Management of Atrial Fibrillation in 2010

John D. Hummel, MD Ohio State University Medical Center Ross Heart Hospital Columbus, Ohio

Learning Objectives

• Understand the risk factors for atrial fibrillation.

• Understand the guidelines for anticoagulation and where there is latitude for physician decision making.

• Be able to determine when patients should be evaluated for curative ablation.

Projected Number of Adults With AF in the US: 1995 to 2050.

6 5 4 3 2 2.08

2.26

2.44

2.66

2.94

3.33

3.80

4.34

4.78

5.16

5.42

5.61

1 0 19 95 20 00 20 05 20 10 20 15 20 20 20 25 Year 20 30 20 35 20 40 20 45 20 50 20 60 Go A, et al. JAMA. 2001;285:2370-2375.

Atrial Fibrillation: Costs to the Health Care System

ALOT!!

35% of arrhythmia hospitalizations Average hospital stay = 5 days Mean cost of hospitalization = $18,800 Does not include: Costs of outpatient cardioversions Costs of drugs/side effects/monitoring Costs of AF-induced strokes

Estimated US cost burden 15.7 billion

Classification of Atrial Fibrillation ACC/AHA/ESC Guidelines

First Detected Paroxysmal (Self-terminating) Persistent (Not self-terminating) Permanent

DIAGNOSTIC WORKUP

Identify Causes and Risk Factors •

Minimum Evaluation

• History and physical – BP, CV dz • Electrocardiogram – WPW, LVH, MI • Echocardiogram – LVH, LAE, EF, Valve Dz • Labs – TSH, Renal fxn, LFTs (Clearance,ETOH) [D-dimer, ESR] •

Additional Testing

• ETT – CAD, Exercise induced SVT / AF • Holter / Event Monitor – Confirm AF and Sxs • TEE – LA clot [CXR] • EPS – SVT triggered AF

AHA / ACC / ECS Guidelines 2006

Incidence of AF Based on Presence or Absence of OSA 20 – 15 – Cumulative Frequency of AF (%) 10 – 5 –

OSA No OSA

Number at Risk OSA No OSA 0 – 0 1 2 3 4 5 6 7 8 Years 9 10 11 12 13 14 15 844 2,209 709 1,902 569 1,616 478 1,317 397 1,037 333 848 273 641 214 502 173 393 134 296 110 217 94 195 70 130 46 94 29 69 8 28 Cumulative frequency curves for incident atrial fibrillation (AF) for subjects < 65 years of age with and without obstructive sleep apnea (OSA) during an average 4.7 years of follow-up. p = 0.002

Gami, et al.

JACC

2007;49:565-71

Goals of Therapy

1. Relieve symptoms 2. Prevent Stroke 3. Prevent Heart Failure

AF: TREATMENT OPTIONS

Rate control Maintenance of SR Stroke prevention

• • • •

Pharmacologic Ca



2+ blockers -blockers Digitalis Amiodarone

•

Nonpharmacologic Ablate and pace Pharmacologic Class IA Class IC Class III



-blocker Nonpharmacologic

• • • •

Pharmacologic Warfarin Thrombin inhibitor Heparin Aspirin Catheter ablation Surgery (MAZE) Pacing

•

Nonpharmacologic Removal / isolation LA appendage Prevent remodeling ACE-I ARB Adapted from Prystowsky, Am J Cardiol. 2000;85:3D-11D.

Risk Factors for Thromboembolism in AF High-Risk Factors

Previous CVA / TIA / Embolism Mitral Stenosis Prosthetic heart valve

Moderate-Risk Factors

Age > 75 yrs HTN CHF DM EF < 35%

Weaker-Risk Factors

Female CAD Thyrotoxicosis Age 65 – 74 yrs

Recommended Therapy

High-risk factor or > 2 moderate-risk factors

Coumadin INR 2-3

(mechanical valve INR > 2.5) 1 moderate-risk factor

ASA or Coumadin

No risk factors

ASA 81-325mg daily

AHA / ACC / ECS Guidelines 2006

D-Dimer Prediction of Risk

Evaluate whether elevated D-dimer levels can predict thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. Single-center, prospective, study of 269 pts with atrial fibrillation treated with warfarin D-dimer levels were measured End points were thromboembolic events and combined cardiovascular events (thromboembolic events, cerebral hemorrhage, myocardial infarction, cardiovascular death). RESULTS: D-dimer levels were elevated (> or =0.5 microg/ml) in 63 (23%) patients.

