N Engl J Med 2024;390:1455-1466

Background

Despite advances in the care of patients after myocardial infarction, there remains residual risk of heart failure and death. The amount of risk parallels the degree of left ventricular systolic dysfunction. Previous studies have shown that the drug class of sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk (especially recurrent heart failure) in multiple clinical situations.

The goal of the placebo-controlled Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial was to determine whether empagliflozin reduced the risk of heart failure or death in patients with acute MI and either a new reduction in LV function or signs of congestion, or both.

Patients

Adult patients who had been hospitalized with MI within 14 days before randomization. There had to be a new LVEF <45% or signs/symptoms of congestion that resulted in treatment during the index hospital admission.

There also had to be another risk factor, which the authors wrote that enriched the risk for heart failure or death. This could include many things: age of 65 years or older; a newly developed LVEF < 35%; a history of MI, atrial fibrillation, or type 2 diabetes; an estimated glomerular filtration rate (GFR) of less than 60 ml per minute per 1.73 m2 of body-surface area; an elevated natriuretic peptide or uric acid level; an elevated pulmonary artery or right ventricular systolic pressure; three-vessel coronary artery disease; peripheral artery disease; or no revascularization for the index myocardial infarction.The key exclusion criteria was the a previous diagnosis of heart failure or any reason that the patient was planning to take SGLT2i.

Baseline Characteristics

The average age of patients was 63 years. Only a quarter were women. More than 80% were white. Approximately 75% of patients had STEMI, the rest, NSTEMI. A total of 78% of the patients had a LVEF < 45%, and 57% had signs or symptoms of congestion that resulted in treatment during the index hospitalization. For the patients with signs or symptoms of congestion, only 20% had a LVEF of at least 45%. 

The most common enrichment factors were age > 65 (50%), Type 2 DM (32%) and 3-vessel CAD (31%). Slightly more than 70% of patients had more than one enrichment factor.

Approximately 20% of patients had an LVEF > 45%. Slightly more than half of patients had an LVEF between 35% and 45%.

Trial Procedures

Randomization was 1:1 to empagliflozin 10mg daily or matching placebo. The trial was conducted between 2020-2023 at 451 sites in 22 countries. The median time from admission to randomization was 5 days. The trial had a streamlined design, with the collection of essential data only, including information about specific safety events, and mainly remote follow-up of patients (by means of a Web-based application or a telephone call) with only a few face-to-face visits; the trial assessed investigator-reported end-point events rather than centrally adjudicated end-point events. Specifically, follow up included a remote visit at 2 weeks, a face-to-face visit at 6 months, and remote visits every 6 months thereafter until the end of the trial, when a final telephone call was performed.

Endpoints

The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis.

The key secondary end points in the prespecified hierarchical testing strategy were the total number of hospitalizations for heart failure or death from any cause, the total number of nonelective cardiovascular hospitalizations or death from any cause, the total number of nonelective hospitalizations for any cause or death from any cause, and the total number of hospitalizations for myocardial infarction or death from any cause.

Trial authors estimated that 532 patients with a primary end-point event would provide the trial with 85% power to detect a 23% lower risk of an event in the empagliflozin group than in the placebo group, with a two-sided type I error of 0.05. However, the trial originally planned to enroll about 3300 patients, with the option to enroll 5000 patients. But then the trial was further increased to 6500 patients.

Key secondary endpoints were assessed using a prespecified hierarchical testing procedure. This began with the primary endpoint.

Results

An interesting aspect of this trial, and more recent post-MI trials is that the ratio of screened to enrolled patients is almost 1:1. Whereas older trials screened many more patients than were enrolled, in EMPACT, only 88 of 6600 screened patients were excluded. In total, approximately 3200 patients were randomized in both arm.

After a median follow-up of 18 months, a primary end-point event — a first hospitalization for heart failure or death from any cause — occurred in 8.2% in the empagliflozin group and in 9.1% in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). 

A look at the two components showed that there were fewer heart failure hospitalizations in the empagliflozin group (3.6% vs 4.7%; HR 0.77 (0.60–0.98)) Overall death were similar in both groups. As for secondary endpoints, total heart failure hospitalizations was 2.4 vs 3.6 events, respectively, per 100 patient-years (rate ratio, 0.67; 95% CI, 0.51 to 0.89). The composite of total heart failure hospitalizations or death were not significantly different (HR 0.87 0.68-1.10). CV death was 4% in both groups.

There were no obvious subgroup effects nor differences in safety.

Conclusions

The addition of empagliflozin did not significantly reduce a composite endpoint of heart failure admissions and death.

Even the reduction in heart failure admissions was modest. Given the medication burden of the typical patient after myocardial infarction, coupled with the high cost of this drug class, we see no strong evidence for routine use of SGLT2i in EMPACT-MI-type patients.

The null results of this trial and PARADISE-MI speak to the beneficial effects of modern post-MI care—including mostly rapid revascularization with PCI. It is difficult to improve on baseline care of the MI patient in 2024.

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