New Developments in Cardiology with Implications in Clinical Practice

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 6,263 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 3,131 patients (16.4%) in the dapagliflozin group and in 610 of 3,132 patients (19.5%) in the placebo group (hazard ratio: 0.82; 95% confidence interval [CI], 0.73−0.92; P < .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: 0.69−0.91); cardiovascular death occurred in 231 (7.4%) and 261 (8.3%) patients, respectively (hazard ratio: 0.88; 95% CI: 0.74−1.05). 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 (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.). Comments: The DELIVER trial can be considered a landmark trial in the therapy of heart failure. While the role of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) was well established by the DAPA-HF trial, its role in heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) was undetermined. The EMPEROR trials demonstrated the benefits of empagliflozin in HFrEF (EMPEROR-Reduced) and HFpEF (EMPEROR-Preserved). However, while EMPEROR-Preserved showed a mortality reduction and symptom benefit in HFmrEF, only symptom benefit was demonstrated in HFpEF. On the other hand, the DELIVER trial has demonstrated, for the first time, a mortality benefit in HFpEF and HFmrEF patients with dapagliflozin. The benefits of dapagliflozin were the same in patients with EF < 60% and EF > 60%. Strengths: The trial evaluated a large sample size and a diverse population, demonstrating the benefits in a variety of patient populations seen in clinical practice. While dapagliflozin (like all agents) remains more useful in HFrEF, this is the first agent which has shown a mortality benefit in HFpEF, which is otherwise a difficult-to-treat population. Implications: As a consequence of the EMPEROR-Reduced and the DELIVER trials, the ACC/AHA/HFSA Heart Failure guidelines 2022 recommend the use of SGLT2 inhibitors in HFpEF with a Class 2A recommendation. For day-to-day practice, it is now possible to prescribe an evidence-based and effective agent in patients with HFpEF, something which was not possible before. The following trials demonstrate the conflicting evidence available in deciding targets for preventive cardiology. To start, the completely Indian MERIFACS study gives an interesting insight into the concept of the “Metabolic Syndrome”.