Heart Failure With Improved Ejection Fraction Is a Rising Focus in Cardiovascular Care

Heart failure (HF) is a complex medical condition that affects millions of patients globally. The disease state is characterized by the heart’s inability to adequately fill with or eject blood.¹ Suboptimal ventricular function can be due to compromises in the function or structure of the heart, and common causes include chronic comorbid conditions such as hypertension or ischemic heart disease.²

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In the United States alone, it is estimated that more than 6.7 million Americans older than 20 years have HF. By 2030, that number is expected to rise to 8.5 million.² Additionally, HF readmission rates are a common metric for which hospitals can be financially penalized; therefore, optimizing care for patients with HF is a top priority among health care professionals for numerous reasons.

Hospital pharmacists are uniquely positioned to care for patients while they are acutely ill and identify medication-related issues that could have contributed to their hospitalization. In the outpatient setting, pharmacists can work to prevent future hospitalizations for patients with HF through various services, such as medication counseling and identifying barriers to care.

Classification and Treatment

The 2022 American Heart Association/American College of Cardiology HF guidelines formally introduced a new category of HF called HF with improved ejection fraction (HFimpEF).¹ Patients with HFimpEF previously had a left ventricular ejection fraction (LVEF) at 40% or less but then saw an improvement in their LVEF to greater than 40%. In the past, different terms such as HF-recovered EF and heart failure with preserved ejection fraction (HFpEF)-improved were used to describe this subset of patients, but they did not accurately represent the true physiologic disease status.^1,3

It is important to note that patients with HFimpEF have not fully recovered from HF, and they are not cured of the disease. Rather, these patients can be more accurately described as in remission from HF.¹ HF is a lifelong disease that requires long-term medical management, and patients can clinically improve or worsen throughout their treatment duration.

At one point, patients with HFimpEF were diagnosed with HF with reduced ejection fraction (HFreF) and were ideally receiving a combination of guideline-directed medical therapy (GDMT) agents with an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, an angiotensin receptor–neprilysin inhibitor, a β-blocker, a sodium-glucose cotransporter 2 inhibitor, or a mineralocorticoid receptor antagonist. Currently, the guidelines recommend that patients with HFimpEF should be continued on GDMT to prevent HF and left ventricular dysfunction relapse.¹ Even patients who may become asymptomatic should continue treatment with GDMT because of the risk of HF relapse with GDMT withdrawal.

Evaluating a patient’s LVEF is essential in diagnosing and managing HF. Ejection fraction, along with other laboratory values and symptoms, is used to classify patients into 1 of the 4 different subsets of HF and influences which treatments will be utilized.

HF, heart failure; HFimpEF, heart failure with improved ejection fraction; HFmrEF, heart failure with mid-range ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction.

Avoiding Misclassification of HFimpEF

Trending a patient’s LVEF is important in tracking the trajectory of their HF and determining their clinical status (Figure¹). Analyzing a patient’s LVEF from at least 2 different occasions is especially important in patients with HFimpEF because they could be mistakenly treated as if they fell under a different category of HF. For example, if a patient with HF receives an echocardiogram in the hospital and their LVEF is 50%, they would be considered to have HFpEF. In this case, the guidelines would not support initiating a β-blocker unless there was a compelling indication. However, if the same patient had a previous echocardiogram showing their LVEF was 35%, they would now fall under the HFimpEF category. This would indicate that the patient’s previous therapies helped improve their LVEF and that they should continue their medication regimen to prevent clinical worsening.

The TRED-HF Trial and Continued GDMT Use

The TRED-HF trial (NCT02859311) was conducted to examine the effects of a phased withdrawal of HF GDMT in patients with previous dilated cardiomyopathy. Between April 2016 and August 2017, 51 patients were enrolled in the study and randomly assigned to either continue their current GDMT regimen (n = 26) or undergo a phased withdrawal of their GDMT agents (n = 25). Patients were included in the study if they were asymptomatic and had their LVEF improved from 40% or less to 50% or greater. Patients also needed to have a normalized left ventricular end-diastolic volume indexed to body surface area and a plasma N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) concentration of less than 250 ng/L.

The primary end point was HF relapse within 6 months and was defined by the presence of a reduction in LVEF by more than 10% and to less than 50%, an increase in left ventricular end-diastolic volume by more than 10% and to higher than the normal range, a 2-fold rise in baseline NT-proBNP concentration and to more than 400 ng/L, or clinical evidence of HF. Baseline characteristics were similar between the 2 groups, but idiopathic dilated cardiomyopathy, previous atrial fibrillation, and previous unplanned HF admissions were more common among patients in the treatment withdrawal group.

Within the first 6 months, 11 (44%) patients in the treatment withdrawal group met the primary end point of HF relapse compared with 0 patients assigned to continue treatment (event rate, 45.7%; 95% CI, 28.5-67.2; P = .0001). Additionally, secondary analyses showed worsening Kansas City Cardiomyopathy Questionnaire scores, reduced LVEF, and nonsignificant increases in NT-proBNP and LV volumes following the withdrawal of HF GDMT. Although a relatively small sample size limits the trial, the results suggest that continued GDMT usage in patients with HFimpEF is crucial in maintaining HF remission.⁴

Conclusion

Most of the published literature surrounding HF treatment is largely dominated by the topics of HFrEF and HFpEF. However, HFimpEF is a significant subset of HF that deserves attention. As medication experts, pharmacists provide valuable input in managing patients with HF and optimizing HF GDMT.

REFERENCES

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063

2. Bozkurt B, Ahmad T, Alexander KM, et al. Heart failure epidemiology and outcomes statistics: a report of the Heart Failure Society of America. J Card Fail. 2023;29(10):1412-1451. doi:10.1016/j.cardfail.2023.07.006

3. Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart failure with recovered left ventricular ejection fraction: JACC Scientific Expert Panel. J Am Coll Cardiol. 2020;76(6):719-734. doi:10.1016/j.jacc.2020.05.075

4. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393(10166):61-73. doi:10.1016/S0140-6736(18)32484-X