The SGLT2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study's 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, "We saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn't see any safety concerns in this very vulnerable and sick patient population," Adriaan A. Voors, MD, University Medical Center Groningen, the Netherlands, said when presenting the trial during the virtual American Heart Association Scientific Sessions 2021.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment's win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor's win ratio for the primary endpoint was 1.36 (95% CI, 1.09 - 1.68, P = .0054), Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality-of-life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Voors told theheart.org | Medscape Cardiology. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug "is not only safe to start early in-hospital, but it's also beneficial to start early in-hospital."
EMPULSE, combined with support from other recent trials, "should be clinical-practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status," Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told theheart.org | Medscape Cardiology.
"For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors — once stabilized and in the absence of contraindications — should be considered a new standard of care," said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of "simultaneous or rapid-sequence initiation" of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction (HFrEF) in patients hospitalized with HFrEF, once they are stabilized, Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings "fill an important gap and are clearly practice changing," agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following the Voors presentation. "Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure."
Of note in the trial, Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. "Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention," she said.
"This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized."
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the "winners," that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared to about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio (HR) of 0.65 (95% CI, 0.43 - 0.99, P = .042). They also were less likely to experience acute renal failure(7.7% vs 12.1% for the control group) or serious adverse events (32.3% vs 43.6%), Voors reported.
Tempting as it might be, the findings can't necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim-Eli Lilly Diabetes Alliance.
American Heart Association Scientific Sessions 2021. Session LBS.05: Building on the Foundations of Treatment: Advances in Heart Failure Therapy. Efficacy and Safety of Empagliflozin in Hospitalized Heart Failure Patients: Main Results From the EMPULSE Trial. Presented November 14, 2021.
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