During an average follow-up period of 756 +/- 221 days: 1.

10 (1.8%/year) thromboembolic events (8 ischemic strokes, 1 transient ischemic attack, 2.

and 1 peripheral embolism 27 (4.8%/year) combined cardiovascular events (10 thromboembolisms, 9 deaths from heart failure, 3 sudden deaths, 2 myocardial infarctions, and 3 cerebral hemorrhages) Patients with elevated D-dimer levels experienced higher thromboembolic and combined cardiovascular events. Sadanaga T, et. AL; J Am Coll Cardiol. 2010 May 18;55(20):2225-3.

Dabigatran vs. Warfarin

Noninferiority trial randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive: 1. Fixed doses of dabigatran — 110 mg or 150 mg twice daily in a blinded fashion 2. Adjusted-dose warfarin in an unblinded fashion The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism.

Results

Primary outcome 1.69% per year in the warfarin group 1.53% per year in the group that received 110 mg of dabigatran (P<0.001 for noninferiority) 1.11% per year in the group that received 150 mg of dabigatran ( P<0.001 for superiority) Major bleeding 3.36% per year in the warfarin group 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). Hemorrhagic stroke 0.38% per year in the warfarin group 0.12% per year with 110 mg of dabigatran (P<0.001) 0.10% per year with 150 mg of dabigatran (P<0.001). Mortality rate 4.13% per year in the warfarin group 3.75% per year with 110 mg of dabigatran (P=0.13) 3.64% per year with 150 mg of dabigatran (P=0.051).

Conclusions

Dabigatran 110 mg had rates of stroke and systemic embolism similar to warfarin with less major hemorrhage.

Dabigatran 150 mg had lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Stuart J. Connolly and the RE-LY Steering Committee and Investigators NEJM Sept 17, 2009, No. 12, Vol 361: 1139-1151

AF THERAPY

ANTITHROMBOTIC RX

AND

RHYTHM CONTROL

OR ?

RATE CONTROL

AFFIRM Trial: Rate vs Rhythm Control Management Strategy Trial • Design – 5-year, randomized, parallel-group study comparing rate control vs. AARx attempt at NSR – Primary endpoint: overall mortality • Patient population – 4060 patients with AF and risk factors for stroke – Minimal symptoms – Mean Age = 69 yo – Hx of hypertension: 70.8% – CAD: 38.2% – Enlarged LA: 64.7% – Depressed EF: 26.0%

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

AFFIRM: All-Cause Mortality

30 25 20 15 10 p=0.078 unadjusted p=0.068 adjusted 5 Rhythm N: Rate N: 0 0 2033 2027 1 1932 1925 2 Time (years) 3 1807 1316 1825 1328 The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

Rate Rhythm 4 780 774 5 255 236

AFFIRM: Adverse Events

Ischemic stroke INR < 2.0

Not taking warfarin Rate 77 (5.5%)* 27 (35%) 25 (32%) Rhythm 80 (7.1%)* 17 (21%) 44 (55%) * p=0.79

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

Time to first recurrence of AF. Time 0 is the day of randomization 100 –

Rate Control

80 –

Rhythm Control

Percent With AF Recurrence 60 – 40 – 20 – Log rank statistic = 58.62

p < 0.0001

0 – 0 N, Events (%) Rate control: Rhythm control: 563, 3 (0) 729, 2 (0) 1 167, 383 (69) 344, 356 (50) 2 98, 440 (80) 250, 422 (60) 3 Time (years) 42, 472 (87) 143, 470 (69) 4 10, 481 (92) 73, 494 (75) 5 6 2, 484 (95) 18, 503 (79) Raitt, et al.

