Cardiovascular-kidney-metabolic overlap in heart failure with preserved ejection fraction: Cardiac structure and function, clinical outcomes, and response to sacubitril/valsartan in PARAGON-HF

Eur J Heart Fail. 2024 Aug;26(8):1762-1774. doi: 10.1002/ejhf.3304. Epub 2024 Jun 26.

Abstract

Aims: Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown.

Methods and results: In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99).

Conclusions: Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden.

Clinical trial registration: ClinicalTrials.gov NCT01920711.

Keywords: Cardiovascular‐kidney‐metabolic; Heart failure; Multimorbidity; Sacubitril/valsartan.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Aged
  • Aminobutyrates* / therapeutic use
  • Angiotensin Receptor Antagonists* / therapeutic use
  • Biphenyl Compounds* / therapeutic use
  • Drug Combinations*
  • Female
  • Glomerular Filtration Rate
  • Heart Failure* / drug therapy
  • Heart Failure* / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Multimorbidity
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / epidemiology
  • Renal Insufficiency, Chronic / physiopathology
  • Stroke Volume* / physiology
  • Tetrazoles / therapeutic use
  • Treatment Outcome
  • Valsartan*

Substances

  • Aminobutyrates
  • Valsartan
  • Biphenyl Compounds
  • sacubitril and valsartan sodium hydrate drug combination
  • Drug Combinations
  • Angiotensin Receptor Antagonists
  • Tetrazoles

Associated data

  • ClinicalTrials.gov/NCT01920711