Design and Rationale of the ANALYZE ST Study: A Prospective, NonRandomized, Multicenter ST Monitoring Study to Detect ACS Events in Implantable Cardioverter Defibrillator Patients C. Michael Gibson MS, MD, Mitchell Krucoff MD, M.D,.S.M. Ajay J. Kirtane, Sunil V. Rao MD, Judith A. Mackall MD, Ray Matthews MD, Samir Saba MD, Ron Waksman MD, David Holmes MD PII: DOI: Reference:
S0002-8703(14)00290-7 doi: 10.1016/j.ahj.2014.05.010 YMHJ 4629
To appear in:
American Heart Journal
Received date: Accepted date:
6 January 2014 28 May 2014
Please cite this article as: Michael Gibson C, Krucoff Mitchell, Ajay J. Kirtane MD,SM, Rao Sunil V., Mackall Judith A., Matthews Ray, Saba Samir, Waksman Ron, Holmes David, Design and Rationale of the ANALYZE ST Study: A Prospective, Non-Randomized, Multicenter ST Monitoring Study to Detect ACS Events in Implantable Cardioverter Defibrillator Patients, American Heart Journal (2014), doi: 10.1016/j.ahj.2014.05.010
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Design and Rationale of the ANALYZE ST Study: A Prospective, Non-
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Randomized, Multicenter ST Monitoring Study to Detect ACS Events in
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Implantable Cardioverter Defibrillator Patients
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C. Michael Gibson, M.S., M.D.a; Mitchell Krucoff, M.D.b; Ajay J. Kirtane, M.D., S.M.c; Sunil V. Rao, M.D.b; Judith A. Mackall, M.D.d; Ray Matthews, M.D.e; Samir Saba, M.D.f; Ron Waksman, M.D.g; David Holmes, M.D.h
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From a the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, b Duke Clinical Research Institute, Durham, North Carolina, c Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, d University Hospitals Case Medical Center, Cleveland, OH, e University of Southern California, Keck School of Medicine, Los Angeles, CA, f Cardiovascular Institute, University of Pittsburg Medical Center, Pittsburg, PA, g MedStar Washington Hospital Center, Washington, DC, h Mayo Clinic, Rochester, MN.
Address for correspondence: C. Michael Gibson, M.S., M.D. 185 Pilgrim Road, Deaconess 319 Boston, MA 02215 Email: [email protected] Phone: 617-632-7754 FAX: 617-632-7760
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ABSTRACT Background: In the setting of ST segment elevation myocardial infarction (STEMI), timely
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restoration of normal blood flow is associated with improved myocardial salvage and survival. Despite improvements in door-to-needle and door-to-balloon times, there remains an unmet need
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with respect to improved symptom-to-door times. A prior report of an implanted device to monitor ST segment deviation demonstrated very short times to reperfusion among patients with
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an acute coronary syndrome (ACS) with documented thrombotic occlusion. The goal of the
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ANALYZE ST study is to evaluate the safety and effectiveness of a novel ST segment monitoring feature using an existing implantable cardioverter defibrillator (ICD) among patients The ANALYZE ST study is a
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with known coronary artery disease (CAD). Methods:
prospective, non-randomized, multicenter, pivotal Investigational Device Exemption (IDE) study
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enrolling 5,228 patients with newly implanted ICD systems for standard clinical indications who
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also have a documented history of CAD. Patients will be monitored for 48 months, during which effectiveness of the device for the purpose of early detection of cardiac injury will be evaluated
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by analyzing the sensitivity of the ST Monitoring Feature to identify clinical acute coronary syndrome events. In addition, the safety of the ST Monitoring Feature will be evaluated through the assessment of the percentage of patients for which monitoring produces a false positive event over the course of 12 months. Conclusions: The ANALYZE ST trial is testing the hypothesis that the ST Monitoring Feature in the Fortify ST ICD system (or other ICD systems with the ST Monitoring Feature) will accurately identify patients with clinical acute coronary syndrome events.
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KEYWORDS Intracardiac Electrogram (IEGM), Acute Coronary Syndrome, Implantable Cardiac Defibrillator,
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ST Elevation MI, quantified self
ABBREVIATIONS
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ACS: Acute Coronary Syndrome
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ACC: American College of Cardiology
AMI: Acute Myocardial Infarction CAD: Coronary Artery Disease
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AECG: Ambulatory Electrocardiogram
EGM: Electrogram
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ECG: Electrocardiogram
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CVD: Cardiovascular Disease
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CEC: Clinical Events Committee
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EKG: Electrocardiogram
ESC: European Society of Cardiology FPR: False Positive Rate
ICD: Implantable Cardioverter Defibrillator IDE: Investigational Device Exemption IEGM: Intracardiac Electrogram IRB: Institutional Review Board MI: Myocardial Infarction PCI: Percutaneous Coronary Intervention
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STEMI: ST-segment Elevation Myocardial Infarction
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TIMI: Thrombolysis in Myocardial Infarction
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INTRODUCTION In the setting of ST segment elevation myocardial infarction, timely restoration of normal
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blood flow is associated with improved myocardial salvage.1 Over the past decade and a half,
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there have been improvements in door-to-needle and door-to-balloon times once a patient presents to the hospital. The potential for myocardial salvage is very time dependent and the
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window of opportunity is very short. Over 15 years, a 30 minute improvement in door-to-needle
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times resulted in a 1% improvement mortality, and a 30 minute improvement in door-to-balloon times contributed, at least in part, to a 5.3% improvement in mortality.2 Thus, very small
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changes in the time to reperfusion early on in the course of ST elevation MI, results in substantial improvements in mortality.3-8
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Recent data, however, have documented that despite dramatic improvements in door-to-
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needle and door-to-balloon times, mortality from MI has not decreased commensurately.9 This has been attributed to the fact that these measures – while effective at improving in-hospital
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reperfusion times – do little to affect the duration from symptom onset to arrival at medical care Despite campaigns to expand public awareness,
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facilities, which remains an unmet need.
average symptom-to-door delays range from 4.1 to 4.7 hours and median delays range from 2 to 2.2 hours.1, 10 The reasons for such delays in symptom-to-door times are numerous and varied, but patients often mistake ischemic symptoms for other medical conditions, such as for gastrointestinal disorders, and there may be a large psychological element of denial.11, 12 There is emerging interest in augmenting vague patient symptoms of ischemia with objective measures of ischemia to prompt the patient to seek emergency evaluation.
