Transcript PREPARE Study Results - Sept 2008

Strategic Programming of Detection and
Therapy Parameters in Implantable
Cardioverter-Defibrillators Reduces Shocks
in Primary Prevention Patients:
Results from the PREPARE (Primary Prevention Parameters
Evaluation) Study1
Bruce L. Wilkoff, MD FACC*; Brian D. Williamson, MD FACC*; Richard S. Stern,
MD FACC*; Stephen L. Moore, DO FACC*; Fei Lu, MD FACC|*; Sung W. Lee,
MD FACC*; Ulrika M. Birgersdotter-Green, MD*; Mark S. Wathen, MD*, Isabelle
C. Van Gelder, MD*; Brooke M. Heubner, MS#; Mark L. Brown, PhD#; Keith K.
Holloman, BA#; for the PREPARE Study Investigators
1
J Am Coll Cardiol 2008; 52:541-50.
* Medtronic Consultant/Advisor & Investigator
# Medtronic Employee
Outline





Background
Methods
Results
Safety
Conclusions
Background
Background



1
In 2002, indications for ICDs were
expanded for “Primary Prevention
Patients” (MADIT II1 and SCD-HeFT2)
Primary prevention patients might be less
tolerant of shocks
Goal: Reduce shocks with specialized
programming
Moss AJ. N Engl J Med. 2002; 346:877-883.
2 Bardy GH. N Engl J Med. 2005; 352:225-237.
Programming Strategy for
Primary Prevention Patients

Build upon programming strategies tested
in previous trials
SCD-HeFT – Rx only for fast rhythms
 PainFREE Rx II – ATP before shock
 EMPIRIC – Prescribed programming for all
ICD recipients utilizing PF II programming and
SVT discriminators


Adapt for Primary Prevention Patients
PREPARE Hypothesis
Strategically chosen ICD VT/VF detection
and therapy parameters can reduce the
combined incidence of device-delivered
shocks, arrhythmic syncope and untreated
sustained symptomatic VT/VF in primary
prevention patients.
Methods
Methods

Prospective, historic cohort controlled study

Primary prevention ICD indications

700 pts

38 Centers, US & Europe

October 2003 – May 2005

1 year follow-up

Medtronic Marquis-based ICDs and leads

Single, dual and Bi-V patients
Bi-V & Non Bi-V Controls

MIRACLE ICD trial – 978 patients enrolled



EMPIRIC trial - 900 patients enrolled



All received Bi-V devices
415 primary prevention patients with physician-tailored
programming
All received dual chamber ICDs
276 primary prevention patients with physician-tailored
programming
Total Control Cohort

691 primary prevention, Bi-V and Non Bi-V
PREPARE Strategies to
Reduce Shocks1

Avoid detecting slower tachycardia

Avoid detecting non-sustained tachycardia

Avoid detecting SVT as VT/VF

ATP therapy for fast VT

High output 1st shock
1
Wilkoff BL, Stern R, Williamson B, et al. Design of the Primary Prevention Parameters
Evaluation (PREPARE) trial of implantable cardioverter defibrillators to reduce patient morbidity.
Trials 2006; 7:18.
VT/VF Detection
Detection
Heart Rate
Beats to
Detect
VF ON
> 250 bpm
30 of 40
FVT Via VF
182-250 bpm
1 seq ATP,
(30 of 40)
30-35J
VT Monitor
167-181 bpm
32
Therapies
30-35 J
None
PR Logic ON: AF/Afl, Sinus Tach (1:1 VT-ST = 66%) or
Wavelet ON: SVT Limit = 200 bpm
Primary Endpoint

Morbidity Index

Spontaneous episodes treated with shocks

Arrhythmic syncope

Untreated sustained symptomatic VT/VF
episodes
Secondary Endpoints

Morbidity-Tachycardia Index


Morbidity Index plus ATP episodes
Time to first shock
 All-cause
 Appropriate
 Inappropriate
Statistical Methods
Primary Analyses

Morbidity Index
Comparison: Events per year of patient
follow-up
 Analysis: Poisson model with GEE
methodology


Time to first shock and time to death
Comparison: Distribution of event times
 Analysis: log-rank test of Kaplan-Meier curves


