According to a randomized controlled trial led by Dr. Michael Gibson, PERFUSE Study Group, Beth Israel Deaconess Medical Center, Boston, Massachusetts, the implantable cardiac system was found to detect early ST-segment deviation and alert patients of a potential occlusive event. Although the trial did not meet its pre-specified primary efficacy endpoint, the report published in the Journal of the American College of Cardiology provided evidence that the device was beneficial among high-risk subjects in the identification of asymptomatic events.
Ischemic time is a major determinant of infarct size, especially in ST-elevation myocardial infarction (STEMI). The total ischemic time plays a pivotal role in salvaging ischemic myocardium and the duration of coronary occlusion has a direct relationship with irreversible cardiomyocyte injury. Since the majority of irreversible injury to the myocardium and fatal ventricular arrhythmias occur within the first hour, early treatment initiation within the first two hours post coronary occlusion is critical in the prevention of myocardial necrosis and other complications. Extending the period of acute myocardial ischemia for more than 20 minutes leads to cardiomyocyte death that begins in the sub-endocardium and extends transmurally towards the pericardium. Therefore, the timely restoration of perfusion in ST-segment elevation myocardial infarction is associated with improved left ventricular function and survival. Until recently, no intervention focused on symptom-to-door time, which can be difficult to measure in MI patients who experience atypical or no symptoms. Rapidly progressive ST-segment changes commonly develop prior to symptom onset and are detectable in silent MI. Therefore, an implantable monitoring device that alerts patients of ST-segment deviation could allow for the early recognition of MI. The AngelMed Guardian® system is a cardiac monitoring and alerting system designed for the early detection of intracardiac ST-segment changes among patients at high risk for MI. This report elaborated on the results of ALERTS (AngelMed for Early Recognition and Treatment of STEMI), a multicenter, randomized trial of an implantable cardiac monitor that could alert patients with rapidly progressive ST-segment deviation.
This multimodal alarm system called the AngelMed Guardian System consists of a battery-operated implantable medical device (IMD) comparable in size to a single chamber pacemaker that is inserted subcutaneously in the upper-left pectoral region and an external device that receives data from a standard steroid eluding pacemaker lead that proceeds through a cardiac vein and into the apex of the right ventricle. The IMD is connected to a programmer that the physician uses to configure and retrieve data from the implantable device. The IMD detects ST- segment shifts and other types of electrogram changes, such as changes in heart rate and rhythm. The IMD utilizes tactile (vibrations) alerts to warn the patient, whereas the external device provides auditory (beeps) and visual (red or yellow flashing indicator light) cues to alert the patient in case of an event. The results of two phase I studies CARDIOSAVER and DETECT reflected that a shift of 3 standard deviations (SD) from a patient’s normal daily ST-segment range on ambulatory intracardiac monitoring could be a sensitive/specific marker for plaque rupture and/or thrombotic coronary occlusion. Moreover, early warning and alerts were associated with a median alert-to-door time of 19.5 minutes for patients at high risk of recurrent coronary syndromes, who typically present with delays of 2 to 3 hours after symptom onset.
“The big take-home messages are that you had a lower false positive rate—that is when you have the alarm on you’re less likely to go into the ER with symptoms alone that cause an unnecessary visit. And then the other message is that there were 42 MIs that were detected where it was just the alarm, there were no symptoms, and that’s pretty powerful. In a certain way, we’re trying to get people to the ER and abort an MI or STEMI before that vessel permanently closes down. The future could mean less invasive, subcutaneous rather than implantable devices. Obviously, everything is moving toward a less and less invasive approach, and ultimately something wearable might be a possibility, things are evolving in a rapid way.”- Dr. C. Michael Gibson, M.D.
