Νεότερα Αντιπηκτικά Χρήση εκτός Κολπικής Μαρμαρυγής Βογιατζής Ιωάννης Διευθυντής Καρδιολογικής Κλινικής Νοσοκομείο Βέροιας
Συγκρίσεις
Πλεονεκτήματα 1. Δεν απαιτείται εργαστηριακός έλεγχος 2. Δεν απαιτείται προσαρμογή της δόσης 3. Δεν υπάρχουν διατροφικές αλληλεπιδράσεις 4. Σπάνιες φαρμακευτικές αλληλεπιδράσεις 5. Ταχεία έναρξη δράσης 6. Ευκολότερες χειρουργικές επεμβάσεις
Φλεβική Θρομβοεμβολή Πνευμονική Εμβολή
Risk factor(s) Calf DVT 80-90% 10-20% Λύεται αυτόματα Σπάνια PROXIMAL DVT >50% Pulmonary embolism Death
Θεραπεία Οξείας VTE
RE-COVER Study Dabigatran 150 mg, BID for 6 months Double Blind, Double Dummy, Non-Inferiority Αρχική θεραπεία παρεντερικά Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study 2.4% Dabigatran = 150mg, BID 2.1% INR = 60% TTR HR = 1.1 (0.65-1.84) TTR = Therapeutic Time in Range Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study Dabigatran Major Bld 1.6% Warfarin Bld 1.9% Major Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER A limitation of the study is that the first dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism Schulman S, et al NEJM 2009;361:2342-2352
Oral rivaroxaban alone for the treatment of symptomatic pulmonary embolism: EINSTEIN PE study
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363:2499-2510
Acute DVT Study Einstein Acute DVT Study INR = 57.7% TTR 3.0% 2.1% TTR = Therapeutic Time in Range Einstein Investigators NEJM 2010;363:2499-2510
Einstein Acute DVT Study 8.1% 8.1% HR = 0.97 (95% CI, 0.76 to 1.22, P=0.77) Einstein Investigators NEJM 2010;363:2499-2510
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority Einstein Investigators NEJM 2012;366:1287-1297
Einstein PE 2.1% INR = 62.7% TTR 1.8% Einstein Investigators NEJM 2012;366:1287-1297
Einstein PE Major Bleeding 2.2% 1.1% Einstein Investigators NEJM 2012;366:1287-1297
Kaplan Meier Cumulative Event Rates. AMPLIFY Study Agnelli G et al. N Engl J Med 2013;369:799-808.
Edoxaban for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study Breaking Wave Off Kanagawa. Katsushika Hokusai 1831 (25.4 x 37.1 cm) colour woodblock print from Hokusai's series Thirty-six Views of Fuji, which are the high point of Japanese prints. The original is at the Hakone Museum in Japan.
Cumulative Event Rate (%) Primary Efficacy Outcome hep / edoxaban (n / N) hep / warfarin (n / N) HR (95% CI) Overall mitt 130 / 4,118 146 / 4,122 0.89 Overall 3.2% 3.5% (0.70 1.13) 4,0 mitt On-Rx 66 / 4,118 1.6% 80 / 4,122 1.9% 0.82 (0.60-1.14) On-Rx 3,0 2,0 TTR : 63.5% 1,0 0,0 0 30 60 90 120 150 180 210 240 270 300 330 360 0.89 0.70 1.13 Time to Event (days) Hazard Ratio 0 1.00 1.50 Edoxaban superior Edoxaban non-inferior
Conclusion (LMW)heparin/edoxaban regimen non-inferior to standard therapy for preventing recurrent VTE consistent efficacy in patients with DVT and PE clinically significant reduction in recurrent VTE in right ventricular dysfunction subgroup less clinically relevant bleeding constant effect over center TTR quartiles dose adaptation (30 mg) effective and safer Attractive regimen for full spectrum of VTE- patients
Επέκταση Θεραπείας
Agnelli G, et al NEJM 2012;1-10
AMPLIFY-EXT Symptomatic Recurrent VTE or VTE Related Death 8.8% 1.7% 1.7% Agnelli G, et al NEJM 2013;368(8):699-708
AMPLIFY-EXT Major-Clinical Relevant Non-Major Bleeding 4.3% 3.2% 2.7% Agnelli G, et al NEJM 2013;368(8):699-708
Double Blind, Randomized Trial Schulman S, et al NEJM 2013;368:709-718
RE-SONATE Study Placebo 5.6% Dabigatran 0.4% Schulman S, et al NEJM 2013;368:709-718
RE-SONATE Study Dabigatran 10.5% Any Bleeding Placebo 5.9% Major or Clinically Relevant Bleeding Dabigatran 5.3% Placebo 1.8% Schulman S, et al NEJM 2013;368:709-718
RE-MEDY Study 1.8% 1.3% Dabigatran Warfarin Schulman S, et al NEJM 2013;368:709-718
RE-MEDY Study Any Bleeding 26.2% 19.4% Warfarin Dabigatran Major Bleeding Dabigatran 0.9% Warfarin 1.3% Schulman S, et al NEJM 2013;368:709-718
Προφύλαξη
Dabigatran for prevention of VTE after major orthopaedic surgery: results Enoxaparin Dabigatran (150 mg) Dabigatran (220 mg) DVT, PE and all-cause mortality (%) RE-NOVATE 6.7 8.6 p<0.0001* 6.0 p<0.0001* RE-MOBILIZE 25.3 33.7 p=0.0009 31.1 p=0.02 RE-MODEL 37.7 40.5 p=0.0005* Major bleeding (%) 36.4 p=0.0345* RE-NOVATE 1.6 1.3 2.0 RE-MOBILIZE 1.4 0.6 0.6 RE-MODEL 1.3 1.3 1.5 *Non-inferior to enoxaparin; inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
Primary Endpoint (%) ADVANCE 2: Primary Efficacy Results 30 RR: 0.62; 95% CI: 0.51 0.74 p<0.0001* 25 20 15 10 5 15.1% n = 975 24.5% n = 997 0 Apixaban 2.5 mg BID Enoxaparin 40 mg Qday *Composite of adjudicated asymptomatic DVT by venography; objectively confirmed symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.
