Key result
Atrasentan resulted in heart failure in 4.0% of patients versus 2.8% with placebo (HR 1.39; 95% CI 0.97-1.99; P=0.072), with early BNP increases during enrichment strongly predicting subsequent HF risk.
Why the study?
Atrasentan reduced kidney failure in type 2 diabetes and CKD but showed a numerically higher incidence of HF hospitalization, prompting evaluation of whether early changes in BNP and body weight predict HF risk.
Do early changes in BNP and body weight during atrasentan treatment predict the risk of heart failure hospitalizations in patients with type 2 diabetes and CKD?
RCT (n=3,668)
Do early changes in BNP and body weight during atrasentan treatment predict the risk of heart failure hospitalizations in patients with type 2 diabetes and CKD?
Hazard Ratio: 1.39 (95% CI 0.97–1.99)
Absolute Event Rate: 4% vs 2.8%
p-value: p=0.072
Early increases in BNP during atrasentan treatment strongly predict subsequent heart failure hospitalization, suggesting that BNP monitoring can identify patients at risk and mitigate this adverse effect while preserving nephroprotective benefits.
Early BNP rise identifies higher HF risk on atrasentan; excluding such patients attenuates HF signal while preserving kidney protection.
BACKGROUND: The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization. OBJECTIVES: The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk. METHODS: Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations. RESULTS: Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78). CONCLUSIONS: In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).
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Smeijer et al. (2022) conducted an RCT in Type 2 diabetes mellitus and chronic kidney disease (n=3,668). Atrasentan vs. Placebo was evaluated on Heart failure hospitalizations (HR 1.39, 95% CI 0.97-1.99, p=0.072). Atrasentan resulted in heart failure in 4.0% of patients versus 2.8% with placebo (HR 1.39; 95% CI 0.97-1.99; P=0.072), with early BNP increases during enrichment strongly predicting subsequent HF risk.
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