Good for heart, less so for kidneys

A pooled analysis of patient-level data from 9,718 heart failure patients who participated in two trials of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, confirmed the drug’s ability to reduce heart failure hospitalizations “across a broad spectrum of ejection fractions,” but the results are not so straightforward with regard to renal protection, according to Milton Packer, MD, of Baylor University Medical Center in Dallas.

Packer reported results from EMPEROR-Pooled during the first Hot Line session of the 2021 European Society of Cardiology’s Digital Experience—the ESC’s all virtual version of its annual congress. Parts of the analysis were published in three different journals: The New England Journal of Medicine, Circulation, and the European Heart Journal.

The pooled analysis was made possible by the unique design of EMPEROR-Reduced and EMPEROR-Preserved, which are a sort of yin and yang of heart failure studies that come under the umbrella of the EMPEROR Trials Program. Packer chairs the executive committee of that program, and he reported the results—all favorable—of EMPEROR-Reduced at the ESC’s 2020 congress, while EMPEROR-Preserved shared the Hot Line 1 spotlight this year with EMPEROR-Pooled.

“EMPEROR-Reduced and EMPEROR-Preserved were sister trials with nearly identical protocols, investigators, and endpoints, separated by an ejection fraction—40%,” Packer explained. The pooled analysis was planned from the outset, and it had its own statistical plan “that was defined at the start of the program.”

While the individual trials focused on heart failure endpoints, the “primary endpoint of EMPEROR-Pooled was major renal outcomes,” he said.

The heart failure outcomes of the two trials were very closely aligned, with the benefit in both studies driven by a significant reduction in heart failure hospitalizations, which Packer emphasized was “a clinically significant finding.” And, in both trials, the magnitude of the benefit decreased as ejection fractions increased so that there was no significant benefit for patients with ejection fractions of 65% or greater.

But Packer added that it is notable that the heart failure benefit with empagliflozin was greater than that observed with sacubitril/valsartan in the PARAGON-HF trial. During a press briefing, BreakingMED asked Packer if he favors using empagliflozin—or any SGLT2 inhibitor—in combination with sacubitril/valsartan, and he reiterated his support for treating heart failure patients with all four of what are termed the pillars of heart failure management: beta-blockers, MRAs, ARNI/ACEi/ARBs, and SGLT2 inhibitors.

“The primary endpoint of EMPEROR-Pooled was a composite of major renal outcomes, which included renal replacement therapy, and a profound sustained decrease in glomerular filtration rate. However, before pooling the two trials, it was critical to first test for heterogeneity of the results. And, amazingly, we found that the results for renal outcomes in the two trials were quite dissimilar,” Packer said. In EMPEROR-Reduced, empagliflozin cut the risk of a major renal outcome by nearly 50%, but in EMPEROR-Preserved, empagliflozin had no effect on major renal events. “The P value for the difference in the effect of empagliflozin on renal events in the two trials was 0.016,” he said.

Packer said additional analysis pointed to a major difference in the effect of the drug starting at 40% ejection fraction, which he said was especially puzzling because “we know that the value of 40% is an arbitrary cut point with no real pathophysiological meaning. So, we dug deeper into the data by re-examining the definition we used for renal events.” In the trials, the researchers agreed to use an EGFR decline of 40% and renal death as the definition of major renal event. “The more conventional definition is an EGFR decline of 50%,” he said. But even when they re-analyzed the data using the 50% EGFR decline, the “effect of empagliflozin was not significant.”

During a panel discussion following his presentation, Packer was asked to weigh in on an evolving discussion about how ejection fractions should be characterized: what is reduced ejection faction, what is preserved and, finally, what is “normal?”

John J. V. McMurray, MD, of the Western Infirmary Glasgow, who chaired the Hot Line session, said, “I think that the 50% threshold is no longer viable, and I think our concept of 40% to 50% as markedly reduced has to be revisited… It may depend upon the drug, but I think 60% to 65% is clearly the normal range.”

Packer agreed that the 50% threshold—meaning that below 50% was reduced EF and above 50% was preserved EF—needs to be replaced.

Another panelist, Frank Ruschitzka, MD, of University Heart Center in Zurich, Switzerland, suggested that “it is time to do away with preserved ejection fraction terminology… less than 65% should be considered mildly reduced and 65% should be normal. Heart failure with normal ejection fraction.”

Packer said that the population of HFpEF patients with ejection fractions of 65% or more are a “unique population that needs to be studied. They have interesting characteristics: dyspnea, a remarkably low BNP level… I’m not sure they actually have heart failure.”

Nonetheless, he concluded that when taken together, “these findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure with a reduced and preserved ejection fraction, including many not effectively treated with currently available agents.”

  1. A pooled analysis of patient level data from almost 10,000 heart failure patients treated with empagliflozin showed reduced HF hospitalizations, irrespective of EF.

  2. The pooled anlaysis of data from two EMPEROR trials found that empagliflozin did not demonstrate a renal benefit in patients with ejection fractions above 40%.

Peggy Peck, Editor-in-Chief, BreakingMED™

Boehringer Ingelheim and Eli Lilly Company funded EMPEROR-Reduced and EMPEROR-Preserved.

Packer was the Chair of the Executive Committee for the EMPEROR Trials Progra and is a consultant to Boehringer Ingelheim and Eli Lilly in matters related to the EMPEROR-Reduced and EMPEROR-Preserved trials and the EMPEROR Trials Program.

Cat ID: 204

Topic ID: 74,204,730,204,3,127,790,192,925,203