Non-Pharmacologic Treatment of...

Pharmacologic and Non-Pharmacologic Treatment of Atrial Fibrillation

October 2019

Otto Costantini MD

Director, Electrophysiology Section

Director, Medical Education and Clinical Research

Summa Health Heart and Vascular Center

Overview

• Scope of the Problem

• Pharmacologic Treatment

o Rhythm vs. Rate control

o Anticoagulation

•Non-pharmacologic Treatment o Pulmonary Vein Isolation (i.e. RFA)

o AVN Ablation/Pacing

The Electrophysiologist World

Arrhythmia Treatment Cure •AVNRT RFA 99% •AVRT/WPW RFA 95% •Atrial Flutter RFA 90% •Atrial Tachycardia RFA 85%

•Atrial Fibrillation Meds vs RFA 60-80%

AF

Po

pu

lati

on

(x 1

000)

Age (years)

Po

pu

lati

on

(x

10

00

)

Atrial Fibrillation

2.3 million

Feinberg et al. Arch Intern Med. 1995;155:471.

500

400

300

200

100

0

30,000

20,000

10,000

0

US population

AF population

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Atrial Fibrillation and Death in the Framingham Heart Study

Circ. 1998;98:946-52

RR 1.3-1.9

Classification of Atrial Fibrillation Classification Description

Paroxysmal Terminates within 7 days of onset

Persistent Continuous for more than 7 days

Longstanding Persistent Persists greater than 1 year

Permanent All attempts to restore sinus rhythm have been abandoned

Lone AF Occurs in patients less than 60 years of age who do not have HTN or evidence of structural heart disease

-Some patients with paroxysmal AF can have episodes that persist, the predominant form determines how it is characterized -cardioversion and antiarrhythmic drug therapy should not alter the classification

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Co-morbidities

•Diabetes

•Hypertension

• Sleep Apnea

•Alcohol Intake

• Hyperthyrodism

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Pharmacologic Considerations

• Rate vs. rhythm control

•No matter which you decide on, you still have to worry about anticoagulation

http://www.aafp.org/afp/2011/0101/afp20110101p61-f3.jpg

Anticoagulation

Anticoagulation

Rate Vs. Rhythm Control

Trial N F/U Endpoint P Value

PIAF 252 1 y Symptoms 0.3

STAF 200 1.8y TM/CVA/CPR NS

RACE 522 2.3y TM/CHF 0.11

AFFIRM 4060 3.5y Total Mortality 0.08

The AFFIRM Trial

•Atrial Fibrillation Follow-up Investigation in Rhythm Management Trial •Age greater than 65 years OR •Age less than 65 years plus a risk factor for stroke: •Hypertension/diabetes • CHF or LVEF < 0.40, prior CVA/TIA • LAE > 50 mm

• 6 hrs of AF in 1 or more episodes in 6 months •Duration <6 months or SR for > 24 hrs

Patient Refusal: 67%

MD Refusal: 31%

0.08

Rate Control Strategy

•Consider in: o Asymptomatic patients o Longstanding persistent o High likelihood of recurrence

•Avoid in: oYounger patients ??? oFirst episode ??? oSymptomatic patients

Pharmacologic Agents for Rate Control

• Calcium Channel Blockers oDiltiazem, Verapamil.

• Slow Sinus Node and AV Node function. Should not be used in Systolic HF

• Beta Blockers oPropranolol (nonselective blocker) / Metoprolol, Atenolol (selective cardio-inhibitory)

• Slow Sinus Node and AV node function.

• Preferred in systolic HF and/or concomitant CAD

•Digoxin. o inhibition of Na-K ATPase and Parasympathomimetic actions oWeak AV nodal blocking agent!

•

Why Sinus Rhythm?

