Turn the Beat Around-Remix: Atrial Fibrillation Guidelines-2014 Updates

Turn the Beat Around-Remix: Atrial Fibrillation Guidelines-2014 Updates Brittany Karns, PharmD Alaska Pharmacists Association Annual Conference - 2015

Disclosures I have no actual or potential conflicts of interest in relation to this presentation. 2

Objectives for Learning: 1. Summarize the major updates to the 2014 AHA/ACC/HRS Atrial Fibrillation Guidelines. 2. Calculate a patient s CHA 2 DS 2 -VASc score. 3. Describe current recommendations for aspirin use in AFib. 4. Compare and contrast FDA approved target specific oral anticoagulant agents. 5. Outline appropriate bridging therapy for oral anticoagulation interruptions for AFib patients. 3

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society - American Heart Association - American College of Cardiology - Heart Rhythm Society - Society of Thoracic Surgery 4

Intent To assist clinicians in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. - Attempt to define practices that meet the needs of most patients - Ultimate judgment must be made by the clinician and patient - Deviations may be appropriate - Engage the patient s active participation 5

Methodology Evidence Based Clinicians - Cardiology - Electrophysiology - Cardiothoracic surgery - Heart failure Organization thematic with recommendations - Introduction/Methodology - Background and Pathophysiology - Clinical Evaluations and Recommendations - Prevention of Thromboembolism: Anticoagulation - Rate Control - Rhythm Control - Specific Patient Groups 6

Guideline Updates in a Nutshell: - Overall Rehaul - Updated Classification of Treatment Effect - More Pathophysiology/Background - Improved Charts - Revised Definitions - Updated Stroke Risk Calculator: CHA 2 DS 2 -VASc - Reduced Indications for Aspirin Therapy - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 7

Updated Classification of Criteria: Guidance Directed Medical Therapy Classification of Recommendation: Estimate of the size of the treatment effect Separation of Class III recommendations: - Recommendation is of no benefit - Recommendation is of associated with harm Level of Evidence: Estimate of the certainty of the precision of the treatment effect Added Recommendations Phraseology: - Comparator verbs - Suggested phrases for writing recommendations 8

Pathophysiology/Background 11

Improved Charts 12

Web Tools Available 13

Term Simplified Definitions: Paroxysmal AF Definition AF that terminates spontaneously or with intervention within 7 days of onset. Episodes may recur with variable frequency. Persistent AF Continuous AF that is sustained >7 days. Longstanding AF Continuous AF of >12 months duration. Permanent AF Permanent AF is used when there has been a joint decision by the patient and clinician to cease further attempts to restore and/or Non-Valvular AF maintain sinus rhythm. Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of the AF. Acceptance of AF may change as symptoms, the efficacy of therapeutic interventions, and patient and clinician preferences evolve. AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair. 14

Guideline Updates: - Overall Rehaul - Updated Classification of Treatment Effect - More Pathophysiology/Background - Improved Charts - Revised Definitions - Updated Stroke Risk Calculator: CHA 2 DS 2 -VASc - Reduced Indications for Aspirin Therapy - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 15

Old, Familiar Tool: Clinically relevant non-major risk factors: Score: C Congestive Heart Failure/LV Dysfunction 1 H Hypertension 1 A Age 65 years 1 D Diabetes Mellitus 1 S 2 Stroke (TIA/TE) 2 16

Gender Correlation with AFib: Women more likely to have stroke! JAMA 2001;285:2370. 17

% Age Correlation with Stroke: 25 20 AF Prevalence Strokes Attributable to AF 15 10 5 0 50-59 60-69 70-79 80-89 Age Range (year) Wolf et al. Stroke 1991;22:983-987. 18

Newer Tool: Clinically relevant non-major risk factors: Score: C Congestive Heart Failure/LV Dysfunction 1 H Hypertension 1 A 2 Age 75 years 2 D Diabetes Mellitus 1 S 2 Stroke (TIA/TE) 2 V Vascular Disease (previous MI, PAD, aortic plaque) 1 A Age 65-74 Years 1 Sc Sex Category (female) 1 - CHA 2 DS 2 -VASc score recommended to assess stroke risk (I-B) 19

