Atrial Fibrillation: Advances in Management Anticoagulation and Heart Rhythm Control in 2013

Anil K. Gehi, MD, FHRS Assistant Professor of Medicine

Program Director, Fellowship in Clinical Cardiac Electrophysiology

University of North Carolina, Chapel Hill

August 24, 2013

Financial Disclosures

• No disclosures

Learning Objectives

• Understand how to stratify risk for stroke and choose appropriate stroke prevention strategy including novel anticoagulants

• Recognize who may be a candidate for rhythm control of AF

• Learn potential benefit of various techniques for rhythm control of AF

Presentation Outline

• Epidemic of AF

• Pathogenesis

• Principles of management

– Stroke prophylaxis

– Rate control

– Consider rhythm control

• Antiarrhythmics

• Catheter ablation of AF

• Conclusions

Major update

Minor update

Major update

Evolution of management of AF

0

500

1000

1500

2000

2500

3000

3500

1940 1950 1960 1970 1980 1990 2000 2010 2020

digitalis

amiodarone

disopyramide sotalol

flecainide

dofetilide

drondarone

dabigatran

ximelagatran

rivaroxaban apixaban

# o

f ar

ticl

es c

ited

in P

ubm

ed

quinidine

warfarin

cardioversion

PVI

MAZE

Epidemiology

• Estimated 2.2 million people in U.S. with AF

• A 66% increase in hospital admissions for AF in last 20 yrs

– Aging population

– Rising prevalence of chronic heart disease

Go et al. JAMA. 2001;285:2370-2375.

Five million Americans with AF by 2040

Relative risk of stroke and mortality with AF

Pathogenesis

Mechanism overview

• Atrial fibrillation initiated by a “trigger”

– Abnormal automaticity / triggered activity at:

• pulmonary venous muscle sleeves

• autonomic ganglia

• non-pulmonary venous sites

• Atrial “substrate” determines whether AF sustains

– Reentrant “rotors” (stable) and “wavelets” (variable)

– Many factors may lead to abnormal atrial substrate

Normal heart

Normal atrial size

+/- heart disease

Mild/mod LAE

Diseased heart

Significant LAE

Paroxysmal AF

“Trigger”

Chronic AF

“Substrate”

Persistent AF

“Trigger/Substrate”

Current paradigm - Spectrum of AF

Stroke prophylaxis

Incidence of stroke by INR

Only INR> 2.0 confers protection

Hylek et al NEJM 2003;349:1019-26

CHADS2 score – predicts stroke risk in AF

VARIABLE POINTS

Congestive Heart Failure 1

Hypertension 1

Age > 75 Years 1

Diabetes Mellitus 1

Prior Stroke or TIA 2

Gage et al JAMA 2001;285:2864-70.

Risk for stroke in atrial fibrillation

0

5

10

15

20

25

0 1 2 3 4 5 6

NR

AF

Ad

jus

ted

Str

ok

e R

isk (

%)

CHADS2 Score

12.5

8.5 5.9

4.0 2.8

18.2

1.9

Gage et al. JAMA 2001;285:2864-70.

Anticoagulation recommendations (CHADS2)

Risk Category Therapy

None/weak risk fx Aspirin

1 mod risk fx Aspirin or Warfarin

1 high or > 1 mod risk fx Warfarin

High Risk

Prev TIA/CVA

Mitral Stenosis

Prosthetic valve

Mod. Risk

>75 yrs

↑BP

LV dysfunction

DM

Weaker Risk

Female gender

65-74yrs

Vascular disease

AHA/ACC/ESC JACC 2006;48:149-246

Stroke prophylaxis: New developments…

Warfarin superior to aspirin/plavix

ACTIVE Investigators Lancet 2006;367:1903-12

Aspirin/Plavix

Warfarin

Aspirin/Plavix

Warfarin

CVA/Embolism/MI/Vasc. Death CVA

ACTIVE W Trial

Schirmer et al, JACC 2010;56:2067-76.

Dabigatran (Pradaxa)

• Stroke or systemic embolism:

– Dabigatran 110 mg dose: (1.53% vs 1.69%/ year) (non-inferior to Warfarin p <0.001)

– Dabigatran 150 mg dose: 134 patients (1.11% vs 1.69%/ year)(superior to Warfarin p< 0.001)

• Bleeding:

– Lower risk of intracranial bleeding (110 mg or 150 mg dose)

– Higher risk of GI bleeding (150 mg dose)

• FDA approved October, 2010

Rivaroxaban (Xarelto)

• Stroke or systemic embolism:

– rivaroxaban 20 mg dose per-protocol: 188 patients (1.7%/ year) (non-inferior to Warfarin p <0.001)

– Adjusted Warfarin dose: 306 patients (2.4%/ year)

• Bleeding:

– no overall difference in bleeding risk although lower intracranial and fatal bleeding with rivaroxaban

• FDA approved July, 2011

Apixaban (Eliquis) • Stroke or systemic embolism:

– Apixaban 5 mg bid (2.5 mg in those >80 yo, <60 kg, Cr > 1.5: 188 patients (1.3%/ year) (superior to warfarin p=0.01)

