AngelMed for Early Recognition and Treatment of STEMI (ALERTS)

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.

Study Overview

• Status: Completed
• Conditions: Acute Coronary Syndrome; Coronary Occlusion; Acute Myocardial Infarction (AMI)
• Intervention / Treatment: Device: Guardian System

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1020
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Cardiology, P.C.
    • Huntsville, Alabama, United States, 35801
      • Heart Center Research/Huntsville Hospital
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Banner Heart Hospital
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center
    • Tucson, Arizona, United States, 85710
      • Southwest Heart Group
  • California
    • Concord, California, United States, 94520
      • John Muir Clinical Research Center
    • Glendale, California, United States, 91204
      • California Clinical Research Foundation
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Mission Viejo, California, United States, 92691
      • Mission Internal Medical Group
    • Orange, California, United States, 92868
      • Orange County Heart Institute and Research Center Hospital
    • Pasadena, California, United States, 91105
      • Huntington Memorial Hospital
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • Sacramento, California, United States, 95819
      • Sutter Memorial Hospital
    • Salinas, California, United States, 93901
      • Salinas Valley Memorial Hospital
    • Santa Rosa, California, United States, 95405
      • Radiant Research
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Bay Pines, Florida, United States, 33744
      • Bay Pines VA Healthcare System
    • Daytona Beach, Florida, United States, 32114
      • Daytona Heart Group
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Gainesville, Florida, United States, 32608
      • NorthFL/South GA VA Health System
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33133
      • Mercy Research Institute
    • Miami Beach, Florida, United States, 33140
      • New Phase Clinical Trials
    • New Smyrna Beach, Florida, United States, 32169
      • Complete Cardiology Care
    • Saint Augustine, Florida, United States, 32086
      • East Coast Institute for Research
    • Tampa, Florida, United States, 33606
      • Univeristy of South Florida
    • Tampa, Florida, United States, 33613
      • Florida Hospital - Pepin Heart Institute
  • Georgia
    • Macon, Georgia, United States, 31201-2102
      • The Medical Center of Central Georgia
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Park Ridge, Illinois, United States, 60068
      • Advocate Medical Group
  • Indiana
    • Bloomington, Indiana, United States, 47403
      • Premier Healthcare
    • Fort Wayne, Indiana, United States, 46804
      • Northern Indiana Research Alliance
    • Merrillville, Indiana, United States, 46410
      • Heart Center of Lake County
    • Muncie, Indiana, United States, 47303
      • Medical Consultants, Pc
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Central Baptist Hospital
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Innovative Medical Research
    • Hammond, Louisiana, United States, 70403
      • Heart Clinic of Hammond
    • Slidell, Louisiana, United States, 70433
      • Louisiana Heart Center
  • Maryland
    • Baltimore, Maryland, United States, 21239
      • MedStar Health Research Institute
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
    • Bethesda, Maryland, United States, 20814
      • Suburban Hospital - Johns Hopkins Medicine
    • Pikesville, Maryland, United States, 21208
      • Woodholme Cardiovacular Associates
    • Takoma Park, Maryland, United States, 20912
      • Washington Adventist Hospital
  • Michigan
    • Bay City, Michigan, United States, 48708
      • McLaren Bay Region
    • Detroit, Michigan, United States, 48201
      • DMC Cardiovascular Institute at Harper-Hutzel Hospital
    • Farmington Hills, Michigan, United States, 48334
      • Detroit Clinical Research Center
    • Flint, Michigan, United States, 48532
      • Cardiology Consultants of East Michigan
    • Grand Blanc, Michigan, United States, 48439
      • Genesys Regional Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Medical Center
    • Lansing, Michigan, United States, 48912
      • Sparrow Clinical Research Institute
    • Mount Clemens, Michigan, United States, 48043
      • McLaren Macomb
    • Petoskey, Michigan, United States, 49770
      • Cardiac & Vascular Research Center of Northern Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Neptune, New Jersey, United States, 07754
      • Jersey Shore University Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • University of Medicine & Dentistry NJ
    • Newark, New Jersey, United States, 07102
      • St. Michael's Medical Center
    • Voorhees, New Jersey, United States, 08043
      • Lourdes Cardiology Services
  • New York
    • Albany, New York, United States, 12205
      • Albany Associates in Cardiology
    • Brooklyn, New York, United States, 11203
      • SUNY downstate Medical Center
    • Buffalo, New York, United States, 14215
      • Buffalo Heart Group - Mercy Hospital of Buffalo
    • Buffalo, New York, United States, 14215
      • Buffalo Heart Group - Millard Fillmore Gates Circle Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Williamsville, New York, United States, 14221
      • Cardiology Group of Western New York
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Rex Healthcare
  • Ohio
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Toledo, Ohio, United States, 43614
      • University of Toledo
    • Toledo, Ohio, United States, 43608
      • Cardiovascular Research Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73135
      • South Oklahoma Heart Research
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Lancaster, Pennsylvania, United States, 17602
      • Lancaster General Hospital
    • Langhorne, Pennsylvania, United States, 19047
      • St. Mary Medical Center Research Institute
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny-Singer Research Institute
    • Sayre, Pennsylvania, United States, 18840
      • Donald Guthrie Foundation for Education & Research
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Wyoming Valley Heart Hospital
    • York, Pennsylvania, United States, 17405
      • Cardiac Diagnostic Associates/York Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital System
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Stern Cardiovascular Center
    • Knoxville, Tennessee, United States, 37934
      • Turkey Creek Medical Center
    • Nashville, Tennessee, United States, 37203
      • St. Thomas Research Institute
  • Texas
    • Amarillo, Texas, United States, 79106
      • Cardiology Center of Amarillo
    • Houston, Texas, United States, 77094
      • West Houston Area Clinical Trial Consultants
    • Houston, Texas, United States, 77008
      • West Houston Area Clinical Trial Consultants
    • Temple, Texas, United States, 76502
      • Scott and White Healthcare
    • Tyler, Texas, United States, 75701
      • Tyler Cardiovascular Consultants
  • Virginia
    • Fredericksburg, Virginia, United States, 22408
      • Cardiology Associates of Fredericksburg
    • Manassas, Virginia, United States, 20109
      • Virginia Cardiovascular Associates
    • Newport News, Virginia, United States, 23601
      • Riverside Regional Medical Center
    • Norfolk, Virginia, United States, 23507
      • Sentara Cardiovascular Research Institute
    • Virginia Beach, Virginia, United States, 23462
      • Cardiovascular Associates, Ltd
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center/Cardiovascular Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has at least one of the following conditions:

