Noncardiac Comorbidities Affect Exercise Capacity and Functional Status in Heart Failure

Noncardiac comorbidities have a significant and cumulative effect on exercise capacity and are associated with worse clinical outcomes in patients with heart failure (HF), according to a study in JACC: Heart Failure.

The cross-sectional study assessed the effects of noncardiac comorbidities on exercise capacity and functional status in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection (HFpEF) using data from 5 clinical trials (HF-ACTION, IRONOUT-HF, NEAT-HFpEF, RELAX-HFpEF, and INDIE-HFpEF).

Exercise capacity was evaluated with peak Vo₂ and 6-minute walking test distance (6MWT), and functional status was assessed with use of the Kansas City Cardiomyopathy Questionnaire (KCCQ).

The analysis included 2777 patients (mean age, 60.3±12.8 years; 67.6% men) with HF, of whom 85% had HFrEF.

Obesity, chronic kidney disease (CKD), diabetes, chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), and anemia were independently negatively associated with peak Vo₂ and 6MWT. Multivariable analysis showed that obesity, followed by diabetes and CKD, had the strongest negative association with peak Vo₂ and 6MWT. Depression, obesity, CKD, stroke, and COPD were associated with a decrease in KCCQ.

The association between noncardiac comorbidities and exercise capacity revealed significant differences between HFrEF and HFpEF for obesity, CKD, and PVD, with all 3 showing a greater limiting effect on peak Vo₂ in patients with HFpEF (P_interaction <.05). Regarding the 6MWT, a similar finding occurred for obesity but not for CKD and PVD. No interaction of noncardiac comorbidities occurred between HFrEF and HFpEF regarding KCCQ.

The cohort had a median cumulative noncardiac comorbidity burden of 3 (IQR, 2-4), and less than 5% of patients had no comorbidities. Patients with HFpEF had a greater median noncardiac comorbidity burden vs those with HFrEF (median, 3 [IQR, 2-4] vs 2 [IQR, 1-3]; P <.001).

The participants with HFpEF had a lower 6MWT and KCCQ score, and peak Vo₂ was not different (P =.068). Each increase in additional noncardiac comorbidity was associated with a comparable progressive decrease in peak Vo₂ and KCCQ, although a more pronounced effect on 6MWT was observed in patients with HFpEF (burden HF type P_interaction =.007).

In the cluster analysis, cluster 3, which included the highest proportion of diabetes and obesity and the lowest proportion of PVD and cancer, had the worst exercise capacity and functional status.

Cox proportional hazards survival analysis adjusted for age, sex, race, and HF type with cluster 1 (highest burden of stroke and cancer) as reference, showed that cluster 2 (oldest patients and the highest proportion of CKD, PVD, and hyperlipidemia) had a 1.60 times increased risk of all-cause mortality (hazard ratio [HR], 1.60; 95% CI, 1.25-2.04; P <.001). The risk in cluster 3 was not significantly different vs cluster 1 (HR, 1.29; 95% CI, 0.97-1.70; P =.076). Each increase in comorbidity was associated with a 1.16 times higher risk of all-cause mortality (HR, 1.16; 95% CI, 1.08-1.26; P <.001) after adjustment for the same variables.

Limitations include the fact that unmeasured covariates may have affected the association between the noncardiac comorbidities and outcome variables. Also, the researchers do not account for the impact or treatment interaction of various drug interventions tested in the different clinical studies.

“Given the common use of KCCQ, 6MWT, and peak Vo₂ as endpoints in randomized controlled trials, knowledge about the importance of NCCs [noncardiac comorbidities] for certain endpoints could allow for better predefined covariate adjustment of trial endpoints,” wrote the investigators.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.