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effectiveness of a simple, implantable system resembling a ventricular pacemaker to monitor changes in ST segment shifts has been previously evaluated. Among 37 patients with a recent
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high-risk acute coronary syndrome, median symptom-to-door times were shortened to 19.5 minutes in patients with a documented thrombotic occlusion. During a median follow up period
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of 1.52 years, ST-segment changes ≥3 SDs were detected in 4 patients, while there were 2 false-
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positive ischemia alarms related to arrhythmias and 1 alarm due to a programming error that did not prompt catheterization.13
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Implantable high fidelity endocardial electrogram platforms have permanently fixed lead
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positions and very low noise levels, both of which constitute major advantages to surface ECG technology for continuous ST segment monitoring. By modifying the software of an existing
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implantable cardioverter defribillator (ICD), it is also possible to monitor ST segment deviation without any modification as to how the leads are implanted for clinical use. St. Jude Medical
An early observational study conducted in Europe using the
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a family of ICD systems.
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and Angel Medical Systems have collaborated to include a diagnostic ST Monitoring Feature in
AnalyST™ and Fortify ST ICD devices equipped with a ST Monitoring Feature enrolled a total
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of 1,121 patients and demonstrated that the device is safe to use in an ICD population, with no
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serious adverse events related to the feature over an average follow up period of 5.3 months (± 2.8 months).14 After a 2 month programming optimization run-in period, only 2.6% of the patients had false positive ST alarms.14 However, during this early post-implant follow up period, no ACS events were reported.14 A study with a longer follow up period in a higher risk population is needed to evaluate the efficacy of such a monitoring device. The goal of the ANALYZE ST study is to evaluate the safety and effectiveness of monitoring ST deviation using an existing ICD among patients with coronary artery disease (CAD).
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Study objectives In the ANALYZE ST study, patients with newly implanted ICD systems or ICD systems
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undergoing generator replacements that also have documented CAD are to be enrolled. After a
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run-in period of 3 months for algorithm optimization (i.e., at the Baseline visit as described later), ST thresholds are programmed, above which the Patient Notifier will be set to alert. The
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feature continuously monitors and stores ST segment deviations during intrinsic rhythm. When a
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rapidly progressive ST segment shift meets or exceeds the programmed detection threshold limit, the algorithm marks it as an ST episode and stores the date, time, heart rate, maximum ST shift,
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and duration of the event. Once the Patient Notifier is triggered by an ST episode detection, the patient will receive several vibratory alerts over a course of 30 hours. Specifically, the Patient
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Notifier delivers four sequences of vibratory alerts (each sequence being two 6-second alerts, 16
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seconds apart) that are 10 hours apart, the shortest waiting interval between sequences that can be programmed. The sequence of vibratory alerts (two 6-second alerts, 16 seconds apart) is
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generic for any alert condition and is not specific to ST episode alerts. Additionally, each patient
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will receive a Merlin@home transmitter and will be enrolled by the physician in the Merlin.net system, allowing for the automatic and direct transmission of baseline and peak ST deviation electrogram waveforms to a physician for review. The combination of patient notification and data transmission via Merlin@home to the physician allows for a robust mechanism to ensure that the vast majority of detected ST episodes by the algorithm are reviewed and addressed per study protocol. The primary objective of the study is to evaluate the safety and effectiveness of the ST Monitoring Feature in the Fortify ST, Fortify Assura ST, and Ellipse ST family of ICD systems (or other ICD systems with the ST Monitoring Feature). Effectiveness of the device will
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be evaluated by analyzing the sensitivity of the ST Monitoring Feature to detect clinical acute coronary syndrome (ACS) events as defined in the protocol in Appendix A and adjudicated by
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an independent Clinical Events Committee (CEC). In addition, the safety of the ST Monitoring
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Feature will be evaluated through the assessment of the percentage of patients that experience a false positive event over the course of 12 months and the number of false positive ST episodes
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that do not coincide with a clinical ACS event per patient-year of follow up.
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The ANALYZE ST study is supported by Saint Jude Medical. The authors are solely
of the paper and its final contents.
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responsible for the design and conduct of this study, all study analyses, the drafting and editing
Study population and patient selection
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The ANALYZE ST study is a prospective, non-randomized, multicenter, pivotal IDE
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study evaluating the Fortify ST ICD system (or other ICD systems with the ST Monitoring Feature). The study intends to include patients with the potential to have ACS events, not
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specifically those who have previously had an ACS event. Device settings are optimized for
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each individual patient’s electrogram (EGM) range of ST levels associated with changes in heart rate. Sustained and progressive deviations beyond the personalized thresholds are programmed as ST episode trigger levels. Optimization of these thresholds is determined by assessment of ST event detection and algorithm programming during an initial 3 month run-in period after initial implantation of a generator with this software feature. In patients whose EGM rhythm or morphology is determined to be unsuitable for chronic ST segment monitoring at the end of the run-in period, the feature is turned off at the Baseline visit and patients are followed for safety. Subjects must be >18 years of age at the time of enrollment in the study. Inclusion criteria are shown in Table 1. Patients should meet the following criteria: (1) have an indication
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for ICD implantation or pulse generator change, (2) have documented coronary artery disease, (3) willing and able to comply with protocol requirements, including participating in all required
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visits, (4) willing to participate in the study and able to sign an Institutional Review Board (IRB)
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approved informed consent form, and (5) willing to and capable of using Merlin@home. A minimum percent stenosis was not included in the definition of documented coronary artery
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disease. With a follow up period extending past 2 years for the majority of patients, excluding
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patients based on a percent stenosis would eliminate otherwise viable study candidates that could contribute meaningful clinical events.
