DELIVER May Demystify Med Therapy in HF With Improved LVEF

In an era when left ventricular ejection fraction (LVEF) has become less critical for guiding drug therapy for some patients with heart failure (HF), it remains helpful for defining HF categories, even as it complicates the lexicon.

There is debate, for example, over best management for HF patients who have responded to therapy well enough to transition from a lower-tier to higher-tier LVEF category.

Such patients with improved ejection fraction (HFimpEF) were, despite their gains in LVEF, still at substantially increased clinical risk in a new secondary analysis from the DELIVER randomized trial.

As recently reported, DELIVER entered HF patients with an LVEF greater than 40%, that is, HF with either mildly reduced or preserved ejection fraction (HFmrEF or HFpEF, respectively). Those assigned to dapagliflozin (Farxiga) vs placebo over 2 years overall showed an 18% drop (P = .0008) in risk for the primary endpoint, worsening HF or cardiovascular (CV) death.

The new analysis centered on the 18% of patients in the trial with an initial LVEF greater than 40%, per entry criteria, but who previously were symptomatic with an LVEF of 40% or lower, that is, HF with reduced ejection fraction (HFrEF).

Such patients in the new analysis, which adds substantially to the scant evidence base for treatment of HFimpEF, were at risk for the primary endpoint to a similar degree as those without a documented HFrEF history.

Table 1. Events per 100 Patient-Years in DELIVER, HFimpEF vs HF With LVEF Consistently Greater Than 40%

Endpoints HFimpEF, n = 1151 LVEF Consistently >40%, n = 5112
Worsening HF or CV death 8.8 8.7
CV death 3.4 3.6


Their ostensible dapagliflozin benefit was comparable as well; they showed a significant 26% decrease in risk for worsening HF or CV death compared to the control group.

Dapagliflozin and other SGLT2 inhibitors lately are core components of guideline-directed medical therapy (GDMT) for heart failure, almost regardless of LVEF. Lacking good data on HFimpEF, the guidelines advise continuing previous GDMT in such cases lest LVEF deteriorate again.

DELIVER patients with HFimpEF, despite previous LVEF improvement, “encountered heightened risks of disease progression, including worsening heart failure events and death, which were comparable to those who have had LVEF consistently over 40%,” Orly Vardeny, PharmD, said when reporting the analysis October 2 at the Heart Failure Society of America (HFSA) 2022 Annual Scientific Meeting, held in National Harbor, Maryland.

The findings from the largest-yet randomized HFimpEF dataset “suggest that patients with heart failure with improved ejection fraction who remain symptomatic may benefit from the addition of a SGLT2 inhibitor to previously instituted GDMT to further reduce morbidity and mortality,” said Vardeny, University of Minnesota, Minneapolis.

The HFimpEF patients in DELIVER benefited significantly from dapagliflozin for both the composite primary endpoint and the CV-death component, for which the risk reduction reached a significant 38%. The difference in the other component, hospitalization or urgent visit for HF, or worsening HF, didn’t attain significance.

“This is a group that has improved with ejection fraction presumably on GDMT, and the fact that they still are having events at rates that are comparable to mildly-reduced or HFpEF was surprising,” Vardeny told | Medscape Cardiology.

Table 2. Outcomes in DELIVER, HFimpEF vs HF With LVEF Consistently Greater Than 40%

Endpoints HR (95% CI)
Worsening HF or CV death 0.74 (0.56 – 0.97
Worsening HF 0.84 (0.61 – 1.14)
CV death 0.62 (0.41 – 0.96)


Whereas an improved LVEF on therapy in patients previously with reduced LVEF was once widely considered management success, “It is just an improvement in ejection fraction, that’s it,” she said. “They still have higher event rates. The improvement does not equal cure.”

Vardeny cautioned against attributing the dapagliflozin primary-endpoint benefit in HFimpEF primarily to the significant drop in CV death and apparent lack of effect on worsening HF.

What seems to be a benefit for CV death “is certainly intriguing and hypothesis-generating,” but it’s only a component of the primary endpoint in a subgroup analysis, she said in an interview.

Indeed, the interaction P value for the CV-death comparison of patients with HFimpEF to those with LVEF consistently greater than 40% failed to reach significance at .088.

But in discussion following Vardeny’s presentation, John G. F. Cleland, MD, PhD, who was not part of the study, compared dapagliflozin’s apparent benefit for CV death in HFimpEF to the lack of such an effect in the overall trial. Moreover, in the 2019 trial that established dapagliflozin as effective in nondiabetic patients with HFrEF, DAPA-HF, CV mortality fell a significant 18%.

That touches on the frequent question of whether, with respect to therapy, HFimpEF should be considered more like HFrEF or closer to HFpEF.

With respect to CV mortality in patients with HFimpEF, “the results look much more like DAPA-HF than the rest of DELIVER,” said Cleland, of the University of Glasgow Institute of Health and Wellbeing, Glasgow, Scotland.

Also, he said to Vardeny, “We should be careful about the definition of heart failure with improved ejection fraction that you’ve adopted.”

As presented, it left out a key HFimpEF criterion specified in the recent universal definition of heart failure, which calls for LVEF improvement to greater than 40% but also by at least 10 absolute percentage points.

By the study’s definition, Cleland cautioned, “somebody could move from perhaps 39% up to 41% and that will be counted as improved.”

The data forms used in DELIVER captured HFimpEF status only by asking, in binary fashion, whether patients had previously been symptomatic with an LVEF of 40% or lower, Vardeny explained to | Medscape Cardiology.

“That’s a big limitation,” she said. “We didn’t collect what that specific EF value was, nor did we collect when that was obtained.”

But given their baseline features, the HFimpEF-categorized patients more resembled the HFrEF group “from which they emerged” than those with HFpEF, she said, “which helps reassure us they are indeed this phenotype.”

At baseline, she had reported, the HFimpEF patients, compared to those with LVEF consistently greater than 40%, were younger, more likely male, less likely White, more likely to have NYHA class II symptoms, and had a lower LVEF.

Their management at baseline also seemed a closer fit to HFrEF than to HFpEF, Vardeny said, as it entailed greater use implantable defibrillators, beta blockers, mineralocorticoid receptor antagonists, and angiotensin-receptor/neprilysin inhibitors.

DELIVER was funded by AstraZeneca. Vardeny discloses receiving research support from AstraZeneca, Bayer, and Cardurion. Cleland disclosed no relevant financial relationships.

Heart Failure Society of America (HFSA) 2022 Annual Scientific Meeting: Presented October 2, 2022.

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