Endpoints When Treating

VT/VF in Patients with ICDs

Programming

Wojciech Zareba, MD, PhD

Professor of Cardiology/Medicine

Director of the Heart Research Follow Up Program ,

University of Rochester, Rochester, NY

Research Grants: Boston Scientific - MADIT, MADIT II, MADIT-CRT, MADIT-RIT, MADIT-CHIC, MADIT-SICD Medtronic - LQTS ICD Registry Zoll, Inc - WEARIT II, WEARIT III, WED-HED Gilead Sciences - TEMPO, HARMONY, LQT3, HCM NIH - RAID, ARVC, LQTS

Disclosures

Trial Primary

Endpoint

Secondary

Endpoint

MADIT Death SCD

MADIT II Death SCD

SCD-HeFT Death SCD

DEFINITE Death SCD

DANISH Death SCD

DINAMIT Death SCD

IRIS Death SCD

COMPANION HF event/Death Death, HF event

MADIT-CRT HF event/Death Death, HF event

RAFT HF event/Death Death, HF Event

ICD/CRT-D Trials

Cumulative Probability of VT/VF or Death by Treatment

(CRT-D vs. ICD only) in patients with LBBB

in MADIT-CRT Patients

Zareba et al. Circulation 2011;123:1061-1072

23%

15%

24% 31%

2-year 3-year

Pro

ba

bilit

y o

f s

ub

se

qu

en

t V

T/V

F/D

eath

0.0

0.2

0.4

0.6

0.8

1.0

Years from 1st VT/VF

0 1 2 3

Unadjusted P=0.722

ICD

CRT-D

Patients at RiskICD 159 60 (0.48) 24 (0.63) 8 (0.67)

CRT-D 200 84 (0.44) 33 (0.57) 7 (0.67)

MADIT-CRT: Cumulative probability of VT/VF/Death

after first VT/VF requiring appropriate ICD therapy

60% at 2 years

40% at 1 year

Ouellet et al. J Am Coll Cardiol 2012;60:1809–16

Association of Rapid Rate NSVT >188 bpm

with Cardiac Events in SCD-HeFT

Chen et al. J Am Coll Cardiol 2013;61:2161–8

Antiarrhythmic Therapy in Patients with VT:

Cardiac Resynchronization Therapy

Pharmacological heart failure therapy

Device programming

VT ablation

Cardiac sympathetic denervation

Antiarrhythmic medications

Antiarrhythmic Therapy in Patients with VT:

Cardiac Resynchronization Therapy

Pharmacological heart failure therapy

Device programming

VT ablation

Cardiac sympathetic denervation

Antiarrhythmic medications

ICD Documented VT/VF Endpoints Serve to Assess Efficacy

and Safety of Antiarrhythmic Therapy in Patients with VT/VF

LBBB Non-LBBB

Cumulative Probability of VT/VF or Death by Treatment (CRT-D

vs. ICD only) in patients with LBBB and Non-LBBB QRS Pattern

in MADIT-CRT Patients

Zareba et al. Circulation 2011;123:1061-1072

HR=0.69

p<0.002 HR=1.11

p<0.574

P value for interaction = 0.028

Reduction in Cardiac Events in Carvedilol vs.

Metoprolol Treated Patients from MADIT-CRT

Study population HF/death VT/VF

HR 95% CI P-value HR 95% CI P-

value

MADIT-CRT 0.70 0.57-0.87 0.001 0.80 0.63-1.00 0.050

CRT-D and LBBB 0.51 0.35-0.76 <0.001 0.57 0.39-0.85 0.005

Ruwald M et al. J Am Coll Cardiol. 2013;61:1518-26

Cumulative Probability of First Inappropriate Therapy

by Treatment Group in MADIT-RIT by Arm

Moss et al, NEJM 2012;367:2275-83

MADIT-RIT: Cumulative risk of high-rate appropriate

therapy by programming arm

VANISH Trial: Ventricular Tachycardia Ablation versus

Escalation of Antiarrhythmic Drugs

Saap et al.

N Engl J Med

2016;375:111-21.

Primary Outcome:

• death at any time or

• VT storm or

• appropriate shock

from ICD after the

30-day treatment

period

VANISH Trial: Primary Outcome According to

Receipt of Amiodarone during the Index

Arrhythmia.

Saap et al. N Engl J Med 2016;375:111-21.

Pharmacologic Antiarrhythmic

Therapy for VT/VF

Trial Intervention Primary Endpoint Secondary

Endpoint

SOTALOL ICD

(n=302)

1999

Sotalol Death or delivery

of a first shock for any

reason

Appropriate ICD

Shocks

SHIELD

(N=663)

2004

Azimilide, Placebo 1) all-cause shocks

plus symptomatic

tachyarrhythmias

terminated by ATP and

2) all-cause

shocks

Appropriate ICD

therapies, defined

as shocks or VT

terminated by ATP

OPTIC

(n=412)

2006

Sotalol, BB,

amiodarone+BB

Cumulative risk of ICD

shocks

Appropriate ICD

shocks

ALPHEE

(n=486)

2011

Celivarone,

Amiodarone, Placebo

Time to first ICD-

treated VT/VF (ATP or

shock) or SCD

Occurrence of ICD

shocks (appropriate

or inappropriate) or

Death

Pharmacological Trials in ICD Patients

Trial Intervention Primary Endpoint Secondary

Endpoint

SHIELD II

(n=240)

Azimilide, Placebo Time-to first

unplanned adjudicated

cardiovascular (CV)

hospitalisation, CV

emergency

department (ED) visit

or CV death.