Practice: What are the CHA 2 DS 2 -VASc scores of the following patients newly diagnosed with atrial fibrillation? - 62 year old male with renal dysfunction, gout, htn, and previous MI who hates exercising and has BMI 35-87 year old female with CHF, htn, DMII, previous stroke, and PAD who lives alone with her dog Tricky-Woo - 45 year old male with PTSD, hyperlipidemia, and chronic knee pain - 45 year old female with PTSD, hyperlipidemia, and chronic knee pain 20

Risk Category CHADS 2 Score Recommended Antithrombotic Therapy No risk factors: 0 No Antithrombotic Therapy One 'clinically relevant non-major' risk factor: 1 Aspirin 75-325mg daily One 'major' risk factor or 2 'clinically relevant non-major' risk factors 2 Oral Anticoagulation 21

Risk Category CHA 2 DS 2 - VASc Score Recommended Antithrombotic Therapy No risk factors: 0 No Antithrombotic Therapy (preferred) Or Aspirin 75-325mg Daily One 'clinically relevant non-major' risk factor: 1 Oral Anticoagulation (preferred) or Aspirin 75-325mg Daily One 'major' risk factor or 2 'clinically relevant non-major' risk factors 2 Oral Anticoagulation 22

Practice: What therapy is indicated for each of the patient s we discussed (No therapy, ASA, Oral Anticoagulant)? - 62 year old male with CHA 2 DS 2 -VASc score of 2-87 year old female with CHA 2 DS 2 -VASc score of 9-45 year old male with CHA 2 DS 2 -VASc Score of 0-45 year old female with CHA 2 DS 2 -VASc score of 1 23

CHA 2 DS 2 -VASc Represents A Practice Shift: Better stratification Greater focus on identification of truly low-risk patients - Need to more INclusive of common stroke RFs 24

CHA 2 DS 2 -VASc Represents A Practice Shift: Stroke Risk Stratification Score CHADS2 CHA 2 DS 2 -VASc 0 1.9% 0.0% 1 2.8% 1.3% 2 4.0% 2.2% 3 5.9% 3.2% 4 8.5% 4.0% 5 12.5% 6.7% 6 18.2% 9.8% 7 9.6% 8 6.7% 9 15.2% 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24 25

Guideline Updates: - Overall Rehaul - Updated Classification of Treatment Effect - More Pathophysiology/Background - Improved Charts - Revised Definitions - Updated Stroke Risk Calculator: CHA 2 DS 2 VASc - Reduced Indications for Aspirin Therapy - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 26

Risk Category CHA 2 DS 2 - VASc Score Recommended Antithrombotic Therapy No risk factors: 0 No Antithrombotic Therapy (preferred) Or Aspirin 75-325mg Daily One 'clinically relevant non-major' risk factor: 1 Oral Anticoagulation (preferred) or Aspirin 75-325mg Daily One 'major' risk factor or 2 'clinically relevant non-major' risk factors 2 Oral Anticoagulation 27

Aspirin vs Warfarin in AF Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. 28

WARFARIN vs PLACEBO ANIPLATELET vs PLACEBO 0 62% 19% WARFARIN vs ANIPLATELET 22% Adapted with permission from Hart et al. 36%

Aspirin Therapy: No studies show benefit for aspirin alone in preventing stroke - Warfarin vs ASA ASA inferior to warfarin with higher bleed risk (BAFTA) - Clopidogrel + ASA < Wararin - in pts with mean CHADS 2 of 2 - Clopidogrel + ASA > ASA alone for prevention, but 57% inc in bleeding, minimal differences between the two - Apixaban vs ASA 5mg daily vs asa 81 or 325mg terminated prematurely due to apixaban superiority (AVERROES) 30

Aspirin Therapy: No studies show benefit for aspirin alone in preventing stroke - BAFTA Warfarin superior in stroke preventin and equal in bleed - AVERROES: Apixaban vs ASA 5mg daily vs asa 81 or 325mg terminated prematurely due to apixaban superiority 31

Guideline Updates: - Overall Rehaul - Updated Classification of Treatment Effect - More Pathophysiology/Background - Improved Charts - Revised Definitions - Updated Stroke Risk Calculator: CHA 2 DS 2 -VASc - Reduced Indications for Aspirin Therapy - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 32