Follow up and treatment protocol
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Patients will be excluded if they meet any of the exclusion criteria listed in Table 2.
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The study will be conducted at up to 200 investigational centers located in the United
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States. These centers will be selected for participation in the study based upon their ability to screen and enroll eligible patients, and perform the required study procedures. It is anticipated
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that 25-30% of centers will be University-based teaching hospitals. To ensure a widespread
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distribution of data and minimize site bias, no more than 15% of the total enrollment will be allowed at any single site. The duration of the study is expected to be approximately 48 months, which will consist of approximately 36 months of enrollment and 12 months of follow up. Patients will be seen at a Programming visit at 1 month post-enrollment when suggested ST thresholds are programmed for the first time, a Baseline visit at 4 months post-enrollment when the ST data is reviewed after the run-in period and algorithm optimization, a 6 month postBaseline visit, a 12 month post-Baseline visit, and every 6 months thereafter until the study is completed.
The patient’s ability to feel the Patient Notifer alert is ascertained at either
Programming or Baseline, prior to the notifier for an ST Episode being turned on. The ST
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Feature will be turned off and the patient followed for safety only if the patient is unable to feel the vibratory notification test during the Programming/BL visits.
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Patients who do not already have a Merlin@home transmitter will receive one at the
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Programming visit and will be enrolled by the physician in the Merlin.net system. For patients who already have a Merlin@home transmitter, the patient’s new device will be paired at the
This system allows the patient’s device to transmit ST data automatically to
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collection.
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clinic during the Programming visit and the Merlin.net system will be updated to include ST data
Merlin.net for physician review upon detection of an ST episode. This automatic transmission of
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data occurs during the night usually while the patient is sleeping (between 2 AM and 4 AM). Since the Merlin.net system is not designed to be an emergency alerting system, the primary
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method of notification of an ST episode is the Patient Notifier. However, the investigator can set
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up alerts to be sent via text, email or phone for ST episodes either for immediate receipt or notification only during regular business hours. Investigators are required to check Merlin.net
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daily (preferable before noon) for new ST episode alerts. Patients and sites will be provided
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written and verbal instructions on how to respond to an alert received via the Patient Notifier or Merlin.net and what to do in the event that they experience symptoms that could be indicative of an ACS event regardless of receiving a vibratory alert. The instructions provided to patients and sites are summarized in Table 3. Patients are also provided a wallet card with written instructions that they are required to carry for the duration of their study participation. Primary and secondary endpoints The primary efficacy endpoint is the sensitivity of the ST Monitoring Feature to detect clinical ACS events. Sensitivity of the ST Monitoring Feature is defined as the number of clinical ACS events that are related to ST episodes divided by the total number of true clinical
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ACS events. A clinical ACS event is considered to be related to the onset of ST episode if the onset of the clinical ACS event occurs within 72 hours after the onset of ST episode. The pre-
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specified hypothesis is that the sensitivity of the ST Monitoring Feature to detect clinical events
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is greater than 50%.15, 16
The primary safety endpoint is the percentage of patients that experience a false positive
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event in 12 months. The percentage of patients with false positive events is calculated as the
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number of patients who experience at least one false positive divided by the number of evaluable patients. A false positive occurs when the onset of a clinical ACS event does not occur within 72
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hours following an ST episode. The pre-specified hypothesis is that the percent of patients who experience false positive events is less than 15%.17-19
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The secondary safety endpoint is the False Positive Rate (FPR). The FPR is the number
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of false positive ST episodes that do not coincide with a clinical ACS event per patient-year of follow up. Only ST segment episodes that occur following the Baseline visit will be included in
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less than 1.9 events.
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this analysis. The pre-specified hypothesis is that the False Positive Rate per year of follow up is
A clinical ACS event is defined any of the following: death due to MI, a new Q-wave MI on a 12 lead ECG, STEMI, biomarker evidence of acute myocardial damage, evidence of new plaque rupture by invasive testing (i.e., IVUS) as adjudicated by the blinded CEC, TIMI myocardial perfusion grade 0 or 1 consistent with acute injury of the myocardium from embolization, new surface ECG St depression or elevation treated with thrombolytic medication, new surface ECG ST depression or elevation with new or progressive flow-limiting ischemia, flow-limiting angiographic stenosis ≥70%, or an event leading to clinically warranted PCI or revascularization as determined by the blinded CEC.
Clinically warranted PCI or
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revascularization was defined as angiographically visualized stenosis ≥70% correlating with the vascular distribution in which a 12-lead surface ECG documents changes consistent with
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ischemia or injury in 2 or more contiguous leads, angiographically visualized stenosis ≥70%
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correlating with a vascular distribution shown to have ongoing ischemia by non-invasive stress testing or myocardial perfusion study, OR new or progressive angiographically visualized
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stenosis ≥70% correlated with new or progressive angina symptoms.
