Insights from PARAGON-HF: Sacubitril/Valsartan Favorably Alter the Biomarkers of Extracellular Matrix Regulation in HFpEF Patients

Background

Studies have postulated that the changes in the myocardial extracellular matrix (ECM) homeostasis have a role to play in the development and progression of heart failure (HF). These changes in EMC homeostasis encompass changes in synthesis, processing, degradation, and turnover of proteins such as fibrillar collagen, and can be detected by analyzing circulatory markers such as N-terminal propeptide of collagen I [PINP] and N-terminal propeptide of collagen III [PIIINP].  Considering the impact of sacubitril/valsartan on natriuretic peptides, it has been hypothesized that these circulating biomarkers are altered by sacubitril/valsartan vs. valsartan alone.

Aim

To determine the impact of sacubitril/valsartan on biomarkers of ECM homeostasis and to determine the association between biomarkers and the primary endpoint (total HF hospitalizations and cardiovascular death) of the “Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction” (PARAGON-HF) study

Patient Profile

• Patients with chronic heart failure with preserved ejection fraction (HFpEF) (age ≥ 50 years) with New York Heart Association (NYHA) functional classes II to IV, and left ventricular ejection fraction (LVEF) ≥45%
• All patients were on diuretic therapy, had evidence of structural heart disease, along with elevated level of natriuretic peptides (with lower thresholds for patients with recent hospitalization for HF and higher thresholds in the presence of atrial fibrillation)

Methods

Study Design

• Substudy of the PARAGON-HF study, which was a multicenter, double-blind randomized clinical trial

Treatment Strategy

• Patients who tolerated both study drugs during sequential run-in period were randomized 1:1 to sacubitril/valsartan or valsartan

Assessments

• Five biomarkers assessed during the study included:
  • Soluble ST2 (sST2)
  • PINP
  • PIIINP
  • Tissue inhibitor of matrix metalloproteinase (TIMP)-1
  • Carboxyl-terminal telopeptide of collagen type (CITP)-I
• Biomarker assessments were conducted at pre-specified baseline (n=1135), at week 16 after randomization (n=1113) and at week 48 after randomization (n=1016)

Outcomes

• The effects of sacubitril/valsartan on the five biomarkers included in the study vs. those of valsartan alone
• Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint of PARAGON HF study [composite of total (first and recurrent) hospitalizations for HF and cardiovascular death]

Results

• The study subjects had high use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, diuretic, and beta-blocker
• The patient characteristics were balanced at baseline in both the study groups except for minor yet statistically significant higher prevalence of stroke (14% vs. 8%; p = 0.01) and hypertension (97% vs. 95%; p = 0.02) in sacubitril/valsartan group.
• At baseline all five biomarkers were higher than published referent control values for the study subjects. Biomarker levels differed by gender, with males having higher sST2, PIIINP, TIMP-1, and CITP-I levels and females having higher PINP levels
• At week 16, post-randomization, as compared with valsartan alone, sacubitril/valsartan significantly decreased TIMP-1, sST2, and PIIINP and increased CITP-I (Table 1). Changes in PINP did not differ significantly between the groups. The findings remained consistent in males, females and in patients with LVEF above or below the median of 57%.

• Reductions in TIMP-1 and sST2 with sacubitril/valsartan vs. valsartan alone remained consistent at week 48 post-randomization. PIIINP and PINP were numerically lower and CITP-I was numerically higher with sacubitril/valsartan vs. valsartan alone, though the difference was statistically insignificant
• As per a multivariate analysis adjusted for seven confounders including LVEF, NT-proBNP, high-sensitivity troponin (hsTNT), and randomized treatment group; changes in TIMP-1 (rate ratio [RR]: 1.23; 95% CI: 1.03 to 1.47; p = 0.02), sST2 (RR: 1.15; 95% CI: 1.02 to 1.31; p = 0.03), and CITP (RR: 1.26; 95% CI 1.03 to 1.55; p =0.03) were associated with primary endpoint.

Conclusions

• Biomarkers that reflect ECM homeostasis (sST2), collagen synthesis (PINP, PIIINP), and collagen degradation and turnover (TIMP-1, CITP) are elevated in HFpEF patients. Sacubitril/valsartan treatment favorably altered these biomarkers
• Considering the role of interstitial myocardial fibrosis in pathogenesis and prognosis of HFpEF these antifibrotic properties of sacubitril/valsartan may be beneficial in patients with HFpEF.

J Am Coll Cardiol. 2020 Aug;76(5):503-514.