Association of cardiovascular-kidney-metabolic multimorbidity with clinical outcomes and guideline-directed medical therapy response in patients with heart failure: a multicentre prospective study

Abstract Background Cardiovascular-kidney-metabolic (CKM) multimorbidity is common in patients with heart failure (HF), but its clinical impact on the Chinese population remains poorly characterized. This study aimed to evaluate the association of CKM multimorbidity with clinical outcomes and the response to guideline-directed medical therapy (GDMT). Methods Based on the GREAT study, this study included 7,339 HF patients from 32 hospitals in an underdeveloped region of China. CKM conditions included atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes. The primary outcome was a composite of 1-yeah cardiovascular death and HF hospitalizations. Secondary outcomes included the individual components of the primary outcome and all-cause death. Competing-risk and Cox models were used to evaluate the association between CKM multimorbidity and clinical outcomes. We also assessed the efficacy of GDMT and the heterogeneity of its benefit across CKM burden strata. Results Overall, 72.1% had ≥ 1 CKM condition and 9.2% had all three. Higher CKM burden was associated with stepwise increased risks of the primary composite endpoint (3 vs. 0 CKM: adjusted Hazard Ratio [aHR] 1.73, 95% CI 1.45–2.07), cardiovascular death (aHR 1.66, 1.26–2.18), HF hospitalization (aHR 1.67, 1.33–2.09), and all-cause death (aHR 2.06, 1.63–2.61) (all p for trend < 0.05). The CKM-associated risk gradient for 1-year outcomes was attenuated by quadruple GDMT (p for trend ≥ 0.05). Although GDMT benefit exhibited no significant heterogeneity across CKM strata, the strongest signal was seen in patients with two CKM conditions (aHR 0.69, 95% CI 0.52–0.91). Conclusions CKM multimorbidity is highly prevalent in this underdeveloped Chinese region and predicts a graded increase in adverse outcomes. Quadruple GDMT attenuated the CKM-related prognostic risk gradient, with the greatest relative benefit in patients with two CKM conditions.