Statistical considerations
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The total number of patients required for enrollment to satisfy both primary and secondary endpoints is determined by the sample size required to ascertain the primary efficacy
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endpoint. The study is powered for sensitivity of the ST Monitoring Feature to detect clinical
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ACS events. The total sample size required for the study is 5,228 patients. Testing assumptions used to carry out the sample size calculation are found in Appendix B. Under these assumptions,
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the subjects to be enrolled in the ANALYZE ST IDE Study are similar to those enrolled in the
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St. Jude Medical Alternans Before Cardioverter Defibrillator Trial (ABCD Trial, IDE G010050); therefore, the expected event rate for this study population is similar to that of the ABCD Trial which had an event rate of less than 0.01 per patient-year (Appendix B).20 With a sample of 5,228 patients, evaluating 41 events would provide 80% power to reject the null hypothesis at a 2.5% significance level to demonstrate a sensitivity of the ST Monitoring Feature of >50%. This is conservatively assuming an attrition rate of 20% from other causes such as death, withdrawal, and lost to follow up. Subsequently, for the purpose of submitting a marketing application to the FDA, data collection will be considered complete when 41 primary endpoint events have occurred as per CEC adjudication. Following clinical data submission, patient follow up will
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continue until study close in order to provide long-term follow up on the family of ICD systems with the ST Monitoring Feature.
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All enrolled patients who have a successful implant or system revision, who have
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completed the Baseline follow up visit, and have the ST Monitoring Feature and Patient Notifier turned on will be included in the evaluation of study endpoints. Data collection towards study
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endpoints will begin after the Baseline visit. The analysis population for all endpoints will be
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subjects with the Fortify® ST (upgraded), Fortify Assura® ST, and Ellipse® ST devices. Data from subjects with Fortify® ST prior to being upgraded will not be used towards analysis.
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The primary safety endpoint will reject the null hypothesis at a 2.5% significance level if the upper bound of the 95% confidence interval for the percent of patient experience false
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positives is less than 15%. The 97.5% upper confidence bound for the expected FPR will be
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calculated based on the confidence interval calculation of a Poisson rate using the exact method. The null hypothesis will be rejected at the 2.5% significance level if the 97.5% upper confidence
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bound is less than 1.9 per patient-year.
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In order to ensure that no patient contributes disproportionately to the numerator of the FPR, safety data will be captured under the assumption that if a patient experiences more than two false positives, then only the first two false positives of that patient will be included in the analysis. For any patient with more than two false positives, the follow up time will be truncated to the date of the second false positive. Efficacy data will be summarized for all true clinical ACS events using the Wilson score interval method for a binomial proportion at the 95% lower confidence bound. Data will be further summarized by additional subgroups as detailed in Appendix B. The null hypothesis will be rejected if the lower confidence bound of 95% lower confidence limit is greater than 50%.
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Preliminary Safety Assessment A preliminary safety analysis to assess the proportion of patients free from complications
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due to unnecessary procedures resulting from false positive events will be conducted on the first
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500 patients to complete 6 months of follow up. This analysis will include all patients with the Patient Notifier turned on at the Baseline visit or the Baseline Upgrade visit and who have
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completed their 6-month follow up visit or 6 months of follow up since being upgraded. A
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Kaplan-Meier estimate of freedom from complications will be provided with a 95% confidence interval calculated using standard errors from Greenwood’s formula. Results of the preliminary
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safety assessment phase will be submitted to the FDA to support the IDE supplement requesting expansion of the study to the full 200 sites and 5,228 patients.
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Conclusion
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The ANALYZE ST study will enroll subjects with newly implanted ICD systems for standard ICD indications or those undergoing generator replacements who have documented
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coronary artery disease. This prospective, non-randomized, multicenter, pivotal IDE study is
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sufficiently powered to demonstrate the safety and efficacy of the ST Monitoring Feature in the Fortify ST, Fortify Assura ST, and Ellipse ST family of ICD systems to detect clinical ACS events. Additional clinical endpoints will evaluate and demonstrate the percentage of false positive events of this feature.
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Table I. Inclusion Criteria Subjects must meet all inclusion criteria to be enrolled in the study:
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1. Have an indication for an ICD implantation or pulse generator change; 2. Have documented coronary artery disease. Documented coronary artery disease is defined as having at least one of the following present: a) evidence of a prior MI on ECG and/or cardiac enzymes; b) prior revascularization (by coronary artery bypass grafting or percutaneous coronary intervention); c) angina and/or ST-T wave abnormalities indicative of ischemia on exercise stress test, nuclear stress test, or echo stress test; d) coronary artery disease diagnosed by coronary angiography. 3. Willing and able to comply with protocol requirements, including keeping all required visits; 4. Willing to participate in the study and able to sign an IRB approved informed consent form; 5. Willing to and capable of using Merlin@home; 6. Be at least 18 years of age when enrolled in the study.
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ICD=Implantable Cardioverter Defibrillator; MI=Myocardial Infarction; ECG=Electrocardiogram; IRB=Institutional Review Board
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Table II. Exclusion Criteria Potential subjects will be excluded from the study if any of the following apply:
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Are pacemaker dependent (defined as a need for ventricular pacing ≥ 20% of the time); Have NYHA Class IV Heart Failure; Have persistent or permanent atrial fibrillation; Have a known history of intermittent Bundle Branch Block; Pregnant or planning a pregnancy during the study participation; Have a life expectancy of < 1 year due to any condition; Are currently participating in a clinical investigation that includes an active arm.
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NYHA=New York Heart Association
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Table III. Instruction Matrix for Patients and Sites
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No alert received
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Patient should contact study physician to receive instructions on where to go for assessment (in-clinic or ED) Physician is to attempt to contact patient with instructions to either come into the clinic or go to the ED for assessment.
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Patient should immediately seek medical attention at the nearest emergency department.
