La terapia anticoagulante orale: quale farmaco scegliere e come usarlo Indicazioni e risultati della TAO nella fibrillazione atriale non valvolare F. Lombardi U.O.C. di Malattie Cardiovascolari Fondazione IRCCS Ospedale Maggiore Policlinico Dipartimento di Scienze Cliniche e di Comunità Università degli Studi di Milano 1 2 3 4 CHA2DS2-VASc Thromboembolic Risk Score www.escardio.org Bleeding Risk – HAS-BLED Score www.escardio.org 7 Di Pasquale et al, Int J Cardiol 2013 Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF An Analysis Including 71,683 Patients from Four Large Randomized Clinical Trials Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA 9 Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients ROCKET AF (Rivaroxaban) 2010 6 Trial of Warfarin vs. Placebo 1989-1993 RE-LY (Dabigatran) 2009 ENGAGE AF-TIMI 48 (Edoxaban) 2013 ARISTOTLE (Apixaban) 2011 10 Stroke Prevention in AF Warfarin vs. Placebo AFASAK-1 (671) SPAF (421) BAATAF (420) CAFA (378) SPINAF (571) EAFT (439) All Trials (n=6) 64% 100% 50% Warfarin Better 0% -50% -100% Warfarin Worse Hart RG, et al. Ann Intern Med 2007;146:857-867. 11 ACTIVE-W: Stroke or SEE TTR ≥ 65% TTR < 65% 0.10 RR = 1.83 RR = 1.11 P = 0.47 0.08 P < 0.0001 0.06 0.04 Clopi + ASA C+A OAC VKA 0.02 0.02 0.04 0.06 Clopi + ASA C+A OAC 0.0 VKA 0.0 Event Rate (%) 0.08 0.10 P-interaction = 0.013 0.0 0.5 1.0 Years Connolly SJ, et al. Circulation 2008;118:2029-2037 1.5 0.0 0.5 1.0 1.5 Years 12 ACTIVE-W: Major Bleeding TTR ≥ 65% TTR < 65% RR = 0.68 P = 0.08 0.03 0.03 0.04 P = 0.027 OAC 0.02 0.02 C+A C+A 0.0 0.01 0.01 OAC 0.0 Event Rate (%) 0.05 RR = 1.55 0.04 0.05 P-interaction = 0.0006 0.0 0.5 1.0 Years Connolly SJ, et al. Circulation 2008;118:2029-2037 1.5 0.0 0.5 1.0 1.5 Years 13 Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban IIa (thrombin) Xa Xa Xa Hours to Cmax 1-3 2-4 3-4 1-2 Half-life, hours 12-17 5-13 12 10-14 80 33* 27 50 Transporters P-gp P-gp P-gp P-gp CYP Metabolism, % None 32 <32 <4 Target Renal Clearance, % CYP = cytochrome P450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013 Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011 Weinz et al. Drug Dispos Metab 2009;37:1056–1064 ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstract Ogata, et al. J Clin Pharmacol 2010;50:743–753 Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342 Bathala, et al. Drug Metab Dispos 2012;40:2250–2255 14 15 NOAC SPAF Trials Drug # Randomized Dose (mg) Frequency Dose Adjustment At Baseline After Randomization Target INR (Warfarin) Design RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Dabigatran Rivaroxaban Apixaban Edoxaban 18,113 14,266 18,201 21,105 150, 110 20 5 60, 30 Twice Daily Once Daily Twice Daily Once Daily No 20 → 15 5 → 2.5 60 → 30 30 → 15 0 21 5 25 No No No >9% 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0 PROBE* 2x blind 2x blind 2x blind *PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ, et al. N Engl J Med 2009;361:1139-1151 Patel MR, et al. N Engl J Med 2011;365:883-891 Granger CB, et al. N Engl J Med 2011;365:981-992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907 16 Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18,113 14,264 18,201 21,105 Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78] Female, % 37 40 35 38 Paroxysmal AF 32 18 15 25 VKA naive 50 38 43 41 Aspirin Use 40 36 31 29 CHADS2 0-1 2 3-6 13 33 32 35 87 30 34 53 47 36 Connolly SJ, et al. N Engl J Med 2009;361:1139-1151 Patel MR, et al. N Engl J Med 2011;365:883-891 Granger CB, et al. N Engl J Med 2011;365:981-992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907 17 Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years 2.0 1.9 1.8 2.8 Median TTR 66 58 66 68 Lost to Follow-Up, N 20 32 90 1 *TTR, time in therapeutic range Connolly SJ, et al. N Engl J Med 2009;361:1139-1151 Patel MR, et al. N Engl J Med 2011;365:883-891 Granger CB, et al. N Engl J Med 2011;365:981-992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907 