Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial

Abstract

Background and aims: An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF.

Methods: The PARAGON-HF trial randomized 4796 patients with heart failure (HF) and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition.

Results: About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥.5). Among patients who were not obese (BMI <30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥.6). Higher BMI and WHtR were both associated with higher risk of total HF hospitalizations, but as compared with BMI, WHtR was linearly associated with HF outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e. 30% or greater). An obesity-survival paradox (i.e. improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on HF outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity.

Conclusions: In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse HF events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF.

Clinical trial registration: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Keywords: Angiotensin receptor–neprilysin inhibitor; Body mass index; Heart failure with preserved ejection fraction; Obesity; Waist-to-height ratio.

structured graphical abstract

Among patients with heart failure (HF) and a preserved ejection fraction (HFpEF, left ventricular ejection fraction ≥45%), body mass index (BMI) was measured in 4796 patients, and waist-to-height ratio (WHtR) was measured in 4534 patients at baseline. Obesity was defined by BMI ≥30 kg/m², and central adiposity was identified as WHtR ≥.5. The associations of these metrics with incidence of the primary composite outcome of total (first and recurrent) HF hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death are depicted as continuous variables.

Figure 1

Unadjusted Incidence rates of key outcomes according to body mass index (BMI), displayed as a continuous variable. Incidence rates of primary composite outcome of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death according to baseline BMI

Figure 2

Unadjusted incidence rates of key outcomes according to waist-to-height ratio (WHtR), displayed as a continuous variable. Incidence rates of primary composite outcomes of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death according to baseline WHtR

Figure 3

Effect of neprilysin inhibition according to body mass index (BMI), displayed as a continuous variable. Treatment effect of sacubitril/valsartan compared with valsartan of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death across a range of BMI

Figure 4

Effect of Neprilysin Inhibition According to waist-to-height ratio (WHtR), Displayed as a Continuous Variable. Treatment effect of sacubitril/valsartan compared with valsartan of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death across a range of WHtR