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Alert received via Merlin.net for Type I ST episode
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Alert received via Patient Notifier for Type I ST episode
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Symptoms potentially indicative of ACS are absent No action required.
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Symptoms potentially indicative of ACS are present Patient should immediately seek medical attention at the nearest emergency department. Patient should immediately seek medical attention at the nearest emergency department.
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S0002-8703(14)00290-7 doi: 10.1016/j.ahj.2014.05.010 YMHJ 4629
To appear in:
American Heart Journal
Received date: Accepted date:
6 January 2014 28 May 2014
Please cite this article as: Michael Gibson C, Krucoff Mitchell, Ajay J. Kirtane MD,SM, Rao Sunil V., Mackall Judith A., Matthews Ray, Saba Samir, Waksman Ron, Holmes David, Design and Rationale of the ANALYZE ST Study: A Prospective, Non-Randomized, Multicenter ST Monitoring Study to Detect ACS Events in Implantable Cardioverter Defibrillator Patients, American Heart Journal (2014), doi: 10.1016/j.ahj.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Design and Rationale of the ANALYZE ST Study: A Prospective, Non-
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Randomized, Multicenter ST Monitoring Study to Detect ACS Events in
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Implantable Cardioverter Defibrillator Patients
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C. Michael Gibson, M.S., M.D.a; Mitchell Krucoff, M.D.b; Ajay J. Kirtane, M.D., S.M.c; Sunil V. Rao, M.D.b; Judith A. Mackall, M.D.d; Ray Matthews, M.D.e; Samir Saba, M.D.f; Ron Waksman, M.D.g; David Holmes, M.D.h
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From a the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, b Duke Clinical Research Institute, Durham, North Carolina, c Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, d University Hospitals Case Medical Center, Cleveland, OH, e University of Southern California, Keck School of Medicine, Los Angeles, CA, f Cardiovascular Institute, University of Pittsburg Medical Center, Pittsburg, PA, g MedStar Washington Hospital Center, Washington, DC, h Mayo Clinic, Rochester, MN.
Address for correspondence: C. Michael Gibson, M.S., M.D. 185 Pilgrim Road, Deaconess 319 Boston, MA 02215 Email: [email protected] Phone: 617-632-7754 FAX: 617-632-7760
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ABSTRACT Background: In the setting of ST segment elevation myocardial infarction (STEMI), timely
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restoration of normal blood flow is associated with improved myocardial salvage and survival. Despite improvements in door-to-needle and door-to-balloon times, there remains an unmet need
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with respect to improved symptom-to-door times. A prior report of an implanted device to monitor ST segment deviation demonstrated very short times to reperfusion among patients with
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an acute coronary syndrome (ACS) with documented thrombotic occlusion. The goal of the
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ANALYZE ST study is to evaluate the safety and effectiveness of a novel ST segment monitoring feature using an existing implantable cardioverter defibrillator (ICD) among patients The ANALYZE ST study is a
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with known coronary artery disease (CAD). Methods:
prospective, non-randomized, multicenter, pivotal Investigational Device Exemption (IDE) study
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enrolling 5,228 patients with newly implanted ICD systems for standard clinical indications who
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also have a documented history of CAD. Patients will be monitored for 48 months, during which effectiveness of the device for the purpose of early detection of cardiac injury will be evaluated
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by analyzing the sensitivity of the ST Monitoring Feature to identify clinical acute coronary syndrome events. In addition, the safety of the ST Monitoring Feature will be evaluated through the assessment of the percentage of patients for which monitoring produces a false positive event over the course of 12 months. Conclusions: The ANALYZE ST trial is testing the hypothesis that the ST Monitoring Feature in the Fortify ST ICD system (or other ICD systems with the ST Monitoring Feature) will accurately identify patients with clinical acute coronary syndrome events.
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KEYWORDS Intracardiac Electrogram (IEGM), Acute Coronary Syndrome, Implantable Cardiac Defibrillator,
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ST Elevation MI, quantified self
ABBREVIATIONS
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ACS: Acute Coronary Syndrome
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ACC: American College of Cardiology
AMI: Acute Myocardial Infarction CAD: Coronary Artery Disease
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AECG: Ambulatory Electrocardiogram
EGM: Electrogram
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ECG: Electrocardiogram
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CVD: Cardiovascular Disease
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CEC: Clinical Events Committee
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EKG: Electrocardiogram
ESC: European Society of Cardiology FPR: False Positive Rate
ICD: Implantable Cardioverter Defibrillator IDE: Investigational Device Exemption IEGM: Intracardiac Electrogram IRB: Institutional Review Board MI: Myocardial Infarction PCI: Percutaneous Coronary Intervention
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STEMI: ST-segment Elevation Myocardial Infarction
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TIMI: Thrombolysis in Myocardial Infarction
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INTRODUCTION In the setting of ST segment elevation myocardial infarction, timely restoration of normal
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blood flow is associated with improved myocardial salvage.1 Over the past decade and a half,
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there have been improvements in door-to-needle and door-to-balloon times once a patient presents to the hospital. The potential for myocardial salvage is very time dependent and the
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window of opportunity is very short. Over 15 years, a 30 minute improvement in door-to-needle
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times resulted in a 1% improvement mortality, and a 30 minute improvement in door-to-balloon times contributed, at least in part, to a 5.3% improvement in mortality.2 Thus, very small
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changes in the time to reperfusion early on in the course of ST elevation MI, results in substantial improvements in mortality.3-8
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Recent data, however, have documented that despite dramatic improvements in door-to-
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needle and door-to-balloon times, mortality from MI has not decreased commensurately.9 This has been attributed to the fact that these measures – while effective at improving in-hospital
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reperfusion times – do little to affect the duration from symptom onset to arrival at medical care Despite campaigns to expand public awareness,
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facilities, which remains an unmet need.
average symptom-to-door delays range from 4.1 to 4.7 hours and median delays range from 2 to 2.2 hours.1, 10 The reasons for such delays in symptom-to-door times are numerous and varied, but patients often mistake ischemic symptoms for other medical conditions, such as for gastrointestinal disorders, and there may be a large psychological element of denial.11, 12 There is emerging interest in augmenting vague patient symptoms of ischemia with objective measures of ischemia to prompt the patient to seek emergency evaluation.
