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Are You Up-to-Date in Your Management of Atrial Fibrillation?

Greg Flaker MD Professor of Medicine University of Missouri

Wes and Simon Sorenson Chair of Cardiovascular Research

June 2015

Consulting agreement

• Pfizer

• Daiichi Sankyo

• Bristol-Myers Squibb

• Janssen Pharmaceuticals

Disclosures

Time Course and Management of AF

European Heart J 2010;31:2369-2429

Treatment Control RR

Study n/N n/N (95% CI Random) 01 Heart Failure

Van Den Berg 2/7 7/11 ●

SOLVD 10/186 45/188 ●

ValHeFT 116/2209 173/2200 ●

Charm 179/2769 216/2749 ●

Subtotal (95%CI) 307/5171 441/5148

02 Hypertension

CAPP 117/5492 135/5493 ●

LIFE 179/4417 252/4387 ●

STOPH2 200/2205 357/4409 ●

Subtotal (95%CI) 496/12114 744/1289

03 Atrial Fibrillation

Madrid 9/79 22/75 ●

Ueng 18/70 32/75 ●

Subtotal (95%CI) 27/149 54/150

04 Post-Myocardial Infarction

TRACE 22/790 42/787 ●

GISSI 665/8865 721/9633 ●

Subtotal (95%CI) 687/9655 763/9633

Total (95%CI) 1517/27089 2002/29220 -1 -2 1 5 10

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Prevention of AF with ACEi/ ARB’s

JACC 2005;45:1832-1839

Atorvastatin and AF

Heart Rhythm 2010;7(10):1475-81

MRI Findings in Lone AF

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CHA2DS2-VASc

Risk Factor Score

Cardiac failure 1

Hypertension 1

Age ≥75 years 1

Diabetes 1

Stroke 2

Risk Factor Score

Cardiac failure 1

Hypertension 1

Age ≥75 years 2

Diabetes 1

Stroke 2

Vascular disease (MI, peripheral arterial disease, aortic atherosclerosis) 1

Age 65-74 years 1

Sex category (female) 1

CHADS2

MI=myocardial infarction. Lip GY, Halperin JL. Am J Med. 2010;123:484-

8. Camm AJ et al. Eur Heart J. 2010:31;2369-429.

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4 5 6 7 8 9

Annual Risk of Stroke (%)

CHADS2

CHA2DS2-VASc

Total Score

8

Improvement of Risk Identification with CHA2DS2-VASc

9

Adapted from Olesen JB et al. Thromb Haemost. 2012;107(6):1172-1179.

1 Year Follow-up

Person-years Events Stroke Rate (95% CI)

CHADS2 score=0 17,327 275 1.59 (1.41-1.79)

CHA2DS2-VASc=0 6919 58 0.84 (0.65-1.08)

CHA2DS2-VASc=1 6811 119 1.75 (1.46-2.09)

CHA2DS2-VASc=2 3347 90 2.69 (2.19-3.31)

CHA2DS2-VASc=3 250 8 3.20 (1.60-6.40)

CHADS2 score=1 22,945 1130 4.92 (4.65-5.22)

CHA2DS2-VASc=1 2069 40 1.93 (1.42-2.64)

CHA2DS2-VASc=2 8516 345 4.05 (3.65-4.50)

CHA2DS2-VASc=3 11,223 652 5.81 (5.38-6.27)

CHA2DS2-VASc=4 1137 93 8.18 (6.68-10.02)

Risk Factor Recommended Therapy

ESC AHA/ACC/HRS

No risk factors CHA2DS2-VASc = 0

Prefer Neither

or ASA 75-325 mg daily Neither

CHA2DS2-VASc = 1 Prefer OAC,

or ASA 75-325 mg daily Neither or ASA or OAC

CHA2DS2-VASc ≥2 TSOAC* > VKA TSOAC* or VKA

Mechanical valve (modern) VKA: INR 2.0-3.0 (AVR) VKA: INR 2.5-3.5 (MVR)

*TSOAC=Target-specific oral anticoagulant (Cove CL, Hylek EM. J Am Heart Assoc. 2013;Oct 23 ESC Guidelines: Camm AJ et al. Eur Heart J. 2012;33:2719-47. AHA/ACC/HRS Guidelines: January CT et al. Circulation, 2014

Anticoagulant, Antiplatelet, or Neither:

Current Guidelines

CHADS-VASc: How Many More AF Patients Will Receive Anticoagulation?

