In patients with heart failure with reduced ejection fraction (HFrEF), a high ratio of urinary cyclic guanosine monophosphate (ucGMP) levels to plasma B-type natriuretic peptide (BNP) levels is associated with better outcomes, with sacubitril/valsartan vs enalapril treatment increasing this ratio, according to findings published in the journal Circulation: Heart Failure.
Investigators sought to evaluate the relationship between ucGMP:BNP ratio and clinical outcomes; the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP:BNP ratio; and the efficacy of sacubitril/valsartan on clinical outcomes, according to baseline ucGMP:BNP ratio using data from the randomized, double-blind, placebo-controlled PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitors With Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure; ClinicalTrials.gov identifier: NCT01035255) trial.
Overall, a total of 2039, 2031, 1959, and 1746 individuals had both ucGMP and BNP measurements available at baseline, at randomization, at 1 month following randomization, and at 8 months following randomization, respectively. The median ucGMP:BNP ratio at baseline was 3.50 (25th-75th percentile, 1.81-6.42). The
3 groups that were defined based on ucGMP:BNP ratio at baseline were tertile 1 (<2.29), tertile 2 (2.29-5.17), and tertile 3 (≥5.18). The primary study outcome was a composite of HF hospitalization or cardiovascular death.
Compared with the lowest tertile, participants in the higher tertiles experienced a lower risk for the primary outcome (tertile 1: reference; tertile 2: hazard ratio [HR], 0.57; 95% CI, 0.45-0.71; tertile 3: HR, 0.54; 95% CI, 0.43-0.67).
Additionally, compared with baseline, the ucGMP:BNP ratio at 1 month and at 8 months following randomization was higher with sacubitril/valsartan treatment than with enalapril therapy, with geometric mean ratios at 1 month and at 8 months of 1.38 (95% CI, 1.27-1.51) and 1.32 (95% CI, 1.20-1.45), respectively. This difference was consistent across tertiles of ucGMP:BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). Further, for all outcomes, the effect of sacubitril/valsartan vs enalapril was consistent across tertiles of ucGMP:BNP ratio at baseline (Pinteraction ≥0.31).
Some limitations of the study include a potential contribution from intrarenal cGMP production in response to neprilysin inhibition, which cannot be excluded. Although the study measured the ucGMP:BNP ratio, the cGMP response to atrial natriuretic peptide (ANP) is greater than to BNP, therefore use of a ucGMO:ANP ratio might have been more informative.
“In patients with HFrEF, a higher ucGMP/BNP ratio was associated with better outcomes,” the study authors wrote. “These findings suggest that the natriuretic peptide-cGMP axis remains intact and responsive in HFrEF and that augmentation of natriuretic peptide-mediated cGMP release could be therapeutically beneficial.”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Butt JH, Ibrahim W, Dewan P, et al.Urinary cGMP (cyclic guanosine monophosphate)/ BNP (B-type natriuretic peptide) ratio, sacubitril/ valsartan, and outcomes in heart failure with reduced ejection fraction: an analysis of the PARADIGM-HF trial. Circ Heart Fail. Published online January 25, 2023. doi:10.1161/CIRCHEARTFAILURE.122.010111