Abdominal obesity may be effect modifier of benefit of MRA therapy in HF patients
Effect of eplerenone in patients with heart failure and reduced ejection fraction: potential effect modification by abdominal obesity. Insight from the EMPHASIS‐HF trial
Obesity is associated with an increased risk of cardio-renal disease, including hypertension, CAD, and adverse cardiac remodeling, as well as progression towards HF . Obese subjects have higher aldosterone levels, which may result in mineralocorticoid receptor (MR) over-activation. Moreover, higher aldosterone levels have been implicated in the development and maintenance of obesity [1,2]. MR Antagonist (MRA) therapy improves outcomes in patients with chronic systolic HF with mild symptoms, in patients with acute post-MI symptomatic systolic HF, and in severe NYHA class III–IV systolic HF [3-5]. However, the influence of established overweight or obesity on the response to MRAs is unknown.
In this post-hoc analysis of EMPHASIS-HF, the interaction between increased adiposity and the clinical benefit from the MRA eplerenone was evaluated, in patients with congestive HF. The double-blind EMPHASIS-HF trial randomized 2587 patients with NYHA class II HF and an EF< 35% (HFrEF) to eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was the composite of CV death or first hospitalization for HF.
The obesity measures were waist circumference (WC) and BMI. Subjects were divided into two WC groups according to the American Heart Association (AHA) defined cut-offs. Men and women with WC values <102 and <88 cm, respectively, were considered to have a normal WC (NWC group), whereas those with WC values ≥102 and ≥88 cm, respectively, were considered to have high WC (HWC group). Subjects were further categorized according to WC quintiles taking into account gender differences. Patients with BMI values ≥30 kg/m2 were classified as obese, while patients with BMI values <30 kg/m2 were characterized as normal-weight and overweight.
- Overall, there were fewer primary endpoints in the eplerenone group (multivariable [mv] HR: 0.63; 95% CI: 0.52–0.75). Similar reductions were seen for all-cause mortality (HR: 0.76; 95% CI: 0.61–0.94), CV mortality (HR: 0.73; 95% CI: 0.58–0.93), and hospitalization for HF (HR: 0.59; 95% CI: 0.48–0.73).
- The effect of eplerenone on the primary outcome was significant in both patients with HWC (mvHR: 0.48; 95% CI: 0.37–0.63) and in patients with NWC (mvHR: 0.77; 95% CI: 0.61–0.98), but significantly stronger in the HWC group as demonstrated by a P-value for the interaction of 0.01.
- Abdominal obesity, i.e. HWC, was not associated with the primary outcome in the placebo group (mvHR: 0.96; 95% CI: 0.76–1.20) whereas it was associated with lower rates for the primary events in the eplerenone group (mvHR: 0.60; 95% CI: 0.45–0.80),(P interaction for eplerenone and HWC=0.01).
- The interaction between eplerenone and HWC only reached statistical significance for the secondary outcomes of CV death and HF hospitalization (P for interaction 0.09 and 0.07).
- The benefit of eplerenone on the rate of the primary outcome seemed to be greater in obese patients (mvHR: 0.49; 95% CI: 0.35–0.71) compared with patients with BMI<30 kg/m2 (mvHR: 0.69; 95% CI: 0.57–0.83).
- When stratifying patients according to the median BMI value of 27 kg/m2, the benefit of eplerenone on the rate of the primary outcome was greater in patients with BMI≥27 kg/m2 (mvHR: 0.50; 95% CI: 0.38–0.65) compared with patients with BMI<27 kg/m2 (mvHR: 0.76; 95% CI: 0.61–0.94; P for interaction=0.018).
- Likewise, the benefit of eplerenone on the rates of hospitalization for HF was greater in patients with BMI≥27 kg/m2 (mvHR: 0.44; 95% CI: 0.33–0.62) compared with patients with BMI<27 kg/m2 (mvHR: 0.68; 95% CI: 0.52–0.88; P for interaction=0.051).
In the EMPHASIS-HF study, eplerenone improved outcomes in HFrEF patients with and without abdominal obesity, although the benefit appeared to be more pronounced among those with abdominal obesity. These findings imply that adiposity measures may help identify responders to MRA therapy in HF patients and it is postulated that part of the known obesity paradox observed in HF trials might be explained by greater benefits derived from MRA treatment by obese individuals.
In their editorial article, Ahmed et al.  note that the data published by Olivier et al., should not be used to make therapeutic decisions for the time being, because they need confirmation with every-day clinical practice data. They observe that although one would expect to see a paradoxical beneficial association in patients in the placebo group, this was not the case. And they conclude:
‘Findings from the EMPHASIS-HF trial demonstrated that eplerenone reduced the risk of poor outcomes in patients with HFrEF, and findings from the current subgroup analyses confirm that the clinical benefits of eplerenone are unaffected by obesity of either type, and that obesity should not be used to determine eligibility for MRA use in patients with HFrEF. Nevertheless, this study provides provocative observations on the possible role of abdominal obesity in patients with mild to moderate HFrEF. Further studies are needed to confirm and extend these observations in larger populations of younger and older HFrEF patients that include women, and patients from diverse racial and ethnic backgrounds. Additionally, it would be important to assess whether excess adiposity plays a role in the treatment response in patients with HF with preserved ejection fraction, who exhibit significant activation of the renin–angiotensin–aldosterone system, but in whom a clinical benefit from the use of MRAs has not been shown, to date.’