Clinical Characteristics and Outcomes in Patients With Heart Failure: Are There Thresholds and Inflection Points in Left Ventricular Ejection Fraction and Thresholds Justifying a Clinical Classification?

Abstract

BACKGROUND: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes. METHODS: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models. RESULTS: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal (“supranormal”) LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion. CONCLUSIONS: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, NCT01920711.

Torsemide Versus Furosemide After Discharge in Patients Hospitalized With Heart Failure Across the Spectrum of Ejection Fraction: Findings From TRANSFORM-HF

“…The finding reported herein that the risk of adverse outcomes, including all-cause mortality and all-cause hospitalization, was similar in patients with HFrEF, HFmrEF, and HFpEF, even after adjusting for confounders, is in contrast to existing literature which primarily supports that patients with HFrEF have worse clinical outcomes. 7,12,13 TRANSFORM-HF, owing to its pragmatic design and method for end point ascertainment, prespecified the use of all-cause death and allcause hospitalization, alone and in combination, as its end points. 8 Previous HF studies have mainly focused on cardiovascular mortality and HF hospitalization and have shown that HFrEF is associated with an increased risk of these compared with HFpEF, which is, in part at least, counterbalanced by the proportionally lower risk of noncardiovascular mortality and hospitalization.…”

What Is a Normal Left Ventricular Ejection Fraction?

“…However, the more patient-relevant metric is absolute benefit. The study by Kondo et al 4 demonstrates that the absolute risk of cardiovascular death and heart failure hospitalization decreases with increasing LVEF. Thus, the relative benefit of treatment, when multiplied by the lower absolute risk, leads to less absolute benefit with SGLT2 inhibitors at a higher LVEF.…”

“…The study by Kondo et al 4 shows that the LVEF-outcome relationship is complex, with different thresholds for increased risk depending on the outcome. Thus, there is no clear range at which we can say the LVEF is normal (optimal health).…”

“…The relationship between LVEF and outcome for those with heart failure is explored in this issue by Kondo and colleagues. 4 The authors merged data from 33 699 patients from 6 randomized controlled heart failure trials. They determined how patient characteristics and several important outcomes varied by LVEF.…”