Emerging Challenges in Primary Care : 2017

Transcription

1 Ø 5/9/17 Emerging Challenges in Primary Care : 2017 Atrial Fibrillation: Reducing Risk and Individualizing Therapeutic Choices Faculty Barbara Hutchinson, MD, PhD, FACC President, Association of Black Cardiologists President, Chesapeake Cardiac Care Annapolis, MD 2 Disclosures Barbara Hutchinson, MD, PhD, FACC serves on the cardiovascular writing committee for ABIM. 3 Ø 1

2 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 ARS Question 1 A 67 yo woman with lone 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 5 Pre-test ARS Question 2 75 yo man with persistent AF, history of CHF, CAD, HTN, CRI, and PVD. Treated with warfarin but INR s 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 6 Ø 2

3 Pre-test ARS Question 3 62 yo woman with paroxysmal AF, HTN, DM, and long history of GERD, on rivaroxaban. Presents to ER 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, and 3 7 Pre-test ARS Question 4 78 yo 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 compensated CHF, HTN, and PVD. 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 8 Pre-test ARS 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 Ø 9 Ø 3

4 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): Fuster V, et al. JACC 2001;38: ; 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: ; Cha M-J, et al. Am J Cardiol 2014;113: Causes and Types of Cerebral Injury in AF Patients Left Atrial Appendage Thrombus Patients Types of Cerebral Injury in AF Ø LAA Thrombus Courtesy of Bruce Usher, MD 2015;25: Large Strokes Little Strokes Large Bleeds Little Bleeds Jacobs V, et al. Trends in Cardiovasc Med 11 Left Atrial Anatomic Characteristics That Affect Stroke Risk in AF Patients Left Atrial Appendage Anatomy Burden Left Atrial Scar Ø Chicken Wing Cactus Windsock Cauliflower 12 Di Biase L, et al. J Am Coll Cardiol 2012;60: Decarett M, et al. J Am Coll Cardiol 2011;57: Ø 4

5 How long does an episode of AF have to last to double your risk of stroke? hours hours hours 4. 6 hours 5. 1 hour 6. 6 minutes Audience Response Question 13 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) hours 2.20 (0.96,5.05) 0.06 ASSERT 2 6 minutes 1.77 (1.01,3.10) minutes 1.87 (1.06,3.28) hours 2.01 ( ) hours 1.86 (1.05,3.29) hours 1.98 (1.13,3.49) hours 1.93 (1.09,3.42) Glotzer T, et al. Circ Arrhythmia Electrophysiol 2009;2: Gold MR, et al. Heart Rhythm 2012;9:S24 (Abstract). 14 Virchow s Triad for Thrombogenesis in Atrial Fibrillation Endothelial Injury Inflammation Fibrosis Endomyocardial injury Extracellular matrix changes Ø Atrial Ø Thromb us Stasis Loss of contractility Atrial dilatation Anatomic variations Prothrombotic State Endothelian injury Inflammation Growth factors (VEGF) Extracellular matrix changes Decreased nitric oxide RAAS Platelet activation 15 Ø 5

6 CASE 1. A 64 yo female is referred for care after her ER presentation for recent onset AF. She has a history of long-standing hypertension and diabetes controlled with exercise and diet. She was sent to you for consideration of anticoagulant therapy. What is her annual risk of stroke using the CHA 2 DS 2 -VASc scoring system? 1) 1-3% 2) 4-6% 3) 7-10% 4) 14-17% 5) I am not sure what the CHA2DS2-VASc scoring system is? Audience Response Question 16 Weighing the Risks and Benefits of Oral Anticoagulation in Patients with AF Risks: Increased risk of: Major bleeding Intracerebral bleeding Minor bleeding Other side effects Inconvenience Risks Benefits Benefits: Decreased risk of: Stroke and emboli Asymptomatic stroke? Cognitive decline 17 Risk of Stroke Assessed by CHADS 2 Score CHADS2 Points C = CHF 1 H = HTN 1 A = Age 75 1 D = DM 1 S = Prior CVA 2 Stroke Rate (% per year) n=120 1 n=463 2 n=523 3 n=337 4 n=220 CHADS 2 Score 5 n=65 6 n=5 Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e Ø 6

