Non-Valvular Atrial Fibrillation: Reducing Risk and Individualizing Therapeutic Choices

Non-Valvular Atrial Fibrillation: Reducing Risk and Individualizing Therapeutic Choices

Faculty John M. Wharton, MD Frank P. Tourville Professor of Medicine Director, Cardiac Electrophysiology Medical University of South Carolina Charleston, SC 2

Disclosures John M. Wharton, MD serves on the research support team for Pfizer, Bristol-Myers Squibb, Biosense Webster, and Toray Industries. Dr. Wharton also serves as a speaker for Medtronic. 3

Learning Objectives 1. Identify those patients at risk for cardioembolic stroke who are appropriate candidates for anticoagulation 2. Recognize common misperceptions about anticoagulation risk to improve communication and patient adherence 3. Discuss the management of bleeding in patients on anticoagulants 4. Describe the role of continued anticoagulation in the setting of emerging non-pharmacologic therapy 4

PRE-TEST QUESTIONS 5

Consider a 67 y/o woman with AF and no other medical problems. What is the CHA2DS2-VASc score and should oral anticoagulant be prescribed? CHA2DS2-VASc Score Pre-test Question 1 Anticoagulate? 1. 0 No 2. 1 No 3. 1 Yes 4. 2 No 5. 2 Yes 6. 3 Yes 6

Pre-test Question 2 Consider a 75 y/o man with persistent AF, history of HF, CAD, HTN, CKD, and PAD. Treated with warfarin but INRs difficult to keep in the therapeutic range. HAS-BLED score 4, which = 8%-10% annualized risk for major bleeding. Would you treat this patient with: 1. No antiplatelet agent or oral anticoagulant because of his risk of bleeding 2. An antiplatelet agent because of his risk of bleeding 3. A DOAC despite his risk of bleeding 4. A reduced dosage of DOAC because of his risk of bleeding 7

Pre-test Question 3 Consider a 62 y/o woman with paroxysmal AF, HTN, T2DM, and GERD, treated with rivaroxaban. Presents to ED with repeated hematemesis of bright red blood, hypotension, and Hgb 6.1 gm/dl. Last dose of rivaroxaban 1 hour earlier. Which of the following would be appropriate to treat her bleeding? 1. Give activated charcoal by NG tube 2. Give intravenous fluid and blood and emergent GI consult 3. Give fresh frozen plasma 4. Give idarucizumab 5. 1 and 2 6. 1, 2, and 3 8

Pre-test Question 4 A 78 y/o man with persistent AF undergoes successful ablation of AF and atrial flutter. Anticoagulated with dabigatran and takes aspirin for CAD without bleeding complications. History of prior MI, mild HF, HTN, and PAD. One month of loop monitoring 4 months after his ablation was normal. What would you do with his oral anticoagulation: 1. Stop his dabigatran and his aspirin 2. Stop his dagibatran but continue his aspirin 3. Continue his dabigatran and his aspirin 4. Continue his dagibatran but stop his aspirin 9

Pre-test Question 5 Please rate your confidence in your ability to assess stroke risk and manage anticoagulation in patients with atrial fibrillation: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 10

Agenda Estimating Stroke Risk Safety and Efficacy of Oral Anticoagulants Other Options for Stroke Prevention The Role of Primary Care 11

Patient Case: Ann Presentation 64-year-old woman with recent diagnosis of AF Retired editor Married, 3 adult children Presented to ED last week with dizziness and palpitations Treated with IV diltiazem and discharged Duration of AF ~6 hours Medical History Hypertension, 15 years T2DM, 6 years No history of stroke or major bleeding 12

Ann (cont d) Workup BP 120/72 mmhg BMI 25.5 kg/m 2 HR 72 bpm Normal sinus rhythm Lungs clear on auscultation A1C 7.2% Current medications Lisinopril/hydrochlorothiazide 20/25 mg qd Calcium and vitamin D supplement Managing T2DM with diet and daily exercise 13