18 All NOACS: Stroke or SEE Risk Ratio (95% CI) 0.66 (0.53 - 0.82) RE-LY [150 mg] ROCKET AF 0.88 (0.75 - 1.03) ARISTOTLE 0.80 (0.67 - 0.95) ENGAGE AF-TIMI 48 0.88 (0.75 - 1.02) [60 mg] Combined 0.81 (0.73 - 0.91) [Random Effects Model] N=58,541 0.5 Heterogeneity p=0.13 p=<0.0001 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 19 Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0.92 (0.83 - 1.02) p=0.10 Hemorrhagic Stroke 0.49 (0.38 - 0.64) p<0.0001 MI 0.97 (0.78 - 1.20) p=0.77 All-Cause Mortality 0.90 (0.85 - 0.95) p=0.0003 0.2 0.5 Favors NOAC 1 2 Favors Warfarin Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2013 [in-press] 20 All NOACS: Major Bleeding Risk Ratio (95% CI) 0.94 (0.82 - 1.07) RE-LY [150 mg] ROCKET AF 1.03 (0.90 - 1.18) ARISTOTLE 0.71 (0.61 - 0.81) ENGAGE AF-TIMI 48 0.80 (0.71 - 0.90) [60 mg] Combined 0.86 (0.73 - 1.00) [Random Effects Model] p=0.06 N=58,498 0.5 Heterogeneity p=0.001 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 21 Secondary Safety Outcomes Risk Ratio (95% CI) 0.48 (0.39 - 0.59) ICH p<0.0001 1.25 (1.01 - 1.55) GI Bleeding 0.2 p=0.043 0.5 Favors NOAC 1 2 Favors Warfarin Heterogeneity ICH, p=0.22 GI Bleeding, p=0.009 Ruff CT, et al. Lancet 2013 [in-press] 22 Subgroups: Stroke or SEE Age Gender Diabetes Prior Stroke or TIA CrCl CHADS2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0.85 (0.73 - 0.99) p=0.38 ≥75 0.78 (0.68 - 0.88) Female 0.78 (0.65 - 0.94) Male 0.84 (0.75 - 0.94) No 0.83 (0.74 - 0.93) Yes 0.80 (0.69 - 0.93) No 0.78 (0.66 - 0.91) Yes 0.86 (0.76 - 0.98) <50 0.79 (0.65 - 0.96) 50-80 0.75 (0.66 - 0.85) >80 0.98 (0.79 - 1.22) 0-1 0.75 (0.54 - 1.04) 2 0.86 (0.70 - 1.05) 3-6 0.80 (0.72 - 0.89) Naive 0.75 (0.66 - 0.86) Experienced 0.85 (0.70 - 1.03) <66% 0.77 (0.65 - 0.92) ≥66% 0.82 (0.71 - 0.95) 0.5 Ruff CT, et al. Lancet 2013 [in-press] 1 Favors NOAC p=0.52 p=0.73 p=0.30 p=0.12 p=0.76 p=0.31 p=0.60 2 Favors Warfarin 23 Subgroups: Major Bleeding Age Gender Diabetes Prior Stroke or TIA CrCl CHADS2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0.79 (0.67 - 0.94) p=0.28 ≥75 0.93 (0.74 - 1.17) Female 0.75 (0.58 - 0.97) Male 0.90 (0.72 - 1.12) No 0.71 (0.54 – 0.93) Yes 0.90 (0.78 - 1.04) No 0.85 (0.72 - 1.01) Yes 0.89 (0.77 - 1.02) <50 0.74 (0.52 - 1.05) 50-80 0.91 (0.76 - 1.08) >80 0.85 (0.66 - 1.10) 0-1 0.60 (0.45 - 0.80) 2 0.88 (0.65 - 1.20) 3-6 0.86 (0.71 - 1.04) Naive 0.84 (0.76 - 0.93) Experienced 0.87 (0.70 - 1.08) <66% 0.69 (0.59 - 0.81) ≥66% 0.93 (0.76 - 1.13) 0.2 Ruff CT, et al. Lancet 2013 [in-press] 0.5 Favors NOAC 1 2 Favors Warfarin p=0.29 p=0.12 p=0.70 p=0.57 p=0.09 p=0.78 p=0.022 24 Low Dose Regimens Efficacy & Safety Outcomes Dabigatran 110 mg & Edoxaban 30 mg Risk Ratio (95% CI) 1.03 (0.84 - 1.27) Stroke or SEE p=0.74 1.28 (1.02 - 1.60) Ischemic Stroke p=0.045 0.33 (0.23 - 0.46) Hemorrhagic Stroke p<0.0001 MI 1.25 (1.04 - 1.50) p=0.019 0.89 (0.83 - 0.96) All-Cause Mortality p=0.003 0.65 (0.43 - 1.00) Major Bleeding p=0.05 0.31 (0.24 - 0.41) ICH p<0.0001 0.89 (0.57 - 1.37) GI Bleeding p=0.58 N=26,107 Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0.001 GI Bleeding, p=0.01 0.2 0.5 Favors Low Dose NOAC 1 2 Favors Warfarin Ruff CT, et al. Lancet 2013 [in-press] 25 Dentali et al, Circulation 2012 26 Dentali et al, Circulation 2012 27 From Figure 1 of the Lancet meta-analysis: There were 29 312 patients treated with NOAC drugs and 29 229 patients treated with warfarin. There were 911 stroke or systemicembolism events in the NOAC group and 1107 in the warfarin group. The absolute risk of an event was 3.1% on a NOAC drug and 3.8% on warfarin. The reduction in absolute risk was 0.7%. In this case, 141 of 142 patients treated with a NOAC drug received no benefit over warfarin. Again, our AF patient has a 96.9% chance of not having an embolic event on a NOAC drug and a 96.2% chance of not having one on warfarin. Novel Oral Anticoagulants vs Warfarin: The Truth is Relative John