7 Comparison of CHADS2 and CHA2DS2- VASc Scoring Systems CHADS2 CHA2DS2 -VASc Risk Factor Points Points CHF 1 1 Hypertensi on 1 1 Age > Diabetes 1 1 Prior Stroke Vascular Disease Scoring System Age Female Annualized Stroke Risk Total Score CHADS2 CHA2DS2- VASc Lip GY, Halperin JL. Am J Med 2010;123(6):84-488; Olesen JB, et al. Br Med J 2011;342:d AHA/ACC/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 January CT, et al. Circulation 2014;129: Doi; /CIR ACC/AHA Clinical Performance and Quality Measures state CHA2DS2-VASc score must be documented and shared decision making documented 20 Heidenriech PA, et al. J Am Coll Cardiol 2016 (in press). doi.org/ /j.jacc What is the one AF therapy that has been shown to decrease mortality in AF patients? 1. Antiarrhythmic drug therapy 2. Catheter ablation 3. Surgical maze procedure 4. Left atrial appendage closure 5. Oral anticoagulation Audience Response Question 21 Ø 7

8 Anticoagulation in AF Stroke Risk Reductions Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate Reduction of all-cause mortality RRR 26% Reduction of stroke RRR 62% 100% 50% 0-50% -100% Hart et al. Ann Intern Med 1999;131: Narrow Therapeutic-Safety Window With Warfarin Assessed by INR Measurement 20 Therapeutic Window Odds Ratio Intracranial Bleeding 5 Ischemic Stroke 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: Data from Odén A, Fahlén M, Hart RG. Thromb Res 2006;117: Freeman WD, Aguilar MI. Expert Rev Neurother 2008;8(2): Aguilar MI, et al. Mayo Clin Proc 2007;82(1): TTR with Warfarin Therapy Anticoagulation Clinic-Based Warfarin Dosing Samsa, 2000 (n=43) 0.60 Menzin, 2005 (n=600) 0.62 Hylek, 2007 (n=306) 0.58 Nichol, 2008 (n=351) 0.68 Subtotal 0.63 Community-Based Warfarin Dosing Samsa, 2000 (n=61) 0.47 Samsa, 2000 (n=125) 0.36 McCormick, 2001 (n=174) 0.51 Matchar, 2003 (n=363) 0.56 Matchar, 2003 (n=317) 0.49 Matchar, 2003 (n=317) 0.52 Go, 2003 (n=7445) 0.63 Shen, 2007 (n=11,016) 0.55 Nichol, 2008 (n=756) 0.42 Subtotal 0.51 Overall Effect 0.55 TTR TTR = time in therapeutic range. TTR (95% CI) Baker WL, et al. J Manag Care Pharm. 2009;15(3): Ø 8

9 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 (%) Low Risk 59.9% Untreated Moderate Risk High Risk 56.5% 57.9% Untreated Untreated CHADS 2 Score *Hatched area represents the proportion of patients with uninterrupted therapy over 180 days following initial warfarin prescription. 25 Zimetbaum PJ, et al. Am J Med. 2010;123(5): Biases Decreasing the Usage of Oral Anticoagulation in High Risk Patients Advanced age Perceived bleeding risk History of prior bleeding Perceived fall risk Multiple co-morbidities Ability to comply with OAC Female gender (possibly) African-American and Hispanic populations Decreased socioeconomic background Beyth RJ et al. J Gen Intern Med 1996;11(12); ; Pugh O, et al. Age Ageing 2011;40(6): ; Bhave PD, et al. Heart Rhythm 2015;12(7): ; Thomas KL, et al. J Am Heart Assoc 2013;2(5):e Limitations to Use of Warfarin in AF Patients at Risk for Strokes Active bleeding and/or bleeding risk Risk of falling or head trauma Difficulty maintaining therapeutic INR Concern about bleeding and/or drug interactions Allergic reaction to warfarin Patient preference 27 Ø 9

