New Oral AntiCoagulants (NOAC) in 2015

New Oral AntiCoagulants (NOAC) in 2015 William R. Hiatt, MD Professor of Medicine and Cardiology University of Colorado School of Medicine President CPC Clinical Research

Disclosures Received research grant support from: Bayer Healthcare, Janssen J&J Drugs and indications discussed in this presentation may be non-approved and off-label in certain jurisdictions

Rivaroxaban Highly selective anti-xa Cmax 2.5-4 h T ½ 5.8-9.2 h Absorbed and excreted renal + fecalbiliary in its active form 80% oral bioavailability No effect on bleeding time, INR ~2 at peak Once daily (mainly)

Apixaban Highly selective anti-xa Cmax 3 h T ½ 8-14 h Eliminated renal + fecal-biliary and oxidative metabolism High oral bioavailability Twice daily

Dabigatran etexilate Highly selective anti-iia (thrombin inhibitor) Cmax 2 h T ½ 8-14 h Eliminated 80% renal 6.5% oral bioavailability Once daily in prophylaxis, twice daily in treatment of VTE

Assessment of anti-xa drugs Qualitative assessment PT for rivaroxaban Don t use INR No screening test for apixaban Quantitative assessment Anti-factor-Xa assay, standardized and calibrated for the respective anticoagulant No therapeutic ranges have been validated

VTE Prophylaxis in Orthopedic Surgery

More effective Odds Ratio Rivaroaban vs Enoxaparin Major and clinically relevant bleeding Vs. enoxa 30 bid 2.0 Worst Unequal durations 1.5 0.1 0.5 1 1.5 2.0 0.5 Best 0.1 Safer

More effective Odds Ratio Apixaban vs Enoxaparin Major and clin relevant bleeding 2.0 Worst 1.5 0.1 0.5 1 1.5 2.0 Vs. enoxa 30 bid 0.5 Best 0.1 Safer

More effective Odds Ratios Dabigatran 220 mg vs Enoxaparin Major and clin relevant bleeding 2.0 Worst 1.5 0.1 0.5 1 1.5 2.0 0.5 Vs. enoxa 30 bid Best 0.1 Safer

Conclusion Ortho Surgery vs Enoxaparin Rivaroxaban more effective but there is some more bleeding Apixaban is more effective without more bleeding (or, vs enox 30 BID, similar but with less bleeding) Dabigatran is similar in effect and some more bleeding (but less effective and less bleeding vs enox 30 BID)

Atrial fibrillation (Stroke Prevention)

NOACs vs. Warfarin in AF Trade off HR major bleed 1.5 1.4 Worst 1.3 1.2 1.1 R 1 HR stroke & SE 0.5 1.5 D150 0.9 D110 0.8 Best A 0.7 0.6 0.5 Trade off

RE-LY in perspective Category Warfarin vs placebo Warfarin vs Warfarin low dose Warfarin vs ASA Warfarin vs ASA + clopidogrel Warfarin vs ximelagatran Warfarin vs dabigatran 150 Camm J.: Oral presentation at ESC on Aug 30th 2009 http://www.escardio.org/congresses/esc- 2009/webcasts/pages/sunday.aspx Meta-analysis of ischaemic stroke or systemic embolism 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment

Apixaban - AVERROES Apixa ASA RR P= 5 mg bid 81-324 Outcome N=2809 N=2791 Stroke & SE (ITT) 1.6 % 3.6 % 0.46 <0.001 Death 3.4 % 4.4 % 0.79 0.07 Major bleeding 1.4 % 1.2 % 1.14 0.56 ICH 0.4 % 0.3 % 1.09 0.83 DMC recommended early termination at 1 st analysis of efficacy Connolly S. NEJM 2011

Intracranial bleedings, AF studies NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 1,2 27 (0.23) 90 (0.76) 0.30 0.19-0.45 Dabi 150 1,2 38 (0.32) 90 (0.76) 0.41 0.28-0.60 Riva 3 55 (0.5) 84 (0.7) 0.67 0.47-0.93 Apixaban 4 52 (0.33) 122 (0.80) 0.42 0.30-0.58 0.0 0.5 1.0 1.5 2.0 Favors NOAC Not head-to-head comparison for illustrative purpose only Direct comparisons cannot be made between the studies. Adapted from references 1 4 1. Connolly et al. NEJM 2009;361:1139 51; 2. Connolly et al. NEJM 2010;363:1875 6; 3. Patel et al. NEJM 2011;365:883 91; 4. Granger et al. NEJM 2011;365:981 92 Favors warfarin

Mortality Dentali F et al. Circulation. 2012;126:2381-2391 Copyright American Heart Association, Inc. All rights reserved.

