Adiposity-Related Anthropometrics and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Participant-Level Pooled Analysis of Randomized Clinical Trials

BACKGROUND: Obesity is highly prevalent among individuals with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) and is associated with increased risk of disability and death.

OBJECTIVES: The purpose of this study is to explore the association between different adiposity-related anthropometrics and clinical outcomes in this population.

METHODS: In this participant-level pooled analysis of 5 international randomized trials that enrolled adults with HFmrEF/HFpEF, the association between adiposity-related anthropometrics (body mass index [BMI], waist circumference [WC], and waist-to-height ratio [WHtR]) and heart failure (HF) and mortality outcomes was evaluated, overall and by age and sex. Independent and combined associations between BMI and/or WHtR and outcomes were also assessed.

RESULTS: At baseline, BMI was available in 21,479 participants, and WC and WHtR were available in 7,827. Overall, 46% had BMI ≥30 kg/m2 and 95% had elevated WC or WHtR. Among those with BMI <30 kg/m2, 89% had excess abdominal adiposity, especially older and female participants. Sex (Pinteraction = 0.003) and race (Pinteraction = 0.046) modified the association between BMI and WHtR, such that women vs men had higher WHtR at higher BMI, and Asian and Black participants had higher WHtR at lower BMI. Although BMI exhibited complex J- and U-shaped associations with clinical outcomes, higher WHtR was linearly associated with increased risk of HF and mortality events. Younger participants exhibited the steepest associations between BMI or WHtR and cardiovascular death or HF hospitalization (Pinteraction <0.001 for both). Independent of BMI, higher WHtR was associated with adverse outcomes. Independent of WHtR, higher BMI was associated with HF hospitalization. Participants with elevated BMI and WHtR experienced higher rates of cardiovascular death or HF hospitalization vs those with elevated BMI or WHtR alone.

CONCLUSIONS: These data from 5 large-scale HFmrEF/HFpEF clinical trials further question the utility of BMI as the sole measure to define obesity. WC or WHtR assessment identifies a substantial number of individuals with abdominal obesity despite BMI <30 kg/m2, and may enhance risk stratification beyond BMI alone in HFmrEF/HFpEF. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213; Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711; Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve] (NCT00095238); Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM-Preserved] (NCT00634712).