10 Let s Return to CASE 1. A 64 yo female is referred for care after her ER presentation for recent onset AF. She has a history of longstanding hypertension and diabetes controlled with exercise and diet. She has been sent to you for consideration of anticoagulant therapy. What should she be treated with? 1) ASA 2) ASA+ clopidogrel 3) Warfarin 4) DOAC 5) None of the above Audience Response Question 28 Aspirin vs Placebo Reduction of Risk of Thromboembolism in AF AFASAK I SPAF I EAFT ESPS II LASAF UK-TIA All trials=6 Relative Risk Reduction (95% CI) 22% (2%-38%) Aspirin Hart et al. Ann Intern Med 1999;131: Antiplatelet Therapy in AF ACTIVE-W: 6706 randomized patients; trial stopped ACTIVE-A: 7554 randomized patients; median follow-up of 3.6 years Outcome/Year (%) P =.0003 Clopidogrel + ASA Warfarin P =.001 P =.53 Outcome/Year (%) P =.01 P<.001 Clopidogrel + ASA ASA P< 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: ACTIVE Investigators. N Engl J Med. 2009;360(20): Ø 10

11 Effect of Intensity of Oral Anticoagulation on Stroke Survival in AF Probability of Survival P=.002 Aspirin Warfarin, INR 2 Warfarin, INR <2 None Days After Admission Hylek EM, et al. NEJM 2003; 349: Newer Anticoagulants Activated Factor X Inhibitors *Apixaban Betrixaban *Edoxaban *Rivaroxaban *FDA approved at the present time. Novel Vitamin K Antagonist ATI-5923 *Warfarin Extrinsic Pathway Activation Intrinsic Pathway Activation Factor X Factor Xa Factor X Direct Thrombin Inhibitor *Dabigatran Etexilate Activated Factor X Inhibitors Prothrombin Direct Thrombin Inhibitors Fibrinogen Thrombin Fibrin Ma TKW, et al. Pharmacology and Therapeutic 2010; doi; /j.pharmthera Characteristics of Direct Oral Anticoagulants (DOAC s) Drug Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism of action Thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor T 1/ hours 5-9 hours 12 hours 6-12 hours Regimen BID QD BID QD Peak to trough ~7x 12x 3-5x ~3x Renal excretion of absorbed drug Potential for drug interactions ~80% 35-45% 25-30% 35% P- glycoprotein inhibitor CYP3A4 substrate and P- glycoprotein inhibitor CYP3A4 substrate and P- glycoprotein inhibitor CYP3A4 substrate and P- glycoprotein inhibitor 33 T 1/2 = half-life; CYP3A4 = cytochrome P450 3A4. Usman MH, et al. Curr Treat Cardiovasc Med 2008;10(5): Ø 11

12 DOAC Dosages by FDA Approved Indication Indication Dabigatran Rivaroxaban Apixaban Edoxaban AF DVT/PE Long-term DVT/PE risk reduction THR or TKR Prophylaxis 150 mg bid if CCl >30 cc/ min 75 mg bid if CCl cc/ min 150 mg bid If CCl >30 cc/ min 150 mg bid If CCl >30 cc/ min Not FDA Approved 20 mg qd if CCl >50 cc/min 15 mg qd if CCl cc/min 15 mg qd bid X21 days; then 20 mg qd 5 mg bid 2.5 mg bid if 2 of the 3: Age 80 yrs Weight 60 kg Creatinine 1.5 mg/ dl 10 mg bid X 7 days; Then 5 mg bid 60 mg qd If CCl cc/min 30 mg qd If CCl cc/min Contra-indicated If CCl >95 cc/min UFH/LMWH X5-10 d Then 60 mg qd if CCl >50 cc/min 30 mg qd if CCl cc/min 20 mg qd 2.5 mg bid Not FDA Approved 10 mg qd X12 days TKR X35 days THR 2.5 mg bid Not FDA Approved 34 RE-LY Trial: Primary Efficacy and Safety Endpoints Percent/Year *P<.001 P<.001 P =.003 Dabigatran 110 mg is not FDA approved for this indication; for informational purposes only P<.001 Dabigatran 110 mg Dabigatran 150 mg Warfarin INR Avg TTR: 67% 1.0 P<.001 P= Stroke/Systemic Embolism Major Bleed Intracranial Hemorrhage *Noninferiority; Superiority. MI = myocardial infarction; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy. Connolly SJ, et al. N Engl J Med 2009;361(12): Connolly SJ, et al. N Engl J Med 2011;363: MI 35 ROCKET AF: Primary Efficacy and Safety Outcomes P=0.58 P=0.02 P=0.12. P=0.02 Stroke and Non-CNS Embolism *P<0.001 for noninferiority of rivaroxaban vs warfarin; Superiority. Patel MR, et a. N Engl J Med Published online August 30, Safety 36 Ø 12