Swedish Registry Eur Heart J 2012;33:1431-3

AVERROES DESIGN

R

36 countries, 522 centres

AF and ≥ 1 risk factor,

demonstrated or

expected

unsuitable for VKA

APIXABAN 5mg BID 2.5 mg BID in selected patients

5,600 patients

ASA (81-324 mg/d)

Double-Blind

Primary Outcome: Stroke or systemic embolism (intention to treat analysis)

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NEJM 2011; 364: 806-17

NOAC’s vs. Warfarin Efficacy and Safety in non-valvular AF*

* Hemodynamically significant MS, mechanical or biological prosthetic valve or repair

Silent AF 56 yo Catholic priest s/p MI and stroke • normal coronary arteries, LVEF 30% • carotid Duplex < 50% lesions bilaterally • normal hypercoagulable work-up • ICD implanted

N Engl J Med 2002;346(26):2066

Devices for AF: Living Better Electrically

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AF “burden”

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Sleep apnea and AF Subclinical AF and Risk of Stroke

NEJM 2012;366:120-9

How Much AF Is Needed to Put the Patient at Risk of Stroke?

93 yo white female hospitalized for TIA symptoms

• s/p MI and pacemaker

• history of hypertension

• Neurologist performs CT and echo, continues aspirin

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Cryptogenic Stroke and Underlying AF The Crystal-AF Study

22 NEJM 2014;370:2478-86

The Reveal LINQ ICM System The Complete Monitoring Solution

Mobile

Alerts

Streamlined Reports

Improved CareLink®

User Interface

Patient

Assistant

MyCareLink™

Patient Monitor

Simplified Insertion

Procedure

Reveal LINQ™ ICM

Wireless

Cellular

Bridging

80 yo white female with an end of life pacemaker. She has hypertension, a history of a stroke, and paroxysmal atrial fibrillation. She is treated with warfarin.

How do you manage warfarin in this high risk

patient prior to pulse generator replacement? 1. Hold warfarin, bridge with UFH or LMWH. 2. Hold warfarin, perform surgery when INR<1.5. 3. Replace device with a therapeutic INR.

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Bridge or Continue Coumadin for Device Surgery Randomized Trial

(Bruise Control) Warfarin arm

• Perform surgery with INR <3.0 <3.5 with one or more mechanical valves

Heparin arm

• LMWH stopped > 24 hours before surgery

Heparin stopped 4 hours before surgery

• Either restarted 24 hours after, continued until INR therapeutic

Bruise Control Results

0

3

6

9

12

15

18

Hematoma n=66

Embolic Event n=2

Bridge

Warfarin

NEJM 2013;368:2084-93

% n=338 n=343

P<0.001

Classification of Elective Surgical Interventions

According to Bleeding Risk

EPS = Elecrophysiology study, ICD = Implantable cardioverter-defibrillator, RF = Radiofrequency, SVT = Supraventricular tachycardia, TURP = Transurethral resection of the prostate

Heidbuchel H, et al. Europace. 2013;15:625-651.

Anticoagulation Cessation Not Required

Interventions with Low Bleeding Risk

Interventions with High Bleeding Risk

Dental interventions Endoscopy with biopsy Complex left-side ablation

Extraction of 1-3 teeth Prostate/bladder biopsy Spinal/epidural anesthesia

Peridontal surgery EPS or RF ablation for SVT Diagnostic lumbar puncture

Incision of abscess Angiography Thoracic surgery

Implant positioning Pacemaker/ICD implant Abdominal surgery

Ophthalmology Major orthopedic surgery

Cataract or glaucoma surgery Liver biopsy

Endoscopy without surgery TURP

Superficial surgery Kidney biopsy

Dabigatran Apixaban Rivaroxaban

No Important bleeding risk and/or adequate local hemostatis possible: perform at trough level (i.e. ≥12 h after last intake)

