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PREPARE Study Results Sept by mikeholy


									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
   Background
   Methods
   Results
   Safety
   Conclusions
   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

1 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.
   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
       All received Bi-V devices
       415 primary prevention patients with physician-tailored

   EMPIRIC trial - 900 patients enrolled
       All received dual chamber ICDs
       276 primary prevention patients with physician-tailored

   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

1Wilkoff 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
                                  Beats to
Detection     Heart Rate          Detect      Therapies
VF ON         > 250 bpm           30 of 40    30-35 J
                                             1 seq ATP,
FVT Via VF    182-250 bpm         (30 of 40)

VT Monitor    167-181 bpm         32          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
        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
       Analysis: Poisson model with GEE
   Time to first shock and time to death
       Comparison: Distribution of event times
       Analysis: log-rank test of Kaplan-Meier curves

   Intent-to-treat principle1
1   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
     Analysis: Cox proportional hazards

   Intent-to-treat principle
       Baseline Characteristics
                  PREPARE       Control
                   (n=700)      (n=691)       P-value
Age, Mean  SD    67.4  12.2   65.5  11.7    0.003
Male                 79%           77%          0.3
EF Mean  SD      27.6  10.4   24.7  9.8    <0.001
Ischemic CM          70%           57%        <0.001
Hypertension         57%           48%        <0.001
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
                  PREPARE Control
Medication         (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      Control
                        (n=700)     (n=691)
Device Type
  Non Bi-Ventricular   452 (65%)   276 (40%)
   Single chamber      110 (16%)      0
   Dual Chamber        342 (49%)   276 (40%)
  Bi-Ventricular       247 (35%)   415 (60%)

Unsuccessful implant    1 (<1%)      N/A
   Therapy Rate Threshold

                    PREPARE       Control     P-value
Rate Threshold,      182 bpm      176 bpm     < 0.001
Median (25%, 75%)   (182, 182)   (162, 188)
ATP Programming
Number of intervals to detect
             PREPARE      Control
   NID        (n=700)     (n=691)
 12 of 16    7 (1%)     397 (58%)

 18 of 24   4 (<1%)     291 (42%)

 24 of 32    0 (0%)     1 (<1%)

 30 of 40   687 (99%)       0
                     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                          Episodes1

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,
Time to First Shock: All-Cause
Time to First Shock: Appropriate
Time to First Shock: Inappropriate
                                                  Pts (%) Events
Adverse Event                                         (n=700)
Syncope and near-syncope                          131 (18.7%) 290
   Arrhythmia-related                               27 (3.9%) 31
True syncope                                        31 (4.4%) 40
     Arrhythmia-related                             11 (1.6%) 12
     Related to PREPARE programming                 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
        Death Related to PREPARE
   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
Undersensing with Longer NIDs1
   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
   Avg number of US between onset and
    shock was 2
   Avg time from onset to shock increased
    from 6 to 9.5 secs
1Brown 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.
   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
            Percent of patients receiving an all-cause shock
            Percent of patients receiving an inappropriate shock
   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
   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

     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
     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.

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