AF, Strokes, and Cognitive Decline Worse Outcomes with Embolic Strokes Major cause of strokes in elderly >70,000 strokes per year in US 15% of strokes in US due to AF 5% of AF patients have symptomatic and 15-25% have asymptomatic strokes Stroke risk persists in asymptomatic patient with AF Dementia increased 2-3X with AF Lin HJ et al. Stroke. 1996;27(10):1760-1764. Fuster V, et al. JACC 2001;38:1231-65; Benjamin EJ, et al. Circulation 1998;98:946-52; Duli DA, et al. Neuroepidemiol 2003;22:118-23; Page RL, et al. Circulation 2003;107:1141-45; Cha M-J, et al. Am J Cardiol 2014;113:655-661. 14

Stroke Risk and AF Duration from Implantable Device Diagnostics Study AF Duration RR (95% CI) p Value TRENDS 1 20 second - <5.5 hours 0.98 (0.34,2.82) 0.97 5.5 hours 2.20 (0.96,5.05) 0.06 ASSERT 2 6 minutes 1.77 (1.01,3.10) 0.047 30 minutes 1.87 (1.06,3.28) 0.03 6 hours 2.01 (1.14-3.54) 0.02 12 hours 1.86 (1.05,3.29) 0.02 24 hours 1.98 (1.13,3.49) 0.02 48 hours 1.93 (1.09,3.42) 0.02 1. Glotzer T, et al. Circ Arrhythmia Electrophysiol 2009;2:474-480. 2. Gold MR, et al. Heart Rhythm 2012;9:S24 (Abstract). Ø 1 TRENDS: N = 2486. Ø 2 ASSERT: N = 2580. 15

Risk of Stroke Assessed by CHADS 2 Score 20 18.2 CHADS2 Points C = CHF 1 H = HTN 1 A = Age 75 1 D = DM 1 S = Prior CVA 2 Stroke Rate (% per year) 15 10 5 1.9 2.8 4.0 5.9 8.5 12.5 0 0 n=120 1 n=463 2 n=523 3 n=337 4 n=220 5 n=65 6 n=5 CHADS 2 Score Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198. 16

Comparison of CHADS2 and CHA2DS2- VASc Scoring Systems Scoring System Annualized Stroke Risk CHADS2 CHA2DS2 -VASc Risk Factor Points Points CHF 1 1 Hypertensi on 1 1 Age >75 1 2 Diabetes 1 1 Prior Stroke Vascular Disease 2 2 --- 1 Age 65-74 --- 1 Female --- 1 Total Score CHADS2 CHA2DS 2-VASc 0 1.9 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 Lip GY, Halperin JL. Am J Med 2010;123(6):84-488; Olesen JB, et al. Br Med J 2011;342:d124. 17

2014 ACC/AHA/HRS AF Guidelines: Recommendations for Anticoagulation CHA2DS2- VASc* Recommended Anticoagulation 0 No therapy 1 No therapy; warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, or ASA may be considered 2 Valvular Disease Warfarin, dabigatran, rivaroxaban, apixaban, edoxaban Warfarin with INR 2.0-3.5 January CT, et al. Circulation 2014;129:000-000. Doi; 10.1161/CIR.0000000000000041 2016 ACC/AHA Clinical Performance and Quality Measures state CHA2DS2-VASc score must be documented and shared decision making documented Heidenriech PA, et al. J Am Coll Cardiol 2016 (in press). doi.org/10.1016/j.jacc.2016.03.521 18

Warfarin Remains Underutilized Retrospective cohort study of 171,393 patients to assess the utilization of warfarin within 30 days of an AF/flutter diagnosis among different risk strata* Total (n=171,393) Newly Diagnosed AF/Flutter (n=51,907) Pre-Existing AF/Flutter (n=119,486) Treated with Warfarin (%) 60 50 40 30 20 10 Low Risk 59.9% Untreated 40.1 49.0 34.7 43.5 Moderate Risk 56.5% Untreated 50.7 50.8 40.0 46.1 43.5 43.0 42.1 43.0 40.6 40.8 40.2 High Risk 57.9% Untreated 39.7 36.3 40.4 39.7 43.0 39.1 0 0 1 2 3 CHADS 2 Score 4 5 6 *Hatched area represents the proportion of patients with uninterrupted therapy over 180 days following initial warfarin prescription. 19 Zimetbaum PJ, et al. Am J Med. 2010;123(5):446-453.