– Adjusted Warfarin dose: 306 patients (1.6%/ year)

• Bleeding:

– Less bleeding with apixiban compared with warfarin (2.1% vs 3.1%, p<.001)

• Mortality

– All-cause death reduced with apixiban (3.5% vs 3.9%, p=.047)

• FDA approved Dec, 2012

Advantages of new drugs over warfarin

• Rapid onset

• Predictable effect with fixed dosing (no monitoring)

• Limited food / drug interactions

• Short half-life – no need for bridging

• More convenient for patient

• More convenient for physician

• Potential for greater use

• Potentially more cost effective (no monitoring, fewer adverse events)

• Possible superior efficacy

• Possibly superior safety

Disadvantages of new drugs over warfarin

• No routine monitoring

– Cannot titrate dose

– Determination of failure of therapy vs poor compliance

– Can’t measure drug activity if needed

• Short half-life

– Effect declines quickly if compliance poor

– Poor compliance may affect efficacy more that with warfarin

• No antidote

• Potential dose adjustment for renal dysfunction

• Cost

Who do I put onto a new drug?

• Intolerant of warfarin

• Tired of warfarin

• Unwilling to take warfarin

• Unstable INR

• Unable to get INR

• Offer to new patients

Comparisons Drug Dabigatran Rivaroxaban Apixaban

Peak (hours) 2-3 2.5-4 3-3.5

½ life (hours) 7-17 3-9 8-15

Dosing Twice daily* Once daily Twice daily

Elimination Renal (80%) Renal (60%) Renal (25%)

Dose reduce CrCl<30-50 CrCl<15-50 **

Drug-drug interactions P-glycoprotein CYP 3A4,

P-glycoprotein

CYP 3A4

Drug-food interactions None None None

Reversal, consider Charcoal, PCC Charcoal, PCC Charcoal,

PCC

Dialyzable Yes No No

*Keep in original bottle / blister pack (no pill boxes); must use in 60 days

**2 of the following: Age ≥ 80, Weight ≤ 60 kg, Creatinine ≥ 1.5 mg/dl

Comparisons Trial Re-LY ROCKET-AF ARISTOTLE

Drug Dabigatran Rivaroxaban Apixaban

Dosage 150, 110 BID 20 (15) QD 5 (2.5) BID

N 18,113 14,266 18,206

Design Open-label Double-blind Double-blind

CHADS2 (mean) 2.1 3.5 2.1

TTR* 64% 55% 62%

Stroke (vs warfarin) Better Equal Better

Bleeding (vs warfarin) Equal Equal Better

Cost** $294.36 / mo $278.01 / mo NA

*Time in therapeutic range

**warfarin $4 / month + monitoring

Bottom line – novel anticoagulants

• Use of any anticoagulant much better than aspirin / nothing in high risk patients

• New drugs more similar than they are different

• No studies comparing agents – results not suited for comparisons

– Study design

– Different populations

– INR control

• Cost vs convenience

Problems with current anticoagulation recommendations

• CHADS2 score will be 1 in approximately 1/3 of patients – what to do?

• With newer drugs which are safer / easier to use, perhaps lower threshold for anticoagulation

• Consider using CHA2DS2 – VASc for patients with an intermediate risk for stroke

CHA2DS2 – VASc

• CHF

• Hypertension

• Age > 75 (2 pts)

• Age > 65 (1 pt)

• Diabetes

• Prior stroke / TIA (2 pts)

• Vascular disease

• Sex category (female)

Score Stroke (%/yr)

• 0 0

• 1 0.7

• 2 1.9

• 3 2.3

• 4 3.9

• 5 4.5

• 6 4.7

• 7 10.1

• 8 14.2

Better way to assess risk of bleeding: HAS-BLED score

• Hypertension

• Abnormal renal or liver function (1 point each)

• Prior stroke

• Bleeding

• Labile INRs

• Elderly (>65 yrs)

• Drugs (anti-platelet) or excessive alcohol (1 point each)

Score Bleeds/100 pt yrs

• 0 1.13

• 1 1.02

• 2 1.88

• 3 3.74

• 4 8.70

Risk of bleeding

• HAS-BLED > CHADS2

– Risk of warfarin may outweight benefit

– Newer therapies may be safer…

LA appendage occlusion device (WATCHMAN)

Holmes et al Lancet, 2009; 374:534-542

LA appendage occlusion device (LARIAT)

Rate control: New developments…

RAte Control Efficacy in Permanent Atrial

Fibrillation

A Randomized Comparison of Lenient Rate Control versus

Strict Rate Control Concerning Morbidity and Mortality

RACE II

Permanent AF > 80 bpm

lenient strict

HR < 110 bpm

(12 lead ECG)

HR < 80 bpm (12 lead ECG)

and

HR < 110 bpm

(at 25% of maximal exercise)

Primary endpoint: composite of death, stroke, hospitalization

Cumulative incidence primary outcome

Strict 303 282 273 262 246 212 131

Lenient 311 298 290 285 255 218 138

Lenient

Strict

Cu

mu

lati

ve

Inci

den

ce (

%)

14.9%

12.9%

months

Rhythm control: New developments…

Benefit of sinus rhythm?