ALERTS was designed such that high-risk ACS subjects (N ¼ 907) were randomized to the control (alarms deactivated) or treatment group for 6 months, after which alarms were activated in all subjects. The primary safety endpoint was defined as the absence of system-related complications (>90%). The composite primary efficacy endpoint included cardiac/unexplained death, new Q-wave myocardial infarction, or detection to presentation time >2 h. According to the publication, safety was met with 96.7% freedom from system-related complications (n ¼ 30). A total of 30 subjects developed 31 complications. Device-related infections were observed in 11 patients, while 20 subjects had the implantable system removed. Of these 20, 11(1.2%) system extractions were due to infection, 3(0.3%) for persistent pain at the incision site, 2(0.2%) for erosion, 2(0.2%) for device malfunction, 1(0.1%) for perforation, and 1(0.1%) for cosmetic issues. On the other hand, the efficacy endpoint for a confirmed occlusive event within 7 days was not significantly reduced in the treatment compared with control group (16 of 423 [3.8%] vs. 21 of 428 [4.9%], posterior probability ¼ 0.786). The posterior probabilities for the 7-day and 30-day look-back windows were 0.7856 and 0.9177 respectively (which did not reach a statistically significant posterior probability at or above 0.975). Nevertheless, within a 90-day window, alarms significantly decreased detection to arrival time at a medical facility (51 min vs. 30.6 h; Pr [pt < pc] >0.999). In an expanded analysis using data after the randomized period, positive predictive value was higher (25.8% vs. 18.2%) and false positive rate significantly lower in the ALARMS ON group (0.164 vs. 0.678 false positives per patient-year; p < 0.001). The results showcased that the primary efficacy endpoint of cardiac or unexplained death, new Q-wave MI, and detection-to presentation time >2 h following a confirmed occlusive event within 7 days was numerically, but not statistically reduced among patients in the ALARMS ON treatment group. However, it was important to note that when the observation window was extended to 50, 70, and 90 days in a prespecified analysis to include the majority of confirmed occlusive events in the control group, and an exploratory dual baseline ECG analysis was used to reduce noise, a significant reduction in the primary endpoint was observed.
Highlighting an important feature in the study, Gibson et al. mentioned, “No prompt is currently available for patients experiencing an asymptomatic ACS event. Aggressive follow-up via device interrogation was needed among the control group to capture all silent MIs, which typically account for approximately 30% of all MIs and are historically associated with increased rates of morbidity and mortality. The rate of silent MI is even higher among certain populations, such as women, diabetic patients, and older patients. In this study, 42 silent ACS events were detected by an alert only (PPV of 20.0%). Further, alarming was associated with a reduction in the rate of new onset of LV dysfunction (LVEF <40%, an incidence of 33.3% vs. 4.0%) at discharge following a confirmed occlusive event. Although the duration of follow-up in this study was limited, a reduction in post-MI LV dysfunction of this magnitude may be associated with improved long-term outcomes. This is the first system to alert high-risk ACS subjects of a potential coronary occlusive event.” The authors emphasized that the system did not appear to cause excess utilization of resources or expose subjects to unneeded risk, as the FPR was reduced in subjects presenting due to alarms (with or without symptoms) compared with subjects presenting with symptoms alone. Additionally, the system did not appear to cause subjects to ignore symptoms in the absence of a confirmatory alarm, as 625 symptom-only presentations in ALARMS ON subjects were observed. Therefore, the Guardian system could be extremely useful in clinical practice through the detection of potential coronary occlusive events, thereby reducing time to treatment among ACS subjects deemed to be at high risk for a recurrent event.
Acknowledging the study limitations, it was noted by the investigators that there was an unanticipated low event rate. Second, no difference in hard clinical outcomes was observed between the treatment and control groups, such as cardiovascular or unexplained death. Third, there was an unexpected variation in the primary endpoint including the discrepancies in ECG tracings and the extended time between event detection and presentation. Notably, due to this variation, the primary efficacy endpoint was only met using the dual baseline ECG analysis and extending the look-back window to at least 50 days. However, even after taking all these facts into account, the large delay between event detection and presentation served to further highlight the need for a device such as the Guardian system, and all pre-specified results demonstrated a trend in favor of the system. The ALERTS Clinical Study demonstrated both safety and efficacy, as the risks were associated with the implantation of the IMD, none of which had any lasting morbidity. Through the reduction of the symptom-to-door time, the Guardian device provides a new ability for the early detection of a disease process bearing high morbidity and mortality, thereby influencing both individual patients and public health. Taking a step further from implanted devices, research on the use of subcutaneous devices or non-invasive devices performing the same function could be considered as the next step. Evidence from the REHEARSE-AF Study has showcased the ability of contact and contact-free devices including smartwatches and smartphone algorithms in the identification of arrhythmias and this arena requires further exploration.
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