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