Non-Valvular Atrial Fibrillation: Reducing Risk and Individualizing
Therapeutic Choices
§ John M. Wharton, MDFrank P. Tourville Professor of Medicine Director, Cardiac ElectrophysiologyMedical University of South Carolina Charleston, SC
Faculty
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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.
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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
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PRE-TEST QUESTIONS
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 No2. 1 No3. 1 Yes4. 2 No5. 2 Yes6. 3 Yes
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Pre-test Question 1
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 bleeding2. An antiplatelet agent because of his risk of bleeding3. A DOAC despite his risk of bleeding4. A reduced dosage of DOAC because of his risk of
bleeding 7
Pre-test Question 2
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 tube2. Give intravenous fluid and blood and emergent GI
consult3. Give fresh frozen plasma4. Give idarucizumab5. 1 and 26. 1, 2, and 3
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Pre-test Question 3
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 aspirin2. Stop his dagibatran but continue his aspirin3. Continue his dabigatran and his aspirin4. Continue his dagibatran but stop his aspirin
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Pre-test Question 4
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
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Agenda
§ Estimating Stroke Risk
§ Safety and Efficacy of Oral Anticoagulants
§ Other Options for Stroke Prevention
§ The Role of Primary Care
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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
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Ann (cont’d)
Workup§ BP 120/72 mmHg
§ BMI 25.5 kg/m2
§ 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
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AF, Strokes, and Cognitive Decline
§ 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
Worse Outcomes with Embolic Strokes
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.
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Study AF Duration RR (95% CI) p Value
TRENDS1 20 second - <5.5 hours 0.98 (0.34,2.82) 0.97
≥5.5 hours 2.20 (0.96,5.05) 0.06
ASSERT2 ≥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
Stroke Risk and AF Duration from Implantable Device Diagnostics
1. Glotzer T, et al. Circ Arrhythmia Electrophysiol 2009;2:474-480.
2. Gold MR, et al. Heart Rhythm 2012;9:S24 (Abstract).
Ø 1TRENDS: N = 2486. Ø 2ASSERT: N = 2580.
Risk of Stroke Assessed by CHADS2 Score
Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198.
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5
15
10
0
1.9 2.8
4.0 5.9
8.5
12.5
18.2
0 n=120
1 n=463
2 n=523
3 n=337
4 n=220
5 n=65
6 n=5
CHADS2 Score
Stro
ke R
ate
(% p
er y
ear)
CHADS2 Points C = CHF 1 H = HTN 1 A = Age ≥75 1 D = DM 1 S = Prior CVA 2
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Comparison of CHADS2 and CHA2DS2-VASc Scoring Systems
CHADS2 CHA2DS2-VASc
Risk Factor Points Points
CHF 1 1
Hypertension
1 1
Age >75 1 2
Diabetes 1 1
Prior Stroke
2 2
Vascular Disease
--- 1
Age 65-74 --- 1
Female --- 1
Total Score
CHADS2 CHA2DS2-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
Scoring System Annualized Stroke Risk
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 Warfarin, dabigatran, rivaroxaban, apixaban, edoxaban
Valvular Disease
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
*Hatched area represents the proportion of patients with uninterrupted therapy over 180 days following initial warfarin prescription. Zimetbaum PJ, et al. Am J Med. 2010;123(5):446-453.
Warfarin Remains UnderutilizedRetrospective cohort study of 171,393 patients to assess the utilization of warfarin
within 30 days of an AF/flutter diagnosis among different risk strata*
Newly Diagnosed AF/Flutter (n=51,907) Total (n=171,393) Pre-Existing AF/Flutter (n=119,486)
CHADS2 Score
60
40
30
20
10
0 0 1 2 3
Trea
ted
with
War
fari
n (%
)
4 5 6
50 49.0
40.1
34.7
50.7
43.5 40.0
50.8
40.6
46.1 43.0 42.1 43.5 43.0
40.8 40.2 36.3
40.4 43.0
39.7 39.1 39.7
Low Risk 59.9%
Untreated
Moderate Risk 56.5%
Untreated
High Risk 57.9%
Untreated
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Anticoagulation and DOACS
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Ø What does the data say?
Anticoagulation in AFStroke Risk Reductions
(N= 2900)
Hart et al. Ann Intern Med 1999;131:492-501.
Warfarin Better Control Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
100% 50% 0 -50% -100%
Aggregate
Reduction of stroke
RRR 62%
Reduction of all-cause mortality
RRR 26%
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Narrow Therapeutic-Safety Window With Warfarin Assessed by INR Measurement
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.
INR
Odd
s Rat
io
Intracranial Bleeding
Ischemic Stroke
Therapeutic Window
5 6 8 1 2 3 4 7 0
5
20
15
10
ICH is the most lethal form of stroke with 30-day mortality rates of 30-55%1,2
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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.
