AF in Clinical Practice: Personalizing the Management of Atrial Fibrillation and Venous Thromboembolism

Transcription

1 AF in Clinical Practice: Personalizing the Management of Atrial Fibrillation and Venous Thromboembolism

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Steering Committee George Honos, MD Clinical Conundrums Program Chair Cardiologist Chief of cardiology Medical Director of CV Program, CHUM Associate Professor of Medicine, Université de Montréal Montreal, Quebec Benjamin Bell, MD Internist Staff General Internist North York General Hospital Lecturer, University of Toronto Member, Thrombosis Canada Toronto, Ontario Paul Dorian, MD Cardiologist Director, Division of Cardiology Professor of Medicine St. Michael's Hospital University of Toronto Toronto, Ontario Jeffrey Habert, MD Family Physician Assistant Professor University of Toronto Dept. of Family and Community Medicine Toronto, Ontario Pierre Julien, MD Family Physician Fédération des médecins omnipraticiens du Québec Saint-Eustache, Quebec Sylvain Lanthier, MD Neurologist Neurovascular Program, CHUM Associate Professor, University of Montreal Montreal, Quebec L. Brent Mitchell, MD Cardiac Electrophysiologist Professor, Department of Cardiac Sciences Libin Cardiovascular Institute of Alberta University of Calgary Calgary, Alberta Daniel Ngui, MD Family Physician Clinical Lead, Fraser Street Medical Clinical Associate Professor UBC Department of Family Medicine Vancouver, British Columbia Daniel Paquette, MD Directeur adjoint Direction de la formation professionnelle Fédération des médecins omnipraticiens du Québec Montreal, Quebec Andre Roussin, MD Internist Associate professor of Medecine Assistant head, Internal medecine service Director of the Vascular laboratory, CHUM-HND University of Montreal CHUM and Montreal Heart Institute Montreal, Quebec

4 Learning Objectives Upon completion of this activity, participants should be able to: Select personalized treatment options for stroke prevention in atrial fibrillation using current Canadian Practice Guidelines supplemented with reassuring Real World experience Assess and optimally manage bleeding risks in patients perioperatively or with a past history of a gastrointestinal bleed Determine optimal antithrombotic therapy in AF patients with specific and common co-morbidities, including advanced age, prior stroke or TIA, worsening renal function, CAD, or risk of noncompliance with medical therapy

5 Atrial Fibrillation (AF) and Stroke...The Facts AF affects 1-2% of Canadians and prevalence increases with age 1 About 6% of Canadians over age 65 years live with AF AF is an independent predictor of stroke (RR = 5) 2 AF accounts for 15% - 20% of all strokes 3 Individuals with paroxysmal, persistent or permanent AF are all at increased risk of stroke AF AGE STROKE AF is the leading preventable cause of stroke AF is not diagnosed until after CVA in ⅓ of AF strokes 4 Subclinical (asymptomatic) AF accounts for about 10% of cryptogenic strokes AF related embolic strokes are often severe: 25% mortality, 60% disabled 5 AF patients with an absolute risk of embolic stroke of > 1.5% per year require longterm anticoagulation represents over 95% of Canadians with AF 6 1. Heart and Stroke Foundation of Canada web site 2. AFib Invest Group Arch Intern Med Singer DE et al. Chest Sanna T et al NEJM 2014;370: Sally Lee et al. BMJ Open 2011;1:e CCS AF Guidelines. Can J Cardiol. 2014; 30:

6 Stroke Results in Significant Disability 22% of men and 25% of women who have a stroke die within a year 51% of men and 53% of women under the age of 65 who have a stroke die within 8 years Of patients still alive at 6 months, about one third are dependent on others for help with daily activities The majority of stroke survivors need community services such as physiotherapy, occupational and speech/language therapy Thom T, et al. American Heart Association. Circulation 2006; 113: e85 e151

7 Stroke severity in patients with AF % of patients Effect of first ischemic stroke in patients with AF (n=597) 1 60% 50% 40% 30% 20% 10% 0% Gladstone DJ et al. Stroke. 2009; 40: Disabling Fatal

8 AF-Related Strokes Are More Severe Among patients who had a stroke, those with AF experienced a: 70% increase in in-hospital mortality ** *The Copenhagen stroke study, a prospective community-based study. n=1,197 **In hospital mortality: 72 deaths, n=217 with AF vs. 171 deaths n=968 without AF Discharge to own home: n=104 with AF vs. 662 deaths n=968 without AF Length of hospital stay: 50.4 days with AF vs days without AF Jorgensen, et al. Stroke 1996;27: % decrease in the relative chance of discharge to own home 20% increase in the length of hospital stay compared to those without AF

9 Facts About Atrial Fibrillation (AF) Approx. 350,000 Canadians are living with AF 1 ~ 6% of the population >65 years of age live with AF 2 After the age of 55, the risk of developing AF doubles every 10 years 2,3 25% of Canadians >75 years of age will develop AF 4 AF is an independent predictor of stroke (RR = 5) 4 AF accounts for 15% - 20% of all strokes 4, 1. Canadian Heart and Stroke Foundation. 2. Sacco, et al. Stroke. 1997;28(7): ; 3. Benjamin, et al. JAMA. 1994;271:840-4; 4. Canadian Stroke Prevention Intervention Network.

