NOAC 2015: What Have We Learned?

NOAC 2015: What Have We Learned? Milan Gupta, MD Canadian Cardiovascular Research Network University of Toronto, McMaster University www.ccrnmd.com

Disclosures Honoraria / Research Grants Abbott, Aegerion Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Miraculins, Novartis, NovoNordisk, Pfizer, Roche, Sanofi, Servier, Takeda Co-author and/or reviewer for 2010, 2012, 2014 CCS AF Guidelines

Key Lesson NOACs are preferred over warfarin

Warfarin in AF: High Efficacy Stroke Death 67% 26% Effect of VKA compared to placebo 1. Hart RG et al. Ann Intern Med. 2007;146:857-867; 2. CCS 2012 AF Guidelines Can J Cardiol. 2012; 28:125-136

Using Warfarin Remains Challenging Only 55% of AF patients without contraindications receive warfarin *1 Mean TTR is low in patients receiving warfarin Rose et al (N=124,551) 2 58% Patients (%) (n=1064) (n=1596) (n=3707) (n=3752) (n=963) Age (y) 11,082 patients with nonvalvular atrial fibrillation 55% overall use 1 Baker et al (N=22,237) Rose et al (N=3104) Sarawate et al (N=470) McCormick et al (N=174) 3 4 5 6 29% 55% 51% 67% 0 20 40 60 80 100 Mean TTR (%) 1. Go AS et al. Ann Intern Med. 1999;131(12):927-934. 2. Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29. 3. Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252. 4. Rose AJ et al. J Thromb Haemost. 2008;6(10):1647-1654. 5. Sarawate C et al. J Thromb Thrombolysis. 2006;21(2):191-198. 6. McCormick D et al. Arch Intern Med. 2001;161(20):2458-2463.

Warfarin use in general practice: Discontinuation Patients using warfarin (%) 100 80 60 40 20 0 0 2 4 Years after starting treatment 6 Age 40 64 yrs Age 65 69 yrs Age 70 74 yrs Age 75 79 yrs Age 80 84 yrs Age 85 + yrs Gallagher AM, et al. J Thromb Haemost 2008;6:1500-6. 432HQ14NP06915-01

New Anticoagulants vs. Warfarin Stroke (ischemic or hemorrhagic) or Systemic Embolism Connolly SJ, et al. N Engl J Med 2009;361:1139-51. Patel MR, et al. N Engl J Med 2011;365:883-91. Granger CB, et al. N Engl J Med 2011;365:981-92. Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

New Anticoagulants vs. Warfarin Major Bleeding Connolly SJ, et al. N Engl J Med 2009;361:1139-51. Patel MR, et al. N Engl J Med 2011;365:883-91. Granger CB, et al. N Engl J Med 2011;365:981-92. Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

New Anticoagulants vs. Warfarin Intracranial Hemorrhage Connolly SJ, et al. N Engl J Med 2009;361:1139-51. Patel MR, et al. N Engl J Med 2011;365:883-91. Granger CB, et al. N Engl J Med 2011;365:981-92. Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

New Anticoagulants vs. Warfarin Mortality Connolly SJ, et al. N Engl J Med 2009;361:1139-51. Patel MR, et al. N Engl J Med 2011;365:883-91. Granger CB, et al. N Engl J Med 2011;365:981-92. Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

Canadian oral anticoagulant use for AF: Gradual increase in OAC use 450 416 400 (thousands) 350 300 250 216 200 150 100 50 200 0 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Prescriptions NOAC (SPAF) Warfarin (50%) OAC (SPAF) NOAC, novel oral anticoagulant; OAC, oral anticoagulant; SPAF, stroke prevention in atrial fibrillation; SPAF Market = Warfarin at 50%, Xarelto 10 mg removed. Source: IMS GPM (May, 2014). 432HQ14NP06915-01

NOACs in 2015

Key Lessons How much AF is enough AF? Special populations Management of bleeding / reversal CCS guidelines 2014

How much atrial fibrillation is atrial fibrillation? Any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or at least 30 seconds on a rhythm strip, should be considered as AF Camm et al. European Heart Journal 2010:31;2369-2429

Even short durations of AF are associated with an increased risk of stroke/se >24 hours: >6 hours: >6 minutes: Increased risk of stroke/se HR: 1.98 (CI 1.11 3.51, p=0.02) Increased risk of stroke/se HR 2.00 (CI 1.13 3.55, p=0.02) Increased risk of stroke/se HR 1.76 (CI 0.99 3.51, p=0.05) Healey et al. N Engl J Med 2012;366:120-9

ARTESiA: Design Pacemaker or implanted defibrillator CHA 2 DS 2 -VASC score >3 1 episode of SCAF lasting 6 minutes (and <24 hours) No history of clinical AF Apixaban 5 mg BD 2.5 mg BD in selected patients Double-blind R 3,719 patients ASA (80 100 mg/day) Primary outcome: ischaemic stroke or SE SCAF, subclinical atrial fibrillation. Clinicaltrials.gov identifier: NCT01938248 432HQ14NP06915-01

Key Lessons How much AF is enough AF? Special populations Management of bleeding / reversal CCS guidelines 2014

Stroke and Bleeding in AF Patients With Moderate CKD (Stage 3) Aspirin-treated patients with Stage 3 CKD vs. egfr 60 ml/min AVERROES Trial Outcome egfr 60 Stage 3 CKD ml/min %/y HR (95%CI) Stroke / SE 2.8 5.6 2.0 (1.4 2.9) Major bleeding All-cause mortality 0.8 2.2 2.6 (1.4 4.9) 3.3 7.1 2.2 (1.6 3.0) Hart RG, et al. Presented at AHA Scientific Sessions, 2011.