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effectiveness of a simple, implantable system resembling a ventricular pacemaker to monitor changes in ST segment shifts has been previously evaluated. Among 37 patients with a recent
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high-risk acute coronary syndrome, median symptom-to-door times were shortened to 19.5 minutes in patients with a documented thrombotic occlusion. During a median follow up period
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of 1.52 years, ST-segment changes ≥3 SDs were detected in 4 patients, while there were 2 false-
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positive ischemia alarms related to arrhythmias and 1 alarm due to a programming error that did not prompt catheterization.13
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Implantable high fidelity endocardial electrogram platforms have permanently fixed lead
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positions and very low noise levels, both of which constitute major advantages to surface ECG technology for continuous ST segment monitoring. By modifying the software of an existing
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implantable cardioverter defribillator (ICD), it is also possible to monitor ST segment deviation without any modification as to how the leads are implanted for clinical use. St. Jude Medical
An early observational study conducted in Europe using the
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a family of ICD systems.
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and Angel Medical Systems have collaborated to include a diagnostic ST Monitoring Feature in
AnalyST™ and Fortify ST ICD devices equipped with a ST Monitoring Feature enrolled a total
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of 1,121 patients and demonstrated that the device is safe to use in an ICD population, with no
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serious adverse events related to the feature over an average follow up period of 5.3 months (± 2.8 months).14 After a 2 month programming optimization run-in period, only 2.6% of the patients had false positive ST alarms.14 However, during this early post-implant follow up period, no ACS events were reported.14 A study with a longer follow up period in a higher risk population is needed to evaluate the efficacy of such a monitoring device. The goal of the ANALYZE ST study is to evaluate the safety and effectiveness of monitoring ST deviation using an existing ICD among patients with coronary artery disease (CAD).
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Study objectives In the ANALYZE ST study, patients with newly implanted ICD systems or ICD systems
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undergoing generator replacements that also have documented CAD are to be enrolled. After a
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run-in period of 3 months for algorithm optimization (i.e., at the Baseline visit as described later), ST thresholds are programmed, above which the Patient Notifier will be set to alert. The
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feature continuously monitors and stores ST segment deviations during intrinsic rhythm. When a
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rapidly progressive ST segment shift meets or exceeds the programmed detection threshold limit, the algorithm marks it as an ST episode and stores the date, time, heart rate, maximum ST shift,
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and duration of the event. Once the Patient Notifier is triggered by an ST episode detection, the patient will receive several vibratory alerts over a course of 30 hours. Specifically, the Patient
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Notifier delivers four sequences of vibratory alerts (each sequence being two 6-second alerts, 16
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seconds apart) that are 10 hours apart, the shortest waiting interval between sequences that can be programmed. The sequence of vibratory alerts (two 6-second alerts, 16 seconds apart) is
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generic for any alert condition and is not specific to ST episode alerts. Additionally, each patient
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will receive a Merlin@home transmitter and will be enrolled by the physician in the Merlin.net system, allowing for the automatic and direct transmission of baseline and peak ST deviation electrogram waveforms to a physician for review. The combination of patient notification and data transmission via Merlin@home to the physician allows for a robust mechanism to ensure that the vast majority of detected ST episodes by the algorithm are reviewed and addressed per study protocol. The primary objective of the study is to evaluate the safety and effectiveness of the ST Monitoring Feature in the Fortify ST, Fortify Assura ST, and Ellipse ST family of ICD systems (or other ICD systems with the ST Monitoring Feature). Effectiveness of the device will
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be evaluated by analyzing the sensitivity of the ST Monitoring Feature to detect clinical acute coronary syndrome (ACS) events as defined in the protocol in Appendix A and adjudicated by
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an independent Clinical Events Committee (CEC). In addition, the safety of the ST Monitoring
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Feature will be evaluated through the assessment of the percentage of patients that experience a false positive event over the course of 12 months and the number of false positive ST episodes
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that do not coincide with a clinical ACS event per patient-year of follow up.
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The ANALYZE ST study is supported by Saint Jude Medical. The authors are solely
of the paper and its final contents.
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responsible for the design and conduct of this study, all study analyses, the drafting and editing
Study population and patient selection
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The ANALYZE ST study is a prospective, non-randomized, multicenter, pivotal IDE
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study evaluating the Fortify ST ICD system (or other ICD systems with the ST Monitoring Feature). The study intends to include patients with the potential to have ACS events, not
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specifically those who have previously had an ACS event. Device settings are optimized for
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each individual patient’s electrogram (EGM) range of ST levels associated with changes in heart rate. Sustained and progressive deviations beyond the personalized thresholds are programmed as ST episode trigger levels. Optimization of these thresholds is determined by assessment of ST event detection and algorithm programming during an initial 3 month run-in period after initial implantation of a generator with this software feature. In patients whose EGM rhythm or morphology is determined to be unsuitable for chronic ST segment monitoring at the end of the run-in period, the feature is turned off at the Baseline visit and patients are followed for safety. Subjects must be >18 years of age at the time of enrollment in the study. Inclusion criteria are shown in Table 1. Patients should meet the following criteria: (1) have an indication
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for ICD implantation or pulse generator change, (2) have documented coronary artery disease, (3) willing and able to comply with protocol requirements, including participating in all required
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visits, (4) willing to participate in the study and able to sign an Institutional Review Board (IRB)
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approved informed consent form, and (5) willing to and capable of using Merlin@home. A minimum percent stenosis was not included in the definition of documented coronary artery
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disease. With a follow up period extending past 2 years for the majority of patients, excluding
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patients based on a percent stenosis would eliminate otherwise viable study candidates that could contribute meaningful clinical events.