13 ARISTOTLE Trial: Efficacy and Safety Results P=0.047 P < P < P=0.01 P < Stroke or Systemic Embolism Death from Any Cause ISTH Major Bleeding Intracranial Bleeding Net Clinical Outcomes* *Net clinical outcomes: Stroke, system embolism, or major bleeding. **Apixaban is not FDA approved. Granger CB, et al. N Engl J Med Published online August 30, ENGAGE-AF: Primary Efficacy and Safety Outcomes P=0.08 Ø Event Rate/100 Pt-Years P=0.08 P=0.10 P=0.006 P<0.001 P<0.001 P<0.001 P<0.001 Giugliano RP, et al. N Engl J Med 2013;369: DOI: /NEJMoa CASE 2. A 68 yo female with hypertension, DM, and a TIA 2 years ago who has had AF for the past 3 years unable to maintain INR in therapeutic range with warfarin 1) What is her CHA2DS2-VASc Score 2) Should a DOAC be used? 39 Ø 13

14 Comparison of Direct Oral Anticoagulants Relative to Warfarin Strokes + Systemic Emboli Intracranial Hemorrhage Major Bleeding Dabigatran 1 * Rivaroxaban 2 Apixaban 3 Edoxaban 4 * Meta Analyses No Difference All Decreased Apixaban Decreased MI Xa Decreased IIa Increased Mortality No Difference Fatal Xa Decreased Bleeding ++ Significantly better; + Trend to being better; 0 No difference; - Trend to being worse *Dabigatran 150 mg bid; Edoxaban 60 mg qd. 1) Connolly SJ, et al. N Engl J Med 2009; 361: ) Granger CB, et al. N Engl J Med 2011;365(11): ) Patel MR, et al. N Engl J Med 2011;365(10): ) Giugliano RP, et al. N Engl J Med 2013;369: CASE 2. A 68 yo female with hypertension, DM, and a TIA 2 years ago who has had AF for the past 3 years unable to maintain INR in therapeutic range with warfarin Issues to be addressed: 1) What about the bleeding risk? 2) What can be done to minimize bleeding using the HAS-BLED score 3) Does the risk of bleeding preclude her benefits from a DOAC? 41 Annual Risk* of Fatal Bleeding with Dabigatran 1, Rivaroxaban 2, Apixaban 3, and Edoxaban 4 DOAC Warfarin RR (95% CI) p Value RE-LY: 150 mg ( ) ROCKET-AF ( ) ARISTOTLE ( ) ENGAGE-AF: mg 4 ( ) *Percent of patients/year 1) Connolly SJ, et al. N Engl J Med 2009; 361: ) Patel MR, et al. N Engl J Med 2011;365(10): ) Granger CB, et al. N Engl J Med 2011;365(11): ) Giugliano RP, et al. N Engl J Med 2013;369: <0.001 < < Ø 14

