Abstract
BACKGROUND
Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.
METHODS
We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.
RESULTS
Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups.
CONCLUSIONS
Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction.
Discussion
In this randomized, placebo-controlled trial involving patients with heart failure and a mildly reduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of the primary composite outcome, worsening heart failure or cardiovascular death, than placebo, with no appreciable difference in benefit among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, or in other subgroups. Each of the three components of this composite outcome was less common in the dapagliflozin group than in the placebo group. In addition, dapagliflozin resulted in fewer total worsening heart failure events and cardiovascular deaths and a lower symptom burden than placebo. The incidence of adverse events was similar to that in the placebo group.
In a previous trial (DAPA-HF; Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin reduced the risk of worsening heart failure or cardiovascular death among patients with heart failure and a left ventricular ejection fraction of 40% or less.1 The results of the DELIVER trial extend those of the DAPA-HF trial to patients with heart failure and a left ventricular ejection fraction of more than 40% and are consistent with the overall results of the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), which assessed the effects of empagliflozin in patients with a left ventricular ejection fraction of more than 40%.10 The rationale for the dual primary analyses in our trial (i.e., evaluation of the primary outcome in patients with a left ventricular ejection fraction of less than 60% in addition to the overall patient population) was based on concern about a potential declining benefit in patients with an ejection fraction in the normal range that had been observed in several previous trials of neurohormonal modulators.6,15 Although the EMPEROR-Preserved trial suggested some potential attenuation of benefit in the highest part of the range of ejection fraction,8 we observed no evidence of heterogeneity with respect to left ventricular ejection fraction in the DELIVER trial, with similar overall treatment effects among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%. This finding suggests that the benefit of SGLT2 inhibition is likely to extend throughout the full range of ejection fraction.
The DELIVER trial was designed with broader inclusion criteria than those used in previous trials involving similar populations in that we enrolled patients who were hospitalized or recently hospitalized, for whom evidence-based therapy is limited, as well as those with heart failure and a left ventricular ejection fraction that had improved to more than 40% at the time of enrollment.4 Our data suggest that these understudied groups also benefit from dapagliflozin.
The most recent guidelines of the American Heart Association, American College of Cardiology, and Heart Failure Society of America designated SGLT2 inhibitors as class IIA, level B, for the treatment of heart failure with a mildly reduced or preserved left ventricular ejection fraction.4 The results of the DELIVER trial may inform future guidelines and provide further guidance for their broader use in clinical practice. Although the risk of cardiovascular death was not significantly lower with dapagliflozin than with placebo, the rate of cardiovascular death among patients who received placebo was substantially lower among patients with a left ventricular ejection fraction of more than 40% than among those in the DAPA-HF trial with a reduced ejection fraction (3.8 events per 100 patient-years in DELIVER vs. 7.9 events per 100 patient-years in DAPA-HF), and DELIVER was not powered to assess the effect of dapagliflozin on cardiovascular death alone. Trials in higher-risk populations, or of longer duration, or pooled analyses of several trials would be needed for robust evaluation of benefits with respect to mortality.
This trial has some limitations. The use of specific inclusion and exclusion criteria may have limited the generalizability of our findings. Less than 5% of the patients enrolled were Black, although this percentage was proportional to the population percentage on a regional basis (Table S8). Owing to the Covid-19 pandemic, assessment of symptom burden was limited to patients for whom an 8-month assessment was planned or performed before March 11, 2020, although results were similar in all patients for whom data were available. Because all the subgroups in the DELIVER trial were underpowered, within-subgroup results should be interpreted cautiously.
Among patients with heart failure and a mildly reduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of the primary composite outcome (worsening heart failure or cardiovascular death), in fewer worsening heart failure events and cardiovascular deaths, and in a lower symptom burden, with no excess of adverse events. Findings were consistent across prespecified subgroups, including those defined according to left ventricular ejection fraction. These data provide further evidence to support the use of an SGLT2 inhibitor as essential therapy in patients with heart failure, regardless of the presence or absence of type 2 diabetes mellitus or left ventricular ejection fraction.
SOURCE: NEJM
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