Noncardiac Versus Cardiac Mortality in Heart Failure With Preserved, Midrange, and Reduced Ejection Fraction

Background A thorough analysis of noncardiac determinants of mortality in heart failure ( HF ) is missing. Furthermore, evidence conflicts on the outcome of patients with HF and no or mild systolic dysfunction. We aimed to investigate the prevalence of noncardiac and cardiac causes of death in a cohort of chronic HF patients, covering the whole spectrum of systolic function. Methods and Results We enrolled 2791 stable HF patients, classified into HF with reduced ejection fraction ( HF r EF ; left ventricular ejection fraction [EF] <40%), HR with midrange EF ( HF mr EF ; left ventricular EF 41–49%), or HF with preserved EF ( HF p EF ; left ventricular EF ≥50%), and followed up for all‐cause, cardiac, and noncardiac mortality (adjudicated as due to cancer, sepsis, respiratory disease, renal disease, or other causes). Over follow‐up of 39 months, adjusted mortality was lower in HF p EF and HF mr EF versus HF r EF (hazard ratio: 0.75 [95% CI, 0.67–0.84], P <0.001 for HF p EF ; hazard ratio: 0.78 [95% CI , 0.63–0.96], P =0.017 for HF mr EF ). HF r EF had the highest rates of cardiac death, whereas noncardiac mortality was similar across left ventricular EF categories. Noncardiac causes accounted for 62% of deaths in HF p EF , 54% in HF mr EF and 35% in HF r EF ; cancer was twice as frequent as a cause of death in HF p EF and HF mr EF versus HF r EF . Yearly rates of noncardiac death exceeded those of cardiac death since the beginning of follow‐up in HF p EF and HF mr EF . Conclusions Noncardiac death is a major determinant of outcome in stable HF , exceeding cardiac‐related mortality in HF p EF and HF mr HF . Comorbidities should be regarded as main therapeutic targets and objects of dedicated quality improvement initiatives, especially in patients with no or mild systolic dysfunction.