EMPACT-MI: Another SGLT2 Inhibitor Miss Post-MI

The sodium–glucose cotransporter 2 (SGLT2) inhibitor class of medications benefits patients with diabetes, heart failure, and chronic kidney disease.

Results of the EMPACT-MI placebo-controlled randomized trial confirmed that adding incremental benefit to the well-established post–myocardial infarction (MI) treatment regimen is a tougher task.

EMPACT-MI asked a simple question: Does adding empagliflozin to standard post-MI medications in patients who had an acute MI reduce a composite endpoint of hospitalization for heart failure or death from any cause?

The EMPACT-MI Trial

Entry criteria included either a newly developed left ventricular ejection fraction (LVEF) ≤ 45% or signs/symptoms of congestion that required treatment. Patients needed to have one additional "enrichment factor," which elevated the risk for heart failure. The most common enrichment factor was age ≥ 65 years.

Background therapy included a renin-angiotensin modulator (82%), beta-blocker (87%), statins (95%), and diuretics (65%). Nearly all of the patients received revascularization.

The investigators enrolled slightly more than 6500 patients in multiple centers. The average age of these patients was 64 years, 25% were female, and 75% qualified with an ST-segment MI. The authors don't provide a mean LVEF, but they write that nearly 80% of patients had an LVEF < 45%. A review of Table 1 reveals that about a quarter had an LVEF < 35% and 20% had an LVEF > 45%.

The median time from admission to randomization was 5 days.

Results for Empagliflozin

After 18 months of follow-up, the rate of primary outcome events was similar in both arms: 8.2% in the empagliflozin arm vs 9.1% in the placebo arm for a hazard ratio (HR) of 0.90 (95% CI, 0.76-1.06; P = .21). These events were split nearly evenly between death and heart failure hospitalization.

All-cause death did not differ between treatment arms (5.5% vs 5.2% for placebo). Rate of first heart failure events was 23% lower in the empagliflozin arm (HR, 0.77; 95% CI, 0.60-0.98). The total number of heart failure hospitalizations was also lower in the empagliflozin arm (HR, 0.67; 95% CI, 0.51-0.89). The rate of death due to cardiovascular causes was 4% in both arms. Of note, the authors published a separate manuscript detailing the heart failure hospitalization endpoints. Adverse events were similar in both groups.

SGLT2 Inhibitors in MI: Comments

In the pre-revascularization era, post-MI care focused on relieving the complications of myocardial damage. Afterload reduction, beta-blockers, and defibrillators effectively reduced the sequalae of damaged heart muscle. The risk for hospitalization or death was high. There was room for improvement.

Everything has changed — for the better. Modern-day MI care is a good news/bad news situation. For patients, it's great news; for industry, not so much.

In fact, MI care is now the crown jewel of cardiology. Emergent revascularization aborts most of the myocardial damage. The lesson of the REDUCE-AMI trial, which I wrote about, is that even beta-blockers cannot be shown to help post-MI patients in this era. That's because there is usually minimal myocardial damage.

In any disease, when the risk for the primary outcome goes down, so does the ability of new therapies to improve outcomes.

It's the same for SGLT2 inhibitors. The 10% reduction in the primary endpoint of this trial is both modest and not statistically significant. The null result occurred despite increasing the sample size of the study due to fewer-than-expected events. This is quite similar to the results of the DAPA-MI trial, which also found no meaningful reduction in important cardiac outcomes with another SGLT2 inhibitor, dapagliflozin. While DAPA-MI excluded patients with diabetes, about a third of patients in EMPACT-MI had diabetes — and still a null primary endpoint.

The angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan had the same issue against ramipril in the PARADISE-MI trial. In that trial of post-MI patients with a mean LVEF of 36%, the ARNI did not significantly reduce the composite primary outcome of cardiovascular death or incident heart failure vs ramipril.

In all of these cases, the problem is not the new drugs. The "problem" is that the comparators are good. When an MI occurs, acute revascularization provides the vast majority of the benefit. Antiplatelet drugs reduce stent thrombosis, statins reduce future atherosclerotic events, and when there is left ventricular dysfunction, basic afterload reduction with ACE inhibitors provides the majority of benefit. This is all good news.

SGLT2 inhibitors have shown efficacy in certain types of patients. Two large trials now show that post-MI patients are not among them, which is fine; SGLT2 inhibitors help plenty of patients.

Proponents will point you to the reduction in heart failure events. In this case, they have even found a way to publish a positive manuscript after a null result in the main trial.

The problem with this is (a) it's a subanalysis when the main trial results are negative, (b) heart failure hospitalizations represent a fraction of total hospitalizations, and (c) these are high-cost drugs.

If I have a patient who had an acute MI who has a strong indication for SGLT2 inhibitors (diabetes or chronic kidney disease), I would be happy to use the drugs.

If, however, the patient is similar to those in EMPACT-MI or DAPA-MI, the evidence does not suggest a benefit. So, I would not add to my patient's pill burden.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.