Anticoagulation and DOACS Ø What does the data say? 20

Anticoagulation in AF Stroke Risk Reductions (N= 2900) Warfarin Better Control Better AFASAK SPAF BAATAF Reduction of all-cause mortality RRR 26% CAFA SPINAF EAFT Aggregate Reduction of stroke RRR 62% 100% 50% 0-50% -100% Hart et al. Ann Intern Med 1999;131:492-501. 21

Narrow Therapeutic-Safety Window With Warfarin Assessed by INR Measurement 20 Therapeutic Window Odds Ratio 15 10 Intracranial Bleeding 5 Ischemic Stroke 0 1 2 3 4 5 6 7 8 INR ICH is the most lethal form of stroke with 30-day mortality rates of 30-55% 1,2 Adapted from Fuster V, et al. J Am Coll Cardiol 2011;57(11):e101-e198. Modified with permission from Hylek EM, Singer DE. Ann Intern Med 1994;120:897-902. Data from Odén A, Fahlén M, Hart RG. Thromb Res 2006;117:493-499. 1. Freeman WD, Aguilar MI. Expert Rev Neurother 2008;8(2):271-290. 2. Aguilar MI, et al. Mayo Clin Proc 2007;82(1):82-92. 22

Antiplatelet Therapy in AF ACTIVE-W: 6706 randomized patients; trial stopped ACTIVE-A: 7554 randomized patients; median follow-up of 3.6 years 8 P =.01 Outcome/Year (%) 6 5 4 3 2 1 P =.0003 Clopidogrel + ASA Warfarin P =.001 P =.53 Outcome/Year (%) 7 6 5 4 3 2 1 Clopidogrel + ASA ASA P<.001 P<.001 0 Vascular Event Stroke Major Bleeding 0 Vascular Event Stroke Major Bleeding ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. ACTIVE Investigators. Lancet. 2006;367:1903-1912. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-2078. 23

Newer Anticoagulants Activated Factor X Inhibitors Apixaban Betrixaban Edoxaban Novel Vitamin K Antagonist Rivaroxaban *Warfarin Extrinsic Pathway Activation Intrinsic Pathway Activation Factor X Factor Xa Factor X Direct Thrombin Inhibitors Activated Factor X Inhibitors Prothrombin Thrombin Dabigatran Etexilate Direct Thrombin Inhibitors Fibrinogen Fibrin Ma TKW, et al. Pharmacology and Therapeutic 2010; doi;10.1016/j.pharmthera.2010.09.005 24

Comparison of Efficacy and Safety of DOAC s to Warfarin: Meta-Analysis of Randomized Trials Ø Strokes and Systemic Emboli Ø Ø Major Bleeding Ø Ruff CT, et al. Lancet 2014; 383(9921): 955 962 Ø http://dx.doi.org/10.1016/s0140-6736(13)62343-0 25

Annual Risk* of Fatal Bleeding with DOACs DOAC Warfarin RR (95% CI) p Value RE-LY: 150 mg 1 0.23 0.33 0.70 (0.43-1.14) 0.15 ROCKET-AF 2 0.2 0.5 0.49 (0.55-0.83) <0.001 ARISTOTLE 3 0.06 0.25 0.27 (0.13-0.53) <0.0001 ENGAGE-AF: 60 mg 4 0.21 0.38 0.55 (0.36-0.84) <0.001 *Percent of patients/year 1) Connolly SJ, et al. N Engl J Med 2009; 361:1139-1151. 2) Patel MR, et al. N Engl J Med 2011;365(10):883-891. 3) Granger CB, et al. N Engl J Med 2011;365(11):981-992. 4) Giugliano RP, et al. N Engl J Med 2013;369:2093-2104 26

