NOACs Update PD Dr. Jan Steffel Leitender Arzt, Klinik für Kardiologie Co-Leiter Rhythmologie Universitätsspital Zürich

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1 NOACs Update 2016 PD Dr. Jan Steffel Leitender Arzt, Klinik für Kardiologie Co-Leiter Rhythmologie Universitätsspital Zürich

2 Conflict of Interest Statement o o o o Consulting: Amgen, Astra Zeneca, AtriCure, Bayer, Biosense Webster, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Daiichi-Sankyo, Medtronic, Pfizer, Sanofi-Aventis, SJM Speaker honoraria: Astra Zeneca, Bayer, Biosense Webster, Biotronik, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Pfizer, Roche, Sanofi-Aventis, SJM, Sorin, Zoll Grants (through institution): Bayer, Biotronik, Boston Scientific, Daiichi- Sankyo, Medtronic, St. Jude Medical Co-president CorXL o Collaboration with TIMI study group (ENGAGE AF-TIMI 48)

3 Phase III AF trials: All-cause mortality Relative Hazard Ratio (95% CI) RE-LY: 110 mg BID RE-LY: 150 mg BID Dabigatran ROCKET-AF: 20 mg QD Rivaroxaban (safety AT) ARISTOTLE: 5 mg BID Apixaban ENGAGE-AF: 30 mg QD ENGAGE-AF: 60 mg QD Edoxaban P=0.13 P=0.051 P=0.073 P=0.047 P=0.006 P= Favors NOAC Favors warfarin For illustrative purpose only! No head-to-head comparisons! 1. Connolly et al. N Engl J Med 2009;361: ; 2. Patel et al. N Engl J Med 2011;365: Granger et al. N Engl J Med 2011;365: ; 4. Giugliano et al. N Engl J Med 2013; e-pub ahead of print

4 Real Life Data aims to complement Clinical Trial Data Clinical trial RLE study Patients are selected by stringent protocol criteria Treatment / observation is defined in the protocol Methodology aims for reducing bias when a randomized design is used Patients are selected by the treating physician Over- and under-reporting of events possible Observation of real-life subgroups possible

5 FDA Study on Medicare Patients FDA, Mai

6 XANTUS: Study Objective and Design Objective: Prospective Real world study on the safety profile of rivaroxaban in patients wit nvaf N=6,784 Population: Consecutively enrolled adult patients with NVAF receiving rivaroxaban for stroke/non- CNS SE prevention Rivaroxaban: treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature Final visit: 1 year # Primary outcomes: major bleeding (ISTH definition), all-cause mortality, any other adverse events Secondary outcomes: symptomatic thromboembolic events (stroke, SE, TIA) and MI, non-major bleeding events (all adjudicated centrally by an independent committee (CAC ) blinded to individual patient data) * Exact referral dates for follow-up visits not defined (every 3 months recommended) # For rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed 1. Camm AJ, et al, Vasc Health Risk Manag Camm AJ, et al, Eur Heart J 2015.

7 REVISIT-US - Significant Reduction in the Combined Endpoint for Rivaroxaban vs. VKA Rivaroxaban was associated with a Significant 47% reduction in ICH vs. VKA Comparable rate of ischemic stroke vs. VKA Significant 39% reduction in the combined endpoint of ICH and ischemic stroke vs. VKA Rivaroxaban VKA HR (95% CI) Rivaroxaban vs. VKA Rate (%/year) Rate (%/year) HR (95% CI) Rivaroxaban vs. VKA ICH ( )* Ischemic stroke ( ) Combined ( )* *p<0.05 vs. VKA 0,125 0,25 0, Favors Rivaroxaban Favors VKA L.CH.MKT.HC DE Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at:

8 Unadjusted major bleeding incidence (% / year) US retrospective real-world database research (MarketScan commercial & Medicare supplemental database) Unadjusted incidence rates of major bleeding (in-patient bleeding per 100 person-year) and adjusted HR 1* for apixaban vs warfarin Adapted from Lip et al Adjusted HR=0.52 (95% CI: ) 4.66 % Warfarin (n=12,713) 2.35 % Apixaban (n=2,402) Data from retrospective real-world research, not a randomised controlled trial Of the 2,402 apixaban patients, 85.6% received apixaban 5 mg BD *Cox-proportional hazards model was used to assess the risk of first major bleed across index OAC prescription categories, adjusted for age, gender, region, embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of stroke or transient ischaemic attack, history of bleeding, Charlson comorbidity index, and co-medications at baseline. Lip GYH et al. Real world comparison of major bleeding risk among non-valvular atrial fibrillation patients newly initiated on apixaban, dabigatran, rivaroxaban or warfarin. Poster presented at: ESC Congress; 29 August 2 September, 2015: London, UK. Poster P6217.