10 Risk of stroke in AF patients AF increases the risk of ischemic stroke by 3 to 5 times 1 25 % 23.5 % 9.9 % 0 % 1.5 % 2.8 % yr yr yr yr ~ 20% of all strokes are caused by AF 2 Risk of stroke in AF patients by age group 2 1. European Heart Rhythm Associations, et al. Eur Heart J. 2010;31(19): Wolf PA, et al. Stroke. 1991;22(8):983-8

11 Case-fatality rate Bedridden patients (%) AF patients have increased post stroke mortality and morbidity With AF Without AF Mortality Morbidity 41.2 % % days 1 year 0 With atrial fibrillation Without atrial fibrillation Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-23; Marini C, et al. Stroke. 2005;36(6):

12 Incidence of Stroke in Paroxysmal is as High as Sustained AF in Patients Taking OAC or Combined Antiplatelet Therapy The RR of paroxysmal AF compared to sustained AF was 0.94 (95% CI 0.63 to 1.40, p =0.755) Stroke risk same, irrespective of AF type N=6706 AF patients Hohnloser SH, Pajitnev D, Pogue J, et al. J Am Coll Cardiol. 2007;50(22): Copyright Canadian Heart Research Centre This presentation may not be reproduced without written authorization from the Canadian Heart Research Centre

13 Figure 4 Probability of detection of paroxysmal AF based on the number of atrial premature beats (APB) Gladstone et al. Stroke. 2015;46:

14 Embolic Stroke The Facts Vitamin K antagonist therapy (e.g. warfarin) reduces risk by 66% Non vitamin K antagonist Oral Anticoagulants (NOACs) are as effective or even superior with less risk of intracerebral bleeding Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365: Rietbrock S,. Am Heart J.2008;156:57 64

15 Comparison of NOACs vs. warfarin for prevention of stroke Stroke or systemic embolism Apixaban 5 mg BID Dabigatran 110 mg BID Dabigatran 150 mg BID Superiority P-value <0.001 Rivaroxaban 20 mg OD 0.12 Ischemic stroke 0.92 Superiority P-value Apixaban 5 mg BID Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg OD HR (95% Cl) COMPARATOR BETTER WARFARIN BETTER Conolly SJ, et al. N Engl J Med. 2010;363:1875-6; Patel MR, et al. N Engl J Med. 2011;365:883-91;

16 Comparison of NOACs vs. warfarin for bleeding risk Intracranial hemorrhage Apixaban 5 mg BID Dabigatran 110 mg BID Superiority P-value <0.001 <0.001 Dabigatran 150 mg BID Rivaroxaban 20 mg OD Major bleeding < Superiority P-value Apixaban 5 mg BID Dabigatran 110 mg BID 0.80 < Dabigatran 150 mg BID Rivaroxaban 20 mg OD HR (95% Cl) 1.25 COMPARATOR BETTER WARFARIN BETTER Conolly SJ, et al. N Engl J Med. 2010;363:1875-6; Patel MR, et al. N Engl J Med. 2011;365:883-91; Granger CB, et al. N Engl J Med. 2011;365:

17 Balancing Stroke Prevention and Bleeding Risk BLEEDING RISK Older age Female sex Uncontrolled hypertension Diabetes mellitus Decreased renal function (CrCl <85 ml/min/1.73 m 2 ) Prior stroke History of bleeding Anemia (hematocrit <40%) ASA or NSAIDs use SSRI/SNRI History of labile INR STROKE PREVENTION WITH NOAC The benefits of taking new oral anticoagulant (NOAC) therapy for stroke prevention outweigh the risk of bleeding in most cases, and the focus should be on reversing modifiable causes of bleeding. Skanes et al. Can J Cardiol 2012;28(2):

18 Prediction of Stroke in NVAF: CHADS 2 Stroke rate/ 100 patient-years CHADS 2 Gage BF et al. JAMA 2001;285:

19 The CCS Algorithm for OAC Therapy in AF Age 65 NO YES OAC* Stroke/TIA/peripheral embolism or Hypertension or Heart failure or Diabetes Mellitus (CHADS 2 risk factors) NO CAD or Arterial vascular disease (coronary, aortic, peripheral) NO YES YES OAC* ASA No Antithrombotic Therapy CCS AF Guidelines. Can J Cardiol. 2016; 32:

20 Operational Definition of Non Valvular Atrial Fibrillation (NVAF) Valvular AF includes : Mechanical heart valve Rheumatic moderate or severe mitral valve stenosis (MS) * NVAF therefore includes : Mitral regurgitation (MR) Aortic stenosis (AS) Aortic insufficiency (AI) Remote (3-6 months) tissue prosthetic heart valve Remote (3-6 months) surgical valve repair * It is uncertain whether patients with only mild MS or post mitral commissurotomy should be regarded as Valvular AF. Macle L et al. Can J Cardiol 31: , 2015 De Caterina R, et al. Eur Hear J 2014;35:

21 NOACs vs Warfarin RCTs Baseline Characteristics RE-LY a (Dabigatran) ROCKET-AF b (Rivaroxaban) ARISTOTLE c (Apixaban) ENGAGE AF d (Edoxaban) Randomized, N 18,113 14,264 18,201 21,105 Age, y 72±9 73 [65-78] 70 [63-76] 72 [64-78] Female, % Paroxysmal AF, % VKA naive, % Aspirin use, % CHADS a. Connolly SJ, et al. N Engl J Med. 2009;361: [3]; b. b. Patel MR, et al. N Engl J Med. 2011;365: [4]; c. c. Granger CB, et al. N Engl J Med. 2011;365: [5]; d. d. Giuliano RP, et al. N Engl J Med. 2013;369: [6]

