Key result
Sacubitril/valsartan drives a ~16% greater reduction in hsTnT vs enalapril in ADHF.
Why the study?
Circulating hsTn and sST2 reflect myocardial stress, and cGMP reduces cardiac afterload and preload, but the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and ADHF were not defined.
Does sacubitril/valsartan improve biomarkers of myocardial stress and injury compared to enalapril in patients stabilized after acute decompensated heart failure?
RCT (n=694)
Double-blind
Randomized
Yes
Does sacubitril/valsartan improve biomarkers of myocardial stress and injury compared to enalapril in patients stabilized after acute decompensated heart failure?
Effect estimate: 16% greater reduction
p-value: p=<0.001
In patients with acute decompensated heart failure, in-hospital initiation of sacubitril/valsartan significantly reduces biomarkers of myocardial injury and hemodynamic stress compared to enalapril.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Generally speaking PIONEER was a very important trial for 3 reasons. First, it illustrates that initiation of sacubitril valsartan in hospitalized patients with heart failure leads to a more substantial reduction in NT-proBNP compared to enalapril. This is important because reduction in natriuretic peptides are an excellent surrogate for the benefits of the drug. Secondly, perhaps even more importantly, it shows that this strategy is safe. It's important to understand that the PARADIGM-HF study which was the pivotal phase 3 trial that got sacubitril valsartan available to patients focused on [those] that were stable ambulatory patients. Whereas acutely decompensated heart failure patients were not studied in PARADIGM.”
“We are seeing a reduction in NT-proBNP in acute heart failure patients early on, one that also appears to be accompanied by end-point benefits. I think seeing the concordance is quite promising, in that it suggests the natriuretic peptide decreases are a potentially reliable surrogate for improved clinical outcomes.”
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB use or prior diagnosis of heart failure.”
Sacubitril/valsartan accelerates biomarker declines in ADHF; extends ARNI benefits from chronic HFrEF to early decompensated phases.
AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS: PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION: Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION: NCT02554890 clinical.trials.gov.
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Morrow et al. (2019) conducted an RCT in Acute decompensated heart failure with reduced ejection fraction (n=694). Sacubitril/valsartan vs. Enalapril was evaluated on Change in high-sensitivity cardiac troponin T (hsTnT) concentration at 4 weeks (16% greater reduction, p=<0.001). Sacubitril/valsartan led to a 16% greater reduction in hsTnT and a 9% greater reduction in sST2 at 4 weeks compared with enalapril in patients with acute decompensated heart failure.
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