Death

Time-to first all-cause adjudicated shock

Time-to first adjudicated outpatient ICD-related appointment

TEMPO

(n=313)

Eleclazine, Placebo Total number of ICD

interventions (ATP or

shock) at 24 weeks

Arrhythmia burden

(untreated and

treated VTs)

RAID

(n=1,012)

Ranolazine, Placebo Time to first ICD-

treated VT/VF (ATP or

shock) or Death

VT/VF, Death,

recurrent VT/VF

Ongoing/Unpublished Pharmacological Trials in ICD

Patients

VT/VF Endpoints

• VT/VF requiring ICD therapy (ATP or shock)

• VT/VF requiring ICD therapy or death

• VT/VF requiring ICD shocks

• VT/VF requiring ICD shocks or death

• VT/VF and arrhythmic death or SCD

• VT/VF storms (usually defined as at least 3 episodes in 24 hours)

• Fast VT/VF treated and untreated, including NSVT

• Time to first event

• Cumulative number of events over time

• Rate of events over 100 person-years

• Eliminate expected VT/VF in terminal stage

Nonsustained Self-terminating VF – is it an Endpoint?

ALPHEE Trial: Recurrent episodes of the primary end point (VT/VF-

triggered ICD intervention or sudden death. Percentage of patients

by number of events (limited to a maximum of 10 per patient)

Kowey et al. Circulation 2011;124:2649-60

Mean cumulative number of the first 10 events per patient in

ALPHEE Trial.

Kowey et al. Circulation 2011;124:2649-60

Pro

ba

bilit

y o

f s

ub

se

qu

en

t V

T/V

F/D

eath

0.0

0.2

0.4

0.6

0.8

1.0

Years from 1st VT/VF

0 1 2 3

Unadjusted P=0.722

ICD

CRT-D

Patients at RiskICD 159 60 (0.48) 24 (0.63) 8 (0.67)

CRT-D 200 84 (0.44) 33 (0.57) 7 (0.67)

MADIT-CRT: Cumulative probability of VT/VF/Death

after first VT/VF requiring appropriate ICD therapy

Ouellet et al. J Am Coll Cardiol 2012;60:1809–16

MADIT-CRT: Number of Patients with Repeated

VT/VF Episodes

VT/VF Endpoints Determined by ICD

Programming

• ICD programming should be uniform but many patients will

have prior VT/VF and VT zone will be programmed 10-20

bpm above previously documented VT which might range

from 160-220 bpm

• Not all VT episodes are synonymous with sudden cardiac

death

• Appropriate ICD therapy but unnecessary is significantly

reduced by delayed activation

Programming of Implantable Devices

Programming of Implantable Devices

CRM Device Generated Data Variables

Algorithm - variable

EGM Collections - reporting

Data efficiency - memory and power

limitations

Integrated Sensors

User specified programming

Language Is Everything !

Definitions are critical !

• Machine algorithms increasingly complex

• Need for consistent interpretation of events

• International data acquisition the norm: geographic

clinical practice variability

• Pre-specify the data available to the device event

adjudication committee

• Consider sampling analysis/memory limitations

Analytic Complexity Appropriate Device Therapy

Appropriate ATP therapy only (ATP without shock);

Appropriate ATP and appropriate shock (at least one ATP and one shock)

Appropriate shock only (no preceding or accompanying ATP)

Inappropriate Device Therapy

Inappropriate ATP only

Inappropriate ATP therapy and inappropriate shock

Inappropriate shock only

Inappropriate ATP and appropriate ATP

Inappropriate ATP and appropriate shock

Inappropriate shock and appropriate shock

Appropriate ATP and inappropriate shock

Lack of Appropriate Device Therapy

Sustained VT or VF without device therapy terminated spontaneously

Sustained VT or VF without device therapy continuing under rate cut-off

Sustained supraventricular arrhythmia (atrial fibrillation, other atrial rhythms) not

treated with ATP

or shock

Other Causes of Lack of Appropriate Device Therapy

VT undersensing

VF undersensing

Other explain _________________________________________________

Device therapy not delivered but not required

Unable to determine - Insufficient or confounding interrogation data available to make

determination

• Is VT burden the right endpoint?

If yes at what rate VT?

• How to deal with VT/VF below VT thresholds?

• Should death be included or just cardiac death or

sudden cardiac death as part of the primary

endpoint?

• How to trust devices without adjudication?

Questions