Racial differences in low natriuretic peptide levels: Implications for heart failure clinical trials

Some patients with heart failure (HF) have low natriuretic peptide (NP) levels. It is unclear whether specific populations are disproportionately excluded from participation in randomized clinical trials (RCT) with inclusion requirements for elevated NPs. We investigated factors associated with unexpectedly low NP levels in a cohort of patients hospitalized with HF, and the implications on racial diversity in a prototype HF RCT.

We created a retrospective cohort of 31,704 patients (age 72 ± 16 years, 49% female, 52% Black) hospitalized with HF from 2010 to 2020 with B-type natriuretic peptide (BNP) measurements. Factors associated with unexpectedly low BNP levels (<50 pg/mL) were identified using multivariable logistic regression models. We simulated patient eligibility for a prototype HF trial using specific inclusion and exclusion criteria, and varying BNP cut-offs.

Unexpectedly low BNP levels were observed in 8.9% of the cohort. Factors associated with unexpectedly low BNP levels included HFpEF (aOR 3.76, 95% CI: 3.36, 4.20), obesity (aOR 1.96, 95% CI: 1.73, 2.21), self-identification as Black (aOR 1.53, 95% CI: 1.36, 1.71), and male gender (aOR 1.45, 95% CI: 1.31, 1.60). Applying limited clinical inclusion and exclusion criteria from PARAGLIDE-HF disproportionately excluded Black patients, with impairment in renal function having the greatest impact. Adding thresholds for BNP of ≥35, ≥50, ≥67, ≥100, and ≥150 pg/mL demonstrated the risk of exclusion was higher for Black compared to non-Black patients (RR = 2.03 [95% CI: 1.73, 2.39], 1.90 [95% CI: 1.68, 2.15], 1.63 [95% CI: 1.48, 1.81], 1.38 [95% CI: 1.28, 1.50], and 1.23 [95% CI: 1.15, 1.31], respectively).

Nearly 10% of patients hospitalized with HF have unexpectedly low BNP levels. Simulating inclusion into a prototype HFpEF RCT demonstrated that requiring increasingly elevated NP levels disproportionately excludes Black patients.