Impact of Multimorbidity on Mortality in Heart Failure With Mildly Reduced and Preserved Ejection Fraction

BACKGROUND: How different combinations of comorbidities influence risk at the patient level and population level in patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction is unknown. We aimed to investigate the prevalence of different combinations of cardiovascular and noncardiovascular comorbidities (ie, multimorbidity) and associated risk of death at the patient level and population level. METHODS: Using patient-level data from the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) and PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction), we investigated the 5 most common cardiovascular and noncardiovascular comorbidities and the resultant 45 comorbidity pairs. Cox proportional hazard models were used to calculate the population-attributable fractions for all-cause mortality and the relative excess risk due to interaction for each comorbidity pair. RESULTS: Among 6504 participants, 95.2% had at least 2 of the 10 most prevalent comorbidities. The comorbidity pair with the greatest patient-level risk was stroke and peripheral artery disease (adjusted hazard ratio, 1.88 [95% CI, 1.27–2.79]), followed by peripheral artery disease and chronic obstructive pulmonary disease (1.81 [95% CI, 1.31–2.51]), and coronary artery disease and stroke (1.67 [95% CI, 1.33–2.11]). The pair with the highest population-level risk was hypertension and chronic kidney disease (CKD; adjusted population-attributable fraction, 14.8% [95% CI, 9.2%–19.9%]), followed by diabetes and CKD (13.3% [95% CI, 10.6%–16.0%]), and hypertension and diabetes (11.9% [95% CI, 7.1%–16.5%). A synergistic interaction (more than additive risk) was found for the comorbidity pairs of stroke and coronary artery disease (relative excess risk due to interaction, 0.61 [95% CI, 0.13–1.09]), diabetes and CKD (relative excess risk due to interaction, 0.46 [95% CI, −0.15 to 0.77]), and obesity and CKD (relative excess risk due to interaction, 0.24 [95% CI, 0.01–0.46]). CONCLUSIONS: The risk associated with comorbidity pairs differs at the patient and population levels in heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. At the population level, hypertension, CKD, and diabetes account for the greatest risk, whereas at the patient level, polyvascular disease and chronic obstructive pulmonary disease are the most important.