Empagliflozin Post-Acute Myocardial Infarction

By Michael H. Crawford, MD, Editor

SYNOPSIS: A prespecified further analysis of the EMPACT-MI trial has shown that patients within two weeks of an acute myocardial infarction who are at risk for heart failure who receive empagliflozin compared to placebo have significantly fewer episodes of heart failure hospitalizations over a median follow-up of 18 months.

SOURCE: Hernandez AF, Udell JA, Jones WS, et al. Effect of empagliflozin on heart failure outcomes after acute myocardial infarction: Insights from the EMPACT-MI Trial. Circulation 2024;149:1627-1638.

The Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial was designed to assess clinical outcomes after myocardial infarction (MI) and showed that the primary composite endpoint of time to first hospitalization for heart failure (HF) or all-cause death was not reduced.¹ The Hernandez et al report is a prespecified analysis of HF hospitalizations (HFH) and other HF events in the EMPACT-MI trial, which was an international, randomized, parallel-group, double-blind, placebo-controlled, event-driven trial.

Enrolled patients were adults hospitalized within 14 days of an acute MI (ST or non-ST elevation) who had either a left ventricular ejection fraction (LVEF) < 45% or symptoms/signs of congestion requiring treatment, plus one enriching factor such as age ≥ 65 years, history of MI, atrial fibrillation, type 2 diabetes, glomerular filtration rate (GFR) < 60 mL/min/1.73 m², elevated natriuretic peptides, elevated pulmonary artery pressure, three-vessel coronary artery disease, peripheral artery disease, newly developed LVEF < 35%, or no revascularization for the index MI. Patients with a previous diagnosis of HF or who were taking sodium glucose cotransporter-2 (SGLT2) agents were excluded.

Patients were randomized to placebo or 10 mg of empagliflozin daily in addition to standard care. Patients had a virtual visit at two weeks and an in-person visit at six months, followed by virtual visits every six months until the end of the study. The outcomes of interest for this report from EMPACT-MI are time to first HFH and total HFH. Also, various subgroups of the study population were assessed to evaluate the consistency of the results. From 2020 to 2023, 6,522 patients were randomized at 451 sites in 22 countries. Of these patients, 78% had an EF < 45% and 57% had symptoms or signs of congestion. Age ≥ 65 years was present in 50%, diabetes was present in 32%, and three-vessel disease was present in 31%. Median follow-up was 18 months, and 97% of the patients contributed to the final data.

Overall, there were 355 total HFH (5%). HFH occurred in 148 patients in the empagliflozin group compared to 207 patients in the placebo group (rate ratio, 0.67; 95% confidence interval, 0.51-0.89; P = 0.006). These results were consistent across baseline patient subgroups such as age, sex, race/ethnicity, type of MI, diabetes, GFR, or treatment with other HF medications. Among those not on standard treatment for HF at discharge, fewer patients were started on such therapy in the empagliflozin group. The authors concluded that in patients with LV dysfunction or congestion after acute MI, empagliflozin reduced the risk of HF after discharge.

COMMENTARY

This is another of what probably will be a dozen papers published from this trial. A critic or cynic might say why not just publish all the data once and tell us for which patients they think we should prescribe this relatively new drug? There are several reasons for this fragmented approach.

First, fully analyzing all the data collected in one of these big trials would delay the reporting of the main findings. Second, most journals would not accept a paper with all the data; it would be too long. Third, as the data are analyzed, other hypotheses may emerge that are worth exploring in the database. One can only hope that eventually someone will write a review article that puts the whole trial into clinical perspective.

There are a few points worth mentioning about the results of this analysis of the EMPACT-MI data. First, surprisingly few patients overall developed HF (5%). Although < 10% of patients were taking the standard drugs used for HF at baseline, their introduction during the trial was not prohibited, and guidelines concerning the treatment of post-MI patients recommend prophylactic therapy with beta-blockers and renin-angiotensin system antagonists for many patients. Also, after the six-month in-person visit, there was no review of outpatient medications.

In addition, the authors point out that only HFH were counted, not episodes of outpatient HF. When known outpatient episodes of HF were considered, the total increased from 355 to 581, but this likely is an undercount. Also, during the conduct of the trial, COVID and war in some of the countries may have limited physician and hospital visits, resulting in underestimation of HF. Finally, there was no central adjudication of events.

Consistent with the overall trial results paper, there was no reduction in mortality in the Hernandez analysis either. Thus, we are being asked to consider prescribing an expensive new drug to a large number of post-MI patients at risk for HF for a 33% reduction in HFH, which occurs in about 5% of such patients over 18 months. I am not sure this is going to merit a class 1 indication, but there are probably some patients who would benefit from receiving an SGLT2 agent.

REFERENCE

Butler J, Jones WS, Udell JA, et al. Empagliflozin after acute myocardial. N Engl J Med 2024;390:1455-1466.