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Some groups tend to have lower natriuretic peptide levels, making these biomarkers less than ideal for the selection of participants in trials on heart failure with preserved ejection fraction (HFpEF), a secondary analysis of TOPCAT suggested.

Generally, each standard-deviation increase in natriuretic peptide levels was tied to more cardiovascular deaths, heart failure hospitalizations, and aborted cardiac arrests (adjusted HR 1.36, 95% CI 1.22-1.54) over 2.4 years of follow-up, reported Scott Solomon, MD, of Brigham and Women's Hospital in Boston, and colleagues, in

Yet some subgroups started off with higher levels of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide. Concentrations varied by up to half a standard deviation in those with:

• Age >70s
• Non-black race
• BMI <30
• Waist circumference <102 cm (about 40 in) for men or 88 cm for women
• Estimated glomerular filtration rate <60 mL/min/1.73 m²
• History of atrial fibrillation (Afib)

It would be better to have markers that are less sensitive to systematic variation across heterogeneous subsets for use in screening for trials, the investigators emphasized.

Their study was based on TOPCAT participants from the Americas region who had left ventricular ejection fractions of ≥45% and available natriuretic peptide measurements (n=1,057). Median B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide concentrations were 257 ng/L and 959 ng/L, respectively, in this group.

Back in 2013, the main finding from the trial was that spironolactone (Aldactone) was a flop for HFpEF. It took a post-hoc study to show that the drug did work in North and South America, however, as it was apparently undermined by a large number of patients enrolled in Russia who never took the study drug.

Additionally, TOPCAT Americas enrolled almost half of patients based on them meeting a natriuretic peptide threshold, rather than having a history of heart failure hospitalization.

"Applying a single natriuretic peptide threshold for trial entry may contribute to unbalanced selection and may result in an underrepresentation of certain subgroups. Natriuretic peptide thresholds are often used in trials as a risk enrichment strategy, but this approach may exclude patients in these subsets who truly have HFpEF and who experience high rates of cardiovascular events," Solomon's group said.

It is relevant, then, that several ongoing trials of HFpEF therapies (namely , , and ) are applying natriuretic peptide thresholds that differ according to Afib status, while device trials such as take into account BMI in their natriuretic peptide thresholds for trial eligibility, the authors suggested.

A study limitation was the reliance on the subgroup of TOPCAT that had natriuretic peptide measurements available, they said.

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