monitoring (7 months) TOTAL LMWE/VKA Acute phase (10 days) Post-acute phase 92 15 107 199-542 306-649 Only LMWE 1.936-1.936 462-462 EBPM: enoxaparina; dosaggio medio: 100 UI axa/kg di peso corporeo BID; per un adulto di 70 Kg: costo medio/die: 9.22 (prezzo massimo di cessione al SSN) Fase acuta: enoxaparina + warfarin Fase post-acuta: solo warfarin; dosaggio medio: 5mg/die; costo medio/die: 0.07 Il costo della terapia con rivaroxaban è stato calcolato assumendo 2,2 (costo medio europeo dei prezzi in Germania, UK, Danimarca, Spagna, Francia, Irlanda, Belgio, Austria) I costi del monitoraggio dell INR per warfarin sono stati calcolati sulla base delle tariffe nazionali/regionali e assumendo una frequenza del controllo da 11 visite (1 visita ogni 20 giorni) a 30 visite visita alla settimana).