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Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF

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. 1.

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Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF

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  1. 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 1

  2. 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

  3. Comparative PK/PD of NOACs CYP = cytochromeP450; 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 ClinPharmacol2010;50:743–753 Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342 Bathala, et al. Drug MetabDispos 2012;40:2250–2255

  4. 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

  5. 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

  6. 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

  7. 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]

  8. 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]

  9. 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]

  10. 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]

  11. 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]

  12. 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

  13. 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]

  14. 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 14

  15. Research Support: Daiichi Sankyo, AstraZeneca Consultant and Advisory Boards: BoehringerIngelheim, Daiichi Sankyo, Bristol-Meyers Squibb Disclosures 15

  16. 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 16 Hart RG, et al. Ann Intern Med 2007;146:857-867.

  17. 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

  18. First to contain data from all 4 phase 3 warfarin-controlled trials Robust sample size Precision in assessing relative benefit of NOACs in key clinical subgroups Effects of agents on important secondary outcomes Pooled data for FXa and thrombin inhibitors Target key coagulation enzymes Trials share similar design Agents used interchangeably clinically and grouped together by Guidelines Separate meta-analysis of low dose dabigatran and edoxaban Comprehensive picture of the NOACs as a therapeutic option Meta-Analysis 18

  19. Comparative PK/PD of NOACs CYP = cytochromeP450; 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 ClinPharmacol2010;50:743–753 Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342 Bathala, et al. Drug MetabDispos 2012;40:2250–2255

  20. 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

  21. 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

  22. 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

  23. 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]

  24. 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]

  25. 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]

  26. 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]

  27. 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]

  28. 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

  29. 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

  30. 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

  31. 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]

  32. NOACs significantly reduce stroke (19%) Primarily driven by reduction in hemorrhagic stroke (51%) NOACs significantly reduce mortality (10%) Trend toward less bleeding Substantial reduction in ICH (52%) Increased GI bleeding (25%) The relative efficacy and safety of NOACs consistent across a wide spectrum of AF patients Even less bleeding when INR not as well controlled Low dose NOAC regimens reduce mortality and have a very favorable bleeding profile but more ischemic events Differences in agents, patients, and trials may not be accounted for Heterogeneity major bleeding and GI bleeding Conclusions 32

  33. BACK – UP 33

  34. Factor Xa Inhibitors: Stroke or SEE Risk Ratio (95% CI) 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 Combined 0.86 (0.78 - 0.94) [Random Effects Model] p=0.0011 N=46,443 0.5 1 2 Favors NOAC Favors Warfarin Heterogeneity p=0.65

  35. Factor Xa Inhibitors: Bleeding Risk Ratio (95% CI) 1.03 (0.89, 1.18) ROCKET 0.70 (0.61, 0.81) ARISTOTLE 0.80 (0.71, 0.90) ENGAGE AF-TIMI 48 0.83 (0.68, 1.02) Combined [Random Effects Model] 2 1 0.5 N=46,400 Favors NOAC Favors Warfarin Heterogeneity p=0.0006

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