When does enhanced monitoring for atrial fibrillation add · PDF fileWhen does enhanced monitoring for atrial fibrillation add value? Jonathan P. Piccini, MD, MHS, FHRS Associate Professor

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

[email protected]

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