Percent Percent Apixaban for Prevention of VTE After Major Orthopaedic Surgery Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients Total VTE and All-Cause Mortality (%) Major Bleeding (%) 30 26,6 30 25 25 20 15,6 20 15 10 10,6 8,6 6,8 15 10 5 5 1,3 1,6 3,0 0 0 0 5mg 10mg Apixaban (Total Daily Dose) 20mg Warfarin (INR 1.8-3.0) Enoxaparin (30mg bid) 0 5mg 10mg Apixaban (Total Daily Dose) 20mg Warfarin (INR 1.8-3.0) Enoxaparin (30mg bid) Lassen et al. Blood 2006
Percent Percent Apixaban for the Treatment of DVT: The Botticelli-DVT Study Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients Composite of Symptomatic Recurrent VTE and Deterioration of Thrombotic Burden (%) Major Bleeding (%) 10 10 9 8 7 6 5 4 3 2 1 0 6,0 5mg bid 5,6 10mg bid Apixaban 2,6 20mg bid 4,2 LMWH/ fondaparinux + VKA 8 6 4 2 0 0,8 5mg bid 0 10mg bid Apixaban 0,8 20mg bid 0 LMWH/ fondaparinux + VKA Büller, Eur Heart J 2006
Rivaroxaban an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in total knee arthroplasty surgery
Incidence (%) RECORD3 20 15 Total VTE RRR 49% Enoxaparin 40 mg od Rivaroxaban 10 mg od 10 5 0 Major VTE Symptomatic VTE Major bleeding RRR 62% RRR 65% 18.9% 9.6% 2.6% 1.0% 2.0% 0.7% 0.5% 0.6% NS
Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with low molecular weight heparin after total hip arthroplasty
Incidence (%) RECORD2: summary 10 8 Total VTE Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily 6 Major VTE 4 2 0 9.3% RRR 78.9% RRR 87.8% Symptomatic VTE Major bleeding RRR 80.1% 2.0% 5.1% 0.6% 1.2% 0.2% 0.1% 0.1%
Συστάσεις ACCP guidelines: grade 1A recommendation for up to 35 days prophylaxis after elective hip replacement surgery 2004 Geerts et al., 2004
[Bueller H et al. NEJM 2010;363:2499-510] Rivaroxaban in VTE, Secondary Prophylaxis VTE extension study
VTE και χειρουργείο: Πρέπει 1. Προφύλαξη για όλους (σχεδόν) τους ασθενείς. 2. rivaroxaban (or LMWH) θεραπεία για VTE: - rivaroxaban 15 mg PO BID x 3 wks 20 mg QD - dalteparin 200 U/kg SC QD - enoxaparin 1 mg/kg SC BID (or 1.5 mg/kg QD) 3. Οι περισσότερες VTEs μπορούν να αντιμετωπιστούν εξωνοσοκομειακά 4. Μακρόχρονα LMWH αντί warfarin ή NOAC για πολλούς ασθενείς με καρκίνο
VTE και χειρουργείο: ΔΕΝ Πρέπει 1. Get excited about tiny filling defects called clots or small PE 2. Order hypercoagulability testing for unexplained VTE 3. Order an IVC filter unless recent PROXIMAL DVT and anticoagulation not possible 4. Forget to order prophylaxis for (almost) all patients
Επιβαρυμένοι Ασθενείς
ADOPT Apixaban 2.5 mg BID Enoxaparin 40mg, Qday Goldhaber S, et al NEJM 2011;365(23):2167-2177
ADOPT Study Endpoint VTE during parenteral Rx Apixaban 2.5 mg BID Control 1.73% 1.61% Enox VTE at 30 days 2.71% 3.06% Major Bleed 35 days Placebo RRR 1.06 95% CI 0.69-1.63 Non-Inferior P=NS 0.87 95% CI 0.62-1.23 Superior P=NS 0.47% 0.19% 2.58 P=0.04 CR Bleeding 35 days 2.67% 2.08% 1.28 P=0.12 Goldhaber S, et al, NEJM, 2011; 365: 2167-2177
Cohen A, et al NEJM 2013;368:513-523
MAGELLAN Study Endpoint Rivaroxaban 10 mg, Qday Control VTE at 10 days 2.7% 2.7% Enox VTE at 35 days 4.4% 5.7% Major Bleed 35 days placebo RRR 0.97 95% CI 0.713-1.334 Non-Inferior P=0.0025 0.77 95% CI 0.618-0.962 Superior P=0.021 1.1% 0.4% 2.9 P=0.0004 CR Bleeding 35 days 4.1% 1.7% 2.5 P < 0.0001 Cohen A, et al NEJM 2013;368:513-523
Επιβαρυμένοι ασθενείς UFH and LMWH VTE prophylaxis agents in moderate to high risk medically-ill Apixaban and Rivaroxaban non-inferior in short term Px (not FDA approved) Apixaban and Rivaroxaban major bleeding in extended use (not FDA approved) We need to define the extended use group!!!!!!!!!!!!!!!!
