ALERTS: Implantable STEMI Detector Trial Misses Primary End Point

Batya Swift Yasgur MA, LSW

April 09, 2019

The AngelMed Guardian implantable cardiac monitor (Angel Medical Systems) designed to alert high-risk acute coronary syndrome (ACS) patients that they are having a myocardial infarction (MI) failed to meet its primary efficacy end point, study results show.

The AngelMed for Early Recognition and Treatment of STEMI (ALERTS) trial randomized patients who had high-risk ACS or coronary artery bypass grafting during the 6 months preceding device implantation to receive either activated or inactivated alerts (ALARMS ON and ALARMS OFF, respectively) from the device.

Both groups had the same 7-day rates of cardiac or unexplained death, new Q-wave MI, and detection-to-presentation time over 2 hours, the composite primary efficacy end point, regardless of whether the device was actually activated.

On the other hand, safety was demonstrated with 97% freedom from system-related complications.

Moreover, an expanded analysis showed that devices did reduce the rate of false-positive situations and identified a substantial number of silent MIs.

The study was terminated early because of discrepancies in the ECG tracings that affected the primary end point.

"Overall, the implantable cardiac system was safe and the rate of complications was low. However, the ALERTS trial failed to meet the prespecified primary efficacy end point of the randomized trial," write lead author C. Michael Gibson, MS, MD, and colleagues from the PERFUSE Group.

"Nonetheless, in an expanded analysis including data both during and after the randomized portion of the trial, the PPV [positive predictive value] was higher and the FPR [false-positive rate] was lower among the ALARMS ON group," suggesting that "the system may be beneficial in the identification of symptomatic and asymptomatic occlusive coronary events among high-risk ACS subjects," the authors write.

"Greater experience with this technology could facilitate systematic methods to translate early detection of acute ischemic events into improvement in left ventricular function and long-term clinical outcomes," they conclude.

The data were presented at CRT 2019 and published online March 3 in the Journal of the American College of Cardiology.

Early Marker

"Rapidly progressive ST-segment changes in the absence of an increased heart rate represent supply-related ischemia and are an early marker of cute coronary artery occlusion," the authors write.

These changes associated with MI can precede symptom onset and occur even among asymptomatic patients, leading to interest in an implantable monitoring device (IMD) that alerts patients of rapid, progressive ST-segment changes, they state.

The AngelMed Guardian implantable cardiac monitor was approved by the US Food and Drug Administration (FDA) in 2018 for use in patients with a history of ACS who remain at high risk for recurrent events, based on the ALERTS study.

In March 2016, the FDA's Circulatory Systems Devices Panel had voted against approval, concluding that the benefits did not outweigh the risks.

The ALERTS study was a "randomized, prospective clinical trial evaluating the safety and efficacy of the system in the early detection and alerting of rapidly progressive ST-segment shifts potentially indicative of ACS events."

All high-risk patients (older than 21 years; n = 907) received the implantable system.

At 7 to 14 days, they were randomized 1:1 to either the control group (n = 456), in which the alert was inactivated (ALARMS OFF) or to the treatment group (n = 451), in which the alert was activated (ALARMS ON).

Patients were required to present within 6 months of a high-risk ACS or multivessel coronary artery bypass graft surgery. Enrollment required at least one additional criterion, including diabetes mellitus, renal insufficiency, or a Thrombolysis In Myocardial Infarction (TIMI) risk score of at least 3.

The IMD, which is implanted under the skin in the left pectoral region and connected to a right ventricular apical pacemaker lead, captures and stores electrogram data, rapidly detecting progressive ST-segment shifts. If a shift is detected, the device alerts the patient to seek medical attention.

The device saves data from up to 24 hours before to 8 hours after a triggered alarm, which can be retrieved for review. For this trial, the device detected events and collected cardiac data, even in the control group, where the alert was inactivated.

After randomization, participants were followed at 1, 3, and 6 months, and then every 6 months, after which the control patients had the alerting feature activated and were given an external alerting device.

End Point Definitions

"Late arrival" was defined as detection-to-door time of more than 2 hours for a confirmed occlusive event.

In the control group, the device was interrogated for event detection and detection-to-door times were calculated during the 7 days prior to hospital presentation (a 7-day "look-back" period).

In an exploratory analysis, a 90-day interval was selected to detect silent ACS events.

The primary safety end point was the absence of system-related complications that required a system revision or invasive intervention to resolve in at least 90% of subjects through the 6-month follow-up.

The primary efficacy end point for the randomized period was a composite end point of:

  • cardiac or unexplained death

  • new Q-wave MI

  • detection-to-presentation time of more than 2 hours for a documented coronary occlusion event.

Cardiac death was defined as "a death directly related to the electrical or mechanical dysfunction of the heart."

To define Q-wave MI, the researchers used a "dual baseline" ECG analysis requiring that the presence of new Q waves be persistent from baseline across subsequent ECGs.

Secondary efficacy end points included the individual components of the primary composite end point, as well as:

  • time from detection to presentation

  • incidence of any MI (Q-wave plus non-Q-wave MI) and incidence of new plaque rupture

  • significant disease progression, determined by the angiographic core laboratory.

