AngelMed for Early Recognition and Treatment of STEMI

Study Overview
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Brief Summary
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A prospective, randomized multicenter study of subjects with a high-risk of having a myocardial infarction (MI) due to acute coronary syndrome or bypass surgery. There is no differential intervention administered to the two arms of the ALERTS Study. The study evaluates whether or not a patient alarm from the Guardian System will provide benefit (e.g. shorten pre-hospital delay) compared to symptoms-only ER presentation in the event of a heart attack. An amendment to the data analysis protocol was collaboratively created by AngelMed and FDA, and was adopted by AngelMed on 4/22/2017.

Detailed Description
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There are over one million acute myocardial infarctions (AMI) each year in the United States with more than 400,000 of these resulting in death. Early identification of AMI, and prompt treatment has been shown to significantly improve clinical outcomes. Experimental and clinical studies have shown that most of the irreversible damage to the myocardium occurs during the first two hours after coronary occlusion. Milavetz et al. demonstrated that successful reperfusion therapy within two hours was associated with the greatest degree of myocardial salvage. According to Boersma, et al., restoration of flow, regardless of the method used, can abort infarction within the first 30 minutes after coronary occlusion, and the benefit of fibrinolytic therapy compared with placebo is considerably higher in patients treated within 2 hours after symptom onset than in those treated later.2 Further, evidence exists that expeditious restoration of flow in the obstructed infarct artery after the onset of symptoms in patients with the most severe type of MI, ST elevation MI (STEMI) is a key determinant of short and long-term outcomes regardless of whether reperfusion is accomplished by fibrinolysis or percutaneous coronary intervention (PCI). Therefore, the early arrival at the hospital for a reliable diagnosis and initiation of treatment is paramount to improve the outcomes of myocardial infarction. However, despite efforts at educating the public over the past decade, the mean time from AMI symptom onset to arrival at a hospital for treatment has remained, disappointingly, at 2.5-3.0 hours. The largest proportion of the total pre-hospital delay is the interval between the onset of symptoms and the decision to seek medical treatment. Finnegan et al. described that the reasons for delay in seeking medical evaluation generally stem from patient misconceptions about symptom experience, expectations, and attribution. In many cases, patients expect the type of heart attack that they often see in movies or on television: the kind of crushing chest pain that drops a person to the ground. The reality is that many heart attacks are much quieter, causing only mild chest pain or discomfort or other symptoms such as shortness of breath or diaphoresis. If patients would take action during the first hour following symptom onset, many lives and significant cost could be saved. It is technically possible to monitor EKGs and detect an acute infarction, even if the patient is unaware that he or she is experiencing a heart attack. However, currently available systems have limitations in the home environment. Twelve lead EKG systems require a clinically trained individual to place them. Holter monitors suffer from limitations in the ability to detect ST deviation due to low compliance and are limited in practice to 24 to 72 hours of monitoring. Systems using surface leads are all subject to noise and other artifacts from patient movement and body orientation, particularly if the patient is ambulatory. A potentially ideal solution is to implant a device that measures heart signals from inside the heart and will alert the patient when it detects electrogram characteristics set by the physician as worthy of medical evaluation.

Official Title
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AngelMed for Early Recognition and Treatment of STEMI

Conditions
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Acute Myocardial Infarction (AMI), Coronary Occlusion, Acute Coronary Syndrome

