Medical Management Atrial Fibrillation

Stuart Beldner, MD, FHRSAssistant Professor NSLIJ Hofstra School of Med

None

Disclosures

“There’s no reason to panic. While it is true that one of the crew members is ill, slightly ….”

A-Fib

ECG Recognition

Absence of discrete P waves Chaotic atrial activity Ventricular rate irregularity

Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, renin-angiotensin-aldosterone system.

January C T et al. Circulation. 2014;130:e199-e267

Copyright © American Heart Association, Inc. All rights reserved.

Term Definition

Paroxysmal AF •AF that terminates spontaneously or with intervention within 7 d of onset.•Episodes may recur with variable frequency.

Persistent AF •Continuous AF that is sustained >7 d.

Longstanding persistent AF

•Continuous AF >12 mo in duration.

Permanent AF •The term “permanent AF” is used when the patient and clinician make a joint decision to stop further attempts to restore and/or maintain sinus rhythm.•Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of AF.•Acceptance of AF may change as symptoms, efficacy of therapeutic interventions, and patient and clinician preferences evolve.

Nonvalvular AF •AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.

2014 AF guidelines classification of AF

65 year old man presents to his doctor’s office for his routine physical and is found to be in atrial fibrillation. ◦ 1. rate control and anticoagulation◦ 2. electrical cardioversion◦ 3. electrical cardioversion plus antiarrhythmic

therapy◦ 4. ablation

Trial Year nPrimary End

Point

HR (Rate vs Rhythm Control)

P

PIAF3 2000 252 Improvement AF symptoms

1.10 0.31

AFFIRM1 2002 4060 Overall mortality 0.87 0.08

RACE2 2002 522 Composite 0.73 0.11

STAF4 2003 200 Composite 1.09 0.99

HOT CAFE5 2004 205 Composite 1.98 >0.71

AF-CHF6 2008 1376 Cardiovascular mortality

0.94 0.59

PABA-CHF15 2008 81 Composite Multiple <0.001

Rate versus Rhythm Trials

Trials such as AFFIRM and RACE, did NOT prove that rate-controlled and anticoagulated AF is as good as NSR.◦ They show that a rhythm control strategy using

an ITT analysis, suggests equivalence in at least some populations.

◦ These trials do NOT disprove that sinus rhythm would be better than AF in regard to QOL if one were to actually attain and maintain it with a safe and effective therapy.

Should We Truly Believe that AF and NSR are really equal?

0

10

20

30

40

50

60

70

80

90

100

R 2 Mo 4 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr

Rate Arm

Rhythm Arm

AFFIRM: Prevalence of Sinus Rhythm at Follow-up

Pati

en

ts in

Sin

us

Rh

yth

m,

%

Time

The AFFIRM Investigators. NEJM: 2002; 347: 1828-1833

5 fold increase in risk for stroke*

◦ AF strokes are usually more severe than nonAF strokes

3 fold risk of heart failure **

2 fold risk of dementia*** and mortality *

Atrial Fibrillation Complications

*Kannel et al. Am J of Coll. 1998**Wang et al. Circu. 2003*** Ott et al. Stroke 1997.

HR (99%)1.06 (1.05 – 1.08)1.56 (1.20 – 2.04)1.57 (1.18 – 2.09)1.56 (1.17 – 2.07)1.78 (1.25 – 2.53)1.70 (1.24 – 2.33)0.74 (0.55 – 0.98)1.36 (1.03 – 1.80)0.50 (0.37 – 0.69)1.42 (1.09 – 1.86)0.53 (0.39 – 0.72)1.49 (1.11 – 2.01)

Atrial Fibrillation: Follow-up Investigation of Rhythm Management

Time dependant, on treatment, Multivariate Analysis of Survival

FactorAge (per year)CADCHFDiabetes SmokingStroke/TIANormal LVEFMitral RegurgWarfarinDigoxinSinus RhythmAA drug

0.2

0.4

0.6

1.2

1.0

0.8

1.4

1.6Better Worse

-6

-5

-4

-3

-2

-1

0

1

2

3

4

Physical Fx GeneralHealth

Social Fx Vitality

NSR

AF

-60

-40

-20

0

20

40

60

80

HR Rest ExerciseDuration

Effects on Maintaining Sinus Rhythm on QOL and Exercise Capacity: SAFE-T Investigators

HR Peak

SF-3

6 C

han

ge in

On

e Y

ear

Singh BN, et al, NEJM 2005; 352:1861-72.