Mandrola DisclosuresDecember 18, 2013 28 From Figure 1: There were 31 830 patients treated with NOAC drugs and 25 661 treated with warfarin. There were 186 ICH events in the NOAC group and 317 in the warfarin group. The absolute risk for ICH was 0.58% with NOAC drugs and 1.24% with warfarin. The NOAC drugs prevented 131 ICHs. The absolute difference between the two groups was a mere 0.65%. Said another way: for 151 of 152 patients treated, there was no difference between NOAC drugs and warfarin. That means we can tell an AF patient similar to the 60 000+ enrolled in the three randomized clinical trials that he or she has a 99.4% chance of not having an ICH on a NOAC drug and a 98.8% chance of not having one on warfarin. Novel Oral Anticoagulants vs Warfarin: The Truth is Relative John Mandrola DisclosuresDecember 18, 2013 29 Heartwire Two New Analyses Link Dabigatran to MI Risk Michael O'Riordan July 11, 2013 The risk of MI with dabigatran was also highlighted at the recent 2013 Congress of the International Society on Thrombosis and Haemostasis meeting in Amsterdam, the Netherlands. Jonathan Douxfils (University of Namur, Belgium), along with senior author Dr Jean-Michel Dogné (University of Namur), presented data from a dose-response meta-analysis of randomized, controlled trials (RCTs) with outcome data from MI and cardiac events[3]. Ten studies were included in the meta-analysis. Among the 23 839 dabigatran-treated patients, there were 292 MIs. Overall, the risk of MI was increased 32% compared with the comparator arm, an increase that was statistically significant. Among patients treated with the 150-mg dose, the risk of MI was 41% to 45% higher in the dabigatran arm. The risk of MI only trended toward statistical significance among those treated with the 110-mg dose (p=0.057). 30 Apostolakis et al, Chest 2013 31 Apostolakis et al, Chest 2013 32 Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients ROCKET AF (Rivaroxaban) 2010 6 Trials of Warfarin vs. Placebo 1989-1993 RE-LY (Dabigatran) 2009 ENGAGE AF-TIMI 48 (Edoxaban) 2013 ARISTOTLE (Apixaban) 2011 33 Nuove indicazioni? ACS Prosthetic valves Stent thrombosis 54 ATLAS ACS 2 TIMI 51 The trial randomized 15 526 ACS patients to one of the two doses of rivaroxaban or placebo for a mean of 13 months and up to 31 months. All patients were taking low-dose (75-100 mg) aspirin and 93% were also on clopidogrel. Results of Combined Rivaroxaban Doses vs Placebo End point Rivaroxaban combined doses (%) CV death/MI/stroke* 8.9 Major non-CABG bleeding 2.1 ICH 0.6 Fatal bleeding 0.3 Placebo (%) p 10.7 0.6 0.2 0.2 0.008 <0.001 0.009 0.66 Results of Rivaroxaban 2.5 mg Twice Daily Dose vs Placebo End point Rivaroxaban 2.5 mg twice daily (%) CV death/MI/stroke* 9.1 CV death 2.7 All-cause death 2.9 Major non-CABG 1.8 bleeding ICH 0.4 Fatal bleeding 0.1 Placebo (%) HR (95% CI) p 10.7 4.1 4.5 0.6 0.84 (0.72–0.97 ) 0. 66 (0.51–0.86) 0.68 (0.53–0. 87) 3.46 (2.08–5.77) 0.02 0.002 0.002 0.001 0.2 0.2 2.83 (1.02–7.86) 0.67 (0.24–1.89) 0.04 0.45 The US Food and Drug Administration (FDA) has turned away a proposed expanded indication for rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) and rejected the new oral anticoagulant as a treatment for patients with acute coronary syndrome (ACS) [1] . The FDA issued a complete response letter (CRL) to the manufacturer today. This is the third time the agency has denied the supplemental new drug application (sNDA) for the rivaroxaban ACS indication, but the decision is hardly surprising given last month's FDA advisory committee meeting. In addition to denying the sNDA for rivaroxaban in ACS to reduce the risk of MI, stroke, or death, the FDA also denied an expanded indication for rivaroxaban in ACS patients to reduce the risk of stent thrombosis. The company had proposed using rivaroxaban in combination with standard antiplatelet therapy. (Feb 14,2014).
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