• Sinus rhythm is the best rate control. o Not too fast o Usually not too slow (Be careful in the elderly with sinus node dysfunction) o Appropriate rates with exercise. •Atrial systole improves cardiac output o Patients with systolic dysfunction need their atrial kick • Regularity (not just VR) improves cardiac output and symptoms

• Effects of AF on LV function

Exercise Capacity

LV Ejection Fraction

The problem: Antiarrhythmic Drugs Effectiveness

50 49

25

49

30

37

61

28

0

10

20

30

40

50

60

70

Sinus Rhythm

Placebo

Quinidine

Norpace

Procainamide

Flecainide

Propafenone

Sotalol

Amiodarone

The problem: Safety: Pro- Arrhythmias and Extra-Cardiac Side Effects

Who is this? 1946-???

Miles Vaughan Williams 1918-2016

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Circa 1975

The Action Potential

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The Action Potential and The ECG

Class 1 Drugs and the ECG

Class 1 Drugs- Na Channel Blockers

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Flecainide (Tambocor) - 1C • Prolongs QRS & slows conduction in the atrium • The good news - effective in preventing AFib • The bad news – increased mortality in post MI patients • Therefore, contraindicated in pts with CAD • Can speed up conduction in the AV node •Must use AV Nodal Blocker with it! • Twice-a-day (100 - 300 mg/day)

• Renal Excretion

•Most common side-effects oheadache, dizziness, asthenia, blurred vision, hair loss.

Propafenone (Rythmol) - 1C

• Similar story to flecainide

• Three times a day (300 -900 mg/d).

•Weak -blockade

• Liver metabolism

•Neurologic symptoms, metallic taste, GI disturbances

Class 3- K Channel Blockers

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Sotalol (BetaPace) – Class 3

•No increase in QRS duration or slowing of conduction • Racemic mixture (D-L Sotalol): type III effect and -blockade •Dose-related Torsades de Pointes oHistory of sustained VT or VF oFemale gender oHistory of CHF oDose greater than 320 mg/day. • -blocker effects predominate at lower doses, and type III effects at higher

doses • Less effective at conversion acutely to sinus • Renal excretion

Dofetilide (Tikosyn) – Class 3

• Selective IKr blocker

•Approved for AFib

• Renal excretion

• Few non-cardiac side-effects

• Risk of Torsades de Pointes is high

• Safe in patients with structural heart disease including low EF (DIAMOND-HF)

•Multiple restrictions may be a factor in safety

• 58% suppression of AF in SAFIRE-D

• Reverse Use Dependance

The Canadian Trial of Atrial Fibrillation

NEJM 2000 342:913-920

SAFE-T trial

NEJM 2005

Dofetilide

Dofetilide in HF - DIAMOND CHF

Pro Arrhythmia: Dofetilide

X 10 minutes

Amiodarone – Class 1,2,3,4

• Blocks everything- Uniformly slows conduction everywhere • Less frequent pro-arrhythmia-mainly bradycardia • Zillions of active metabolites; poor bio-availability, onset of action is slow,

drug accumulates in adipose, half-life months • Liver metabolism •Doesn’t increase risk of SCD •Most effective drug in AF

•Decreases ICD shocks

•Non-cardiac side-effects

oliver, lung, thyroid, CNS, photosensitivity

• Interacts with warfarin and digoxin.

Dronedarone (MULTAQ) – Class 3

• Similar to Amiodarone, but lacks iodine moiety oLacks end-organ side effects

o Increases serum Cr, but the GFR is unchanged

• Better than placebo in SR maintenance

• 1/3 the potency of Amiodarone

•Avoid in CHF (EF< 40%) o 4.3% increase in absolute risk of death

Dronedarone (Multaq): How good?

• Contraindicated in patients with HF

• The hope: amiodarone without the side effects

• The reality: amiodarone lite

J Cardiovasc Electrophysiol, Vol. 21, pp. 597-605, June 2010)

Guidelines for Management of Atrial Fibrillation: Strategies for Rhythm Control

• Most patients do not need to “go to the ED”

• If the rate is very fast and they are having CP or they are in HF… sure!

• Otherwise:

• If CHADS VASC score is >1: Anti Coagulate

• If rate is > 100: rate control

• Refer to cardiology

• … or now you can start an antiarrhythmic drug

What to do when patients present to the office in AFib

1. Class 1C Drugs can be started as an outpatient at low doses in patients with structurally normal hearts

2. All patients started on Class 1C drugs should get an exercise stress test to observe for pro-arrhythmia and to rule out significant coronary artery disease.

