When does enhanced monitoring for atrial fibrillation add value?

Jonathan P. Piccini, MD, MHS, FHRS

Associate Professor of Medicine

Duke Clinical Research Institute

Duke University Medical Center

jonathan.piccini@duke.edu

DisclosuresResearch Grants

• AHRQ

• ARCA biopharma

• Boston Scientific

• German AFNet

• Gilead

• Johnson & Johnson

• ResMed

• St Jude Medical

Consulting

• BMS/Pfizer

• GSK

• Johnson & Johnson

• Laguna Pharmaceuticals

• Medtronic

• Spectranetics

Full disclosures available at

https://www.dcri.org

Controls

Post MI

AF

AF Adversely Affects QoL

*

**

*

54

68 71 68

59

70

85

7678

8892

81

0

20

40

60

80

100

120

General Health Physical Function Social Function Mental Health

SF-3

6 S

co

re

Dorian P, et al. J Am Coll Cardiol. 2000;36:1303-1309.

*P < .05 AF vs controls

Stroke

CV Hospitalization

Heart Failure

TIA

Death

Natural History of Atrial Fibrillation

Piccini J P et al. Eur Heart J 2014;35:250-256

The importance of outcomes beyond stroke

Death

Heart Failure

No. at Risk

Persistent 11485 11255 10962 8113 4975 2134

Paroxysmal 2490 2451 2404 1830 1216 498

Adjusted HRparoxysmal =

0.79 (0.67 – 0.94)

p=0.0061

Persistent AF is associated with worse survival

Steinberg, BS. Eur Heart J. 2014; In press.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0 6 12 18 24 30

Ra

te o

f a

ll-c

au

se

mo

rta

lity

Months since randomization

Persistent AF

Paroxysmal AF

AFB is associated increased risk of hospitalization in pacemaker patients:

BRADYCARE

Mittal S, et al. HRS Scientific Sessions. 2015

• Pts <67 years HR 1.81 (95% CI 1.11-2.94)– Independent of clinical

stroke.

• Strongly associated with duration of exposure to AF

de Bruijn RF. JAMA Neurol. 2015;72:1288-94Alznet.org

Effectiveness Endpoints in Trials of Surgical Interventions for AF

Primary Endpoints

• Electrocardiographically documented AT/AF ≧30 seconds

• Antiarrhythmic therapy

• Cardioversion

• Repeat surgical/catheter ablation

Secondary Endpoints

• AF burden

• Symptom scores

• Quality of life

• Exercise tolerance

• LVEF

• Atrial transport function

• Left atrial size

CDRH. Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation.

February 15, 2013

Effectiveness Endpoints in Trials of Surgical Interventions for AF

Primary Endpoints

• Electrocardiographically documented AT/AF ≧30 seconds

• Antiarrhythmic therapy

• Cardioversion

• Repeat surgical/catheter ablation

Secondary Endpoints

• AF burden

• Symptom scores

• Quality of life

• Exercise tolerance

• LVEF

• Atrial transport function

• Left atrial size

CDRH. Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation.

February 15, 2013

Marina Urena et al. Circulation. 2015;131:469-477

24-Hour Continuous ECG Monitoring before TAVR

Marina Urena et al. Circulation. 2015;131:469-477

Cerebrovascular events within 30-days after TAVR

Scirica BM, et al. Europace 2015;17:32-37

Effect of ranolazine on AF in NSTEMI (MERLIN TIMI 36):

continuous ECG during the first 7 days

Scirica BM, et al. Europace 2015;17:32-37

Clinical AF events in patients treated with ranolazine or placebo

PASCAL: Importance of AF burden in clinical trials

Placebo 200 mg bid 400 mg bid 600 mg bid

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20M

ed

ian

Perc

en

t C

han

ge f

rom

Baselin

e

11.2

-12.6

-54.4

-74.2

p=0.07 p=0.013 p=0.0013

ITT Population, % Change in AFB from Baseline

Dose Response: p=<0.0001

Jonckheer-Terpstra test

N=18

N=20

N=18

N=15

Wilcoxon rank sum test vs Placebo

Ezekowitz M et al; Abstract

DADs

EAD

↑[Ca2+]i NCX

↑[Na+]i

Enhanced Late INa Causes and/or contributes to

EP Mechanisms of Arrhythmias

↑QTc

VT

Triggers

Substrate

Abnormal

automaticity

Endo

Epi

∆APD

Dispersion

Spatial Temporal

Late INa

4

GS-6615 (eleclazine)

GS967

EP Phenotype

Belardinelli et al, Heart Rhythm 12: 440-448, 2015 Belardinelli et al, Heart Rhythm 12: 440-448, 2015

Enhanced Late Ina and Arrhythmogenesis

Changes in AF Burden Over 12 Weeks

≥70% Reduction in AFB Overall Changes in AFB

Reiffel JA. Circ Arrhythm Electrophysiol. 2015;8:1048-56.

CAT HF: Arrhythmia Substudy DesignOverall CAT-HF

Population

MV-triggered ASV Control Arm

~50 dual-chamber devices

~50 dual-chamber devices

1 and 2 Events at 0, 3, 6 months

Arrhythmia Core Lab Adjudication

R

Genotype-Directed Therapy of AF in HF: Bucindolol

b1389 Arg/Arg (n = 441; 36 events)

Hazard Ratio = 0.26 (0.12 – 0.57)P-value = 0.0003

Risk reduction 74%

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0 6 12 18 24 30 36 42 48

Prob

abili

ty o

f Ev

ent-

Free

Sur

viva

l

Months After Randomization

Placebo

Bucindolol

Hazard Ratio = 1.01 (0.56 – 1.84)P-value = 0.969

b1389 Gly carriers (n = 484; 44 events)

No risk reduction

Interaction p = 0.008

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0 6 12 18 24 30 36 42 48

Prob

abili

ty o

f Ev

ent-

Free

Sur

viva

l

Months After Randomization

Placebo

Bucindolol

Aleong R. JACC Heart Fail. 2013;1:338-34

LVEF <0.50, Class II-III HF w/in 90 days No contra-indications to b-blockers

b1389 Arg/Arg genotype

Recent onset Sx

AF, 1 wk – 1 yr;Class I-III HF

Bucindolol Toprol-XL

ECV @ 3 wks if still in AF

1° Endpoint = Recurrent AF or ACM at 24 weeksCo-Primary for Phase 2b = AF Burden

n = 100

(310)

n = 100

(310)

Time 0 (chemical conversion to SR or ECV)

AF free/event: from 24 hrs after ECV

Genetically Targeted Therapy for the Prevention of Symptomatic AF in Patients With Heart Failure (GENETIC-AF)

ClinicalTrials.gov Identifier:NCT01970501

Overaccessorize much?

Patch-Based Holter Monitoring

Smart Phone-Based Event Monitoring

Chung EH. J Electrocardiol. 2015;48:8-9

Monitoring DofetilideAntiarrhythmic Drug Therapy

“Pill in Pocket” Anticoagulation: react.com

Slide courtesy of Rod Passman, Northwestern University.

Conclusions

• AF symptoms are the tip of the iceberg

• AF burden is an important biosignature– Associated with a variety of important outcomes

including stroke, hospitalization, and all-cause mortality

• AF burden can assist in trials, particularly in early clinical development

Summary• Safety first.

• Be aggressive with your ACT targets

• Bridging therapy is associated with a higher risk of bleeding complications– Emerging theme >> Anticoagulation transitions carry more risk than

continued anticoagulation

• Once a diagnosis of AF is made, stroke prophylaxis should be guided by risk stratification alone (and not rhythm)

Duke Center for Atrial Fibrillation