Abstract
The AngelMed Guardian System is an implantable device similar to a single chamber pacemaker that continuously monitors the intracardiac electrogram for evidence of ST segment shift indicating acute coronary artery occlusion. The system aims to reduce time to presentation by alerting patients to present to a medical facility whether symptoms are present or not. In March 2016, the US Food and Drug Administration (FDA) assembled a meeting of the Circulatory System Devices Panel to review the results of the AngelMed for Early Recognition and Treatment of STEMI (ALERTS) pivotal trial and the accompanying premarket approval (PMA) application for regulatory approval of the AngelMed Guardian System in the US. In this review, we examine the ALERTS trial methodology and results, and describe the FDA panel’s deliberations and recommendations.
1
Introduction
The AngelMed Guardian System (Angel Medical Systems, Shrewsbury, New Jersey) aims to provide early alerts to patients suffering from coronary artery occlusion in order to prompt earlier presentation to a medical facility for therapy, even before symptoms are present. The system comprises three components: an implantable medical device akin to a single chamber pacemaker, an external device that the patient carries on their person, and a programmer that the physician uses to program and retrieve data from the implantable device ( Fig. 1 ). The implantable device analyzes ST segment shift, relative to the PQ segment, in real time on a beat-to-beat basis through a single active-fixation lead implanted in the right ventricular apex. Every 90 s, the implantable device acquires 10 s of electrogram data to serve as baseline. The patient’s personalized baseline electrogram is continuously updated based on the last 24 h of data. The device algorithm generates an emergency alert if it identifies ST change >3 SDs from the patient’s personalized baseline, during a normal heart rate and lasting >2 min. If ST shift is detected, the implantable device vibrates, and the external device flashes and sounds an auditory alarm prompting the patient to call 911. Other abnormalities, such as high heart rate, arrhythmia or artifact, trigger a less urgent “see your doctor” alert on the external device.
The AngelMed Guardian System already has regulatory approval in Europe. Angel Medical Systems submitted a premarket approval (PMA) application based on the results of the pivotal AngelMed for Early Recognition and Treatment of STEMI (ALERTS) trial . The US Food and Drug Administration (FDA) assembled a Circulatory System Devices Panel meeting on March 16, 2016 to review the results of the ALERTS trial and to consider the PMA application. The results of the ALERTS trial, the FDA analysis and the panel’s deliberations are presented herein.
2
Detection of coronary artery occlusion
Dr. Holmes, Mayo Clinic, Rochester, MN, introduced Angel Medical System’s presentation by describing the unmet need for earlier recognition of heart attack in order to prompt swifter presentation to a medical facility for treatment. More than one third of acute myocardial infarctions occur without chest pain . Silent myocardial infarction is most common in women, diabetics, and the elderly. At present, patients and physicians rely on symptoms to prompt presentation to a medical facility. Significant advances have been made in the last decade to reduce the door-to-balloon time for patients with acute myocardial infarction after presentation, but median time from symptoms to presentation at a medical facility remains in the order of 2–3 h. Attempts to address this delay with patient education have not shown significant benefit . The AngelMed Guardian aims to reduce the time to presentation by alerting the patient to ST segment shift even in the absence of symptoms.
Dr. Krucoff, Duke University School of Medicine, Durham, NC, described the rationale for continuous ST segment monitoring to detect sudden coronary occlusion. Preclinical studies in pigs demonstrated that rapid ST segment shift measured by intracardiac electrogram occurs rapidly after coronary artery occlusion . Clinical studies also confirmed that ST segment shift occurs rapidly (within 15 s) in humans following coronary balloon occlusion . Rapidly progressive ST segment changes are highly specific for acute coronary artery occlusion supplying viable myocardium. ST segment shift of ≥2 mm occurs on average 22 s after acute coronary artery occlusion in both men and women. The concept behind the AngelMed Guardian System is that early identification of ST changes caused by abrupt coronary occlusion could prompt early presentation for reperfusion therapy. Such a technology would be particularly useful in patients who do not experience the typical symptoms of chest pain.
2
Detection of coronary artery occlusion
Dr. Holmes, Mayo Clinic, Rochester, MN, introduced Angel Medical System’s presentation by describing the unmet need for earlier recognition of heart attack in order to prompt swifter presentation to a medical facility for treatment. More than one third of acute myocardial infarctions occur without chest pain . Silent myocardial infarction is most common in women, diabetics, and the elderly. At present, patients and physicians rely on symptoms to prompt presentation to a medical facility. Significant advances have been made in the last decade to reduce the door-to-balloon time for patients with acute myocardial infarction after presentation, but median time from symptoms to presentation at a medical facility remains in the order of 2–3 h. Attempts to address this delay with patient education have not shown significant benefit . The AngelMed Guardian aims to reduce the time to presentation by alerting the patient to ST segment shift even in the absence of symptoms.