15 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* Camm AJ, et al. Eur Heart J 2010;31(19): Pisters R. Chest. 2010;138: Lip GY, et al. Am J Med. 2010;123(6): 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: ; Apostolakis S, et al. Thromb Haemost 2013;110: ; 44 Roldan V, et al. J Am Coll Cardiol 2013;62: High-Risk Patients Benefit Most From Anticoagulation Mixed Retrospective and Prospective Cohort of Patients With AF Between 1996 and CHADS 2 Score Worse With Warfarin Better With Warfarin Net clinical benefit - events prevented per 100 person-years Singer DE, et al. Ann Intern Med 2009;151(4): Ø 15

16 Thromboembolic Events, Recurrent Hemorrhage, and Death After Warfarin Interruption for GI Bleeding Should Anticoagulation Be Reinitiated After a GI Bleed? Thromboembolic Events Death Recurrent GI Bleeding When warfarin restarted When warfarin not restarted There are no prospective trials evaluating restarting oral anticoagulation after major GI bleeding. Witt DM, et al. Arch Intern Med (on line: ).Doi: /archinternmed Anticoagulation for Stroke Prevention in AF Patients with Valvular Heart Disease Warfarin is the only FDA approved oral anticoagulant for patients with significant valvular heart disease All DOAC s are contra-indicated in the absence of adequate date demonstrating their efficacy 2014 ACC/AHA/HRS Guidelines define nonvalvular AF as that which occurs in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitralvalve repair. January CT, et al. Circulation 2014;129: Doi; /CIR Dabigatran Versus Warfarin in Patients with Mechanical Heart Valves (RE-ALIGN Trial) First Embolic Event First Bleeding Event Eikelboom JW, et al. N Engl J Med 2013, September 1. DOI: /NEJMoa Ø 16

17 CASE 3. A 77 yo male with long-standing DM and AF for the past 3 years has been on dabigatran without any cerebrovascular events or bleeding episodes. He requires a colonoscopy for colon cancer surveillance and you are asked about bridging his anticoagulant care for his procedure. Should bridging anticoagulant therapy be used? 1) Continue dabigatran uninterrupted 2) Stop dabigatran 3 days prior to procedure; no bridging 3) Stop dabigatran 3 days prior to procedure; bridging with enoxaparin 4) Don t know Audience Response Question 49 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 50 Peri-Procedure 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<0.001 P<0.001 Ø P=NS P=NS Ø *With low molecular weight heparin or unfractionated heparin. Ø Douketis JD, et al. Thromb Haemost 2015;113: Ø 17

18 ROCKET-AF: Effect of Electrical and Pharmacological Cardioversion and AF Ablation on Outcomes 60" 50" 40" 30" 20" 10" 0" CVA/Emb" CV"Deaths" All"Deaths" CVA,"Emb,"and"CV" CVA,"Emb,"and"all"Deaths" Hospitaliza?ons" Hospitaliza?ons"or"CV" Rivaroxaban" Warfarin" Be sure to document that patient has been compliant in taking DOAC; if any question then TEE prior to restoration of sinus rhythm by AAD, cardioversion, or ablation. 52 Piccini JP, et al. J Am Coll Cardiol 2013;61(19): Direct Oral Anticoagulants: Other Safety Considerations Spinal/Epidural Hold 2-3 days Major Surgery: Hold 2-3 days AF Ablation Pregnancy Uninterrupted or hold night before or day of procedure Avoid Nursing Mother Avoid Geriatric Useful (check GFR) Renal Failure Decrease dosage Hepatic Failure Avoid if moderate-severe Refer to Package Inserts of specific DOAC for detailed information 53 Important Drug Interactions to Consider When Starting DOAC s Drug Interaction Mechanism Recommendations Dronedarone-Dabigatran Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan Carbamazepine, phenytoin, rifampin, St. John s wort Aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, dipyridamole, NSAID s P-glycoprotein inhibition by dronedarone decreases dabigatran absorption Strong CYP3A4 inhibition decreased hepatic clearance of DOAC s to increase anticoagulation Strong CYP3A4 induction increases hepatic clearance of DOAC s to decrease anticoagulation Anti-platelet agents inhibit platelet function to increase risk of bleeding Avoid concomitant use Stagger dosing Use Xa inhibitor or warfarin Avoid concomitant use Can halve apixaban dosage Use warfarin Avoid concomitant use Use warfarin Avoid or limit concomitant use when possible Ø 18