A coprimary end point included superiority for PPV and noninferiority for FPR, and was prespecified prior to analysis.

The primary safety end point was met with 96.7% freedom (posterior probability >0.999).

There were 31 system-related complications in 30 (3.3%) patients, with infections as the predominant cause of complications.

In total, 20 patients had the implantable system removed: 11 (1.2%) for infection; three (0.3%) for persistent pain at the incision site; two (0.2%) for erosion; two (0.2%) for device malfunction; one (0.1%) for perforation; and one (0.1%) for cosmetic issues.

Notably there was no permanent morbidity or disability from any system-related complications.

The occurrence of an ACS event was described as "low."

Improved Time-to-Door Arrival

When the prespecified single baseline ECG and the 7-day look-back period was applied, the incidence of the primary composite end point did not differ between the control and the treatment groups (4.9% vs 3.8%; posterior probability = .786).

The primary composite efficacy end point with multiple look-back windows by single baseline ECG and dual baseline ECG in the control vs the treatment group was 4.7% vs 3.1% (posterior probability = .8833).

Although no significant reductions using the additional look-back windows were observed, the difference trended toward significance at 90 days (6.8% vs 3.8%; Pr [pt<pc] = .974).

When the researchers applied a nonprespecified analysis using dual baseline ECGs for assessment, they found a significant reduction in the primary composite end point for the 50-day, 70-day, and 90-day look-back windows.

Moreover, when they used the prespecified 7-day look-back window, they found that the median time from IMD detection to arrival at a medical facility was 51 minutes for treatment subjects, compared with 30.6 hours for control subjects (Pr [pt<pc] > .999).

Arrival within 2 hours of a detected and confirmed coronary occlusion occurred in 85% of the treatment group but only 5% of the control group, with the majority of control patients presenting after 7 days.

The posterior probability of superiority did not reach statistical significance, although there was a numerical reduction in new Q-wave MI, using single and dual baseline ECGs at prespecified look-back windows — results that remained consistent among a subset of patients at higher risk for a silent MI.

Left ventricular ejection fraction (LVEF) was assessed among subjects with a confirmed occlusive event and was found to be significantly higher in the treatment group than in the control group.

Fewer False Positives

Through the entire follow-up period, PPV in the ALARMS ON group for alerts with or without symptoms was 25.8%, compared with a PPV of 18.2% for symptoms in the ALARMS OFF group.

A total of 42 silent MIs were detected in the ALARMS ON group (PPV, 20.0%), which would not have otherwise been detected in the ALARMS OFF group.

Additionally, the FPR was significantly lower in the ALARMS ON (with or without symptoms) than in the ALARMS OFF group (0.164 vs 0.678 false positives per patient-year; < .001).

The authors emphasize that the overall false positive for all ALARMS ON emergency visits was 0.499 per patient-year (< .001), demonstrating a 26% reduction compared with ALARMS OFF.

They note that this is "the first system to alert high-risk ACS subjects of a potential coronary occlusive event."

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," they continue.

The Guardian system may therefore "be useful in clinical practice in detecting potential coronary occlusive events and in reducing time to treatment among ACS subjects deemed to be at high risk for a recurrent event," they conclude.

Back to the Drawing Board

Commenting on the study for theheart.org | Medscape Cardiology, Frederick Welt, MD, Margaret Amundsen Professor of Cardiology and vice chair of clinical affairs, Department of Medicine, University of Utah Health Science Center, Salt Lake City, said that the device "expands on a lot of technologies that are being introduced to remotely monitor patients and try to prevent rehospitalization or get people timely care when an issue comes up."

On the other hand, "as the authors say, it's a failed study and they didn't meet their primary efficacy end point, so everything has to be taken with a little bit of a grain of salt," continued Welt, who is also associate chief, Division of Cardiovascular Medicine and Director, Cardiac Catheterization Laboratory.

"The technical issues with the device may speak to the device needing some improvement in terms of its collection of ECGs," he noted.

Welt, who was not involved with the study, pointed out that the post hoc analyses suggested that the device "may detect patients who otherwise wouldn't have had a coronary event recognized, so that's an interesting signal, but they [the researchers] will still need to go back to the drawing board to see how they can improve things."

He added that implanting the device is an "invasive procedure" and there were some infections among subjects.

"Although none led to sepsis, infection is a concern whenever there is anything indwelling, so the signal that this is helping detect MIs early would have to be very strong for us to think about routinely putting in these devices."

In December 2018, Angel Medical Systems applied for Bankruptcy and received court approval Monday for its Chapter 11 debt-for-equity reorganization on February 14, "which paves the way to bring to market The AngelMed Guardian System, the Company's implantable cardiac monitor and patient alerting system," according to a company press release.

The company reported that its attorney told the judge that Angel Medical Systems is "poised and ready to launch" its implantable device.

Gibson and coauthors report receiving research grant support from Angel Medical Systems. Welt reports no conflicting interests.

J Am Coll Cardiol. Published online March 3, 2019. Abstract

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