3. Patients started on Dofetilide need to be started as in-patients to observe for QTc prolongation.

4. Sotalol has been started as an outpatient in small studies. Controversial whether it should be.

5. Amio has a lower risk of pro-arrhythmia

Take Home Points:

6. Long Term Follow Up of Amiodarone patients should include TSH routinely. PFTs if symptoms develop

7. Watch for Sinus Node Dysfunction. Elderly Patients will get more bradycardic with all AA drugs other than dofetilide

8. Watch for Renal Failure. Most of these drugs are contraindicated or need to have dose adjustments

Check BMP ~every 6 months

Take Home Points:

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Strategies for Rhythm Control in Patients with Paroxysmal and Persistent AF

Current Guidelines

• Main goal of catheter ablation for treatment of AF is to isolate the Pulmonary Veins from the body of the Left Atrium

• Approach is based on the finding that the electrical impulses that trigger AF originate at the connection of the veins with LA

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History of Catheter Ablation

History of Catheter Ablation

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Proposals concerning the mechanisms of AF

Mechanism of Atrial Fibrillation

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Common lesion sets employed in AF Ablation

Pulmonary Vein Isolation

3-D Navigation Systems

• Determine efficacy of catheter ablation compared to AAD in treating symptomatic AF

• 159 patients who did not respond to at least 1 antiarrhythmic drug and who experienced at least 3 AF episodes within 6 months

• 103 patients underwent ablation and 56 underwent AAD (Amiodarone not allowed)

THERMOCOOL-AF Trial

THERMOCOOL-AF

• Most common method is radiofrequency current applied in a point by point mode which leads to cellular necrosis by tissue heating

• Requires only limited use of Fluoro because guidance is through the use of an Electro-anatomical mapping system

• Requires extensive training

• Restricted to specialized centers and has limited the availability

Radio-Frequency Ablation vs. Cryo-Ablation

• Second most common method is the use of cryogenic energy applied with a balloon in a single step mode which leads to necrosis by freezing

• Requires more extensive fluoro guidance to position the balloon catheter at the pulmonary veins

• Creates a circular lesion around each vein in a simple manner

• Study designed to compare the performance of well established but complex RF approach with the simpler but unproven cryo balloon approach.

• Multicenter, Randomized, Non-Inferiority trial

• Included patient with symptomatic PAFib that was refractory to AAD

• Primary Endpoint – Time to AF recurrence/Prescription of AAD/Repeat Ablation

FIRE AND ICE Trial

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FIRE AND ICE Trial

• Multicenter, Prospective, Randomized Trial designed to test the hypothesis that ablative therapy for AF is more effective than AAD in a population of symptomatic AF patients followed for 3 years

• Primary end point = composite of death, stroke, bleeding, or cardiac arrest

• Secondary end points = All cause mortality, total mortality/hospitalization, AF recurrence

CABANA Trial

CABANA Trial

• Baseline Characteristics Median Age 67

37% Women

10% Minorities

43% had Paroxysmal AF

80% HTN

25% Diabetes

19% CAD

10% Prior CVA

15% CHF

57% CHADS2VASC greater than 2

CABANA Trial

CABANA Trial

• The trial included 397 patients with symptomatic paroxysmal or persistent AFib and a LVEF of ≤35 percent who were randomized to receive either RF ablation or conventional AAD.

• Largest trial to utilize catheter ablation in HF patients

• Median F/U of 40 months

• Primary outcome – composite of death from any cause or worsening HF

• Secondary outcome – death from any cause, HF hospitalization, CVA, Cardiovascular death

CASTLE-AF Trial

CASTLE-AF Trial

Monitoring

Conclusions

•Anticoagulation for Atrial Fibrillation should be guided by the CHA2DS2VASC Score.

• Rate vs. Rhythm control should be guided by patient’s symptomatology and preference

• Rhythm Control can be achieved with anti-arrhythmic drugs at the expense of long term side effects and pro-arrhythmia.

•Ablation of Atrial Fibrillation is an acceptable method for rhythm control, and the only hope for a cure. Recurrences are frequent.