Empagliflozin after a heart attack did not cut heart failure or death

SGLT2 inhibitors have been one of the clearest success stories in cardiology. Empagliflozin, first a diabetes drug, went on to cut cardiovascular events in heart failure and in chronic kidney disease, and that record created a strong expectation that it would help in another high-risk setting: the weeks after a heart attack, when the damaged heart is most likely to tip into failure. EMPACT-MI, published in the New England Journal of Medicine, put that expectation to a formal test — and the expectation did not hold [s1].

The result is a negative trial, and it is worth dwelling on precisely because the drug works so well elsewhere.

What EMPACT-MI did

EMPACT-MI was an event-driven, double-blind, randomised, placebo-controlled trial [s1]. It enrolled patients who had been hospitalised for an acute myocardial infarction and were at risk for heart failure, and assigned them in a 1:1 ratio to empagliflozin 10 mg daily or placebo, in addition to standard care, within 14 days after admission [s1]. A total of 3260 patients were assigned to empagliflozin and 3262 to placebo, and they were followed for a median of 17.9 months [s1].

The primary endpoint was a composite of hospitalisation for heart failure or death from any cause, assessed as time to the first event [s1]. The trial is registered as NCT04509674 and was funded by Boehringer Ingelheim and Eli Lilly [s1][s2].

The numbers

A first hospitalisation for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events per 100 patient-years, respectively [s1]. The hazard ratio was 0.90 (95% CI, 0.76 to 1.06; P = 0.21) — a difference that did not reach statistical significance [s1].

Breaking the composite apart shows where the signal was and was not. A first hospitalisation for heart failure occurred in 118 patients (3.6%) on empagliflozin against 153 (4.7%) on placebo (hazard ratio, 0.77; 95% CI, 0.60 to 0.98) [s1]. But death from any cause was essentially unchanged: 169 deaths (5.2%) on empagliflozin and 178 (5.5%) on placebo (hazard ratio, 0.96; 95% CI, 0.78 to 1.19) [s1]. Adverse events were consistent with the drug's known safety profile and similar between the groups [s1].

Why a negative trial here still matters

The honest headline is the one the investigators drew: among patients at increased risk for heart failure after a heart attack, empagliflozin did not significantly lower the risk of a first heart-failure hospitalisation or death compared with placebo [s1].

The nuance is in the components. The heart-failure piece moved in the expected direction and its confidence interval excluded no effect [s1] — consistent with everything known about SGLT2 inhibitors and heart failure. What empagliflozin did not do was change the harder, less malleable outcome of death, and because the trial's primary endpoint bundled the two together, the overall result came out neutral [s1]. A drug can genuinely reduce heart-failure admissions and still fail a composite that death dominates.

That distinction is easy to lose when a trial is summarised as a win or a loss. EMPACT-MI is best read as evidence that routinely starting empagliflozin in every post-infarction patient at risk for heart failure does not deliver the broad outcome benefit seen in established heart-failure populations — not as evidence that the drug is useless after a heart attack. Where overt heart failure or another approved indication is present, the case for the drug rests on those trials, not on this one.

It is also a useful corrective to extrapolation. The reason a trial was run at all is that benefit in one cardiovascular setting does not automatically transfer to another, even for a drug with a strong track record and even when the biological rationale looks sound. A companion trial of a different SGLT2 inhibitor started after myocardial infarction reached a broadly similar neutral conclusion on its primary endpoint, which strengthens rather than undercuts the message here.

What to watch

EMPACT-MI does not close the question of how to prevent heart failure after a heart attack; it narrows it. The separation on heart-failure hospitalisations invites longer or differently targeted studies — for instance, in patients with the clearest early signs of failing cardiac function, rather than a broad at-risk population [s1]. For now, the practical takeaway is modest and specific: a positive result in heart failure and kidney disease did not reproduce as a mortality or composite benefit in the post-infarction setting, and the data say so without spin.

This article is informational and does not constitute medical advice.

Sources

• [s1] Empagliflozin after Acute Myocardial Infarction. New England Journal of Medicine, 6 April
  2024. https://doi.org/10.1056/NEJMoa2314051
• [s2] EMPACT-MI: A Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack. ClinicalTrials.gov identifier NCT04509674, US National Library of Medicine. https://clinicaltrials.gov/study/NCT04509674