Antiarrhythmic Drugs for AF

Class I: ◦ Class IC: propafenone (also very weak β-blocker), flecainide

(no β-blockade effects) Sustained-release propafenone (Rythmol SR) and

flecainide are bid; Propafenone appears to be less proarrhythmic

◦ Class IA: disopyramide, quinidine, procainamide No longer included in the ACC/AHA/ESC algorithm Disopyramide may be useful in vagally induced AF

Class III:◦ Sotalol (class III plus β-blocker)◦ Dofetilide (pure class III)◦ Amiodarone (class III plus class I, II, IV); highly overused◦ Dronedarone (similar to amiodarone with different

pharmacokinetics and markedly reduced organ toxic potential)

Dronedarone Clinical TrialsTrial Study Design Dronedarone Effects

ERATO Dronedarone vs placebo Significant decrease in ventricular rates (24-hr Holter and maximal exercise)

DAFNE Dronedarone vs placebo Efficacy vs placebo in time to first AF recurrence with 400 mg bid dose

EURIDIS and ADONIS

Dronedarone vs placebo in1237 patients with AF/AFL

Significant and consistent reduction in first recurrence of AF/AFL; comparable safety vs placebo

ANDROMEDA Dronedarone vs placebo in627 patients with severe HF

Excess mortality risk vs placebo (n=25 vs n=12; HR, 2.13; P=.03); trial stopped early

DIONYSOS Dronedarone vs amiodarone in 504 patients with persistent AF

Mixed observations

ATHENA

PALLAS

Dronedarone vs placebo in4628 high-risk AF patients

Dronedarone vs placebo in 3236 patient with permanent AF

● Efficacy against AF ● Reduction in CV mortality and hospitalization● Reduction in additional end pointsa 2.29-fold increase in the coprimary end point of stroke, MI, embolism, or cardiovascular death events, compared to placebo, and led to a halt in a planned 10,800-patient international randomized trial

ATHENA: Summary

Results show dronedarone significantly prolongs the time to AF recurrence compared with placebo

No significant difference was found between placebo and dronedarone in all-cause mortality

Dronedarone reduced CV mortality, CV hospitalizations, ACS, arrhythmic deaths, and stroke

Adverse events occurring significantly more frequently with dronedarone than with placebo included bradycardia, QT-interval prolongation, diarrhea, nausea, rash, and an increase in the serum creatinine level

Total discontinuation rates for dronedarone and placebo were identical, no pulmonary or thyroid toxicity was evident, and there were no TDP/VF deaths in the “high-risk” AF population in dronedarone-treated patients

Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

RATE VS RHYTHM CONTROL

100

80

20

40

% P

atie

nts

Fre

e of

S

ympt

omat

ic A

F

2 4 6 8 10 12

Months

60Amiodarone*

Sotalol**Propafenone**

Hx of Two Failed Drugs***

* Roy et al NEJM, 2000**Antman et al, JACC 1990

***Crijns et al, AJC 1991

#Natale et al JACC 2001

Atrial Flutter #

Efficacy of Antiarrhythmic Drug Therapy for A Fib Gold Standard for Judging Ablative Therapy

AFFIRM

AFFIRM TRIAL – Rhythm Control Arm Overestimate AF control with drug (No Sxs) Increased Mortality? (The prevalence of sinus rhythm in the

rhythm-control group at follow-up was 82.4 percent, 73.3 percent, and 62.6 percent at one, three, and five years, respectively.)

Ranalozine (Ranexa)◦ Has a greater effect on the late sodium current

(late > peak) which should make it more effective in ischemic patients.

Vernakalat◦ Ikur Blocker

New Pharmacologic Rhythm Control Agents

Ranexa (ranolazine) Approved for the treatment of chronic

stable angina An atrially effective compound,

substantially inhibiting peak Na+ current mainly in the atria and has been shown to decrease the incidence of atrial fibrillation in an in vitro model.

