Proof of Benefit in Acute MI Again Evades an SGLT2 Inhibitor

ATLANTA — The SGLT2 inhibitor empagliflozin (Jardiance) did not exactly prevent deaths and heart failure (HF) events when initiated atop other standard therapies for acute myocardial infarction (MI), the EMPACT-HF trial found, but cumulative risk did go down.

Between empagliflozin and placebo groups, there was no difference in time-to-first-event analysis of hospitalizations for HF or deaths from any cause over approximately 18 months (8.2% vs 9.1%), which came out to 5.9 and 6.6 events per 100 patient-years, respectively (HR 0.90, 95% CI 0.76-1.06), reported Javed Butler, MD, MPH, MBA, of Baylor Scott and White Research Institute in Dallas.

Notably, while mortality alone appeared unchanged with empagliflozin (5.2% vs 5.5%), there was a 22% reduction in first hospitalizations for HF (3.6% vs 4.7%, HR 0.77, 95% CI 0.60-0.98), Butler reported at the American College of Cardiology (ACC) annual meeting.

A secondary analysis showed that empagliflozin reduced first and recurrent HF events by 33% (RR 0.67, 95% CI 0.51-0.89). There was also less need for diuretics, renin-angiotensin modulators, and mineralocorticoid receptor antagonists after discharge among patients randomized to empagliflozin.

“The totality of evidence suggests the benefit of empagliflozin for heart failure risk reduction in patients post-AMI without prior heart failure,” Butler said, adding that this benefit is consistent with what has been shown “with empagliflozin in other trials in adjacent patient populations.”

EMPACT-HF’s main findings were simultaneously published in The New England Journal of Medicine. Its secondary analysis of total HF hospitalizations was published separately in Circulation.

An estimated 12-15% of patients with MI are hospitalized with HF in the year following their MI, and the presence of HF symptoms at time of MI has been identified as a strong predictor of mortality. It had been hoped that the established HF benefits of SGLT2 inhibitors might extend to the acute MI setting.

This was supported by the EMMY trial, which showed that starting patients on empagliflozin in the acute phase of a large MI resulted in reduced natriuretic peptide concentration, increased left ventricular ejection fraction, and decreased cardiac volume over the next half year.

However, in DAPA-MI, investigators were unable to show that the SGLT2 inhibitor dapagliflozin (Farxiga) prevents death from cardiovascular causes or hospitalization for HF after acute MI. This was a trial deemed inconclusive due to lower than expected event rates, however, despite clear improvements in cardiometabolic measures for the dapagliflozin arm.

EMPACT-HF, too, was “obviously a challenging trial” in which event rates overall were quite low, commented ACC panelist James Januzzi Jr., MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston. He suggested that work is needed to understand who is at risk of developing symptomatic HF despite the “excellent therapies” both in and out of the cath lab for acute MI.

Patrick O’Gara, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, agreed that his interest is in “whether you can pick out who would most likely benefit” from SGLT2 inhibitors.

During a press conference, O’Gara said that the concept of finding heart attack survivors who would benefit further from SGLT2 inhibition adds to a “challenging set of circumstances” when people already get confused about their many medications, pay a lot for them, and sometimes experience side effects.

EMPACT-HF was conducted from 2020 to 2023 in 22 countries. Investigators had adult patients randomized to empagliflozin 10 mg (n=3,260) or placebo (n=3,262) daily in addition to standard of care within 14 days of hospital admission for MI.

Participants were all judged to be at high risk for subsequent HF based on either evidence of a newly developed left ventricular ejection fraction of less than 45% or signs or symptoms of congestion that resulted in treatment during the index hospitalization. Excluded were patients with a previous diagnosis of HF, as well as those who were taking or planning to take SGLT2 inhibitors.

Butler reported similar baseline characteristics between empagliflozin and placebo groups. Average age was just over 63, with about a quarter women. Over 83% of people were white. Nearly 75% of the patients who underwent randomization presented with ST-segment elevation myocardial infarction (STEMI), and revascularization for the index MI was performed in 89.3%.

Median time from MI admission to randomization was 5 days. Follow-up lasted a median 17.9 months.

Adverse events (AEs) were consistent with the known safety profile of empagliflozin. Serious AEs did not differ significantly between treatment and control groups (23.7% vs 24.7%).

Study authors acknowledged the lack of central adjudication for the trial’s endpoints. Other limitations include the effects of conducting the trial during the COVID-19 pandemic, and some participating sites being affected by war.

O’Gara added that the trial may have had too short a follow-up to show a clinical benefit of empagliflozin.

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