22 Efficacy and Safety of NOACs SSE NOAC (events) Warfarin (events) RR (95% Cl) ARISTOTLE 212/ / ( ) RE-LY* 134/ / ( ) ENGAGE AF-TIMI 296/ / ( ) 0.10 ROCKET AF 269/ / ( ) 0.12 Combined (random) 911/ / ( ) < Heterogeneity: I 2 =47%, p=0.13 Major Bleeding NOAC (events) Warfarin (events) Favours NOAC Favours Warfarin RR (95% Cl) ARISTOTLE 327/ / ( ) < RE-LY* 375/ / ( ) 0.34 ENGAGE AF-TIMI 444/ / ( ) ROCKET AF 395/ / ( ) 0.72 Combined (random) 1541/ / ( ) 0.06 p p Heterogeneity: I 2 =83%, p= Favours Favours NOAC Warfarin Data are n/n unless otherwise indicated. RR: risk ratio; SSE: stroke or systemic embolism. *Dabigatran 150 mg twice daily; Rivaroxaban 20 mg once daily; Apixaban 5 mg twice daily; Edoxaban 60 mg once daily. 1. Ruff et al. Lancet. 2014;383:

23 Reducing the Risk of ICH: A Major Advantage of NOACs In comparison to VKA, NOACs reduce ICH risk by half (RR: 0.48 [95% CI: ]) 1 Intracranial hemorrhage Study or Subgroup Risk Ratio 95% CI Risk Ratio 95% CI Apixaban 5 mg BID [0.30, 0.58] Dabigatran 110 mg BID [0.20, 0.47] Dabigatran 150 mg BID [0.27, 0.60] Edoxaban 30 mg QD [0.21, 0.43] Edoxaban 60 mg QD [0.34, 0.63] Rivaroxaban 20 mg QD [0.47, 0.93] Favours NOAC Favours Warfarin CI: confidence interval; RR: relative risk. 1. Ruff et al. Lancet. 2014;383:955-62; 1. Granger et al. N Engl J Med. 2011;365:981-92; 2. Connolly et al. N Engl J Med. 2009;361: ; 3. Giugliano et al. N Engl J Med. 2013;369: ; 4. Patel et al. N Engl J Med. 2011;365:

24 NOACs as Compared to Warfarin Indirect Comparisons from the Clinical Trials APIXABAN 1 (ELIQUIS) DABIGATRAN (PRADAXA) DABIGATRAN (PRADAXA) EDOXABAN 60 (LIXIANA) RIVAROXABAN 3 (XARELTO) Stroke/SE Major Bleed Intracranial Bleed GI Bleed All Cause Death To date there are no head-to-head trials between apixaban, dabigatran, edoxaban and rivaroxaban, therefore comparative efficacy and safety have not been established Significant Increase Significant Reduction Non-Significant Difference 1. Granger et al., NEJM 2011; 365: Connolly et al., NEJM 2009; 361: Patel et al., NEJM 2011; 365: Giuliano RP et al NEJM 2013; 369:2091

25 Stroke Prevention in AF: Clinical Pharmacology and Dosing of NOACs APIXABAN (ELIQUIS) DABIGATRAN (PRADAXA) EDOXABAN (LIXIANA) RIVAROXABAN (XARELTO) Mechanism of action Direct Factor Xa inhibitor Direct thrombin inhibitor Direct Factor Xa inhibitor Direct Factor Xa inhibitor Oral bioavailability ~50% ~6.5% 62% % Pro-drug No Yes No No Food effect No No No Yes (needs to be taken with food) Renal clearance ~27% 85% 50% 36% * Mean half-life (t 1/2 ) ~12 h 11-17h 10-14h 5-13 h T max 3-4 h h 1-2h 2-4 h Recommended daily dose Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, Daiichi Sankyp Inc. Lixiana (edoxaban) Product Monograph. November 2, mg BID 150 mg BID 60 mg QD 20 mg QD * Rivaroxaban is 66% renally cleared and its active metabolite is 36% renally cleared

26 Considerations for Dosing of NOACs NOAC APIXABAN (ELIQUIS) DABIGATRAN (PRADAXA) EDOXABAN (LIXIANA) USUAL STARTING DOSE DOSING ADJUSTMENT CRITERIA 5 mg BID 2.5 mg BID if any 2 of the following criteria: - Age 80 years - Body weight 60 kg - Creatinine 133 μmol/l 150 mg BID 60 mg OD 110 mg BID if - Age >80 or - > 75 + one hemorrhagic risk factors or CrCl ml/min 30 mg OD if - If CrCl ml/min or - body weight 60 kg or - concomitant use of P-gp inhibitors (ex: quinidine, dronedarone) except amiodarone and verapamil RIVAROXABAN (XARELTO) 20 mg OD taken with food 15 mg OD taken with food if - CrCl ml/min Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, Daiichi Sankyp Inc. Lixiana (edoxaban) Product Monograph. November 2, 2016.

27 Bleeding-related Mortality RESEARCH ARTICLE Risk of Fatal Bleeding in Episodes of Major Bleeding with New Oral Anticoagulants and Vitamin K Antigonists: A Systematic Review and Meta-Analysis NOAC VKA Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Atrial fibrillation population ARISTOTLE ,9% 0.86 (0.33, 1.35) ENGAGE AF-TIMI ,0% 0.67 (0.46, 1.00) J-ROCKET AF ,9% 0.36 (0.04, 3.76) RE-LY % 0.74 (0.45, 1.23) ROCKET AF % 0.44 (0.27, 0.72) Subtotal (95%) % 0.66 (0.52, 0.84) Total events Heterogeneity: Tau 2 = 0,01; Chi 2 = 4,40, df= 4 (P= 0,35); 1 2 = 9% Test for overall effect: Z = 3,39 (P = 0,0007) Major bleeds occurring on NOAC therapy are 34% less likely to lead to death than bleeds occurring with VKAs Hylek EM, et al. J Am Coll Cardiol 2014; 63(20): Piccini JP, et al. Eur Heart J 2014; 35(28): Giuliano RP et al NEJM 2013; 369:2091 Majeed A, et al. Circulation 2013; 128(21): PLoS One, 2015; 10(9):e Published online 2015 Setp 18. doi: /journal.pone