MERLIN TIMI 361 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes)◦ 6,560 patients with prior chronic angina ◦ A neutral effect on overall mortality◦ Suggested (P= 0.08) a 26% reduction

in new onset atrial fibrillation. The incidence of significant arrhythmias

was screened with holter monitoring

JACC 2009;53:1510-6

0

50

100

Placebo Ranolazine

75 (2.3%) 55

(1.7%)

P= 0.08

Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress AF

Burashnikov A et al. JACC 2010

HARMONY A Phase 2, Proof of Concept, Randomized,

Placebo-Controlled, Parallel Group Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination on Atrial Fibrillation Burden in Subjects With Paroxysmal Atrial Fibrillation ◦ Primary endpoint

The effect of ranolazine and of low dose dronedarone when given alone and in combination at different dose levels on atrial fibrillation burden (AFB) over 12 weeks of treatment

the combination of ranolazine (Ranexa, Gilead Sciences) and dronedarone (Multaq, Sanofi) appeared to lower the burden of atrial fibrillation (AF) by >70% over three months in 45% to 60% of patients with the paroxysmal form of the arrhythmia

Kowey et al. Presented at HRS 2014

A 59-year-old woman is referred to you for management of permanent atrial fibrillation that she has had for three years. The referring physician reports that recently performed echocardiography revealed normal findings. The patient's current medications are dabigatran and metoprolol, 50 mg daily.

During your initial evaluation, the patient says she feels well and has no symptoms. A 12-lead electrocardiogram shows a resting heart rate of 100 beats per minute (bpm).

(A) Continue the current drug regimen and schedule follow-up evaluation(B) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 70 bpm during rest and less than 120 bpm during moderate exercise(C) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 110 bpm during moderate exercise (D) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 130 bpm during moderate exercise

2006 guidelines for AF recommended◦ target heart rates of 60 to 80 bpm at rest and 90

to 115 bpm during moderate exercise AFFIRM

◦ no higher than 80 bpm at rest and no higher than 110 bpm during a 6-minute walk test, and an average heart rate no higher than 100 bpm over 18+ hours of Holter monitoring with no rates >100% of maximal age-predicted heart rate, as well

RACE◦ Resting heart rate < 100 bpm

Rate control

Primary outcome was similar in lenient and strict control arms (12.9% vs. 14.9%)

Stroke ↓ with lenient control (1.6% vs. 3.9%, p < 0.05)

CHF (3.8% vs. 4.1%), CV death, PPM implantation (0.8% vs. 1.4%) were similar

RACE II

Trial design: Patients with permanent AF were randomized to lenient (resting heart rate [HR] <110 bpm) or strict rate control (resting HR <80 bpm). Patient follow-up was 3 years.

Results

Conclusions

Van Gelder IC, et al. N Engl J Med 2010;Mar 15:[Epub]

(p = 0.001)*

Lenient control

(n = 311)

Strict control

(n = 303)

Primary endpoint

• Lenient rate control easier to achieve than strict control, and noninferior for clinical outcomes

• Most patients had lower CHADS2 score. Safety and efficacy in patients with higher CHADS2 score will need to be explored

• Needs to be tested in patients with significant LV dysfunction

0

10

30

% 12.9

14.9

%

(p = NS)

20

* For noninferiority

2.9 3.9

30

20

10

0CV mortality

1. Nothing2. ASA3. ASA + Plavix4. NOAC or Vit K antagonist5. NOAC + ASA

62 year old female has symptomatic paroxysmal atrial fibrillation. History is negative for hypertension, heart failure, diabetes mellitus, vascular disease, or prior stroke. You reccomend:

CHADS2 Scorestroke risk patients with nonvalvular AF not treated with Anticoagulation According to CHADS index

CHADS2 Risk Criteria Score

Prior stroke or TIA

Age > 75

Hypertension

Diabetes Mellitus

Heart Failure

2

1

1

1

1

Patients Adjusted Stroke RiskCHADS2 Score

120

468

528

337

65

5

1.9 (1.2 – 3.0)

2.8 (2.0 - 3.8)

4.0 (3.1 – 5.1)

8.5 (6.3-11.1)

12.5 (8.2-17.5)

18.2 (10.5-27.4

0

1

2

3

4

5

CHA 2 DS 2 -VASc Risk Factor Score C ongestive heart failure/LV dysfunction 1 H ypertension 1 A ge > 75 y 2 D iabetes mellitus 1 S troke/TIA/TE 2 V ascular disease 1 A ge 65-74 y 1 S ex category (ie female gender) 1

Refining Risk Stratification in AF

Summary of Recommendations for Risk-Based Antithrombotic Therapy.

