Therapy-related changes in natriuretic peptides (NPs) modestly correlated with longer-term treatment effects on hospitalization for heart failure (HF) but not with effects on all-cause mortality, according to results of a study presented by Muthiah Vaduganathan, MD, MPH, at ACC.18. The results were also published in the JACC: Heart Failure. 

A trial-level analysis was conducted of 16 phase III randomized HF trials including 48,844 patients. Trial-level estimates of treatment effects on NPs and clinical outcomes were determined using data on the change in NPs in the two treatment groups over ≥1 month follow-up. The analysis focused on data for all-cause mortality and hospitalization for HF. Between-group differences in the change in log-transformed NPs were plotted against the magnitude of the treatment effect on clinical endpoints. Weighted Pearson correlation coefficients were calculated for average control- or placebo-corrected changes in NPs and the longer-term treatment effects on clinical endpoints.

The median follow-up for clinical endpoints was 28 months. NP data were available for a median 748 patients. The analysis showed that treatment-induced changes in NPs were not well correlated with treatment effects on all-cause mortality (weighted r=0.12). No correlations between changes in NPs and treatment effects on all-cause mortality were observed according to timing of NP sampling and other major trial factors.

Treatment-induced effects on NPs were signficantly correlated with treatment effects on hospitalization for HF (weighted r=0.63). Correlations between NP changes and treatment effects were consistently observed with respect to timing of NP assessment. Significant correlations between NP changes and hospitalization for HF were observed across key trial-level subgroups, including trials completed in the last decade, trials using NT-proBNP assays, and trials assessing renin-angiotensin-aldosterone system inhibitors.

According to the investigators, this analysis highlights issues with reliance on short-term NP changes in phase II trials to predict the long-term response in a subsequent phase III trial. “The use of NPs cannot reliably be utilized to estimate the probable effect of a drug or device on the risk of death,” they wrote.

The investigators urged caution in using NPs as the primary strategy for decision-making in phase II trials or for determining the most appropriate drug doses to evaluate in phase III trials.

In an editorial comment, James L. Januzzi Jr., MD, FACC, wrote “The authors found changes in NP concentrations were surprisingly not correlated to effect of treatment on all-cause mortality, but appeared modestly correlated to occurrence of HF hospitalization. The correlation with hospitalization was much stronger in studies of renin-angiotensin-aldosterone system inhibitors.” Their results affirm that more knowledge is required before biomarkers can be acceptable clinical trial endpoints.

Keywords: ACC18, ACC Annual Scientific Session, Renin-Angiotensin System, Follow-Up Studies, Natriuretic Peptide, Brain, Peptide Fragments, Natriuretic Peptides, Heart Failure, Biomarkers

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