Pairwise, Propensity Matched Comparison of DOAC s to Warfarin in Large US Insurance Database DOAC vs Warfarin N=76,354 EFFICACY Stroke + Systemic Emboli Apixaban N=7695 Dabigatran N=14,307 Rivaroxaban N=16,175 0.67 (0.46-0.98)* 0.98 (0.76-1.26) 0.93 (0.72-1.19) Ischemic Stroke 0.83 (0.53-1.29) 1.06 (0.79-1.42) 1.01 (0.75-1.36) Hemorrhagic Stroke SAFETY Major Bleeding 0.45 (0.34-0.59)*** Intracranial Bleeding 0.35 (0.14-0.88)* 0.56 (0.30-1.04) 0.61 (0.35-1.07) 0.24 (0.12-0.50)*** GI Bleeding 0.51 (0.37-0.70)*** 0.79 (0.67-0.94)** 1.04 (0.90-1.20) 0.36 (0.23-0.56)*** 0.51 (0.35-0.75)*** 1.03 (0.84-1.26) 1.21 (1.02-1.43)* Ø *p<0.05. **P<0.01. ***P<0.001. Ø Yao X, et al. J Am Heart Assoc 2016:5:e003725 Ø 27

HAS-BLED Bleeding Risk Score Letter Clinical Characteristic Score H Hypertension 1 A Abnormal Renal and Liver Function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly (age >65 yrs) 1 D Point Score System Drugs and Alcohol (1 point each) 1 or 2 Bleeding Risk Score Bleeding Risk* 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 12.50 6 0 7 --- 8 --- 9 --- Camm AJ, et al. Eur Heart J 2010;31(19):2369-2429. Pisters R. Chest. 2010;138:1093-1100. Lip GY, et al. Am J Med. 2010;123(6):484-488. 28

Utility of CHA 2 DS 2 -VASc in Predicting Major Bleeding Risk with Oral Anticoagulation Risk of Thromboembolism and Any Severe Bleeding in Stockholm Annualized Percent Risk CHA2DS2-VASc Score However, HAS-BLED has much higher discriminatory performance for predicting major bleeding compared to CHADS2 or CHA2DS2-VASc scores Forslund T, et al. Eur J Clin Pharmacol 2014;70:1477-1485; Apostolakis S, et al. Thromb Haemost 2013;110:1074-1079; Roldan V, et al. J Am Coll Cardiol 2013;62:2199-2204. 29

To Bridge or Not to Bridge 30

Transient Interruption of Oral Anticoagulants Prior to Procedures Risk of stroke is increased with transient discontinuation of OAC in high risk AF patients All DOAC s have a black box warning cautioning about this risk Post hoc analyses do not demonstrate a greater risk than with warfarin discontinuation Possible role of bridging therapy not well studied Major goal Limit duration of interruption as much as is safely possible 31

Periprocedural Bridging Anticoagulation* During Warfarin and Dabigatran Interruption in RE-LY Ø Percent of Patients with Event Ø Stroke or Major Bleeding Ø Systemic Embolus Ø P=NS P=NS Ø P<0.001 P<0.001 *Using low molecular weight heparin or unfractionated heparin Douketis JD, et al. Thromb Haemost 2015;113:625-632. 32

Potential Reversal Agents of DOACs for Severe or Life-threatening Bleeding Intervention Dabigatran Rivaroxaban Apixaban Edoxaban Oral activated charcoal Yes Yes Yes Yes Hemodialysis Yes No No? Hemoperfusion with activated charcoal Yes Possible Possible? Fresh frozen plasma No No No No PCC-4 factor* Possible Possible Possible Possible Idarucizumab Yes No No No Andexanet-alfa** No Yes Yes Yes *4 factor prothrombin complex concentrate is not FDA approved for DOAC reversal **Investigational drugs Ansell JE. J Thromb Thrombolysis 2015 (Oct 15). 33