1
Intent-to-treat principle1
HRS LBCT presentation used per-protocol principle
Statistical Methods
Adjusted Analyses

Morbidity Index
Adjustment: Stratified by propensity score
 Analysis: Primary analysis repeated for five
strata with balanced baseline covariates


Time to first shock and time to death
Adjustment: Baseline variables added to
model
 Analysis: Cox proportional hazards


Intent-to-treat principle
Results
Baseline Characteristics
PREPARE
(n=700)
Control
(n=691)
P-value
67.4  12.2
65.5  11.7
0.003
79%
77%
0.3
27.6  10.4
24.7  9.8
<0.001
Ischemic CM
70%
57%
<0.001
Hypertension
57%
48%
<0.001
Age, Mean  SD
Male
EF Mean  SD
NYHA
0.06
Class 0/I/II
59%
54%
Class III-IV
41%
46%
Hx of AF/Afl/AT
33%
20%
<0.001
Baseline Medications
Medication
PREPARE Control
(n=700)
(n=691)
P-Value
Anti-Arrhythmic
12%
20%
<0.001
Beta-Blocker
84%
73%
<0.001
ACE Inh or ARBs
84%
83%
0.91
Implant and Device Type
PREPARE
(n=700)
Control
(n=691)
Non Bi-Ventricular
452 (65%)
276 (40%)
Single chamber
110 (16%)
0
Dual Chamber
342 (49%)
276 (40%)
247 (35%)
415 (60%)
1 (<1%)
N/A
Device Type
Bi-Ventricular
Unsuccessful implant
Therapy Rate Threshold
Rate Threshold,
Median (25%, 75%)
PREPARE
Control
P-value
182 bpm
(182, 182)
176 bpm
(162, 188)
< 0.001
ATP Programming
Number of intervals to detect
PREPARE
(n=700)
Control
(n=691)
7 (1%)
397 (58%)
18 of 24
4 (<1%)
291 (42%)
24 of 32
0 (0%)
1 (<1%)
30 of 40
687 (99%)
0
NID
12 of 16
Morbidity Index
(Primary Endpoint)
Incidence rate (events/pt-yr): 0.26 PREPARE vs. 0.69 Control
Incidence rate ratio: PREPARE / Control = 0.38 (62% relative reduction), p=0.003
Ratio adjusted for baseline characteristics = 0.44 (56% relative reduction), p=0.002
Shocked
1
Episodes
Incidence rate (events/pt-yr): 0.26 PREPARE vs. 0.69 Control
Incidence rate ratio: PREPARE / Control = 0.37 (63% relative reduction), p=0.003
Ratio adjusted for baseline characteristics = 0.42 (58% relative reduction), p=0.001
1
Peterson B and Rogers T. Medtronic data on file. August 2008.
Secondary Endpoint

Morbidity Tachycardia Index:

Morbidity Index events
Spontaneous episodes treated with shocks
 Arrhythmic syncope
 Untreated sustained symptomatic VT/VF episodes
 Spontaneous episodes treated with ATP


Incidence rate lower for PREPARE
0.70 PREPARE vs. 1.96 Control
 Ratio of 0.36 (64% relative reduction); p=0.02
 Ratio of 0.34 (66% relative reduction); p<0.001


Adjusting for baseline characteristics
Patients Shocked at One year1
* Results remain significant after adjusting for differences in baseline characteristics.
** Not significant after adjusting for differences in baseline characteristics.
1 Wilkoff BL, Williamson BD, Stern RS, et al. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces
shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol. August 12,
2008;52(7):541-550.
Time to First Shock: All-Cause
Time to First Shock: Appropriate
Time to First Shock: Inappropriate
Safety
Syncope
Adverse Event
Syncope and near-syncope
Arrhythmia-related
True syncope
Arrhythmia-related
Related to PREPARE programming

Pts (%) Events
(n=700)
131 (18.7%) 290
27 (3.9%) 31
31 (4.4%) 40
11 (1.6%) 12
9 (1.3%) 10
10 events identified as possibly or probably related to PREPARE
programming in 9 patients.