  1. Diabetes (Type I or Type II)
  2. Compromised renal function (Cr > 1.2 mg/dl or creatinine clearance less than 50)
  3. 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:

  1. Post-menopause or amenorrheic during the past year
  2. Surgical sterilization
  3. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; 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; There is no intervention in this study. The device is a diagnostic only.
Other: Control; 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; There is no intervention in this study. The device is a diagnostic only.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Angel Medical Systems
• Collaborators: Symbios Clinical

Publications and helpful links

General Publications

• Holmes DR Jr, Krucoff MW, Mullin C, Mikdadi G, Presser D, Wohns D, Kaplan A, Ciuffo A, Eberly AL 3rd, Iteld B, Fischell DR, Fischell T, Keenan D, John MS, Gibson CM. Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events. J Am Coll Cardiol. 2019 Oct 22;74(16):2047-2055. doi: 10.1016/j.jacc.2019.07.084.
• Gibson CM, Holmes D, Mikdadi G, Presser D, Wohns D, Yee MK, Kaplan A, Ciuffo A, Eberly AL 3rd, Iteld B, Krucoff MW. Implantable Cardiac Alert System for Early Recognition of ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol. 2019 Apr 23;73(15):1919-1927. doi: 10.1016/j.jacc.2019.01.014. Epub 2019 Mar 3.
• Rogers T, Steinvil A, Torguson R, Waksman R. Overview of the 2016 US Food and Drug Administration Circulatory System Devices Panel Meeting on the AngelMed Guardian System. Circulation. 2016 Jul 19;134(3):262-4. doi: 10.1161/CIRCULATIONAHA.116.023081. No abstract available.
• Gibson MC, Krucoff M, Fischell D, Fischell TA, Keenan D, Abueg C, Patel C, Holmes D. Rationale and design of the AngeLmed for Early Recognition and Treatment of STEMI trial: a randomized, prospective clinical investigation. Am Heart J. 2014 Aug;168(2):168-74. doi: 10.1016/j.ahj.2014.05.008. Epub 2014 May 24.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2008
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 17, 2017

Study Registration Dates

• First Submitted: October 24, 2008
• First Submitted That Met QC Criteria: October 27, 2008
• First Posted (Estimate): October 28, 2008

Study Record Updates

• Last Update Posted (Actual): March 14, 2018
• Last Update Submitted That Met QC Criteria: March 9, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Acute Coronary Syndrome; Coronary Occlusion; Acute Myocardial Infarction (MI); ST Shift
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease; Myocardial Infarction; Infarction; Acute Coronary Syndrome; Coronary Occlusion
• Other Study ID Numbers: ALERTS Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: When we have completed review with the FDA, the IPD will will be made available.