Antithrombotic Therapy: Warfarin and the Target Specific Oral Anticoagulants are all acceptable first line agents for anticoagulation in non-valvular Afib Treatment should be individualized based on shared decision making Target Specific Oral Anticoagulants (TSOACs) - Direct Thrombin Inhibitor Dabigatran - Factor Xa Inhibitors Rivaroxaban, Apixaban (Edoxaban) 33

34

RE-LY (Dabigatran): Stroke Dabigatran 110mg vs Warfarin Non-inferiority P-value < 0.001 Superiority P-value 0.34 Dabigatran 150mg vs Warfarin < 0.001 < 0.001 Margin = 1.46 Connolly, et al. N Engl J Med 2009;361:1139-51 0.50 0.75 1.00 1.25 1.50 HR (95% CI) 35

RE-LY (Dabigatran): Efficacy Dabigatran 110 mg Dabigatran 150 mg Stroke/SEE 0.91 (0.74-1.11) 0.66 (0.53-0.82) Ischemic Stroke 1.11 (0.89-1.40) 0.76 (0.60-0.98) Hemorrhagic Stroke 0.31 (0.17-0.56) 0.26 (0.14-0.49) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 1.0 2.0 36 Dabigatran Better Warfarin Better

RE-LY (Dabigatran) - Safety Dabigatran 110 mg Dabigatran 150 mg Major Bleed 0.80 (0.69-0.93) 0.93 (0.81-1.07) ICH 0.31 (0.20-0.47) 0.40 (0.27-0.60) GI Bleed 1.10 (0.86-1.41) 1.50 (1.19-1.89) MI 1.29 (0.96-1.75) 1.27 (0.94-1.71) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 1.0 2.0 Dabigatran Better Warfarin Better 37

ROCKET AF (Rivaroxaban) - Stroke Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment N = 14,143 1.70 2.15 0.79 (0.65, 0.95) 0.015 ITT N = 14,171 2.12 2.42 0.88 (0.74, 1.03) 0.117 0.5 1 2 Rivaroxaban better Warfarin better Patel, et al. N Engl J Med 2011;365(10);883-891 38

ROCKET AF (Rivaroxaban) - Efficacy Event Rivaroxaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P-value Ischemic Stroke Hemorrhagic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581 0.26 0.44 0.59 (0.37-0.93) 0.024 MI 0.91 1.12 0.81 (0.63-1.06) 0.121 Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073 Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289 Patel, et al. N Engl J Med 2011;365(10);883-891 39

ROCKET AF (Rivaroxaban) - Safety Event Major and Clinically Relevant Bleed Rivaroxaban (%/yr) Warfarin (%/yr) 14.9 14.5 Major Bleed 3.6 3.4 Fatal Bleed 0.2 0.5 Hazard Ratio (95% CI) 1.03 (0.96-1.11) 1.04 (0.90-1.20) 0.50 (0.31-0.79) P-value 0.44 0.58 0.003 ICH 0.5 0.7 0.67 (0.47-0.93) 0.02 Patel, et al. N Engl J Med 2011;365(10);883-891 40

AVERROES (Apixaban) VS ASPIRIN Stroke or Systemic Embolic Event Major Bleeding 0.05 0.04 Aspirin 0.020 0.015 Apixaban 0.03 0.02 0.01 P < 0.001 Apixaban 0.010 0.005 P < 0.001 Aspirin 0.00 0 3 6 9 12 18 0.000 0 3 6 9 12 18 HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75) Connolly SJ, et al. N Engl J Med 2011 (epub) 41

ARISTOTLE (Apixaban) - Stroke HR 0.79 (0.66 0.95) (1.60 %/yr) 21% RRR (1.27 %/yr ) P (non-inferiority) < 0.001 P (superiority) = 0.011 Granger CB, et al. NEJM 2011; 365:981-992 42

ARISOTLTE (Apixaban) - Efficacy Outcome Stroke or systemic embolism Apixaban (N = 9120) Event Rate (%/yr) Warfarin (N = 9081) Event Rate (%/yr) HR (95% CI) P Value 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) < 0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or allcause death Myocardial infarction 4.49 5.04 0.89 (0.81, 0.98) 0.019 0.53 0.61 0.88 (0.66, 1.17) 0.37 Granger CB, et al. NEJM 2011; 365:981-992 43

ARISTOTLE (Apixaban) - Safety Event Apixaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P-value ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80) < 0.001 ICH 0.33 0.80 0.42 (0.30-0.58) < 0.001 GUSTO Severe 0.52 1.13 0.46 (0.35-0.60) < 0.001 Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37 Granger CB, et al. NEJM 2011; 365:981-992 44