9 Net clinical benefit: CHADS-VASC vs. HAS-BLED Event rates / 100 pys for ischemic stroke and intracranial hemorrhage were calculated using data from the Danish study population for patients on no treatment and on warfarin Using data from recent trials of the new OACs, the event rates for ischemic stroke and intracranial hemorrhage were estimated for the Danish population Banerjee et al., Thromb & Hemost 2012

10 Net clinical benefit: CHADS-VASC vs. HAS-BLED Banerjee et al., Thromb & Hemost 2012

11 Net clinical benefit: CHADS-VASC vs. HAS-BLED Banerjee et al., Thromb & Hemost 2012

12 Idarucizumab Enriquez et al., Europace 2014

13 REVERSE-AD Pollack et al., NEJM 2015

14 REVERSE-AD Pollack et al., NEJM 2015

15 Andexanet Alfa Reversal of anticoagulation by factor Xa inhibitors 1 S419 Factor Xa Inhibitor A419 Factor Xa Inhibitor GLA Catalytic Domain GLA S Factor Xa S S S Andexanet Alfa Recombinant engineered version of human factor Xa Acts as a factor Xa decoy High affinity for all direct factor Xa inhibitors Changed in a way that catalytic activity is eliminated (serine alanine) and prothrombin cleavage is prevented GLA domain removed to prevent anticoagulation effect 1. Lu G, et al. Nature Medicine 2013;19(4):446-51

16 ANNEXA-A / ANNEXA-R Siegal et al., NEJM 2015

17 PROTECT-AF long-term data Reddy et al., JAMA 2014

18 PROTECT-AF long-term data Reddy et al., JAMA 2014

19 PREVAIL over time Waksman and Pendyala. AJC 2015

20 Summary and Take Home Message NOACs are standard therapy for stroke prevention in AF Real World data very consistent Net Clinical Benefit matters for patients! Direct antagonists are available (idarucizumab) or just around the corner (for Xa inhibitors) LAA occluder: Good option for special patient populations (esp contraindicated for anticoagulation)

21 NOACs Update 2016 PD Dr. Jan Steffel Leitender Arzt, Klinik für Kardiologie Co-Leiter Rhythmologie Universitätsspital Zürich

22 LAAOs vs. NOACs NOACs in real world vs. LAAO in real world (efficacy and safety) Not all AF is created equal o Valvular vs. non-valvular o "Paroxysmal" vs. "Persistent" many shortcomings! Careful in extrapolating "off-label" use of NOACs and LAAOs o No data for patients with contraindication for anticoagulation (PROTECT-AF vs. ASAP) Careful in extrapolating (rather) small scale trials to the entire AF population, and combining trial results

23 LAAOs vs. NOACs NOACs in real world vs. LAAO in real world (efficacy and safety) Not all AF is created equal o Valvular vs. non-valvular o "Paroxysmal" vs. "Persistent" many shortcomings! Careful in extrapolating "off-label" use of NOACs and LAAOs o No data for patients with contraindication for anticoagulation (PROTECT-AF vs. ASAP) Careful in extrapolating (rather) small scale trials to the entire AF population, and combining trial results All strokes from LAA? How does LAAO compare with NOACs? o Beware of cross-trial comparisons Only a well-designed RCT will answer this question!

24 ENGAGE-AF: "Increased Risk of Falls" In ENGAGE-AF, investigators prospectively categorized patients as having an increased risk of falling particularly if they had any of the following 8 criteria at randomization: A prior history of falls Lower extremity weakness Poor balance Cognitive impairment Orthostatic hypotension Use of psychotropic drugs Severe arthritis Dizziness Steffel et al., submitted (presented at AHA 2015)

25 Edoxaban versus Warfarin in Patients with an Increased Risk of Falls Fall Risk No Fall Risk (n = 900, 4%) (n = 20205, 96%) p-value Male gender 51% 62% <0.001 Age (years) <0.001 CHADS 2 score (mean) <0.001 CHA 2 DS 2 VASc score (mean) <0.001 CHADS 2 score >3 39% 22% <0.001 History of Stroke (incl. TIA) 41% 28% <0.001 CrCl (ml/min, median) <0.001 TTR (warfarin arm, median) Steffel et al., submitted (presented at AHA 2015)

26 Edoxaban versus Warfarin in Patients with an Increased Risk of Falls ahr 1.2 ( ) 2,7 1,8 Stroke/SEE ahr 1.4 ( ) 9,1 5,1 *** All cause death / Stroke / SEE ahr 1.5 ( ) 7,1 3,9 All-cause death *** ahr 1.3 ( ) 4,7 2,7 * At risk ahr 1.4 ( ) 0,9 0,5 Not at risk 4,7 ahr 1.9 ( ) 1,7 Major bleed ICH Bone Fracture due to Fall *** Steffel et al., submitted (presented at AHA 2015)

27 Edoxaban versus Warfarin in Patients with an Increased Risk of Falls ,8 HDE At risk 10,0 9,3 Warfarin At risk 7,8 HDE Not at risk 7,1 Warfarin Not at risk 5,4 5,4 5,6 4,8 3,9 4,2 2,8 1,5 1,8 Stroke/SEE All cause death/stroke/see All-cause death Majo Steffel et al., submitted (presented at AHA 2015)

28 Edoxaban versus Warfarin in Patients with an Increased Risk of Falls Steffel et al., submitted (presented at AHA 2015)