Editorial
A number of therapies that have been shown to be effective in patients with chronic heart failure, including beta-blockers, mineralocorticoid receptor antagonists, and renin–angiotensin system inhibitors, have also been shown to be beneficial in patients with evidence of left ventricular systolic dysfunction, pulmonary congestion, or both after an acute myocardial infarction.1 However, the effectiveness of an agent in patients with chronic heart failure does not necessarily imply that the agent will be effective in patients who have had an acute myocardial infarction. For example, despite the effectiveness of sacubitril–valsartan in decreasing the risk of death from cardiovascular causes or hospitalization for heart failure among patients with chronic heart failure and a markedly or minimally reduced left ventricular ejection fraction (LVEF),2 in the PARADISE-MI trial (Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction),3 sacubitril–valsartan was not superior to ramipril in decreasing the incidence of death from cardiovascular causes or incident heart failure after an acute myocardial infarction. Similar to sacubitril–valsartan, sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of death from cardiovascular causes or hospitalization for worsening heart failure among patients with a reduced LVEF4 and among those with a preserved LVEF.5 However, whether treatment with SGLT2 inhibitors can also lower these risks among patients who have had an acute myocardial infarction is unclear.
Butler et al.6 now report in the Journal the results of the EMPACT-MI trial (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction), in which empagliflozin at a dose of 10 mg daily was compared with placebo with respect to the risk of a first hospitalization for heart failure or death from any cause (composite primary end point) among patients who had been hospitalized for acute myocardial infarction. Eligibility criteria included either an LVEF of less than 45% or signs or symptoms of pulmonary congestion (or both), as well as one of 12 risk-enrichment factors (e.g., an age of ≥65 years). During a median follow-up of 17.9 months, empagliflozin was not superior to placebo in decreasing the risk of a primary end-point event (8.2% vs. 9.1% of patients), with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). With respect to the components of the primary end point, a first hospitalization for heart failure occurred in 3.6% of the patients in the empagliflozin group and in 4.7% of those in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 5.2% and 5.5%, respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19).
Because first hospitalization for heart failure was assessed as part of a composite exploratory end point, the authors could not draw definitive conclusions about the effects of empagliflozin on this outcome; nevertheless, the findings suggest the possibility of a lower risk of heart-failure events with empagliflozin than with placebo. At the time of trial enrollment, many patients had evidence of heart failure — 40% of the patients were taking loop diuretics, and close to 50% of the patients in whom the N-terminal pro–B-type natriuretic peptide concentration was measured had very elevated levels (≥1400 pg per milliliter). Yet the incidence of hospitalization for heart failure was lower and tended to occur earlier in the placebo group of the EMPACT-MI trial than in the placebo groups of contemporary trials of empagliflozin that included patients with chronic heart failure with a reduced LVEF4 or without a reduced LVEF.5 Left ventricular dysfunction, pulmonary congestion, or both during the early period after myocardial infarction occur in the context of marked inflammation, neurohumoral activation, myocardial stunning, and left ventricular remodeling. However, with time, the risk of cardiovascular events decreases markedly as these processes subside, and prompt revascularization, as occurs in the majority of patients (including those in the EMPACT-MI trial), leads to substantial reversal of myocardial stunning.1 Thus, some of the patients in this trial probably recovered, with a resulting lower risk of subsequent heart failure.
Whether the receipt of empagliflozin therapy after myocardial infarction may modify pathophysiological changes that lead to heart failure remains uncertain. The EMMY trial (Empagliflozin in Acute Myocardial Infarction),7 which showed that empagliflozin modestly but significantly improved cardiac remodeling after myocardial infarction, suggests that it may. Alternatively, any effect that empagliflozin may have had on hospitalization for heart failure in the EMPACT-MI trial could simply reflect its beneficial effects in patients at risk for chronic heart failure and in those with established chronic heart failure. A landmark analysis of the effect of empagliflozin on the time to a first hospitalization for heart failure or death from any cause within 3 months after myocardial infarction may help to answer these questions.
Although at least one enrichment factor was needed for inclusion in the EMPACT-MI trial, as in the PARADISE-MI trial the planned sample size was increased owing to a lower than expected rate of the primary end-point event. The rates of heart-failure events and death from cardiovascular causes in the EMPACT-MI trial were approximately 50% lower and more than 67% lower, respectively, than in a past trial that included a similar population8 and were much lower than in contemporary observational studies that included persons at higher risk for heart failure.9 With improvements in background therapies, event rates or effect sizes can easily be overestimated in cardiovascular trials. This raises the question of whether alternative, yet appropriate10 outcome measures (e.g., the total number of events rather than the first event, investigator-reported events rather than centrally adjudicated events, or heart-failure events that did not lead to hospitalization) to increase rates of the primary end-point event should be used. Whether the use of such measures would have affected the results of the EMPACT-MI trial is unclear.
The good news is that the prognosis for patients with left ventricular dysfunction, congestion, or both after an acute myocardial infarction has improved markedly. The challenge is that the identification of additional effective therapies is increasingly difficult, especially because a large percentage of patients who have had an acute myocardial infarction promptly undergo reperfusion.
The results of the trial by Butler et al. do not support the routine use of SGLT2 inhibitors in patients who have had an acute myocardial infarction and are at increased risk for heart failure. However, in patients with indications for SGLT2 inhibitor therapy, such as type 2 diabetes and chronic kidney disease, a recent myocardial infarction may provide an opportunity to initiate treatment with these agents and decrease the risk of heart failure.
References
For references, check the original article at: nejm.org