Follow up and treatment protocol
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Patients will be excluded if they meet any of the exclusion criteria listed in Table 2.
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The study will be conducted at up to 200 investigational centers located in the United
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States. These centers will be selected for participation in the study based upon their ability to screen and enroll eligible patients, and perform the required study procedures. It is anticipated
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that 25-30% of centers will be University-based teaching hospitals. To ensure a widespread
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distribution of data and minimize site bias, no more than 15% of the total enrollment will be allowed at any single site. The duration of the study is expected to be approximately 48 months, which will consist of approximately 36 months of enrollment and 12 months of follow up. Patients will be seen at a Programming visit at 1 month post-enrollment when suggested ST thresholds are programmed for the first time, a Baseline visit at 4 months post-enrollment when the ST data is reviewed after the run-in period and algorithm optimization, a 6 month postBaseline visit, a 12 month post-Baseline visit, and every 6 months thereafter until the study is completed.
The patient’s ability to feel the Patient Notifer alert is ascertained at either
Programming or Baseline, prior to the notifier for an ST Episode being turned on. The ST
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Feature will be turned off and the patient followed for safety only if the patient is unable to feel the vibratory notification test during the Programming/BL visits.
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Patients who do not already have a Merlin@home transmitter will receive one at the
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Programming visit and will be enrolled by the physician in the Merlin.net system. For patients who already have a Merlin@home transmitter, the patient’s new device will be paired at the
This system allows the patient’s device to transmit ST data automatically to
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collection.
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clinic during the Programming visit and the Merlin.net system will be updated to include ST data
Merlin.net for physician review upon detection of an ST episode. This automatic transmission of
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data occurs during the night usually while the patient is sleeping (between 2 AM and 4 AM). Since the Merlin.net system is not designed to be an emergency alerting system, the primary
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method of notification of an ST episode is the Patient Notifier. However, the investigator can set
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up alerts to be sent via text, email or phone for ST episodes either for immediate receipt or notification only during regular business hours. Investigators are required to check Merlin.net
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daily (preferable before noon) for new ST episode alerts. Patients and sites will be provided
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written and verbal instructions on how to respond to an alert received via the Patient Notifier or Merlin.net and what to do in the event that they experience symptoms that could be indicative of an ACS event regardless of receiving a vibratory alert. The instructions provided to patients and sites are summarized in Table 3. Patients are also provided a wallet card with written instructions that they are required to carry for the duration of their study participation. Primary and secondary endpoints The primary efficacy endpoint is the sensitivity of the ST Monitoring Feature to detect clinical ACS events. Sensitivity of the ST Monitoring Feature is defined as the number of clinical ACS events that are related to ST episodes divided by the total number of true clinical
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ACS events. A clinical ACS event is considered to be related to the onset of ST episode if the onset of the clinical ACS event occurs within 72 hours after the onset of ST episode. The pre-
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specified hypothesis is that the sensitivity of the ST Monitoring Feature to detect clinical events
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is greater than 50%.15, 16
The primary safety endpoint is the percentage of patients that experience a false positive
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event in 12 months. The percentage of patients with false positive events is calculated as the
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number of patients who experience at least one false positive divided by the number of evaluable patients. A false positive occurs when the onset of a clinical ACS event does not occur within 72
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hours following an ST episode. The pre-specified hypothesis is that the percent of patients who experience false positive events is less than 15%.17-19
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The secondary safety endpoint is the False Positive Rate (FPR). The FPR is the number
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of false positive ST episodes that do not coincide with a clinical ACS event per patient-year of follow up. Only ST segment episodes that occur following the Baseline visit will be included in
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less than 1.9 events.
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this analysis. The pre-specified hypothesis is that the False Positive Rate per year of follow up is
A clinical ACS event is defined any of the following: death due to MI, a new Q-wave MI on a 12 lead ECG, STEMI, biomarker evidence of acute myocardial damage, evidence of new plaque rupture by invasive testing (i.e., IVUS) as adjudicated by the blinded CEC, TIMI myocardial perfusion grade 0 or 1 consistent with acute injury of the myocardium from embolization, new surface ECG St depression or elevation treated with thrombolytic medication, new surface ECG ST depression or elevation with new or progressive flow-limiting ischemia, flow-limiting angiographic stenosis ≥70%, or an event leading to clinically warranted PCI or revascularization as determined by the blinded CEC.
Clinically warranted PCI or
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revascularization was defined as angiographically visualized stenosis ≥70% correlating with the vascular distribution in which a 12-lead surface ECG documents changes consistent with
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ischemia or injury in 2 or more contiguous leads, angiographically visualized stenosis ≥70%
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correlating with a vascular distribution shown to have ongoing ischemia by non-invasive stress testing or myocardial perfusion study, OR new or progressive angiographically visualized
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stenosis ≥70% correlated with new or progressive angina symptoms.