Dr. Krucoff, Duke University School of Medicine, Durham, NC, described the rationale for continuous ST segment monitoring to detect sudden coronary occlusion. Preclinical studies in pigs demonstrated that rapid ST segment shift measured by intracardiac electrogram occurs rapidly after coronary artery occlusion . Clinical studies also confirmed that ST segment shift occurs rapidly (within 15 s) in humans following coronary balloon occlusion . Rapidly progressive ST segment changes are highly specific for acute coronary artery occlusion supplying viable myocardium. ST segment shift of ≥2 mm occurs on average 22 s after acute coronary artery occlusion in both men and women. The concept behind the AngelMed Guardian System is that early identification of ST changes caused by abrupt coronary occlusion could prompt early presentation for reperfusion therapy. Such a technology would be particularly useful in patients who do not experience the typical symptoms of chest pain.
3
The alerts trial: methodology and results
The pivotal ALERTS trial was designed to test safety and effectiveness but not sensitivity and specificity of the Guardian System. The primary safety endpoint was >90% complication-free rate at 6 months. The primary effectiveness endpoint was a composite 6-month endpoint of late arrival (time to presentation >2 h) for a confirmed acute coronary syndrome (ACS) event, new Q-waves at 6 months, and cardiac or unexplained death. The trial design was a Bayesian adaptive design used to adjust sample size based on interim treatment effect, with interim analysis planned every 300 patients after 600 patients randomized, up to maximum 3000 patients. The ALERTS trial enrolled high-risk patients with a history of coronary artery disease: 97% of patients had a history of reperfusion/revascularization, 24% had previous ST elevation myocardial infarction (STEMI), 27% had previous non-ST elevation myocardial infarction (NSTEMI), and 44% had a history of unstable angina ( Table 1 ). Mean Thrombolysis in Myocardial Infarction (TIMI) risk score was approximately 3.5% in both arms.
| Characteristic | Treatment group (n = 451) | Control group (n = 456) |
|---|---|---|
| Age (years) | 59 ± 11 | 60 ± 10 |
| Sex (female) | 30% | 34% |
| Ejection fraction (%) | 54 ± 9 | 54 ± 9 |
| Diabetes | 46% | 49% |
| History of smoking | 69% | 71% |
| History of reperfusion/revascularization | 98% | 97% |
| History of renal insufficiency | 16% | 18% |
| Previous STEMI | 24% | 25% |
| Previous NSTEMI | 28% | 28% |
| History of silent MI | 6% | 6% |
| History of unstable angina | 44% | 44% |
| TIMI risk score | 3.7 ± 1.0 | 3.6 ± 1.0 |
Angel Medical Systems did not believe that the predictive model accurately accounted for new Q-waves at 6 months and therefore could not predict the correct number of subjects to enroll. As a result, enrollment was stopped after 1020 patients enrolled, despite the interim analysis after 600 and 900 patients enrolled suggesting that enrollment should continue. Of the 1020 patients enrolled, 910 patients had the AngelMed Guardian implanted. 451 patients in the therapy arm had the device activated, and 456 patients had the device programmed to record but not to alert to serve as a control arm. The patients in the control arm had alerts activated after 6 months. Angel Medical Systems justified the 6-month study duration on the grounds that it would be difficult ethically to deny patients in the control arm the benefit of alerts beyond 6 months.
Dr. Gibson, Harvard Medical School, Boston, MA, presented the results of the ALERTS trial on behalf of Angel Medical Systems. The primary safety endpoint was >90% complication-free rate. 30 patients suffered a total of 31 complications, of which 11 had a device-related infection and 8 underwent system extraction ( Table 2 ). This corresponded to a complication-free rate of 96.7% with a posterior probability >0.9999, meaning the primary safety endpoint was met. There were 6 deaths in total, of which 4 patients died from cardiac or unexplained causes (3 in the therapy arm and 1 in the control arm). Interrogation of the AngelMed Guardian System after death revealed that all 4 had detected ST segment shift prior to death. Overall, serious adverse events at 6 months occurred in 1% of implanted patients. 60 ACS events in 45 patients occurred during the 6 months of follow-up. Cardiac enzymes, ECG (electrocardiogram), or angiography confirmed 94% of events. The trial permitted nuclear stress imaging as a confirmatory test in patients with negative cardiac enzymes, which differs from standard guidelines for the diagnosis of ACS. Angiographic features of ACS were total occlusion, thrombus, or plaque rupture with ulceration. Severe stenoses without these high-risk features were not counted as ACS events.
| Event type | n (%) |
|---|---|
| Infection | 11 (1.2) |
| Battery failures | 2 (0.2) |
| Pocket pain, protruding device | 9 (0.9) |
| Lead dislodgement, migration, malfunction | 6 (0.6) |
| Perforation | 2 (0.2) |
| Lead adaptor replacement | 1 (0.1) |
| Total | 31 (3.3) |
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