TSOAC Landmark Trials: Pivotal study TSOAC vs. warfarin (INR 2-3) DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN RE-LY Open-label ROCKET-AF Double-blind ARISTOTLE Double-blind ENGAGE-TIMI Double-blind Mean CHADS 2 score 2.1 3.5 2.1 2.8 Mean Time in Therapeutic Range Efficacy: Reduction in all stroke, systemic embolism Safety: Major bleeding Mortality 64% 55% 62% 68% Superior Non-Inferior Superior Non-Inferior Similar Similar Superior Superior Favorable trend Favorable trend Superior Favorable trend 45

TSOAC Indications: - Non-Valvular Atrial Fibrillation - VTE/PE: Apixaban, Rivaroxaban - CHA 2 DS 2 VASc Score 1 46

TSOAC Exclusions: - Prosthetic heart valve - Clinically significant valvular disease - Indication other than NVAF Or VTE (Rivaroxaban, Edoxaban) - Following acute stroke or TIA - Active endocarditis - Active pathological bleeding - Known significant liver disease - Previous hypersensitivity reaction - Pregnancy/Breastfeeding - Increased bleeding risk - Anemia (Hgb <10g/dL) or Thrombocyopenia (Plt <100,000/uL) - Hepatic and Renal considerations - Drug-Drug Interactions 47

TSOAC Differentiation: Additional indications: - DVT/PE: Rivaroxaban, Edoxaban Administration: - Twice Daily Therapies: Dabigatran, Apixaban - Once Daily Therapies: Rivaroxaban, Edoxaban - Must take with food: Rivaroxaban - Cannot be crushed/opened: Dabigatran Adverse reactions - GI Bleed: Dabigatran, Rivaroxaban - Increased risk of extracranial bleed: Dabigatran - Increased bleeding assoc. age 75yo: Dabigatran, Rivaroxaban - CAD/MI increase: Dabigatran 48

TSOAC Differentiation cont: Drug-Drug Interactions - P-Glycoprotein substrate: ALL Inhibitors: (Azoles, verapamil, amiodarone, dronedarone, quinidine, clarithromycin) Inducers: Do NOT use wih Dabigatran, Edoxaban (phenytoin, carbamazepine, rifampin, St Johns wort) - Cyp3A4 substrates: Rivaroxaban, Apixaban Elimination - Mod/severe hepatic impairment (Child-Pugh B&C): Apixaban, Edoxaban - Dialyzable: Dabigatran - Renal limitations: Dabigatran: CrCl <30mL/min Rivaroxaban: CrCl <30mL/min Apixaban: CrCl <25mL/min or serum creatinine (SCr) >2.5 mg/dl Edoxaban : CrCl <50mL/min OR 95mL/min 49

TSOAC Monitoring: DO REQUIRE MONITORING - Renal function - Bleeding - Tolerance - Adherence - No routine monitoring of anticoagulation activity DO have some impact on INR 50

Items for Consideration: TSOACs vs Warfarin - Cost - Compliance - When level of anticoagulation is desirable - Reversal Options - Access to Health Care Shared Decision Making - Risk factors - Tolerability - Patient Preference - Potential Drug Interactions - Warfarin: Time Therapeutic 51

Bridging Switching from WARF DABIGATRAN RIVAROXABAN APIXABAN Edoxaban Start TSOAC when INR <2 Start TSOAC when INR <3 Start TSOAC when INR <2 Star TSOAC when Half-life 12-17 hours 5-9 hours 12 hours 10-14 hours Time to Onset 1-2 hours 2-4 hours 3-4 hours 1-2 hours Surgery and Invasive Procedures Anticoagulant Lab testing Discontinue 1-2 days (if CrCl 50 ml/min) or 3-5 days (CrCl <50 ml/min) before invasive procedures or surgery. Consider longer times for higher risk procedures where complete hemostasis is required. None routinely recommended; if urgently needed, aptt, TT (qualitative estimate; presence or absence) Discontinue at least 24 hrs before surgery or procedures with increased bleeding risk. None routinely recommended; if urgently needed, PT, anti-factor Xa (qualitative estimate; presence or absence) Discontinue at least 24 hrs prior to surgery/procedures where risk of bleeding is low and could be easily managed. Discontinue at least 48 hrs prior to surgery/procedures with moderate to high bleeding risk. None routinely recommended; if urgently needed, anti- Factor Xa (qualitative estimate; presence or absence) Discontinue at least 24 hrs prior to surgery/procedures where risk of bleeding is low and could be easily managed. Discontinue at least 48 hrs prior to surgery/procedures with moderate to high bleeding risk. None routinely recommended; if urgently needed, anti-factor Xa (qualitative estimate; presence or absence) 52