Am H J

2006

Implications

• AFFIRM has demonstrated that rate control is an acceptable primary therapy in a selected high-risk subgroup of AF patients with

minimal

symptoms • Continuous anticoagulation seems warranted in all patients with risk factors for stroke – Asymptomatic recurrences

RACE II

• • • • • • • •

Hypothesis:

Lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in pts with permanent AFib Randomly assigned 614 patients with permanent AF to: – lenient rate-control strategy (resting heart rate <110 beats per minute) – strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). Primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years.

Results:

Primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group. (90% confidence interval, –7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets 97.7% vs. 67.0% in the strict-control group; P<0.001 with fewer total visits (75 vs. 684]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups.

Conclusions:

In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve.

Van Gelder, et.al, for the RACE II Investigators

NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

Atrial fibrillation

Rate control – Drug Therapy:

Digoxin – controls resting rate, OK in CHF patients .

Beta, Ca+2 blockers – controls resting and exercise rates.

Best therapy – combination of beta blocker and digoxin.

Even in the best of circumstances pacing support is sometimes required Goal: Chronic afib – mean 24hr HR < 80-90 bpm (?)

APPROACHES TO AF THERAPY

Rate control plus anticoagulation preferred

• • • • • •

No or lesser AF symptoms Longer AF Hx More SHD Toxicity Risk Elderly Greater risk of proarrhythmia Rhythm control preferred

• • • • •

Greater AF symptoms Symptoms despite rate control Younger age No or lesser SHD Rx option of class IC AAD

In anticoagulation candidates, continue anticoagulation indefinitely

Atrial Fibrillation

• Duration of AF is the best predictor of recurrent AF after cardioversion 100 80 60 40 20 0 *P = <0.02

Initial Dittrich HC. Am J Cardiol. 1989;63:193-197.

* Length of time in AF prior to cardioversion < 3 Months 3 - 12 Months > 12 Months One month post-CV Six months post-CV

Rhythm Control for AF: Commonly Used Oral Antiarrhythmic Drugs

Class IA Quinidine Procainamide Disopyramide Class IC Propafenone Propafenone SR Flecainide Class III Sotalol Amiodarone Dofetilide

Procainamide, disopyramide, and amiodarone are not FDA-approved for treatment of AF.

Miller and Zipes. In: Braunwald, et al (eds). Heart Disease. 6th ed. 2001.

AF Efficacy: Maintaining NSR > 6 Months

70 60 50 40 30 20 10 0 No drug Quin Diso Prop Flec Sot Dof Azim Amio

ORGAN TOXICITY

• Examples: – Lupus, agranulocytosis, thrombocytopenia, optic neuritis, pulmonary fibrosis, hepatitis, etc.

• Negligible: – Dofetilide, flecainide, propafenone, sotalol, dronedarone • Acceptable: – Azimilide, disopyramide • High: – Amiodarone, procainamide, quinidine

Drug-Induced Proarrhythmia - Torsades

Factors Which Influence Ventricular Proarrhythmia Risk

• Hypokalemia, hypomagnesemia • Long QT at baseline • CHF / Decreased EF / Ventricular hypertrophy • Bradycardia • Female gender • Reduced drug metabolism or clearance • Amiodarone and Dronedarone has lowest risk (drondedarone cannot be started if baseline QTc>/=500)

AARx Choice

Heart disease None Vagal afib HTN CAD CHF/Substantial LVH Antiarrhythmic IC or Dronedarone Disopyramide IC (if no sig. LVH) then dronedarone Sotalol Amiodarone

Prevention of atrial fibrillation by Renin Angiotensin system inhibition Meta analysis of published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation A total of 23 randomized controlled trials with 87,048 patients were analyzed. In primary prevention: 6 trials in hypertension, 2 trials in myocardial infarction, and 3 trials in heart failure were included.

In secondary prevention: 8 trials after cardioversion and 4 trials assessing the medical prevention of recurrence were included. Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001), but there was substantial heterogeneity among trials. In primary prevention: RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy but not in post-myocardial infarction patients overall. In secondary prevention: RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p <0.00001).