28 Backup slide with fatal bleeding of NOACs vs VKAs in AF and VTE populations Fig 3. Relative Odds for fatal bleeding in treatment indication subgroups. Skaistis J, Tagami T (2015) Risk of Fatal Bleeding in Episodes of Major Bleeding with New Oral Anticoagulants and Vitamin K Antagonists: A Systematic Review and Meta-Analysis. PLoS ONE 10(9): e doi: /journal.pone

29 NOACs Indirect Comparisons Risk of Major Bleed / yr (%) without ASA RELY- 110 NO ASA RELY ASA RELY- 150 NO ASA RELY ASA ROCKET- AF NO ASA ROCKET -AF + ASA ARISTO TLE NO ASA ARISTOT LE + ASA ENGAG E NO ASA WARFARIN ENGAGE + ASA NOACs Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365:

30 AVERROES Study Overall Risk Overall Risk STROKE or Systemic Embolism RR 0.45 (CI to 95 % 0.32 to 0.62) p < Months ASA 3.7 % apixaban 1.6% Major Hemorrhage Months Mean CHADS 2 score at the start : 0-1 : 36 %; 2 : 36 %; 3+ : 28 % 0,0 0,005 0,010 0,015 0,020 RR 1.13 (CI to 95 %, 0.74 to 1.75) p = 0.57 apixaban 1.4 % ASA 1.2 % N=5999 Connolly SJ, et coll. N Engl J Med 2011; 364:

31 NOAC Indirect Comparisons Risk of Major Bleed / yr (%) w/wo ASA RELY- 110 NO ASA RELY ASA RELY- 150 NO ASA RELY ASA ROCKET- AF NO ASA ROCKET -AF + ASA ARISTO TLE NO ASA ARISTOT LE + ASA ENGAG E NO ASA WARFARIN ENGAGE + ASA NOACs Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365: P value not available

32 Major Bleeding (% / Year) Effect of adding double antiplatelet therapy (DAPT) to Warfarin or a NOAC Warfarin dabi-110 dabi No AP = No antiplatelet agent SAP = Single antiplatelet DAP = Dual antiplatelet Active A Writing Group. N Engl J Med 2009;360: Dans Al et al. Circulation 2013;127:634-40

33 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

34 NOAC Antidotes Clinical Trials Andexanet a (PRT064445) Aripazine b (PER977) Antidote for factor Xa inhibitors Recombinant protein binding to factor Xa inhibitor site Antidote for factor Xa inhibitors, direct thrombin inhibitors, low molecular-weight heparins, and fondaparinux Synthetic small molecule; reversal effect through direct binding to anticoagulant Idarucizumab c (BI ) Antidote for direct thrombin inhibitors Fully humanized antibody fragment a. Clinicaltrials,gov; NCT ; b Dolgin E. Nat Med. 2013;19:251(17), c, Clinicaltrials.gov;NCT {18}

35 Co-morbidity considerations in Atrial Fibrillation Co-Morbidity Mechanical (metal) heart valve / Rheumatic mitral stenosis Chronic kidney disease (CrCl<30mL/min) Chronic kidney disease (CrCl 30-49mL/min) Age 80 Stable coronary artery disease Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, Cairns Which OAC for which AF Patient Can J Cardiol 2013; :1-8 Expert Recommendation warfarin absolutely indicated warfarin (NOACs contraindicated) apixaban and rivaroxaban 15 mg preferred apixaban, rivaroxaban or dabigatran110 mg (recommended dose adjustment as per monograph) ASA (Low Risk CHADS 2 = 0 and age < 65 yrs) apixaban or rivaroxaban (if CHADS 2 1) Recent ACS ASA + ticagrelor* x 12 mos (if age < 65 and CHADS 2 = 0) + NOAC x 12 mos (age 65 or CHADS 2 1) Previous gastrointestinal bleeding Dyspepsia apixaban preferred (as per results of 3 pivotal trials) Consider avoiding dabigatran * or prasugrel if PCI and ASA x 3-6 months if PCI performed Granger et al., NEJM 2011; 365: Connolly et al., NEJM 2009; 361: Patel et al., NEJM 2011; 365: Macle L et al Focused Update of the CCS Management of AF. CJC 32;1170

36 Matching the NOAC to the Patient Remember the Modifiable Bleeding Risk Factors Choose the OAC drug considering the patient profile and/or preferences RECURRENT STROKE/TIA DESPITE WELL CONTROLLED VKA Consider agent with superior efficacy for preventing both IS and hemorrhagic stroke D150 PATIENT HAS MODERATE- SEVERE RENAL IMPAIRMENT Ie. CrCI mls/min A R D75 E30 If CrCI<15mls/min, VKA HIGH RISK OF GI BLEEDING A D110 GI SYMPTOMS OR DYSPEPSIA Consider also increased risk of bleeding HIGH RISK OF BLEEDING [HAS-BLED>3] Consider agent with lowest bleed incidence A R E D110 A Patient preference for once daily dosing A= Apixaban, D=dabigatran, E= edoxaban, R=rivaroxaban E R VKA E JACC VOL. 66 NO, 21, 2015 December 1, 2015: Gregory Y.H. Lip

