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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