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 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 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. 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 All received Bi-V devices 415 primary prevention patients with physician-tailored programming EMPIRIC trial - 900 patients enrolled 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 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) 30-35J 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 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 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 model Analysis: Cox proportional hazards Intent-to-treat principle Results 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, 2008;52(7):541-550. Time to First Shock: All-Cause Time to First Shock: Appropriate Time to First Shock: Inappropriate Safety Syncope 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 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 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 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. 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.