37 Key Messages AF is a common and important cause of stroke and needs to be rigorously ruled out in idiopathic stroke Appropriate anticoagulation treatment should be started when indicated in the vast majority of AF patients as per the 2016 CCS guidelines NOACs offer several advantages over warfarin, and should generally be used in preference to warfarin for SPAF as per 2016 CCS guidelines Risk of bleeding should be modified where possible but very rarely outweighs the risk of stroke Patient characteristics and co-morbidities (age, renal function, etc) should be considered when selecting and dosing NOACs Real world evidence provides reassurance and confirmation of the safety of NOACs in SPAF

38 NOACs vs Warfarin : in the Real-World!

39 Clinical trials and Real-World Observational Studies are Different Clinical trials: Interventional, controlled The standard for assessing efficacy and safety of novel therapies Rigorous inclusion & exclusion criteria Randomized and powered to specific endpoints Hypothesis driven Audit, training & quality control Independent endpoint adjudication Real World Data: Non-interventional, observational, registry Describe treatment practices &outcomes Large unselected real world population Retrospective or prospective (e.g. registry) May inform on temporal trends & safety Limited inclusion or exclusion criteria Potential for incomplete reporting Hypothesis generating Some have audit, training & quality control Some have independent endpoint adjudication EFFICACY + SAFETY SAFETY + REASSURANCE

40 Clinical trials and Real-World Observational Studies are Different Randomized clinical trials (RCTs) are the gold standard for demonstrating the clinical efficacy and safety of a drug! When the Real-World observational or registry data (RWD) are consistent with RCT findings, it provides reassurance! However, RWD that are discordant with RCT findings should be interpreted with great caution due to its many inherent limitations!

41 NOACs as Compared to Warfarin Clinical Trials vs Real World Data APIXABAN 1 DABIGATRAN RIVAROXABAN ARISTOTLE STUDY RWD 4 RELY STUDY 2 RWD4 ROCKET STUDY 3 RWD4 Stroke/SE Major Bleed Intracranial Bleed GI Bleed All Cause Death To date there are no head-to-head trials between apixaban, dabigatran and rivaroxaban, therefore comparative efficacy and safety have not been established Granger et al., NEJM 2011; 365: Connolly et al., NEJM 2009; 361: Patel et al., NEJM 2011; 365: YAO et al. J Am Heart Assoc 2016;5:e Significant Increase Significant Reduction Non-Significant Difference

42 Johnny Case

43 Learning Objectives Upon completion of this activity, participants should be able to: Discuss the importance of diagnosing subclinical AF in stroke patients and of anticoagulation strategies to prevent recurring stroke Identify clinical factors from trials and guidelines that may influence the choice of oral anticoagulant in secondary stroke prevention

44 Case 3 Johnny 82 years old

45 Case 3 Johnny 82 years old Test Results - Brain CT: Nonspecific leukoaraiosis or white matter hyperintensities (WMHs) No brain infarct - Echocardiogram: Aortic valve sclerosis - CT Angio of cervicocephalic arteries: Atherosclerotic plaques at carotid bifurcation without stenosis - 24-hour Holter: No atrial fibrillation

46 10 days after discharge, Johnny comes to your office for follow-up Select from one of the available options 1. Continue ASA with 1 month follow-up 2. Refer him to a stroke clinic (8 week wait ) 3. Order another 24-hour (or prolonged) Holter 4. Answer 1. and 3.

47 What percent of stroke is idiopathic? Select from one of the available options 1. 10% 2. 20% 3. 30%

48 Stroke Types and Incidence Other 5% Hemorrhagic stroke 15% Cryptogenic 30% Atherosclerotic cerebrovascular disease 20% Cardiogenic embolism 20% Small vessel disease lacunes 25% Ischemic stroke 85% Albers GW, et al. Chest 2004; 126 (3 Suppl): 438S 512S McGrath et al. Stroke 2012; 43:

49 Idiopathic Stroke and AF Paroxysmal atrial fibrillation is often asymptomatic or subclinical (SCAF) and goes undetected, especially during short intervals of observation. As a result, SCAF can go untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA). SCAF = Subclinical atrial fibrillation Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al. N Engl J Med 2014; 370:

50 AF Detection Increases with Duration of Investigation in Idiopathic Stroke Detection of paroxysmal AF increased from 2% / 24 hours to 15% over 4 weeks N= hour N=284 Incremental Yield of Prolonged ECG Monitoring for the Detection of Atrial Fibrillation in Patients with Cryptogenic Stroke or TIA. Gladstone DJ et al. N Engl J Med 2014;370;

51 Suggested algorithm in ischemic stroke or TIA patients with suspected paroxysmal AF Initial Evaluation 24h Holter Monitor If AF is not detected, recommend additional non-invasive ECG monitoring for AF detection for appropriate candidates, with monitoring duration guided by the APB frequency Suggested minimum target monitoring duration: 2 weeks for patients with infrequent APBs (e.g. <500 APBs/24h) APB = atrial premature beat. Suggested minimum target monitoring duration: 4 weeks for patients with frequent APBs (e.g. >500 APBs/24h) If AF is not detected, consider further non-invasive ECG monitoring or implanted loop recorder for patients with excessive APBs (e.g. >1000 APBs/24h) Gladstone et al. Stroke. 2015;46:

52 Johnny has paroxysmal AF What is his risk of another stroke? Select from one of the available options 1. 2% /year 2. 6% /year 3. 12% /year

