A recent study published in Circulation: Heart Failure¹ has found that multimorbidity, the presence of two or more chronic health conditions, substantially increases the risk of mortality in patients with heart failure who have mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF).

The study analyzed data from two major heart failure trials: TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial, excluding patients randomized in Russia and Georgia) and PARAGON-HF (Efficacy and Safety of Sacubitril/Valsartan Compared to Valsartan on Morbidity and Mortality in Heart Failure with Preserved Ejection Fraction). This analysis included data from 6,504 patients, with multimorbidity affecting over 95% of participants.

At the individual patient level, specific combinations of chronic conditions associated with the highest mortality risks, including: 

• Prior stroke combined with peripheral artery disease: Hazard Ratio 1.88 (95% CI, 1.27–2.79)
• Peripheral artery disease and chronic obstructive pulmonary disease: HR 1.81 (95% CI, 1.31–2.51)
• Coronary artery disease and stroke: HR 1.67 (95% CI, 1.33–2.11)

From a population health perspective, the comorbidity pairs with the greatest contribution to mortality were:

• Hypertension and chronic kidney disease (CKD): accounting for 14.8% of deaths
• Diabetes and CKD: 13.3% of deaths
• Hypertension and diabetes: 11.9% of deaths

Some comorbidity pairs exhibited a synergistic effect, indicating that their combined impact exceeded the risk associated with each condition alone. For instance, patients with both diabetes and CKD faced a 46% higher mortality risk than expected based on either condition.

Dr Ishan Kamat and Dr Ajith Nair, authors of an accompanying editorial titled "The Ubiquity of Multimorbidity: Comorbid Conditions and Mortality in HFpEF," highlight the urgent need for an integrated treatment approach. “The success of therapies for heart failure with preserved ejection fraction may be driven by their impact on multimorbidity rather than heart failure alone," they noted, emphasizing the importance of viewing heart failure as a multisystem disorder requiring holistic management.²

References: 

1. Yang M, Kondo T, Dewan P, et al. Impact of Multimorbidity on Mortality in Heart Failure With Mildly Reduced and Preserved Ejection Fraction. Circ Heart Fail. 2025:e011598. doi: 10.1161/CIRCHEARTFAILURE.124.011598. Epub ahead of print. PMID: 40026147.
2. Kamat I, Nair A. Ubiquity of Multimorbidity: Comorbid Conditions and Mortality in HFpEF. Circ Heart Fail. 2025:e012432. doi: 10.1161/CIRCHEARTFAILURE.124.012432. Epub ahead of print. PMID: 40026148.