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La terapia anticoagulante orale: quale farmaco scegliere e come usarlo

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

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La terapia anticoagulante orale: quale farmaco scegliere e come usarlo

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  1. 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

  2. CHA2DS2-VASc Thromboembolic Risk Score

  3. Bleeding Risk – HAS-BLED Score

  4. Di Pasquale et al, Int J Cardiol 2013

  5. 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

  6. Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients ROCKET AF (Rivaroxaban) 2010 ENGAGE AF-TIMI 48 (Edoxaban) 2013 6 Trial of Warfarin vs. Placebo 1989-1993 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

  7. Stroke Prevention in AF Warfarin vs. Placebo AFASAK-1 (671) SPAF (421) BAATAF (420) CAFA (378) SPINAF (571) EAFT (439) 64% All Trials (n=6) 100% 50% 0% -50% -100% Warfarin Worse Warfarin Better 11 Hart RG, et al. Ann Intern Med 2007;146:857-867.

  8. ACTIVE-W: Stroke or SEE TTR ≥ 65% TTR < 65% P-interaction = 0.013 RR = 1.11 P = 0.47 RR = 1.83 P < 0.0001 Clopi + ASA Clopi + ASA Event Rate (%) VKA VKA Years Years Connolly SJ, et al. Circulation 2008;118:2029-2037

  9. ACTIVE-W: Major Bleeding TTR ≥ 65% TTR < 65% P-interaction = 0.0006 RR = 0.68 P = 0.08 RR = 1.55 P = 0.027 Event Rate (%) Years Years Connolly SJ, et al. Circulation 2008;118:2029-2037

  10. Comparative PK/PD of NOACs CYP = cytochrome P450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine Pradaxa [package insert]. Ridgefield, CT: BoehringerIngelheim 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 ClinPharmacol 2010;50:743–753 Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342 Bathala, et al. Drug MetabDispos 2012;40:2250–2255

  11. NOAC SPAF Trials *PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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

  12. Baseline Characteristics CHADS2 0-1 2 3-6 Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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

  13. Trial Metrics *TTR, time in therapeutic range Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel 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

  14. 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) 0.80 (0.67 - 0.95) ARISTOTLE 0.88 (0.75 - 1.02) ENGAGE AF-TIMI 48 [60 mg] Combined 0.81 (0.73 - 0.91) [Random Effects Model] p=<0.0001 N=58,541 0.5 1 2 Favors NOAC Favors Warfarin Heterogeneity p=0.13 Ruff CT, et al. Lancet 2013 [in-press]

  15. 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 1 2 Favors Warfarin Favors NOAC Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2013 [in-press]

  16. 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) 0.80 (0.71 - 0.90) ENGAGE AF-TIMI 48 Combined 0.86 (0.73 - 1.00) [60 mg] Favors NOAC Favors Warfarin [Random Effects Model] p=0.06 N=58,498 0.5 1 2 Heterogeneity p=0.001 Ruff CT, et al. Lancet 2013 [in-press]

  17. 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 p=0.043 0.2 0.5 1 2 Favors Warfarin Favors NOAC Heterogeneity ICH, p=0.22 GI Bleeding, p=0.009 Ruff CT, et al. Lancet 2013 [in-press]

  18. Subgroups: Stroke or SEE P-Interaction Risk Ratio (95% CI) Age <75 0.85 (0.73 - 0.99) p=0.38 ≥75 0.78 (0.68 - 0.88) Gender Female p=0.52 0.78 (0.65 - 0.94) Male 0.84 (0.75 - 0.94) Diabetes No p=0.73 0.83 (0.74 - 0.93) Yes 0.80 (0.69 - 0.93) Prior Stroke or TIA No p=0.30 0.78 (0.66 - 0.91) Yes 0.86 (0.76 - 0.98) CrCl 0.79 (0.65 - 0.96) p=0.12 <50 50-80 0.75 (0.66 - 0.85) >80 0.98 (0.79 - 1.22) CHADS2Score 0-1 0.75 (0.54 - 1.04) p=0.76 2 0.86 (0.70 - 1.05) 3-6 0.80 (0.72 - 0.89) VKA Status Naive p=0.31 0.75 (0.66 - 0.86) Experienced 0.85 (0.70 - 1.03) Center-Based TTR <66% 0.77 (0.65 - 0.92) p=0.60 ≥66% 0.82 (0.71 - 0.95) 0.5 1 2 Favors NOAC Favors Warfarin Ruff CT, et al. Lancet 2013 [in-press]

  19. Subgroups: Major Bleeding P-Interaction Risk Ratio (95% CI) Age p=0.28 0.79 (0.67 - 0.94) <75 0.93 (0.74 - 1.17) ≥75 Gender 0.75 (0.58 - 0.97) Female p=0.29 0.90 (0.72 - 1.12) Male Diabetes p=0.12 0.71 (0.54 – 0.93) No 0.90 (0.78 - 1.04) Yes Prior Stroke or TIA p=0.70 0.85 (0.72 - 1.01) No Yes 0.89 (0.77 - 1.02) CrCl p=0.57 0.74 (0.52 - 1.05) <50 50-80 0.91 (0.76 - 1.08) 0.85 (0.66 - 1.10) >80 CHADS2Score p=0.09 0.60 (0.45 - 0.80) 0-1 2 0.88 (0.65 - 1.20) 0.86 (0.71 - 1.04) 3-6 VKA Status p=0.78 0.84 (0.76 - 0.93) Naive 0.87 (0.70 - 1.08) Experienced Center-Based TTR p=0.022 0.69 (0.59 - 0.81) <66% 0.93 (0.76 - 1.13) ≥66% 0.2 0.5 1 2 Ruff CT, et al. Lancet 2013 [in-press] Favors NOAC Favors Warfarin

  20. Low Dose Regimens Efficacy & Safety Outcomes Risk Ratio (95% CI) Dabigatran 110 mg & Edoxaban 30 mg 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 0.2 0.5 1 2 Favors Low Dose NOAC Favors Warfarin N=26,107 Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0.001 GI Bleeding, p=0.01 Ruff CT, et al. Lancet 2013 [in-press]

  21. Dentali et al, Circulation 2012

  22. Dentali et al, Circulation 2012

  23. 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 systemic-embolism 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

  24. 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

  25. 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 recent2013 Congress of the International Society on Thrombosis and Haemostasismeeting 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).

  26. Apostolakis et al, Chest 2013

  27. Apostolakis et al, Chest 2013

  28. Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients ROCKET AF (Rivaroxaban) 2010 ENGAGE AF-TIMI 48 (Edoxaban) 2013 6 Trials of Warfarin vs. Placebo 1989-1993 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

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