53 Calculate Johnny s Stroke Risk = 12% 1733 patients from National Registry of Atrial Fibrillation (NRAF) Risk Factor Johnny Score Stroke rate/ 100 patient-years Congestive Heart Failure Hypertension (history of) Age Diabetes Mellitus 1 1 Stroke in the past 2 2 Total Score 5 6 CHADS 2 Gage BF et al. JAMA 2001;285:

54 What do you do now? Select from one or more of the available options 1. Start warfarin 2. Start apixaban 5 mg po bid 3. Start dabigatran 150 mg po bid 4. Start rivaroxaban 20 mg po od 5. Start rivaroxaban 20 mg po od 6. Start edoxaban 60 mg od 7. Other

55 The CCS Algorithm for OAC Therapy in AF Age 65 NO YES OAC* Stroke/TIA/peripheral embolism or Hypertension or Heart failure or Diabetes Mellitus (CHADS 2 risk factors) NO CAD or Arterial vascular disease (coronary, aortic, peripheral) NO YES YES OAC* ASA No Antithrombotic Therapy CCS AF Guidelines. Can J Cardiol. 2016; 32:

56 Relative Risk of Stroke Compared to Placebo Or control No Therapy ASA ASA ASA + Clopidogrel ASA + Clopidogrel Warfarin Warfarin Dabi 110 Warfarin Rivoroxaban Warfarin Apixaban Warfarin Dabi 150 Antithrombotic Therapy in Perspective Stroke Risk Reduction Efficacy % p< % p< % p=0.01 8% p= %* p= % p= % p< Study 0 Meta-Analysis ACTIVE-A ACTIVE-W RE-LY ROCKET AF ARISTOTLE RE-LY data for ROCKET AF RELY and ARISTOTLE is for RR Stroke + SE 2014 CCS AF Guidelines. Can J Cardiol. 2014; 30: Granger C, et al. N Eng J Med. 2011; 365: Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: European Heart Journal 2012; 33: Lancet 2006;367: N Engl J MedHart RG, Pearce LA, Aguilar MI. Ann Intern Med 1997;146: ;360:

57 NOACs as Compared to Warfarin Indirect Comparisons from the Clinical Trials APIXABAN 1 (ELIQUIS) DABIGATRAN (PRADAXA) DABIGATRAN (PRADAXA) EDOXABAN 60 (LIXIANA) RIVAROXABAN 3 (XARELTO) Stroke/SE Major Bleed Intracranial Bleed GI Bleed All Cause Death To date there are no head-to-head trials between apixaban, dabigatran, edoxaban and rivaroxaban, therefore comparative efficacy and safety have not been established Significant Increase Significant Reduction Non-Significant Difference 1. Granger et al., NEJM 2011; 365: Connolly et al., NEJM 2009; 361: Patel et al., NEJM 2011; 365: Giuliano RP et al NEJM 2013; 369:2091

58 Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, Daiichi Sankyp Inc. Lixiana (edoxaban) Product Monograph. November 2, Considerations for Dosing of NOACs NOAC APIXABAN (ELIQUIS) DABIGATRAN (PRADAXA) EDOXABAN (LIXIANA) USUAL STARTING DOSE DOSING ADJUSTMENT CRITERIA 5 mg BID 2.5 mg BID if any 2 of the following criteria: - Age 80 years - Body weight 60 kg - Creatinine 133 μmol/l 150 mg BID 60 mg OD 110 mg BID if - Age >80 or - > 75 + one hemorrhagic risk factors or CrCl ml/min 30 mg OD if - If CrCl ml/min or - body weight 60 kg or - concomitant use of P-gp inhibitors (ex: quinidine, dronedarone) except amiodarone and verapamil RIVAROXABAN (XARELTO) 20 mg OD taken with food 15 mg OD taken with food if - CrCl ml/min

59 You started Johnny on a NOAC. What do you do with the ASA? Select from one of the available options 1. Continue 2. Stop

60 The CCS Algorithm for OAC Therapy in AF Age 65 NO YES OAC* Stroke/TIA/peripheral embolism or Hypertension or Heart failure or Diabetes Mellitus (CHADS 2 risk factors) NO CAD or Arterial vascular disease (coronary, aortic, peripheral) NO YES YES OAC* ASA No Antithrombotic Therapy CCS AF Guidelines. Can J Cardiol. 2016; 32:

61 NOAC Indirect Comparisons Risk of Major Bleed / yr (%) w/wo ASA RELY- 110 NO ASA RELY ASA RELY- 150 NO ASA RELY ASA ROCKET- AF NO ASA ROCKET -AF + ASA ARISTO TLE NO ASA ARISTOT LE + ASA ENGAG E NO ASA ENGAGE + ASA WARFARIN NOACs Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365: P value not available

62 Key Messages Risk of recurrent stroke is high and can be estimated with the CHADS2 score AF is a common cause of stroke, irrespective of AF type, as well as a common cause of idiopathic or cryptogenic stroke Subclinical paroxysmal AF (SCAF) can be overlooked if the investigation is not of sufficient duration to rule it out Anticoagulation therapy with a NOAC is recommended for stroke prevention and preferred over warfarin in the vast majority of AF patients A previous stroke is a risk factor for future stroke in patients with AF, accounting for 2 points in the CHADS 2 index.

63 Case

64 Learning Objectives Upon completion of this activity, participants should be able to: Assess and stratify bleeding risk in patients with AF undergoing different procedures to guide treatment Review the challenges in bleeding management and stopping/restarting NOACs for a procedure and be familiar with current recommendations Implement best evidence and guidelines for pre, peri, and post procedure NOAC management AF = Atrial Fibrillation NOAC = Non Vitamin K antagonist Oral Anticoagulant

65 Case 1

66 Case Eddy comes to see you in your busy office for prescription renewals. He presents you with a pre-op form for his impending cataract surgery and wants to know what he is supposed to do about my blood thinner rivaroxaban 20 mg OD which he has been taking for AF for the last year (previously on warfarin for 5 years).

