Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis

Objective Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality. Methods Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects. Results For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR 5%-points lower LVEF =1.07, 95% CI 1.04 to 1.10; p interaction =0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HR indirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF. Conclusions The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.