19 Potential Reversal Agents of DOAC s 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-alpha** 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). 55 doi /s Let s return to CASE 2. A 68 yo female with hypertension, DM, and a TIA 2 years ago who has had AF for the past 3 years unable to maintain INR in therapeutic range with warfarin You have discussed using a DOAC and her bleeding risks. She was sent to you for consideration of anticoagulation, but she has read about a procedure that would eliminate her AF and she asks if she could have this done. - What is the role of AF ablation for stroke prevention? - What are other non-pharmacological options? 56 Should Patient After AF Ablation Be Chronically Anticoagulated? Retrospective Analysis of the Effect of AF Ablation on Stroke Risk CHADS2 Score No AF (n = 16848) AF Medical (n = 16848) AF Ablation (n = 4212) p Value 0 2.6% 3.7% 1.6% < % 5.4% 1.9% < % 2.2% < % 9.0% 6.1% % 17.6% 9.1% < % 18.6% 13.2% 0.18 Bunch TJ, et al. Heart Rhythm 2013 DOI:10:1016/j.hrthm There are no prospective, randomized trials demonstrating the efficacy or safety of catheter ablation for stroke prevention in AF patients. 57 Ø 19

20 Meta-Analysis Comparing Risks of Thromboembolism and Complications of LAAC Device or DOAC to Warfarin Left Atrial Appendage Closure Device Requires 45 days post implantation of warfarin +ASA and then 6 months of ASA+clopidogrel Sick PB, et al JACC 2007;49: Briceno DF, et al. Circ Arrhythm Electrophysiol 2015;8: Recommendations for Non-Pharmacological Approaches to Stroke Prevention LAA Closure Device: Indicated only when OAC indicated to decrease stroke risk and have an appropriate reason to avoid OAC s due to bleeding or other complications AF Ablation: Present HRS/EHRA/ECAS Consensus Statement recommends continued oral anticoagulation for all patients after ablation with or without recurrent AF if CHA2DS2-VASc 2 1 Holmes DR, Reddy VY. Circ Cardiovasc Interv 2016;9:e doi: /circinterventions Calkins H, et al. Heart Rhythm 2012;9(4): 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 60 Ø 20

21 Bonus Question Can RNs, NPs, and PAs Decrease the Mortality Associated with AF? 61 Randomized Trial of Special Nurse and Guideline Led AF Clinic Versus Usual Physician Care Nurse Led Clinic N=356 Usual Care N=356 HR (95% CI) Primary Endpoint (CV hospitalization & CV death) Cardiovascular Hospitalization 51 (14.3%) 74 (20.8%) 0.65 ( ) 48 (13.5%) 68 (19.1%) 0.66 ( ) Cardiovascular Death 4 (1.1%) 14 (3.9%) 0.28 ( ) Compliance with 6 Recommendations* (Anticoag. only) 81% (99%) 40% (83%) *Baseline echocardiography; TSH; guideline based anticoagulation; guideline based AAD; avoiding rhythm control in asymptomatic patients; avoiding rhythm control in permanent AF. Ø Hendrik JM, et al. Eur Heart J 2012;33(21): Post-test ARS Question 1 A 67 yo woman with lone 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 63 Ø 21

22 Post-test ARS Question 2 75 yo man with persistent AF, history of CHF, CAD, HTN, CRI, and PVD. Treated with warfarin but INR s 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 64 Post-test ARS Question 3 62 yo woman with paroxysmal AF, HTN, DM, and long history of GERD, on rivaroxaban. Presents to ER 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, and 3 65 Post-test ARS Question 4 78 yo 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 compensated CHF, HTN, and PVD. 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 66 Ø 22

23 Post-test ARS 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 Ø 67 Ø 23