67 What is Eddy s Bleeding Risk for Cataract Removal Surgery? Select from one of the available options 1. Low Risk 2. Intermediate Risk 3. High Risk

68 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

69 What would you advise Eddy to do about his rivaroxoban for Cataract Removal Surgery? Select from one of the available options 1. Continue his rivaroxaban 2. Suspend the dose on the day of surgery (take it after the procedure) 3. Skip 2 doses of rivaroxaban (i.e. last dose day -2) 4. Skip 3 doses of rivaroxaban (i.e. last dose day -3) 5. Stop rivaroxaban 5 days pre-operatively

70 CCS 2014 Clinical Practice Recommendations CCS 2014 Clinical Practice Recommendations RECOMMENDATION: We suggest that interruption of anticoagulant therapy in a patient with AF/AFL is not necessary for most procedures with a low risk of bleeding, including cardiac device implantation Conditional Recommendation: Low-Quality Evidence; High Quality Evidence for cardiac device implantation AFL = Atrial Flutter Canadian Journal of Cardiology , DOI: ( /j.cjca )

71 Selection of Invasive / Surgical Procedures 1 Slide Cataract Surgery 2 Slide Cardiac Device Implantation 3 Slide Colonoscopy with Possible Polypectomy 4 Slide Cholecystectomy 5 Slide Prostatectomy for Cancer Go to Key Messages

72 What is Eddy s Bleeding Risk for Cardiac Device Implantation? Select from one of the available options 1. Low Risk 2. Intermediate Risk 3. High Risk

73 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

74 CCS 2014 Clinical Practice Recommendations RECOMMENDATION: A NOAC should be withheld for at least 24 hours (three doses if on apixaban or dabigatran and two doses if on rivaroxaban or edoxaban, including the day of the procedure) prior to cardiac device implantation. NOAC = Non Vitamin K antagonist Oral Anticoagulant Canadian Journal of Cardiology , DOI: ( /j.cjca ) Birnie DH et al., N Engl J Med 2013;368:

75 What is Eddy s Bleeding Risk for Colonoscopy with Possible Polypectomy? Select from one of the available options 1. Low Risk 2. Intermediate Risk 3. High Risk

76 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

77 What would you advise Eddy to do about his rivaroxoban for Colonoscopy with Possible Polypectomy? Select from one of the available options 1. Continue his rivaroxaban 2. Suspend the dose on the day of surgery (take it after the procedure) 3. Skip 2 doses of rivaroxaban (i.e. last dose day -2) 4. Skip 3 doses of rivaroxaban (i.e. last dose day -3) 5. Stop rivaroxaban 5 days pre-operatively

78 CCS 2014 Clinical Practice Recommendations CCS 2014 Clinical Practice Recommendations Intermediate and High Risk of Major Bleed RECOMMENDATION: We recommend that interruption of anticoagulant therapy in a patient with AF or AFL will be necessary for most procedures with an intermediate or high risk of major bleeding (Strong Recommendation, Low-Quality Evidence). AFL = Atrial Flutter Canadian Journal of Cardiology , DOI: ( /j.cjca )

79 Suggested Guide for PRE-OPERATIVE Management of Patients Receiving a NOAC DRUG (DOSE REGIMEN) RENAL FUNCTION PROCEDURES WITH LOW BLEEDING RISK* 12-25% residual anticoagulant effect at time of surgery acceptable PROCEDURES WITH INTERMEDIATE or HIGHBLEEDING RISK* <10% residual anticoagulant effect at time of surgery acceptable Apixaban (twice daily) Normal renal function, mild or moderate impairment (CrCl 30 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Dabigatran (twice daily) Normal renal function or mild impairment (CrCl 50 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3-5 days before surgery/procedure* (i.e. skip 4-8 doses) Moderate renal impairment (CrCl ml/min) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Give last dose 5 to 7 days before surgery/procedure* (i.e. skip 8-12 doses) Rivaroxaban (once daily) Normal renal function, mild or moderate impairment (CrCl 30mL/min) Give last dose 2 days before surgery/procedure* (i.e. skip 1 dose) Give last dose 3 days before surgery/procedure* (i.e. skip 2 doses) *No anticoagulant taken on the day of surgery/procedure. Neuraxial procedures include spinal anesthesia, epidural catheter insertion and epidural catheter removal. ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

80 Suggested Guide for POST-OPERATIVE Management of Patients Receiving a NOAC DRUG Apixaban PROCEDURES WITH LOW BLEEDING RISK Resume on day after surgery (~24 hours post-operative) PROCEDURES WITH INTERMEDIATE or HIGHBLEEDING RISK Resume 2 days after surgery (~48 hours post-operative) Dabigatran Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) Rivaroxaban Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

81 What is Eddy s Bleeding Risk for Elective Cholecystectomy? Select from one of the available options 1. Low Risk 2. Intermediate Risk 3. High Risk

82 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

83 What do we tell Eddy to do about his rivaroxaban for Elective Cholecystectomy? Select from one of the available options 1. Continue his rivaroxaban 2. Suspend the dose on the day of surgery (take it after the procedure) 3. Skip 2 doses of rivaroxaban (i.e. last dose day -2) 4. Skip 3 doses of rivaroxaban (i.e. last dose day -3) 5. Stop rivaroxaban 5 days pre-operatively