Οξέα Στεφανιαία Σύνδρομα
Original Article Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome Μελέτη APPRAISE John H. Alexander, M.D., M.H.S., Renato D. Lopes, M.D., Ph.D., Stefan James, M.D., Ph.D., Rakhi Kilaru, M.S., Yaohua He, M.D., Ph.D., Puneet Mohan, M.D., Ph.D., Deepak L. Bhatt, M.D., M.P.H., Shaun Goodman, M.D., Freek W. Verheugt, M.D., Ph.D., Marcus Flather, M.D., Kurt Huber, M.D., Danny Liaw, M.D., Ph.D., Steen E. Husted, M.D., Jose Lopez-Sendon, M.D., Raffaele De Caterina, M.D., Petr Jansky, M.D., Harald Darius, M.D., Dragos Vinereanu, M.D., Jan H. Cornel, M.D., Frank Cools, M.D., Dan Atar, M.D., Jose Luis Leiva-Pons, M.D., Matyas Keltai, M.D., Hisao Ogawa, M.D., Ph.D., Prem Pais, M.D., Alexander Parkhomenko, M.D., Witold Ruzyllo, M.D., Rafael Diaz, M.D., Harvey White, M.D., Mikhail Ruda, M.D., Margarida Geraldes, Ph.D., Jack Lawrence, M.D., Robert A. Harrington, M.D., Lars Wallentin, M.D., Ph.D., for the APPRAISE-2 Investigators N Engl J Med Volume 365(8):699-708 August 25, 2011
Alexander JH et al. N Engl J Med 2011;365:699-708 Μελέτη APPRAISE
ΑΙΜΟΡΡΑΓΙΕΣ!!!!!! Alexander JH et al. N Engl J Med 2011;365:699-708
Μελέτη ATLAS ACS 2 Mega JL et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1112277
Μελέτη ATLAS ACS 2 End point Rivaroxaban combined doses (%) Placebo (%) p CV death/mi/stroke* 8.9 10.7 0.008 Major non-cabg bleeding 2.1 0.6 < 0.001 ICH 0.6 0.2 0.009 Fatal bleeding 0.3 0.2 0.66
Μηχανικές βαλβίδες
Συγκρίνοντας τις Μελέτες
Total Hip Replacement Drug Thrombosis Bleeding Apixaban Better Equal Dabigatran Equal Equal Rivaroxaban Better Equal LMWH: $25-30/ day Rivaroxaban: $6.75/day Dabigatran: $7/day
Total Knee Replacement Drug Thrombosis Bleeding Apixaban Better Equal Dabigatran Equal Equal Rivaroxaban Better Equal LMWH: $25-30/ day Rivaroxaban: $6.75/day Dabigatran: $7/day
Prophylaxis All three agents effective 220mg dose of dabigatran not available in US Rivaroxaban approved Oral and cheaper! Apixaban promising
Deep Venous Thrombosis Drug Thrombosis Bleeding Dabigatran Equal Equal Rivaroxaban Equal Equal Warfarin: $4/month + monitoring Rivaroxaban: $486/month Dabigatran: $235/month
Acute Coronary Syndrome Dabigatran No benefit, increased bleeding Apixaban No benefit, increased bleeding Rivaroxaban Benefit but bleeding
Επιλογή Αντιπηκτικού
ΣΥΜΠΕΡΑΣΜΑ Η αντιθρομβωτική αγωγή βρίσκεται υπό αναθεώρηση αντικατάσταση κουμαρινικών Βελτίωση ζωής ασθενών ιατρών Βελτίωση θεραπευτικής ασθενών με υψηλό θρομβοεμβολικό κίνδυνο Διαστρωμάτωση κινδύνου Νεφρική ανεπάρκεια Αξιολόγηση στην κλινική πράξη