Should Patient After AF Ablation Be CHADS2 Score Chronically Anticoagulated? Retrospective Analysis of the Effect of AF Ablation on Stroke Risk No AF (n = 16848) AF Medical (n = 16848) AF Ablation (n = 4212) p Value 0 2.6% 3.7% 1.6% <0.001 1 3.0% 5.4% 1.9% <0.001 2 4.35 7.1% 2.2% <0.001 3 7.4% 9.0% 6.1% 0.06 4 10.7% 17.6% 9.1% <0.001 5 13.9% 18.6% 13.2% 0.18 Bunch TJ, et al. Heart Rhythm 2013 DOI:10:1016/j.hrthm.2013.07.002. There are no prospective, randomized trials demonstrating the efficacy or safety of catheter ablation for stroke prevention in AF patients. 34

Final Points 35

Summary: Use of Oral Anticoagulants in Patients with AF OAC s are underutilized despite their benefits Efficacy and safety of OAC s depend upon accurate assessment of stroke and bleeding risks Document CHA2DS2-VASc score and shared decision process The higher the stroke risk, the greater the relative benefit of OAC, despite the risks of bleeding Major bleeding in patients on DOAC s is treated with conventional supportive therapy and correction of bleeding source; only warfarin and dabigatran have approved reversal agents AF ablation is not an alternative to anticoagulation in high risk patients and LAAC devices are limited to patients who are truly intolerant to or incapable of taking OAC s 36

POST-TEST QUESTIONS 37

Post-test Question 1 Consider a 67 y/o woman with AF and no other medical problems. What is the CHA2DS2-VASc score and should oral anticoagulant be prescribed? CHA2DS2-VASc Score Anticoagulate? 1. 0 No 2. 1 No 3. 1 Yes 4. 2 No 5. 2 Yes 6. 3 Yes 38

Post-test Question 2 Consider a 75 y/o man with persistent AF, history of HF, CAD, HTN, CKD, and PAD. Treated with warfarin but INRs difficult to keep in the therapeutic range. HAS-BLED score 4, which = 8%-10% annualized risk for major bleeding. Would you treat this patient with: 1. No antiplatelet agent or oral anticoagulant because of his risk of bleeding 2. An antiplatelet agent because of his risk of bleeding 3. A DOAC despite his risk of bleeding 4. A reduced dosage of DOAC because of his risk of bleeding 39

Post-test Question 3 Consider a 62 y/o woman with paroxysmal AF, HTN, T2DM, and GERD, treated with rivaroxaban. Presents to ED with repeated hematemesis of bright red blood, hypotension, and Hgb 6.1 gm/dl. Last dose of rivaroxaban 1 hour earlier. Which of the following would be appropriate to treat her bleeding? 1. Give activated charcoal by NG tube 2. Give intravenous fluid and blood and emergent GI consult 3. Give fresh frozen plasma 4. Give idarucizumab 5. 1 and 2 6. 1, 2, and 3 40

Post-test Question 4 A 78 y/o man with persistent AF undergoes successful ablation of AF and atrial flutter. Anticoagulated with dabigatran and takes aspirin for CAD without bleeding complications. History of prior MI, mild HF, HTN, and PAD. One month of loop monitoring 4 months after his ablation was normal. What would you do with his oral anticoagulation: 1. Stop his dabigatran and his aspirin 2. Stop his dagibatran but continue his aspirin 3. Continue his dabigatran and his aspirin 4. Continue his dagibatran but stop his aspirin 41

Post-test Question 5 Please rate your confidence in your ability to assess stroke risk and manage anticoagulation in patients with atrial fibrillation: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 42