84 Suggested Guide for PRE-OPERATIVE Management of Patients Receiving a NOAC DRUG (DOSE REGIMEN) RENAL FUNCTION PROCEDURES WITH LOW BLEEDING RISK* 12-25% residual anticoagulant effect at time of surgery acceptable PROCEDURES WITH INTERMEDIATE or HIGH BLEEDING RISK* <10% residual anticoagulant effect at time of surgery acceptable Apixaban (twice daily) Normal renal function, mild or moderate impairment (CrCl 30 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Dabigatran (twice daily) Normal renal function or mild impairment (CrCl 50 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3-5 days before surgery/procedure* (i.e. skip 4-8 doses) Moderate renal impairment (CrCl ml/min) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Give last dose 5 to 7 days before surgery/procedure* (i.e. skip 8-12 doses) Rivaroxaban (once daily) Normal renal function, mild or moderate impairment (CrCl 30mL/min) Give last dose 2 days before surgery/procedure* (i.e. skip 1 dose) Give last dose 3 days before surgery/procedure* (i.e. skip 2 doses) *No anticoagulant taken on the day of surgery/procedure. Neuraxial procedures include spinal anesthesia, epidural catheter insertion and epidural catheter removal. ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

85 Suggested Guide for POST-OPERATIVE Management of Patients Receiving a NOAC DRUG Apixaban PROCEDURES WITH LOW BLEEDING RISK Resume on day after surgery (~24 hours post-operative) PROCEDURES WITH INTERMEDIATE or HIGH BLEEDING RISK Resume 2 days after surgery (~48 hours post-operative) Dabigatran Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) Rivaroxaban Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

86 What is Eddy s Bleeding Risk for Radical Prostatectomy for Prostate Cancer? Select from one of the available options 1. Low Risk 2. Intermediate Risk 3. High Risk

87 Bleeding Risks for Invasive / Surgical Procedures CCS AF Guidelines. Can J Cardiol. 2016; 32: Thrombosis Canada Clinical Guide. Warfarin: Peri-Operative Management.

88 What do we tell Eddy to do about his rivaroxaban for Radical Prostatectomy for Prostate Cancer? Select from one of the available options 1. Continue his rivaroxaban 2. Suspend the dose on the day of surgery (take it after the procedure) 3. Skip 2 doses of rivaroxaban (i.e. last dose day -2) 4. Skip 3 doses of rivaroxaban (i.e. last dose day -3) 5. Stop rivaroxaban 5 days pre-operatively

89 CCS 2014 Clinical Practice Recommendations CCS 2014 Clinical Practice Recommendations Intermediate and High Risk of Major Bleed RECOMMENDATION: We recommend that interruption of anticoagulant therapy in a patient with AF or AFL will be necessary for most procedures with an intermediate or high risk of major bleeding (Strong Recommendation, Low-Quality Evidence). Canadian Journal of Cardiology , DOI: ( /j.cjca )

90 Suggested Guide for PRE-OPERATIVE Management of Patients Receiving a NOAC DRUG (DOSE REGIMEN) RENAL FUNCTION PROCEDURES WITH LOW BLEEDING RISK* 12-25% residual anticoagulant effect at time of surgery acceptable PROCEDURES WITH INTERMEDIATE or HIGH BLEEDING RISK* <10% residual anticoagulant effect at time of surgery acceptable Apixaban (twice daily) Normal renal function, mild or moderate impairment (CrCl 30 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Dabigatran (twice daily) Normal renal function or mild impairment (CrCl 50 ml/min) Give last dose 2 days before surgery/procedure* (i.e. skip 2 doses) Give last dose 3-5 days before surgery/procedure* (i.e. skip 4-8 doses) Moderate renal impairment (CrCl ml/min) Give last dose 3 days before surgery/procedure* (i.e. skip 4 doses) Give last dose 5 to 7 days before surgery/procedure* (i.e. skip 8-12 doses) Rivaroxaban (once daily) Normal renal function, mild or moderate impairment (CrCl 30mL/min) Give last dose 2 days before surgery/procedure* (i.e. skip 1 dose) Give last dose 3 days before surgery/procedure* (i.e. skip 2 doses) *No anticoagulant taken on the day of surgery/procedure. Neuraxial procedures include spinal anesthesia, epidural catheter insertion and epidural catheter removal. ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

91 Suggested Guide for POST-OPERATIVE Management of Patients Receiving a NOAC DRUG Apixaban PROCEDURES WITH LOW BLEEDING RISK Resume on day after surgery (~24 hours post-operative) PROCEDURES WITH INTERMEDIATE or HIGH BLEEDING RISK Resume 2 days after surgery (~48 hours post-operative) Dabigatran Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) Rivaroxaban Resume on day after surgery (~24 hours post-operative) Resume 2 days after surgery (~48 hours post-operative) ADAPTED FROM Thrombosis Canada Clinical Guide. New/Novel Oral Anticoagulants (NOACs): Peri-Operative Management

92 Key Messages SPAF is of utmost importance and must be considered when optimizing peri-procedural bleeding risk Patients on anticoagulants will frequently require invasive procedures and surgical interventions The decision on what to do need not be complicated and depends on: a) The type of procedure planned and its related bleeding risk b) Consideration of the specific anticoagulant used by the patient c) Knowledge of the patient s renal function Pre and post operative dosing algorithms created by Thrombosis Canada and the CCS guidelines along with product monographs are helpful resources for the peri-procedural management of NOACs SPAF = Stroke Prevention in Atrial Fibrillation