Efficacy and safety of NOACs versus warfarin when egfr is 50mL/min Dabigatran 110 mg Dabigatran 150 mg Rivaroxaban Apixaban HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Stroke or SE 0.77 (0.45 1.32) 0.54 (0.30 0.98) 0.84 (0.57 1.23) 0.79 (0.55 1.14) Major bleeding 0.98 (0.67 1.42) 1.01 (0.70 1.46) 0.95 (0.72 1.26) 0.50 (0.38 0.66)* 0 1 2 0 1 2 0 1 2 0 1 2 Favours Favours Favours Favours Favours Favours Favours Favours dabigatran warfarin dabigatran warfarin rivaroxaban warfarin apixaban warfarin Head-to-head studies do not exist, and direct comparisons between agents may not be made *p for interaction = 0.03. egfr, estimated glomerular filtration rate. Extracted from: Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959-73.

Efficacy and safety of NOACs versus warfarin in the 75 age group Dabigatran 110 mg Dabigatran 150 mg Rivaroxaban Apixaban HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Stroke or SE 0.88 (0.66 1.17) 0.67 (0.49 0.90) 0.80 (0.63 1.02) 0.71 (0.48 0.99) Major bleeding 1.01 (0.83 1.23)* 1.18 (0.98 1.42)* 1.11 (0.92 1.34) 0.63 (0.48 0.82) ICH 0.37 (0.21 0.64) 0.42 (0.25 0.70) 0.80 (0.50 1.28) 0.33 (0.17 0.63) 0 1 2 0 1 2 0 1 2 0 1 2 Favours Favours Favours Favours Favours Favours Favours Favours dabigatran warfarin dabigatran warfarin rivaroxaban warfarin apixaban warfarin Head-to-head studies do not exist, and direct comparisons between agents may not be made * Significant interaction p<0.001. ICH, intracranial haemorrhage. Extracted from: Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959-73.

NOACs and renal function All 3 agents are partly excreted by kidney (unlike warfarin) This is particularly true for dabigatran (80%) No new agent should be used for CrCl < 25-30 (warfarin) Rivaroxaban 15 mg od may be used for CrCl 30-50, Apixaban 2.5 mg bid for increased bleeding risk Renal function should be monitored periodically in all patients receiving new agents (Q6-12 months and with acute illness)

Key Lessons How much AF is enough AF? Special populations Management of bleeding / reversal CCS guidelines 2014

NOAC bleeding management strategies are similar to those for VKAs Bleeding while using a NOAC Mild bleeding Moderate/severe bleeding Life-threatening bleeding Delay next dose or discontinue Reconsider concomitant medication + Supportive measures Mechanical compression Surgical haemostasis Fluid replacement (colloids if needed) RBC substitution if needed Fresh frozen plasma (as plasma expander) Platelet substitution (if platelet count 60 10 9 /L) + Consider PCC 25 U/kg; repeat 1 /2 if indicated apcc 50I E/kg; max 200 IE/kg/day rfviia 90 µg/kg Additional options for dabigatran Maintain adequate diuresis Consider haemodialysis apcc = activated prothrombin complex concentrates; PCC = prothrombin complex concentrates; rfviia = recombinant Factor VIIa Adapted from Heidbuchel H et al. Europace 2013;15:625 51

Assessing coagulation status with NOACs for specific situations Test Dabigatran Rivaroxaban Apixaban Specific HEMOCLOT Anti-Xa Anti-Xa aptt Nonspecific PT TT No effect No effect PT = prothrombin time; TT = thrombin time Personal communication John Eikelboom

Apixaban and dabigatran: 30-Day Mortality Rate after a Major Bleed 1.2 1.0 Apixaban - ARISTOTLE Mortality (%) 0.2 Major ECH associated with apixaban led to less hospitalization or intervention Dabigatran Pooled analysis Mortality (%) 30-day mortality for treatment groups combined 0.8 0.6 HR=0.50; 95% CI 0.33 0.74 Warfarin 0.1 aor=0.56; 95% CI 0.36 0.86; p=0.009 Warfarin 0.4 0.2 Apixaban Dabigatran (combined) Months since first dose Time (days) 0 0.0 0 6 12 18 24 30 0 5 10 15 20 25 30 35 ECH, extracranial haemorrhage Hylek et al. JACC 2014;63:2141 2147 Majeed A et al. Circulation 2013;128:2325 2332