Explanation for lower mortality RE-LY, ROCKET-AF, ARISTOTLE NOACs Warfarin N=28000 N=22000 Deaths 1695 (6.05%) Deaths 1406 (6.39%) ICH 172 50% mortality = 86 ICH 386 50% mortality = 193

Conclusion Stroke Prevention in Atrial Fibrillation New drugs at least as effective as warfarin (dabigatran 150 better) Risk for major bleeding similar (dabigatran 110 and apixaban better) Risk for ICH lower than warfarin

Acute coronary syndromes (ACS) STEMI

Acute Coronary Syndromes Rivaroxaban (ATLAS) reduced the composite of death+mi+stroke compared to placebo. Significant increase in bleeding, dose-dependent.* Apixaban (APPRAISE-2) stopped due to increase in bleeding. Dabigatran in Phase II (RE-DEEM) dose-dependent increase in bleeding. NOACs not a clear option yet! *Mega J et al. ATLAS ASC 2-TIMI 51. NEJM 2012;366;:9-19.

Medically ill

Prophylaxis of VTE in medically ill Rivaroxaban (MAGELLaN), N=8000 Oral rivaroxaban 10 mg od 35 d Patients >40 y hospitalized for acute medical illness with decreased level of mobility R s.c. placebo 10 d Oral placebo 35 d Follow-up to day 90 s.c. Enoxaparin 40 mg od 10 d Ultrasonography on d 10 primary efficacy outcome NI Ultrasonography on d 35 primary efficacy outcome superiority Cohen A et al. ACC 2011

Results First 10 days riva vs enoxa: similar effect 2.7% in both groups (P=0.0025 for noninferiority), more bleeding Major 0.6% vs 0.3% Clinically relevant bleeding 2.8% vs 1.2% Day 11-35 riva vs placebo: better effect, more bleeding with riva Major 0.5% vs 0.1% Clinically relevant bleeding 1.4% vs 0.5%

More effective Relative risk ratios vs. ext placebo Riva MAGELLAN Major + Clin relevant bleeding 2.0 Worst 1.5 Apixa ADOPT Major VTE 0.1 0.5 1 1.5 2.0 0.5 NOACs not yet recommended in extended prophylaxis Best 0.1

Treatment of DVT & PE

Odds ratios vs warfarin, VTE More effective Major + Clin relevant bleeding 2.0 Worst 1.5 Riva DVT Rec. VTE 0.1 0.5 1 1.5 2.0 apixa 0.5 dabi Riva PE Best 0.1 Safer

More effective Odds ratios vs placebo, VTE extended dabi riva Apixa 2.5 mg Apixa 5 mg Major + Clin relevant bleeding 4.0 2.0 Worst 0.1 0.5 1 1.5 2.0 Rec. VTE 0.5 Best 0.1 Safer

NOACs in the elderly and frail Systematic review of 10 RCTs with 25,031 elderly patients ( 75 y) NOACs vs VKA OR 95% CI Major/CRNM bleed 1.02 0.73-1.43 AND NOACs are more effective to prevent stroke in AF population and more effective against recurrence in the VTE population of elderly Sardar P et al. J Am Geriatr Soc 2014;62:857-64

Universal reversal agent? PER977 is a synthetic small molecule Binds to dabigatran, rivaroxaban, apixaban and edoxaban No adverse events in animals Reduced blood loss in animals Stable at room temperature Solution ready in the ambulance (?) Clinical trials about to start Hankey GJ. Curr Cardiol Rep 2014;16:480.

Overall Conclusion The new agents are predictable Very few drug-drug interactions No need for routine lab monitoring Potential for less bleeding Importantly, fewer ICH in SPAF Major bleedings are manageable Critical issues: renal failure, poor compliance and GI-bleeding tendency