RAS inhibition is an emerging treatment for the primary and secondary prevention of AF Schneider MP, et. Al. J Am Coll Cardiol. 2010 May 25;55(21):2299-307

Alternatives to Drug therapy “Non-Pharmacologic Therapy”

 Coumadin – LAA closure (Watchman)  Rate Control – AVN RFA + PCMK  AARx – Adjunctive AFL RFA  AARX – Curative Afib RFA

WATCHMAN

®

LAA Filter System

Complete AVN ablation

Pacemaker Placement

AVN RF ablation

Objective Benefits of AV nodal Ablation 70 60 50 40 30 mean 43 + 8 mean 54 + 7 p < 0.001

20 Before After

A Left ventricular ejection fraction (%)

55 50 mean 34 + 5 45 40 35 30 25 mean 40 + 5 p < 0.003

20 Before After

B Left ventricular end systolic diameter (mm) Rodriguez LM. Am J Cardiol. 1993;72:1137-1141.

Complete AVN Ablation

Advantages:

100% efficacy 85% symptomatic improvement Improved EF (LV remodeling) Eliminates need for rate control drugs

Disadvantages:

Pacemaker dependant

Good Candidates:

Tachy / Brady Syndrome PCMK in Place Elderly – CHF with BiV device Medication refractory / intolerant

60 F with PAF treated with Rythmol

Presented with recurrent tachycardia

Atrial Flutter Circuit

Atrial Flutter Circuit

Atrial Flutter Ablation

Atrial Flutter RFA

Atrial Flutter Ablation

Approximately 15% of AF patients treated with an AA will develop AFL

Advantages:

95% efficacy ≈ 80% arrhythmia control if AARx continued As primary Rx: RFA more effective than AARx

Disadvantages:

Invasive

Good Candidates:

Typical AFL (IVC / TV isthmus) Primary AFL or AARx related AFL

Focal Origin of Atrial Fibrillation

Hassaiguerre M, NEJM, 1998

RA

• 94% of AF triggers from Pulmonary Veins • “90 – 95% of all AF is initiated by PV ectopy”

SVC FO 17 LA Pulmonary Veins 31 IVC 6 11 CS

74 yo medically refractory AF, Echo – Normal AA Rx - Verapamil, Rythmol, Betapace, Norpace

I II III V1 RSPV dist RSPV prox LIPV RA *

Lasso Catheter

Circular Mapping & Ablation Catheter in Right Superior Pulmonary Vein

Atrial Fibrillation Ablation Atrial Shell and Cardiac MRI

45 yo F with medically refractory Highly Symptomatic PAF

45 yo F with Medically Refractory PAF CT Scan / Carto Images – PA View

45 yo with PAF Conversion of AF to NSR, LSPV with AF

Abl Lasso LSPV CS

Current State of Curative Catheter-Based RFA

Procedural Success & Complications

• Total Patients > 1300 (65% PAF) • Expected success @ 1yr – ≈ 70% after first procedure – ≈ 80% after second procedure • Complications ≈ 1 to 3% – Tamponade – 0.6% – Pulmonary vein stenosis – 0.6% – TIA / CVA – 0.5% – Esophageal-LA fistula - 0 – Groin Bleeding / Hematoma (Last 200 pts complications < 1%)

Atrial Fibrillation: Ablation vs Drug Rx.

Ablation 80% success PV stenosis AE fistula TIA/CVA Drug Rx.

50% success Proarrhythmia End Organ Toxicity

No Free Lunch

Torsades AE fistula PV stenosis

Current State of Curative Catheter-Based RFA

Who is a good candidate?

Symptomatic / Frequent AF Limited Heart Dz EF > 35% LA < 5.5cm

No MS / Rheumatic Dz Younger Patients No LA thrombus or Hx of CVA Medically Refractory / Intolerant (Ablation now second line therapy)

Atrial Fibrillation

New Technology Coming Your Patients Way at Ohio State University Stereotaxis – Magnetic Catheter Navigation Ablation Frontiers Cryoablation Balloon Endosense

A-Fib vs. EP Labs

AF TREATMENT GOALS

• AF is rarely life-threatening and is typically recurrent • Treatment goals in symptomatic pts –  frequency of recurrences – –   duration of recurrences severity of recurrences • Minimize risk of tachycardia induced cardiomyopathy • Safety is primary concern