Intervention / Treatment
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* Device: Guardian System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has at least one of the following conditions: Diabetes (Type I or Type II) Compromised renal function (Cr > 1.2 mg/dl or creatinine clearance less than 50) TIMI Risk Score ≥ 3 Presents (within past 6 months) with a high-risk acute coronary syndrome (e.g., Unstable Angina, STEMI or NSTEMI) or has undergone or is scheduled for CABG within 6 months of implantation. Has already undergone coronary angiography and revascularization, unless the physician determines it is appropriate to implant before or during the planned procedure. Lives in a geographic area in close proximity (within 60 minutes by EMS) to any hospital that can treat AMI. Subjects (men or women) at least 21 years of age. Women of childbearing age must have a negative pregnancy test or confirmation of one of the following: Post-menopause or amenorrheic during the past year Surgical sterilization Use of effective contraceptive method Exclusion Criteria: In the investigator's opinion, subject lacks ability to respond appropriately to alarms, e.g., illiteracy, poor memory or cognitive function, dementia or other condition affecting memory function, etc. There is known compromised tissue at the site of lead implantation in the apex of the right ventricle, e.g., prior infarct affecting the RV apex location. A permanent pacemaker or ICD is already in place or the patient is indicated for ICD or pacemaker implantation based on the guidelines published by the American College of Cardiology as Class I and IIa recommendations. Class IIb recommendations are at the investigator's discretion. Subject cannot feel the IMD vibration when placed on top of the skin on the left pectoral side of the chest. Subject has recurrent or persistent atrial fibrillation. Subject has recurrent or persistent non-sinus cardiac rhythm, second or third degree atrioventricular blocks, QRS duration greater than 120 ms, Benign Early Repolarization (BER), or Brugada Syndrome. Subject has left ventricular hypertrophy evidenced by EKG criteria. Subject has any condition preventing the subcutaneous implantation of the Guardian System in a left pectoral pouch, such as: superior vena cava thrombosis, subcutaneous tissue deemed inappropriate for the procedure or prior central venous access via portacath, Hickman, Groshong, or similar placed in a left pectoral location or left side PICC line. Subject has extremely heavy alcohol consumption (participates in binge drinking that leads to alcohol intoxication) or has history of alcohol or illicit drug abuse within past 5 years. There is evidence of unresolved infection (fever > 38° C and/or leukocytosis > 15,000). Subject has history of bleeding disorders or severe coagulopathy (platelets < 100,000 plts/ml; APTT or PT > 1.3 x reference range). Subject has had a hemorrhagic stroke or transient ischemic attack (TIA) in the past 6 months. Subject has other severe diseases, such as cancer or refractory congestive heart failure, associated with limitation of life expectancy (less than 1 year), which may lead to inadequate compliance to the protocol or confusing data interpretation. Subject has clinical conditions such as heart diseases, difficult-to-control blood pressure, difficult-to-control insulin-dependent diabetes or serious prior infections attributed to the diabetes, or others that, at the investigator's discretion, could seriously affect the subject's current clinical condition during study procedures. Subject has previous participation in the DETECT Study, current participation or previous participation in another drug or device study in the past 30 days that conflicts with this study as determined by the study sponsor. Subject has experienced gastro-intestinal hemorrhage in the past 6 months. Subject has any situation in which the use of aspirin is contraindicated for at least 6 months. Subject has epilepsy. Subject has known severe allergies, e.g., peanut, bee sting, etc.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>The Treatment arm has alerting enabled in their device during the 6-month randomization period. Treatment arm patients also have alerting enabled in the post-randomization period. Once a patient arrives at the ER, the standard of care triage process for MI is followed and that is outside of the ALERTS Study protocol. With Amendment the Treatment arm was re-defined as an ALARMS_ON group which included A) Control patients after the randomization period and until database lock (4/1/2014); and, b) Treatment patients both during the randomization period and after the randomization period until database lock (4/1/2014). | Device: Guardian System<br>* There is no intervention in this study. The device is a diagnostic only.<br>|
| Other: Control<br>The Control arm has alerting disabled in their device during the 6-month randomization period. Control arm patients also have alerting enabled in the post-randomization period. Once a patient arrives at the ER, the standard of care triage process for MI is followed and that is outside of the ALERTS Study protocol. With Amendment the Control arm was re-defined as an ALARMS_OFF group which included A) Control patients during the randomization period when the Guardian did not have alarms enabled. | Device: Guardian System<br>* There is no intervention in this study. The device is a diagnostic only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary efficacy objective is to determine that the Guardian System reduces the composite of Cardiac or unexplained death, new Q-wave MI and time to door for a confirmed occlusive event at a medical facility >2 hours. | With Amendment the primary efficacy objective was amended to be a co-primary endpoint which included A) a hypothesis test of superiority for positive predictive value of ER visits in the ALARMS_ON group due to Guardian alerting (with or without concurrent symptoms) compared to ER visits in the ALARMS_OFF group due to symptoms only; AND B) a hypothesis test of non-inferiority for rate of false positive ER visits in the ALARMS_ON group due to Guardian alerting (with or without concurrent symptoms) compared to rate of false positive ER visits in the ALARMS_OFF group due to symptoms only. | Due to Bayesian statistical analysis, the study data will be analyzed after subject enrollment reaches 600, 900, 1200, etc. With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Reduction of the incidence of cardiac death or unexplained death during follow-up - Reduction of the incidence of New Q-wave myocardial infarction in one or more distributions during follow-up- Reduction of the time to door for confirmed STEMI. | With Amendment the secondary efficacy endpoint measures were amended to include Endpoint #1) a hypothesis test of superiority for rate of false positive ER visits in the ALARMS_ON group due to Guardian alerting (with or without concurrent symptoms) compared to rate of false positive ER visits in the ALARMS_OFF group due to symptoms only. | Due to Bayesian statistical analysis, the study data will be analyzed after subject enrollment reaches 600, 900, 1200, etc With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 
| Secondary Endpoint #2 | With Amendment the secondary efficacy endpoint measures were amended to include Endpoint #2) The number of Silent MIs, the percentage in relation to total MIs in the ALARMS ON group, and the percentage of subjects experiencing Silent MIs will be reported (no hypotheses existed for this endpoint) | With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 
| Secondary Endpoint #3 | With Amendment the secondary efficacy endpoint measures were amended to include Endpoint #3) Descriptive statistics for the median, average and distribution of symptom-to-door and alarm-to-door times for STEMI events and the number and percentage of subjects with time-to-door times of < 2 hours will be reported for both the ALARMS ON and ALARMS OFF groups (no hypotheses existed for this endpoint). | With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 
| Secondary Endpoint #4 | With Amendment the secondary efficacy endpoint measures were amended to include Endpoint #4) The time that elapses between the initial patient prompt (alarm or symptom) and arrival at a medical facility will be calculated for all subjects who suffered a STEMI or NSTEMI, and had an associated Guardian alarm (no hypotheses existed for this endpoint). | With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 
| Secondary Endpoint #5 | With Amendment the secondary efficacy endpoint measures were amended to include Endpoint #5: The time that elapses between the initial patient prompt (Alarm or Symptom) and arrival at a medical facility will be calculated for all subjects who suffered an ACS event (STEMI, NSTEMI, or Unstable Angina), and had an associated Guardian System alarm (with or without symptoms) (no hypotheses existed for this endpoint). | With amendment the study period spanned from December 2008 until database lock April 1, 2014. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myocardial Infarction (MI), ST Shift, Coronary Occlusion, Acute Coronary Syndrome