Specific reversal agents in development for novel oral anticoagulants Company Portola Pharmaceuticals Boehringer Ingelheim Compound Reversal for: Status PRT064445/ (andexanet alfa) BI 655075 (idarucizumab) Factor Xa inhibitor Universal No Factor IIa inhibitor No Specific for dabigatran LMWH/ fondaparinux Yes (antithrombinmediated Factor Xa inhibition) Perosphere, Inc. PER977 Universal Universal Universal No Phase II ongoing; 1 phase III started (apixaban/ rivaroxaban); 2 planned (edoxaban) 2 Phase I completed; 3 phase III started 4 Phase I completed 5 1. clinicaltrials.gov, NCT01758432; 2. Portola Pharmaceuticals, 2014; 3. clinicaltrials.gov NCT01688830; 4. clinicaltrials.gov, NCT02104947; 5. clinicaltrials.gov, NCT01826266

Procedural Bleeding Risks LOW (2-DAY RISK OF MAJOR BLEED 0% 2%) Cholecystectomy Abdominal hysterectomy GI endoscopy +- biopsy Pacemaker/defibrillator insertion Simple dental extractions Knee/hip replacement and shoulder/foot/hand surgery Dilatation and curettage Skin cancer excision Hemorrhoid surgery Cataract/no cataract eye surgery HIGH (2-DAY RISK OF MAJOR BLEED 2% 4%) Heart valve replacement Coronary artery bypass Abdominal aortic aneurysm repair Neurosurgical/urologic/head and neck/abdominal/breast cancer surgery) Bilateral knee replacement Transurethral prostate resection Kidney biopsy Vascular and general surgery Any major operation Spyropoulos AC & Doukatis JD. Blood. 2012; 120(15):2954 2961. Prepared by Pfizer-BMS alliance in response to an unsolicited request Not for further distribution 28

A guidelines based approach to AF management Days of withdrawal prior to high bleeding risk procedure egfr ml/min/m 2 apixaban dabigatran rivaroxaban 80 2-3 2-3 2-3 50-80 2-3 3 2-3 30-50 2-3 4 2-3 < 30* 2-3 5 2-3 2014 Focused Update CCS AF Guidelines Can J Cardiol (in press) www.ccs.ca Atrial Fibrillation Guidelines

Key Lessons How much AF is enough AF? Special populations Management of bleeding / reversal CCS guidelines 2014

Comparison of SPRINT-AF (Phase 1) to major OAC registries and RCT s Clinical factor SPRINT-AF* RE-LY ROCKET-AF ARISTOTLE ORBIT-AF Male 62.1% 63.6% 60.3% 64.7% 57% Age 75.7(67.5, 83) 71.5 ± 8.7 73 (65, 78) 70 (63, 76) 75 (68, 82) Hypertension 73.6% 78.9% 90.5% 87.4% 85% Diabetes 29.7% 23.3% 39.9% 24.9% 30% Stroke or TIA 15% 20.0% 54.8% 19.4% 8.5% HF 18.8% 32.0% 62.5% 35.5% 34% Previous MI 16.2% 16.6% 17.3% 14.2% 14.3% Non-Paroxysmal AF 70.3% 67.2% 82.1% 84.7% 50% CHADS 2 2 64.5% 68.1% 100% 66.0% 75% GFR (ml/min/m 2 ) 64 (56, 80) - 67 (52, 86) - 70 (51, 97) Antiplatelet use 27% 39.7% 36.5% 32.8% 34.6% PPI use 26.6% 13.8% - - -

SPRINT-AF: Agreement of between clinician-reported and calculated CHADS 2, CHADS 2 - VASC, and HAS-BLED scores Clinician-reported risk vs. Weighed Kappa (95% CI) CHADS 2 0.42 (95% CI: 0.35, 0.50) CHADS 2 - VASC 0.21 (95% CI: 0.15, 0.28) HAS-BLED 0.14 (95% CI: 0.07, 0.21) CHADS 2 (amongst clinicians who assess risk with CHADS 2 ) HAS-BLED (amongst clinicians who assess risk with HAS-BLED) 0.45 (95% CI: 0.36, 0.54) 0.11 (95% CI: 0.01, 0.27)

The CCS Algorithm for OAC Therapy in AF Age 65 YES OAC* NO Prior Stroke/SE/TIA or Hypertension or Heart failure or Diabetes Mellitus (CHADS 2 risk factors) YES OAC* Consider and modify (if possible) all factors influencing risk of bleeding on OAC (hypertension, antiplatelet drugs, NSAIDs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low egfr, age 75, low body weight)** NO **may require lower dosing CAD or Arterial vascular disease YES ASA (coronary, aortic, peripheral) NO No Antithrombotic We suggest that a NOAC be used in preference to warfarin for non-valvular AF. www.ccs.ca Atrial Fibrillation Guidelines

Summary of Key Lessons Patients > 65y and those with any CHADS risk factor should receive OAC. NOACs are generally preferred over warfarin. Stroke risk is increased with as little as 6 mins of AF whether patients with short AF duration deserve OAC is being studied. NOAC s have consistent efficacy and safety in CKD and in those > 75 y Bleeding on NOACs should be managed as per standard care mortality following a major bleed is lower on NOAC vs. warfarin. Specific antidotes are in development.