Statistical considerations
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The total number of patients required for enrollment to satisfy both primary and secondary endpoints is determined by the sample size required to ascertain the primary efficacy
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endpoint. The study is powered for sensitivity of the ST Monitoring Feature to detect clinical
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ACS events. The total sample size required for the study is 5,228 patients. Testing assumptions used to carry out the sample size calculation are found in Appendix B. Under these assumptions,
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the subjects to be enrolled in the ANALYZE ST IDE Study are similar to those enrolled in the
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St. Jude Medical Alternans Before Cardioverter Defibrillator Trial (ABCD Trial, IDE G010050); therefore, the expected event rate for this study population is similar to that of the ABCD Trial which had an event rate of less than 0.01 per patient-year (Appendix B).20 With a sample of 5,228 patients, evaluating 41 events would provide 80% power to reject the null hypothesis at a 2.5% significance level to demonstrate a sensitivity of the ST Monitoring Feature of >50%. This is conservatively assuming an attrition rate of 20% from other causes such as death, withdrawal, and lost to follow up. Subsequently, for the purpose of submitting a marketing application to the FDA, data collection will be considered complete when 41 primary endpoint events have occurred as per CEC adjudication. Following clinical data submission, patient follow up will
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continue until study close in order to provide long-term follow up on the family of ICD systems with the ST Monitoring Feature.
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All enrolled patients who have a successful implant or system revision, who have
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completed the Baseline follow up visit, and have the ST Monitoring Feature and Patient Notifier turned on will be included in the evaluation of study endpoints. Data collection towards study
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endpoints will begin after the Baseline visit. The analysis population for all endpoints will be
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subjects with the Fortify® ST (upgraded), Fortify Assura® ST, and Ellipse® ST devices. Data from subjects with Fortify® ST prior to being upgraded will not be used towards analysis.
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The primary safety endpoint will reject the null hypothesis at a 2.5% significance level if the upper bound of the 95% confidence interval for the percent of patient experience false
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positives is less than 15%. The 97.5% upper confidence bound for the expected FPR will be
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calculated based on the confidence interval calculation of a Poisson rate using the exact method. The null hypothesis will be rejected at the 2.5% significance level if the 97.5% upper confidence
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bound is less than 1.9 per patient-year.
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In order to ensure that no patient contributes disproportionately to the numerator of the FPR, safety data will be captured under the assumption that if a patient experiences more than two false positives, then only the first two false positives of that patient will be included in the analysis. For any patient with more than two false positives, the follow up time will be truncated to the date of the second false positive. Efficacy data will be summarized for all true clinical ACS events using the Wilson score interval method for a binomial proportion at the 95% lower confidence bound. Data will be further summarized by additional subgroups as detailed in Appendix B. The null hypothesis will be rejected if the lower confidence bound of 95% lower confidence limit is greater than 50%.
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Preliminary Safety Assessment A preliminary safety analysis to assess the proportion of patients free from complications
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due to unnecessary procedures resulting from false positive events will be conducted on the first
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500 patients to complete 6 months of follow up. This analysis will include all patients with the Patient Notifier turned on at the Baseline visit or the Baseline Upgrade visit and who have
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completed their 6-month follow up visit or 6 months of follow up since being upgraded. A
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Kaplan-Meier estimate of freedom from complications will be provided with a 95% confidence interval calculated using standard errors from Greenwood’s formula. Results of the preliminary
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safety assessment phase will be submitted to the FDA to support the IDE supplement requesting expansion of the study to the full 200 sites and 5,228 patients.
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Conclusion
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The ANALYZE ST study will enroll subjects with newly implanted ICD systems for standard ICD indications or those undergoing generator replacements who have documented
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coronary artery disease. This prospective, non-randomized, multicenter, pivotal IDE study is
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sufficiently powered to demonstrate the safety and efficacy of the ST Monitoring Feature in the Fortify ST, Fortify Assura ST, and Ellipse ST family of ICD systems to detect clinical ACS events. Additional clinical endpoints will evaluate and demonstrate the percentage of false positive events of this feature.
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Table I. Inclusion Criteria Subjects must meet all inclusion criteria to be enrolled in the study:
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1. Have an indication for an ICD implantation or pulse generator change; 2. Have documented coronary artery disease. Documented coronary artery disease is defined as having at least one of the following present: a) evidence of a prior MI on ECG and/or cardiac enzymes; b) prior revascularization (by coronary artery bypass grafting or percutaneous coronary intervention); c) angina and/or ST-T wave abnormalities indicative of ischemia on exercise stress test, nuclear stress test, or echo stress test; d) coronary artery disease diagnosed by coronary angiography. 3. Willing and able to comply with protocol requirements, including keeping all required visits; 4. Willing to participate in the study and able to sign an IRB approved informed consent form; 5. Willing to and capable of using Merlin@home; 6. Be at least 18 years of age when enrolled in the study.
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ICD=Implantable Cardioverter Defibrillator; MI=Myocardial Infarction; ECG=Electrocardiogram; IRB=Institutional Review Board
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Table II. Exclusion Criteria Potential subjects will be excluded from the study if any of the following apply:
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Are pacemaker dependent (defined as a need for ventricular pacing ≥ 20% of the time); Have NYHA Class IV Heart Failure; Have persistent or permanent atrial fibrillation; Have a known history of intermittent Bundle Branch Block; Pregnant or planning a pregnancy during the study participation; Have a life expectancy of < 1 year due to any condition; Are currently participating in a clinical investigation that includes an active arm.
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NYHA=New York Heart Association
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Table III. Instruction Matrix for Patients and Sites
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No alert received
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Patient should contact study physician to receive instructions on where to go for assessment (in-clinic or ED) Physician is to attempt to contact patient with instructions to either come into the clinic or go to the ED for assessment.
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Patient should immediately seek medical attention at the nearest emergency department.
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Alert received via Merlin.net for Type I ST episode
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Alert received via Patient Notifier for Type I ST episode
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Symptoms potentially indicative of ACS are absent No action required.
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Symptoms potentially indicative of ACS are present Patient should immediately seek medical attention at the nearest emergency department. Patient should immediately seek medical attention at the nearest emergency department.
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