January C T et al. Circulation. 2014;130:e199-e267

Copyright © American Heart Association, Inc. All rights reserved.

INR D150 VKA (RELY) Rivaroxaban VKA (ROCKET AF) Apixaban VKA (ARISTOLE)

Quartlie 1 1.10% 1.7% (HR= 0.61) 1.5 2 (HR= 0.48) 1.72 2.36 (HR= 0.73)

2 1.10% 2.2% (HR- 0.48) 1.5 2.6 (HR= 0.61) 1.61 1.72 (HR=0.94)

3 1.10% 1.4% (HR= 0.76) 1.5 2.6 (HR= 0.66) 0.86 1.35 (HR= 0.64)

4 1.30% 1.4% (HR= 0.88) 1.2 2.3 (HR= 0.58) 0.91 1.04 (HR= 0.88)

Primary Endpoint – stroke or systemic embolism

INR D150 VKA (RELY) Rivaroxaban* VKA (ROCKET AF)* Apixaban VKA (ARISTOLE)

Quartlie 1 2.40% 3.3% (HR= 0.74) 11.3 14.12 (HR= 0.80) 1.44 2.89 (HR= 0.5)

2 3.20% 3.9% (HR= 0.84) 11.72 12.21 (HR= 0.81) 1.97 3.07 (HR= 0.64)

3 3.60% 3.2% (HR= 1.12) 15.1 14.88 (HR= 1.03) 2.61 3.06 (HR= 0.85)

4 3.20% 3% (HR= 1.08) 20.61 16.72 (HR= 1.25) 2.48 3.31 (HR=0.75)

Major bleeding

* Event rate (100 pt years)

There is evidence from meta-analyses of RCTs that home monitoring of VKA therapy reduces thromboembolic events by 42% compared with usual monitoring.

THIS IS SIMILAR TO THE 33% relative risk reduction with dabigatran 150 mg Bid!!!

Home monitoring of AC

Dose adjusted VKA therapy + ASA is not recommended in stable coronary artery disease◦ SPORTIF

Associated with a nearly 2 fold increase in bleeding with NO significant reduction in stroke or MI.

◦ RE-LY Major bleeding was twice as high in patients on

aspirin AND either dabigatran or wafarin

ASA + Coumadin

No increase in death Nonfatal stroke

◦ CHADS2= 0 2 fewer strokes/1000

◦ CHADS2= 1 6 fewer strokes/1000

◦ CHADS2= 2 11 fewer strokes/1000

◦ CHADS2= 3 – 6 24 fewer strokes/1000

Nonfatal MI◦ 21 fewer/1000

Nonfatal Major Extracranial Bleed◦ 26 more bleeds/1000 (RR= 2.37)

Triple threat(ASA + Plavix + VKA vs ASA+Plavix)

CHEST February 2012

|

Primary Endpoint: Total number of TIMI bleeding events

WOEST

Days

Cum

ula

tive inci

dence

of

ble

edin

g

0 30 60 90 120 180 270 365

0 %

10 %

20 %

30 %

40 %

50 %

284 210 194 186 181 173 159 140n at risk: 279 253 244 241 241 236 226 208

Triple therapy groupDouble therapy group 44.9%

19.5%

p<0.001

HR=0.36 95%CI[0.26-0.50]

Secondary Endpoint (Death, MI,TVR, Stroke, ST)WOEST

Days

Cum

ula

tive inci

dence

0 30 60 90 120 180 270 365

0 %

5 %

10 %

15 %

20 %

284 272 270 266 261 252 242 223n at risk: 279 276 273 270 266 263 258 234

17.7%

11.3%

p=0.025

HR=0.60 95%CI[0.38-0.94]

Triple therapy groupDouble therapy group

The primary purpose of this study is to evaluate the safety for 2 different rivaroxaban treatment strategies and one Vitamin K Antagonist (VKA) treatment strategy utilizing various combinations of dual antiplatelet therapy (DAPT) or low-dose aspirin (ASA) or clopidogrel (or prasugrel or ticagrelor).

PIONEER AF

Thank you