Antithrombotic Recommendations: 53

Antithrombotic Recommendations: 54

Guideline Updates: - Overall Rehaul - Updated Classification of Treatment Effect - More Pathophysiology/Background - Improved Charts - Revised Definitions - Updated Stroke Risk Calculator: CHA 2 DS 2 -VASc - Reduced Indications for Aspirin Therapy - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 55

AF Catheter Ablation: Guidelines discuss greater role for Rhythm Control in general Initial Rhythm Control Strategy before pharmacotherapy: - Recurrent symptomatic paroxysmal AF (IIa-B) - Symptomatic persistent AF (IIb-C) Rhythm control patients refractory or intolerant to at least 1 class I or III antiarrhythmic with: - Symptomatic paroxysmal AF (I-A) - Symptomatic persistent AF (IIa-A) - Symptomatic longstanding (>12months) (IIb-B) CLASS III: HARM - Must be able to anticoagulate during and after procedure (III-C) 56

AF Catheter Ablation: 57

Anticoagulation During Ablation : WARFARIN DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Good datastandard of care Low quality data; most but not all studies suggest similar thromboembolic/b leeding risk Very limited data; published combined analysis of cardioversion and ablation pts; no difference in outcomes with RIVA vs. WARF in very small number of pts No data No data 58

Review/Assessment - Overall Rehaul - Updated Classification of Treatment Effect No Benefit vs Harm - More Pathophysiology/Background - Updated Stroke Risk Calculator: CHA 2 DS 2 VASc What are the new 4 points accounted for in the CHA 2 DS 2 VASc? - Reduced Indications for Aspirin Therapy When is Aspirin preferred? - Addition of Target-Specific Oral Anticoagulants - Which TSOAC is once daily? Which is best - For patients with renal impairment? - Increased Role for Ablation 59

Review: - Overall Rehaul - Updated Classification of Treatment Effect No Benefit vs Harm - More Pathophysiology/Background - Updated Stroke Risk Calculator: CHA 2 DS 2 VASc Includes 4 new points (two additional for age, one for vascular disease, one for gender) - Reduced Indications for Aspirin Therapy Almost no situation in which aspirin is preferred - Addition of Target-Specific Oral Anticoagulants - Dabigatran, Rivaroxaban, Apixaban, (Edoxaban) - Increased Role for Ablation 60

References: 2014 AHA/ACC/HRS Atrial Fibrillation Guideline 1. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validaion of clinical classification schemes for predicting stroke: results from the National Registry of Arial Fibrillation. JAMA 2001;285(22):2864-70. 2. Lip GY, Frison L, Halpeirin JL, Lane DA. Identifying patients at high risk for sroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41(12):2731-8. 3. Target Specific Oral Anicoagulants (TSOACs) Dabigatran (Pradaxa), Rivaroxaban (Xarelto), and Apixaban (Eliquis) Criteria for Use for Stroke Prevention in Nonvalvular Atrial Fibrillation (AF). VA Pharamacy Benefits Managemen Services Medical Advisory Panel, and VISN Pharmacis Execuives, 2014. 4. Coppens et al. The CHA 2 DS 2 -VASc Score Identifies Those Patients With Atrial Fibrillation and a CHADS 2 Score of 1 Who Are Unlikely to Benefit From Oral Anticoagulant Therapy. Eur Heart J. 2013;34(3):170-176. 5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139 51. 6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883 91. 7. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. NEJM 2011;365:981 92. 8. Giugliano RP, Ruff CF, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2013;369:2093-2104. 9. Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 2004;43:1201-8. 10. Van Gelder IC, Haegeli LM, Brandes A, et al. Rationale and current perspective for early rhythm control 61 therapy in atrial fibrillation. Europace. 2011;13:1517-25.

Thank you! 62