Antiplatelet Therapy in AFACTIVE-W:
6706 randomized patients; trial stopped
6
4
0
2
Out
com
e/Ye
ar (%
)
Stroke Vascular Event
Major Bleeding
5
3
1
P = .0003
P = .001 P = .53
Warfarin Clopidogrel + ASA
ACTIVE-A: 7554 randomized patients;
median follow-up of 3.6 years
8
6
4
0
2 Out
com
e/Ye
ar (%
)
Stroke Vascular Event
Major Bleeding
7
5
3
1
P = .01
P<.001
P<.001
ASA Clopidogrel + ASA
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Newer Anticoagulants
Ma TKW, et al. Pharmacology and Therapeutic 2010; doi;10.1016/j.pharmthera.2010.09.005
Novel Vitamin K Antagonist
Activated Factor X Inhibitors
Apixaban
Betrixaban
Edoxaban
Rivaroxaban
Direct Thrombin Inhibitors
Dabigatran Etexilate
Extrinsic Pathway Activation Intrinsic Pathway Activation
Factor X Factor X Factor Xa
Prothrombin Thrombin
Fibrinogen Fibrin
Activated Factor X Inhibitors
Direct Thrombin Inhibitors
*Warfarin
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Ø
Ø Ruff CT, et al. Lancet 2014; 383(9921): 955–962 Ø http://dx.doi.org/10.1016/S0140-6736(13)62343-0
Ø Strokes and Systemic Emboli
Ø Major Bleeding
Comparison of Efficacy and Safety of DOAC’s to Warfarin: Meta-Analysis of
Randomized Trials
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Annual Risk* of Fatal Bleeding with DOACs
DOAC Warfarin RR (95% CI) p Value
RE-LY: 150 mg1 0.23 0.33 0.70 (0.43-1.14) 0.15
ROCKET-AF2 0.2 0.5 0.49 (0.55-0.83) <0.001
ARISTOTLE3 0.06 0.25 0.27 (0.13-0.53) <0.0001
ENGAGE-AF: 60 mg4 0.21 0.38 0.55 (0.36-0.84) <0.001
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
*Percent of patients/year
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Pairwise, Propensity Matched Comparison of DOAC’s to Warfarin in Large US Insurance Database DOAC vs Warfarin N=76,354
Apixaban N=7695
Dabigatran N=14,307
Rivaroxaban N=16,175
EFFICACY
Stroke + Systemic Emboli
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
0.35 (0.14-0.88)* 0.56 (0.30-1.04) 0.61 (0.35-1.07)
SAFETY
Major Bleeding 0.45 (0.34-0.59)***
0.79 (0.67-0.94)** 1.04 (0.90-1.20)
Intracranial Bleeding
0.24 (0.12-0.50)***
0.36 (0.23-0.56)***
0.51 (0.35-0.75)***
GI Bleeding 0.51 (0.37-0.70)***
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 Drugs and Alcohol (1 point each)
1 or 2
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 ---
Point Score System Bleeding Risk
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.
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Utility of CHA2DS2-VASc in Predicting Major Bleeding Risk with Oral Anticoagulation
CHA2DS2-VASc Score
Ann
ualiz
ed P
erce
nt R
isk
Risk of Thromboembolism and Any Severe Bleeding in Stockholm
However, HAS-BLED has much higher discriminatory performance for predicting majorbleeding 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.
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To Bridge or Not to Bridge…
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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
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Periprocedural Bridging Anticoagulation* During Warfarin and
Dabigatran Interruption in RE-LYØ Stroke or Major Bleeding Ø Systemic Embolus
Ø Pe
rcen
t of P
atie
nts w
ith E
vent
Ø P=NS P=NS
Ø P<0.001 P<0.001
Douketis JD, et al. Thromb Haemost 2015;113:625-632.
*Using low molecular weight heparin or unfractionated heparin
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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
Ansell JE. J Thromb Thrombolysis 2015 (Oct 15).
*4 factor prothrombin complex concentrate is not FDA approved for DOAC reversal **Investigational drugs
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Should Patient After AF Ablation Be Chronically Anticoagulated?
CHADS2 Score
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.
Retrospective Analysis of the Effect of AF Ablation on Stroke Risk
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Final Points
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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
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POST-TEST QUESTIONS
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 No2. 1 No3. 1 Yes4. 2 No5. 2 Yes6. 3 Yes
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Post-test Question 1
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 bleeding2. An antiplatelet agent because of his risk of bleeding3. A DOAC despite his risk of bleeding4. A reduced dosage of DOAC because of his risk of
bleeding 39
Post-test Question 2
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 tube2. Give intravenous fluid and blood and emergent GI
consult3. Give fresh frozen plasma4. Give idarucizumab5. 1 and 26. 1, 2, and 3
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Post-test Question 3
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 aspirin2. Stop his dagibatran but continue his aspirin3. Continue his dabigatran and his aspirin4. Continue his dagibatran but stop his aspirin
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Post-test Question 4
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
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