Do HF risk factors influence empagliflozin’s treatment effect after acute MI?

In a secondary analysis of EMPACT-MI among patients with high HF risk after acute MI, empagliflozin reduced the risks of first and total HF hospitalizations but not mortality compared with placebo, regardless of baseline LVEF and/or presence of congestion.

This summary is based on the publication of Udell JA, Petrie MC, Jones WS, et al. - Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction. J Am Coll Cardiol. 2024 Jun 11;83(23):2233-2246. doi: 10.1016/j.jacc.2024.03.405

Introduction and methods

Background

In patients at increased risk of HF following an acute MI (AMI), empagliflozin treatment did not reduce the primary composite endpoint of time to first HF hospitalization or all-cause mortality compared with placebo, as recently shown by the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial [1]. However, the drug did lower the risks of first and total HF hospitalizations and other adverse HF events [1,2].

Aim of the study

In a prespecified secondary analysis of the EMPACT-MI trial, the authors investigated the effect of empagliflozin on reducing HF risk in AMI patients across the spectrum of LVEF and in the presence or absence of congestion.

Methods

The EMPACT-MI trial was a multicenter, double-blind, placebo-controlled, event-driven, superiority, phase 3 RCT. In total, 6522 patients hospitalized for AMI who were at high risk of developing HF based on either newly developed LV systolic dysfunction (documented LVEF <45%) or signs or symptoms of congestion requiring treatment were randomized within 14 days to empagliflozin 10 mg daily or placebo, in addition to standard of care. Patients were also required to have ≥1 additional HF risk factor, such as age ≥65 years, newly developed LVEF <35%, history of MI, eGFR <60 mL/min/1.73 m², or peripheral artery disease. Median follow-up duration was 17.9 months.

Baseline LVEF measurements and documentation of the presence or absence of congestion were available for 6470 patients, of whom 2648 (40.9%) presented with LVEF <45% only, 1483 (22.9%) presented with congestion only, and 2181 (33.7%) had both, whereas 158 (2.4%) had LVEF ≥45% and no congestion—a deviation from the trial protocol.

Outcomes

The study’s primary endpoint was a composite outcome of time to first hospitalization for HF or all-cause mortality. In this analysis, time to first HF hospitalization and total (first and recurrent) HF hospitalizations were also assessed.

Safety analysis comprised the serious adverse events, adverse events leading to discontinuation of the trial drug for ≥7 consecutive days, and adverse events of special interest (including hypotension, volume depletion, and acute kidney injury).

Main results

Outcomes in placebo arm

• Among patients in the placebo arm of the trial, each 10-point reduction in LVEF was associated with an increased risk of first HF hospitalization or all-cause mortality (adjusted HR: 1.49; 95%CI: 1.31–1.69; P<0.0001), time to first HF hospitalization (adjusted HR: 1.64; 95%CI: 1.37–1.96; P<0.0001), and total HF hospitalizations (adjusted rate ratio (RR): 1.89; 95%CI: 1.51–2.36; P<0.0001).
• The presence of congestion was also associated with a higher risk of first HF hospitalization or all-cause mortality (adjusted HR: 1.52; 95%CI: 1.16–1.99; P=0.0023), first HF hospitalization (adjusted HR: 1.94; 95%CI: 1.32–2.86; P=0.0007), and total HF hospitalizations (adjusted RR: 2.03; 95%CI: 1.31–3.16; P=0.0017).
• When the baseline LVEF and congestion status were combined, there was a stepwise higher risk of first HF hospitalization or all-cause mortality (P for trend<0.0001). The highest-risk group comprised patients with baseline LVEF <35% and congestion (adjusted HR: 3.55; 95%CI: 2.45–5.14), and the lowest-risk group were patients with baseline LVEF 35%–44% and no congestion (reference group); the latter had an even lower risk than patients with baseline LVEF ≥45% with or with no congestion (adjusted HR: 1.39; 95%CI: 0.95–2.03). The same pattern was observed for time to first HF hospitalization and total HF hospitalizations.

Outcomes in empagliflozin arm

• Empagliflozin did not reduce the risk of HF hospitalization or all-cause mortality compared with placebo across the range of baseline LVEF categories (<35%, 35%–44%, or ≥45%; P for trend=0.43), congestion status (P for interaction=0.57), or both (P for trend=0.56). When baseline LVEF was analyzed as a continuous variable, there was also no interaction with empagliflozin’s treatment effect (P for interaction=0.96).
• Empagliflozin reduced the risk of first HF hospitalization compared with placebo (adjusted HR: 0.77; 95%CI: 0.60–0.98), irrespective of baseline LVEF category (P for trend=0.79), baseline LVEF level (P for interaction=0.95), congestion status (P for interaction=0.88), or baseline LVEF category plus congestion status (P for trend=0.42). 
• In addition, empagliflozin lowered the risk of total HF hospitalizations compared with placebo (adjusted RR: 0.67; 95%CI: 0.50–0.89), regardless of baseline LVEF category (P for trend=0.97), baseline LVEF level (P for interaction=0.90), congestion status (P for interaction=0.89), or baseline LVEF category plus congestion status (P for trend=0.42).

Safety

• The frequency of serious adverse events was similar in patients treated with empagliflozin (n=3229) and those receiving placebo (n=3234) (23.7% vs. 24.7%), as was the rate of adverse events leading to permanent discontinuation of the study drug (3.8% vs. 3.8%).
• The frequencies of hypotension and volume depletion were also comparable between the empagliflozin and placebo groups (~1.1%), but numerically fewer patients experienced acute kidney injury in the empagliflozin group compared with the placebo group (0.8% vs 1.3%).
• The safety profile of empagliflozin was consistent across baseline LVEF categories and irrespective of congestion status.

Conclusion

In this prespecified secondary analysis of the EMPACT-MI trial among AMI patients at high risk of developing HF, the severity of LV systolic dysfunction and the presence of congestion were associated with adverse outcomes. Empagliflozin treatment reduced first and total HF hospitalizations but not all-cause mortality compared with placebo, regardless of baseline LVEF and/or presence of congestion.

Interestingly, patients in the placebo arm with baseline LVEF ≥45% (with or with no congestion) had a higher risk of first and total HF hospitalizations and the composite outcome of HF hospitalization or all-cause mortality than those with LVEF 35%–44% and no congestion. The authors believe this “suggests that post-MI congestion may be a stronger risk factor for adverse outcomes than moderate [LV systolic dysfunction].”

Find this article online at J Am Coll Cardiol.

References

1. Butler J, Jones WS, Udell JA, et al. Empagliflozin after acute myocardial infarction. N Engl J Med. 2024;390(16):1455–1466.

2. 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. Published online April 6, 2024.