• Is there a rationale for eliminating AF?

• Several hypothetical reasons

– Improved quality of life

– Decreased stroke risk

– Decreased heart failure risk

– Improved survival

• Several trials considered a rate vs rhythm control strategy - PIAF, STAF, RACE, AFFIRM

AFFIRM – NEJM 2002

Problems with AFFIRM (and other rate vs rhythm control studies)

• Significant cross-over – 15% rate-to-rhythm control, 37.5% rhythm-to-rate control

• Anticoagulation not mandated in the rhythm control group (only 70% use compared with 85% in rate control group)

• At 5 yrs follow-up, 35% in rate control group in sinus, 63% in rhythm control group in sinus

On treatment analysis

Lessons of rate vs rhythm trials pre-abalation

• Antiarrhythmic drugs have limited efficacy in maintaining sinus rhythm

• Benefit of sinus rhythm may be offset by harm due to antiarrhythmic drugs

• Anticoagulate patients whether or not adopt a rhythm control strategy

• No harm to rhythm control with drug therapy in the symptomatic AF patient

• With alternate approach to achieving sinus rhythm (ablation), may tilt balance towards benefit in hard outcomes

AF ablation Bordeaux ‘98 – holy grail of EP?

Lessons of catheter ablation experience thus far

• Much more effective than antiarrhythmic drugs

• Relatively low risk procedure in experienced hands

• Recurrence rate does not “plateau” - may require repeat procedures

• Not a “cure” - consider AF a chronic condition

• Significant symptom relief

• Unclear if early aggressive therapy prevents long term consequences – mortality, stroke, CHF, etc

Impact of ablation on mortality and stroke

• 37,908 registry Intermountain Healthcare patients

• 4,212 AF ablation patients

• Non-randomized

Bunch et al, In press, 2012

Impact of ablation on mortality and stroke

• 1,273 registry patients from UK and Australia

• Historical controls (medical therapy, controls without AF)

Hunter et al, Heart, 2012; 98: 48

Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA)

• Prospective, Unblinded, Randomized-Controlled Trial

– A comparison of catheter ablation with medical therapy (rate or rhythm control) in AF patients requiring treatment

• Endpoint

– Primary: Total mortality

– Secondary: Composite of total CV mortality, disabling stroke, serious bleeding, and cardiac arrest

• Inclusion Criteria:

– Paroxysmal, Persistent, or Permanent

– Risk factors for stroke: >65, HTN, DM, CHF, prior CVA/TIA, LA>4.5, EF<35%

• Protocol:

– Randomize 3000 patients to ablation or drug RX (1:1)

– Minimum follow-up for 2 years

What is the current role of a rhythm control strategy?

• Mortality reduction?

– Await CABANA

• Decreased stroke risk?

– Await CABANA

• Freedom from anticoagulation

– Not currently

• Decreased hospitalization

• Cardiomyopathy believed tachycardia-induced

• Symptom relief, improved QOL

AF guidelines

AF guidelines

Heart Disease

LVH None

Flecanide

Propafenone

Dronedarone

Sotalol

Dofetilide

Amiodarone

CAD

Amiodarone

Sotalol

Dronedarone

Dofetilide

CHF

Rhythm control in patients With AF

Catheter

ablation

Dofetilide

Amiodarone

Catheter

ablation

Dofetilide

Amiodarone

Catheter

ablation Catheter

ablation

Approach to Atrial Fibrillation Ablation

• Ablation of “triggers”

– Pulmonary vein isolation

– Non-pulmonary venous triggers?

– Ganglionated plexus ablation?

• Modification of the AF “substrate”

– MAZE and related procedures?

– “Defractionation”?

– Rotor ablation?

• Approach varies center to center

Normal heart

Normal atrial size

+/- heart disease

Mild/mod LAE

Diseased heart

Significant LAE

Paroxysmal AF

“Trigger”

Chronic AF

“Substrate”

Persistent AF

“Trigger/Substrate”

Current paradigm - Spectrum of AF

Higher efficacy Lower efficacy

Paroxysmal AF: pulmonary vein isolation

Persistent AF: PVI + substrate ablation

Persistent AF: PVI + substrate ablation

Pericardioscopic/Thoracoscopic

Epicardial ablation

Convergent Procedure

Persistent AF: Alternative UNC approach

Endocardial ablation

Gehi et al, Heart Rhythm, Jan 2012; 10(1): 22

Conclusions

• Stroke prophylaxis is paramount

– Dabigatran, rivaroxaban, apixiban make life easier

– Cost vs convenience

– Appendage occlusion devices for those at high risk who are contraindicated for anticoagulants

• Individualize rate vs rhythm control decision

– Rhythm control is not harmful – significantly improves symptoms and QOL in patients with AF

– Rhythm control may improve outcomes in selected patients – await CABANA

– Catheter ablation is the most efficacious method for rhythm control – consider in symptomatic patients who fail a trial of antiarrhythmic drugs

Thank you