Low risk High risk Low risk High risk Low risk High risk

CrCl ≥80 ml/min ≥24 h ≥48 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 50-80 ml/min ≥36 h ≥72 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 30-50 ml/min ≥48 h ≥96 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 15-30 ml/min Not indicated

Not indicated

≥36 h ≥48 h ≥36 h ≥48 h

CrCl <15 ml/min No official indication for use

Last intake of drug before elective surgical intervention

Europace (2013) 15;625-651 NEJM 2013;368:2113-24

Resume 48-72 hours (high bleeding risk) or 24 hours (low bleeding risk).

Bridging in ARISTOTLE Blood 2014;124(25):3692-3698

9250 interruptions for at least one invasive procedure

• Dental procedure 15%

• Colonoscopy 10%

• Cataract removal/opthalmology 9%

• Pacemaker/ICD 3.5%

• Cystoscopy 3%

• PCI 2.8%

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Bridging in ARISTOTLE Blood 2014;124(25):3692-3698

Agent Interruption UH/ LMWH

Major Bleeding

TE Event

apixaban 62.5% 11.7% 1.6% 0.4%

warfarin 62.5% 11.7% 1.9% 0.6%

Main conclusions 1) Interruption is common, often with no bridging (low risk

procedure, low risk for stroke?) 2) Low risk of stroke/SE; higher risk of major bleeding. Comparable

between apixaban and warfarin. 3) Low embolic rate and bleeding regardless of interruption or not.

Guidelines for LMWH Bridging

For patients at high risk of thrombotic events with high risk for surgical bleeding:

• Stop LMWH 24 hours (instead of 12 hours) prior to surgery

• Begin LMWH 48-72 hours after (instead of 24 hours) if high risk for bleeding

• Reduced dose LMWH for CrCl <30cc/min

CHEST Feb 2012;141(2 Suppl):e326S-e350S.

The elderly bleeding patient

85 yo white female with AF, s/p MI. On warfarin

(INR=2.5), she is admitted with a GI bleed. CHA2DS2-VASc = 4

Acute management: reversal agent? Long term management 1) no anticoagulation ever 2) restart warfarin, aim for a lower INR 3) use another agent a) aspirin b) dabigatran c) rivaroxaban d) apixaban 33

Anticoagulation reversal

Vitamin K • slow in action…24 hours

Fresh frozen plasma (FFA) • Volume….great for a volume depleted, bleeding patient

• Transfusion related lung injury

Prothrombin complex concentrate (PCC) • 3 (II, IX,X) or 4 factor (II,VII,IX,X)?

• Virally inactivated…an FDA issue

• UM dosing protocol

15IU/kg IBW if INR <5…increases levels by 12.5%

30 IU/IBW if INR > 5…increases clotting factors by 25%

Factor VII • Expensive

All have potential for thrombogenicity and infection.

Reversal of Anticoagulation

Agent Reversal Agents

Warfarin • Oral or IV vitamin K • Fresh-frozen plasma, • 4-factor PCC (prothrombin complex concentrate)

NOACs None, but consider • charcoal • 4-factor PCC

NEJM 2013;368:2113-24

Results

Type and Timing of Reversal Agents for Warfarin Associated Major Bleeding

University of Missouri Oct 2009-January 2013

Clinical Cardiology and Research 2014

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RESOURCES Dabigatran N=741

Warfarin N=421

P-value

Transfusion, n (%) 439 (59) 210 (50) 0.0013

Plasma, n (%) 147 (20) 127 (30) <0.0001

Vitamin K, n (%) 70(9) 115 (27) <0.0001

Mean ICU stay , days (SD)

1.9 3.2 0.03

Invasive procedure, n (%)

79 (9) 59 (14) 0.09

OUTCOMES Dabigatran N=696

Warfarin N=425

P-value

30-day mortality after 1st major bleed

57/627 (9.1) 53/407 (13.0) 0.044

RE-LY Trial: Management of Major Bleeding AF and NSSTEMI

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Circulation, 2010;121:2067-70