None associated with injuries or death
7 patients completed study
2 patients withdrew for other reasons
Mortality
Death Related to PREPARE
Programming




One patient death was adjudicated as being
possibly related to PREPARE programming
Episode of slow VT detected in the monitor zone
that accelerated to VF and was terminated with
the sixth shock
Cause of death was determined to be possibly
related to the prolonged ventricular arrhythmia
Outcome likely the same with nominal
programming for primary prevention patients

Single high-rate therapy zone with or without low-rate
monitoring
Undersensing with Longer NIDs1




1
No difference in the rate of undersensing
between NID=12/16 and NID=30/40 for
induced or spontaneous VF/PVT
No difference in US early vs late in
episode
Avg number of US between onset and
shock was 2
Avg time from onset to shock increased
from 6 to 9.5 secs
Brown M, et al. Longer Ventricular Fibrillation Detection Duration Does Not Increase Rate of
Undersensing: Results from the PREPARE Study. Circulation, vol. 116, no 16, Supplement II,
October 16, 2007, p II-586.
Limitations



Non-randomized trial
Historical control cohort
Differences in baseline characteristics between
PREPARE group and controls

Significant reductions for endpoints remain when
adjusting for differences:



Morbidity Index, Morbidity Tachycardia Index, and shocked
episodes
Percent of patients receiving an all-cause shock
Percent of patients receiving an inappropriate shock
Conclusions
Conclusion

Strategically chosen VT/VF detection and
therapy options targeting primary
prevention patients can safely reduce the
morbidity related to ICD therapy





62% reduction in Morbidity Index
63% reduction in shocked episodes
64% reduction in Morbidity Tachycardia Index
8.5% vs. 16.9% pts shocked at 1 year
3.6% vs. 7.5% pts inappropriately shocked at 1 year
Implications



Large majority of ICD implants are for
primary prevention
Most ICD patients receive too many shocks
Using strategic PREPARE programming to
treat sustained and fast tachycardias with
ATP before shocks should safely reduce
ICD morbidity
Brief Statement for CRT and CRT-ICD Systems
Indications
CRT and CRT-ICD devices are indicated for the reduction of the symptoms of moderate to severe heart failure (NYHA
Functional Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy, and have a left
ventricular ejection fraction ≤35% and a prolonged QRS duration.
The CRT device is also intended to provide rate adaptive pacing for patients who may benefit from increased pacing rates
concurrent with increases in activity. Rate adaptive pacing is intended only for those patients developing a bradycardia
indication who might benefit from increased pacing rates concurrent with increases in activity. Dual chamber and atrial
tracking modes are indicated for patients who may benefit from maintenance of AV synchrony.
CRT-ICD devices are also indicated for ventricular defibrillation for automated treatment of life threatening ventricular
arrhythmias.
Contraindications
Asynchronous pacing is contraindicated in the presence (or likelihood) of competitive or intrinsic rhythms.
Unipolar pacing is contraindicated in patients with an implanted defibrillator or cardioverter-defibrillator (ICD) because it may
cause unwanted delivery or inhibition of defibrillator or ICD therapy.
CRT-ICD devices are contraindicated for patients whose ventricular tachyarrhythmias may have transient or reversible
causes and for patients with incessant VT or VF.
CRT devices are contraindicated for dual chamber atrial pacing in patients with chronic refractory atrial tachyarrhythmias.
Warnings and Precautions
Changes in a patient’s disease and/or medications may alter the efficacy of the device’s programmed parameters.
Patients should avoid sources of magnetic and electromagnetic radiation to avoid possible underdetection, inappropriate
sensing and/or therapy delivery, tissue damage, induction of an arrhythmia, device electrical reset or device damage.
Do not place transthoracic defibrillation paddles directly over the device.
Certain programming and device operations may not provide cardiac resynchronization.
Potential Complications
Potential complications include, but are not limited to, rejection phenomena, erosion through the skin, muscle or nerve
stimulation, oversensing, failure to detect and/or terminate tachyarrhythmia episodes, acceleration of ventricular tachycardia,
and surgical complications such as hematoma, infection, inflammation, and thrombosis.
See the device manuals for detailed information regarding the implant procedure, indications, contraindications, warnings,
precautions, and potential complications/adverse events.
Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician.