Methods/Design
Hypothesis
The PREPARE study examines the hypothesis that a pre-specified strategic profile of tachyarrhythmia detection and therapy parameters is able to reduce the overall morbidity of ICD therapy in patients with primary prevention ICD indications with or without cardiac resynchronization therapy.
Primary endpoint
Shock related morbidity is measured by the Morbidity Index and expressed through the incidence density. However, the reduction of shocked episodes in primary prevention patients via the use of a specific programming profile is useful only if it does not result in an increase in arrhythmogenic syncope and untreated sustained symptomatic VT/VF events. The Morbidity Index measures the benefit of reducing the number of shocks while also accounting for the possible side effects of 1) treating only faster tachyarrhythmias (cycle-lengths greater than 330 ms) and 2) using a longer programmed delay before treating ventricular tachyarrhythmias with defibrillation.
Morbidity index
The components of the Morbidity Index are:
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Syncope (secondary to tachyarrhythmia or presumed tachyarrhythmia)
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Untreated sustained symptomatic VT/VF events
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Episodes of spontaneous ventricular tachyarrhythmia that result in device-delivered shock
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Episodes that result in an inappropriate device-delivered shock.
Incidence Density (ID)
The Morbidity Index incidence density is calculated by dividing the total number of Morbidity Index events by the total number of years of follow-up. The primary endpoint is the difference in Morbidity Index incidence density between the study patients programmed to the PREPARE settings and the control population programmed to physician-tailored programming.
Secondary endpoint
Morbidity Tachycardia Index
The key secondary endpoint is the difference in Morbidity Tachycardia Index incidence density, which adds anti-tachycardia pacing events to the Morbidity Index as a reflection of all tachycardia events, between patients programmed to the PREPARE settings and the control population.
Design
The PREPARE study is a prospective, single arm, multi-center cohort study designed to evaluate the efficacy of a pre-specified strategic profile of VT and VF detection and therapy settings designed for ICD indicated patients with no history of spontaneous sustained symptomatic VT or VF. All study patients received a Medtronic Marquis family ICD system with or without capacity for cardiac resynchronization implanted between October 2003 and April 2005. Approximately 700 patients were enrolled in the United States and the Netherlands and were programmed to the PREPARE parameters and followed for endpoints for 12 months after PREPARE programming.
For the purposes of this study, primary prevention patients are defined as those patients indicated for ICD or CRT + ICD implantation without a baseline history of ventricular fibrillation, ventricular flutter, monomorphic VT, polymorphic VT, or Torsades de Pointes. Patients may have a history of cardiovascular syncope, since the PREPARE findings are intended to be generalized to the primary prevention patient population seen in clinical practice.
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Inclusion criteria required:
spontaneous VT/VF episodes
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Patients were excluded for:
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○ History of spontaneous sustained symptomatic ventricular arrhythmias,
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○ An electrophysiology test in the past, with sustained inducible VT < 180 bpm,
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○ Any ICD implanted greater than 6 months prior to the study,
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○ An ICD implanted within the previous 6 months, with subsequent history of a spontaneous episode of VT or VF appropriately treated with either ATP or shock.
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○ Heart transplant
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○ Mechanical right heart valve.
Control population
The control population consists of the prospectively collected shock, tachycardia and event data combined from two randomized clinical ICD trials; the MIRACLE ICD Trial[
13] and the EMPIRIC Trial. [
11] Both of these trials included both primary and secondary prevention patients, but only the primary prevention patients were included in the control population for the PREPARE analysis.
Originally, the control population included only the primary prevention patient data from the MIRACLE ICD Trial. The MIRACLE ICD Trial was a multi-center randomized trial of 978 CRT-ICD patients, designed to assess the safety and effectiveness of biventricular CRT in primary and secondary prevention patients. However, in contrast to the MIRACLE ICD Trial which enrolled only patients receiving a cardiac resynchronization defibrillator (CRT+ICD), the PREPARE Study includes primary prevention patients implanted with either an ICD or CRT+ICD device. After an interim review of baseline characteristics during the enrollment phase of the PREPARE Trial, it became evident that 65% of the patient population did not require a cardiac resynchronization device. Therefore, the PREPARE Trial population was comprised of patients with more favorable clinical characteristics than the advanced heart failure patients enrolled in the MIRACLE ICD Trial. This imbalance threatened to falsely skew the results of the study, making it difficult to discern whether the potential efficacy of the PREPARE parameters would be the result of the recruitment of patients into the PREPARE study with less severe disease.
To address the imbalanced baseline characteristics between the PREPARE patients and the original control population, the primary prevention patients from the physician-tailored arm of the EMPIRIC study were combined with MIRACLE ICD control patients to produce the control population.
The EMPIRIC study was a multi-center randomized trial of 900 ICD patients, designed to compare standardized vs. physician-tailored VT/VF programming in both primary and secondary prevention patients. [
11] The study was recently completed, and its patient population is thought to better reflect the higher ratio of ICD implant indications seen during enrollment into the PREPARE study than the MIRACLE ICD Trial, reported in 2003. [
13] Additionally, there were a large number of patients (276) randomized in the EMPIRIC Trial to the physician-tailored arm who met the PREPARE Trial definition of primary prevention. These patients, along with the 415 primary prevention patients from the MIRACLE ICD Trial, have been combined, producing a total of 691 patients in the historical control sample.
When compared with PREPARE patient baseline demographics, the patient characteristics of the combined physician-tailored arm are not clinically different. The baseline clinical data for the study and control patients is listed in Table
1. This table includes baseline demographics which were collected in PREPARE, MIRACLE ICD and EMPIRIC. Demographics for MIRACLE ICD and EMPIRIC are shown separately and in combination.
Table 1
Patient Demographics
Gender (N, %)
| | | | |
Male | 555 (79.3%) | 310 (74.7%) | 222 (80.4%) | 532 (77%) |
Female | 145 (20.7%) | 105 (25.3%) | 54 (19.6%) | 159 (23%) |
Age (years)
| | | | |
Mean ± Standard Deviation | 67.4 ± 12.2 | 65.4 ± 11.5 | 65.6 ± 12 | 65.5 ± 11.7 |
Median | 68.7 | 67.9 | 67.3 | 67.7 |
Minimum – Maximum | 19.2 – 92.2 | 31 – 89 | 23.3 – 91.4 | 23.3 – 91.4 |
n (%) | 700 (100%) | 415 (100%) | 276 (100%) | 691 (100%) |
Baseline Left Ventricular Ejection Fraction (%)
| | | | |
Mean ± Standard Deviation | 27.7 ± 10.5 | 21 ± 6.8 | 30.3 ± 11 | 24.7 ± 9.8 |
Median | 25 | 20 | 30 | 25 |
Minimum – Maximum | 5 – 80 | 6 – 35 | 5 – 70 | 5 – 70 |
n (%) | 691 (98.7%) | 413 (99.5%) | 273 (98.9%) | 686 (99.3%) |
Baseline New York Heart Association Classification (N, %)
| | | | |
Class I | 117 (16.7%) | 0 (0%) | 36 (13%) | 36 (5.2%) |
Class II | 297 (42.4%) | 137 (33%) | 102 (37%) | 239 (34.6%) |
Class III | 268 (38.3%) | 237 (57.1%) | 36 (13%) | 273 (39.5%) |
Class IV | 18 (2.6%) | 41 (9.9%) | 3 (1.1%) | 44 (6.4%) |
Not Collected* | 0 (0%) | 0 (0%) | 99 (35.9%) | 99 (14.3%) |
Ischemic Cardiomyopathy
| 488 (69.7%) | 238 (57.5%) | 155 (56.2%) | 393 (57.0%) |
Myocardial Infarction (N, %)
| 421 (60.1%) | 193 (46.6%) | 192 (69.6%) | 385 (55.8%) |
Programming
The strategies for reducing shock morbidity are to 1) reduce over-treatment of self-terminating tachycardias, 2) reduce the mis-identification of supraventricular arrhythmias as ventricular arrhythmias, and 3) terminate ventricular tachycardia with anti-tachycardia pacing as frequently as possible. Since the patients enrolled in this trial had never experienced a sustained ventricular arrhythmia, the parameters were chosen to not treat: 1) slow and presumably less symptomatic tachycardias, and 2) faster but self-terminating arrhythmias.
The exact tachycardia detection and therapy parameters for the PREPARE study are listed in Table
2. In summary two therapy zones are programmed, treating all rhythms of cycle length less than 330 ms that meet the duration criteria of 30 of 40 intervals. A single anti-tachycardia burst is provided for tachycardias between 330 and 240 ms. If the rhythm persists after ATP, a shock is provided. Rhythms faster than 240 ms receive shocks as the first therapy. A monitor zone is provided for tachycardia between 360 and 330 ms. Many SVT discriminators are programmed ON.
Table 2
PREPARE Study VT/VF Programming
INDUCTION
|
VF Detection | ON |
VFDI | 330 ms |
VF NID | 30/40 |
VF RNID | 9/12 |
DUAL CHAMBER
|
AF/AFl | ON |
Sinus Tachcardia | ON |
1:1 VT-ST Boundary | 66% |
Other 1:1 SVT | OFF |
SVT Limit | 300 |
Stability | OFF |
SINGLE CHAMBER
|
Wavelet | On, Match Threshold 70% |
Stability | 40 |
Onset | 88% |
ALL
|
VF Detection | ON |
VFDI | 330 ms |
VF NID | 30/40 |
VF RNID | 9/12 |
FVT | Via VF |
FVTDI | 240 ms |
VT Detection | Monitor |
VTDI | 360 ms |
VT NID | 32 |
HR Timeout | OFF |
VF Rx 1–6 Status | ON |
VF Rx 1–6 Energy | 30 or 35J maximum output of the ICD |
VF Rx 1–4 Pathway | AX->B |
VF Rx 5–6 Pathway | B->AX |
VF Confirmation | YES |
FVT Rx 1–6 Status | ON |
FVT Rx 1 Type | Burst |
FVT Rx 1 Initial # Pulses | 8 |
FVT Rx 1 R-S1 Interval | 88% |
FVT Rx 1 # sequence | 1 |
FVT Rx 1 Smart Mode | OFF |
FVT Rx 2–6 Type | CV |
FVT Rx 2–6 Energy | 30 to 35J maximum output of ICD |
FVT Rx 2–5 Pathway | AX->B |
FVT Rx 6 Pathway | B->AX |
VT Rx 1–6 | OFF |
Other Diagnostic and Therapy parameters | Nominals |
The tachycardia detection and therapy parameters for the MIRACLE ICD and EMPIRIC patients included in the control arm were chosen at the discretion of the investigators and are referred to as "physician-tailored" parameters. [
14]
Data collection
These data are collected at the 6 and 12 month scheduled visits and at unscheduled visits: cardiovascular adverse events, cardiovascular medications, VT/VF and SVT episodes, and patient diary.
Adverse events of syncope, near-syncope, and dizziness are collected between visits in a patient diary and evaluated for arrhythmogenic syncope, i.e. syncope or near syncope caused by a VT/VF or SVT episode, and symptomatic VT/VF events i.e. VT/VF events that result in the symptoms of near syncope or dizziness. All events in the PREPARE, EMPIRIC and MIRACLE ICD Trials will be adjudicated by the PREPARE Adverse Event Advisory Committee (AEAC) to identify arrhythmogenic syncope, near-syncope, and dizziness. The review includes the details surrounding each adverse event and the available EGM data for episodes occurring within 24 hours of the event. For the historical controls, where these adverse events were not as rigorously collected, the event will be adjudicated when the record indicated syncope, near-syncope, or dizziness in the narrative of an adverse event.
The differences in data collection methods between studies are always of concern when utilizing a historical control. There are two particular sources of bias when comparing the primary and key secondary endpoints in the PREPARE study to the historical control data: 1) adverse event collection and 2) incomplete adjudication of VT/VF episodes.
Patients in the PREPARE study are required to record adverse events of syncope, near-syncope, and dizziness in a patient diary, in an effort to increase the probability of collecting all occurrences of these events. By contrast, the MIRACLE ICD study relied on patient recall at study visits, and only system and procedure-related adverse events were collected in the EMPIRIC study. These methods of collection in the historical control group likely led to underreporting of syncope related events, and therefore decreased the probability of arrhythmogenic syncopal or symptomatic VT/VF event discovery during these studies. The expected consequence of this data limitation is that higher rates of arrhythmogenic syncope and symptomatic VT/VF events will be recorded in the PREPARE study.
Not all episodes in the MIRACLE ICD study were originally adjudicated for the spontaneous/induced and true VT/true SVT classifications. To avoid the bias that would be incurred by dropping these episodes with missing information, these will be reviewed and classified by an internal Medtronic VT/VF scientist prior to the completion of the PREPARE study.
Competing interests
1. In the past five years have you received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future?
Dr. Wilkoff: I am a consultant for Medtronic, St. Jude Medical and Guidant. Each of these companies manufactures ICDS.
Dr. Sterns: Medtronic Adverse Event Advisory Committee (AEAC), Medtronic
Lecturer
Dr. Williamson: Medtronic AEAC member
Dr. Wathen: Yes, Medtronic consultant
Holloman, Fieberg, Brown: Yes, salaried employees of Medtronic
2. Is such an organization financing this manuscript (including the article-processing charge)? If so, please specify.
Dr. Wilkoff, Dr. Stern, Dr. Williamson, Dr. Wathen: Holloman, Fieberg, Brown: Yes, Medtronic is paying for the processing fee of this article.
3. Do you hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future? If so, please specify.
Dr. Wilkoff, Dr. Stern, Dr. Williamson, Dr. Wathen: No
Holloman, Fieberg, Brown: Yes, own Medtronic stock
4. Do you hold or are you currently applying for any patents relating to the content of the manuscript?
Dr. Wilkoff, Dr. Stern, Dr. Williamson, Dr. Wathen: Holloman, Fieberg, Brown: No
5. Have you received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript? If so, please specify.
Dr. Wilkoff, Dr. Stern, Dr. Williamson, Dr. Wathen: Holloman, Fieberg, Brown: No
6. Do you have any other financial competing interests? If so, please specify.
Dr. Wilkoff, Dr. Stern, Dr. Williamson, Dr. Wathen: Holloman, Fieberg, Brown: No
Authors' contributions
BLW is Principle Investigator for the study described in the manuscript. BLW made significant contributions to study design, drafting, revising the manuscript, and provided final approval of version to be published. RS served on the AEAC for the study described in the manuscript, participated in revising the manuscript and review prior to final approval of version to be published. BW served on the AEAC for the study described in the manuscript and participated in revising the manuscript and review prior to final approval of version to be published. MW served on the AEAC for the study described in the manuscript, provided input into specific aspects of study design and participated in review of the manuscript and review prior to final approval of version to be published. KH participated in the design of the study described in the manuscript, acquisition, analysis and interpretation of data for the study, drafting and revising the manuscript, and participated in review of the final version to be published. AF performed statistical analysis, participated in modification to the study design, drafting and revising the manuscript, and participated in review of the final version to be published. MB participated in development of the study concept, revisions to the manuscript and review of the final version to be published.