CAD and AF- the EP perspective Association of NSAID and Events after MI

JAMA 2015;313(8):805-814



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Rhythm vs Rate Control AFFIRM Study

NEJM 2002;347:1825-32

AFFIRM Trial Hazard Ratios for Survival

Favorable Unfavorable

CHF

LV Dysfunction

NSR

Warfarin

Digoxin

Rhythm Control Drug

0.5 1.0 1.5

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Circulation 2004;109:1909

Mortality and Antiarrhythmic Drugs SPAF study

JACC 1992; 20: 527-32

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Antiarrhythmic Drugs for AF

NEJM 2000;342:913

Background

• Amiodarone inhibits metabolism of warfarin through the CYP 2C9 pathway and INR values are more difficult to maintain in range.

• Amiodarone is associated with hepatic, thyroid, neurologic, and pulmonary side effects and excess malignancy.

Use of amiodarone in ARISTOTLE n=2051

North America 7%

Latin America 18%

Asia-Pacific 9.5%

Europe 12%

TTR in Different Countries

No amiodarone 63% Amiodarone 57%

Major Events propensity matched analysis

Endpoint Amiodarone

rates (events)

Not

Amiodarone

rate (events)

HR (95% CI)

Amiodarone

(Yes vs. No)

P-value

Stroke/SE 1.6 (50) 1.2 (115) 1.5 (1.03-2.10) 0.0322

Death 4.8 (156) 4.1 (409) 1.2 (0.95-1.41) 0.1577

CV Death 2.65 (87) 2.3 (226) 1.2 (0.91-1.55) 0.2104

Non-CV Death 1.5 (49) 1.1 (109) 1.3 (0.88-1.82) 0.1964

MI 0.3 (10) 0.5 (51) 0.58 (0.27-1.25) 0.1646

Major Bleeding 2.4 (74) 2.1 (199) 1.15 (0.85-1.53) 0.3656

JACC in press

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JACC in press

Amiodarone for Atrial Fibrillation

JACC 2014;64:e1-76



Catheter Based PVI for AF

Success • Approximately 70% with 1 procedure • Up to 85% with a second procedure

Depends on 1) Paroxysmal vs permanent AF 2) Extent of post procedure monitoring 3) Co-morbid conditions (OSA)

RF Ablation vs Antiarrhythmic Drugs For Paroxysmal AF

RAAFT-2 Trial JAMA 2014;311(7):692-99

Editorial by Hugh Calkins: ablation is not curative

Major Complications with PV Ablation 1,049 patients, 7 series

Circulation 2005: 112;1214-31

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Everyone with AF deserves one CV.

Myths about Cardioversion

How Many Patients Undergo Cardioversion?

0%

20%

40%

60%

80%

100%

AFFIRM n=4060

2002

RE-LY n=18,113

2009

ARISTOTLE n=18,201

2011

ROCKET-AF n=14,264

2011

1600

553*

1270

285

Number of patients who underwent at least one cardioversion

AFFIRM Circ Arrhythmia and Electrophysiology 2011;4:465-69 RE-LY Circulation 2011;123:131-6

* electrical conversion only

ARISTOTLE JACC 2014 ;63:1082-7. ROCKET AF JACC 2013;61:1998-2006

If AF has lasted < 48 hours, it is OK to cardiovert without anticoagulation.

Myths about Cardioversion

Conversion of AF <48 hrs Prevention of stroke

AF< 48 hours • n= 3,143

• mean age 61 + 12.4

• mean CHADS =1

JACC 2013;62:1187-92

Conversion of AF <48 hrs Prevention of stroke

US Recommendation (JACC 2014;64(21):2246-80.

• high risk: begin anticoagulation (LMWH or UH, thrombin inhibitor or factor Xa inhibitor) as soon as possible before or after CV, followed by long term anticoagulation (class I)

• low risk: as above or consider no anticoagulation (class IIb)

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powerpoint presentation · endoscopy without surgery turp superficial surgery kidney biopsy ......

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