Results complement findings from larger trials
PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)
Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.
Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.
Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.
No heterogeneity of effect by baseline ejection fraction.
Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.
This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.
The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.
Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.
PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.