Volenrelaxin Shows Worsening Congestion in HFpEF Patients: A Phase 2 Trial Analysis
A recent phase 2 randomized trial investigated the effects of the long-acting human relaxin agonist, volenrelaxin, in patients with recently decompensated heart failure with preserved ejection fraction (HFpEF). The study revealed that, despite some indication of improved left atrial (LA) function at lower doses, treatment with volenrelaxin was associated with worsening congestion across multiple measures – imaging, laboratory findings, and clinical assessments. These findings do not support the use of volenrelaxin as a therapy for this patient population.
The trial evaluated multiple dosages of volenrelaxin, though researchers noted a lack of clear dose-response relationships or meaningful treatment interaction based on dosage.A key limitation of the study was its early termination before achieving the target enrollment, which reduced the statistical power. Plasma volume was estimated using a validated formula, rather than direct measurement, and circulatory congestion was not assessed via invasive hemodynamics, a practical consideration given the trial’s size.
Though, the study leveraged validated biomarkers - NT-proBNP – and echocardiographic measures (E/e′) to estimate circulatory congestion, building on previous research demonstrating their reliability29, 30, 31. The researchers acknowledge the study was not powered to evaluate clinical heart failure (HF) events and therefore cannot draw conclusions regarding the impact of volenrelaxin on hard outcomes.
The cohort studied comprised patients with advanced HFpEF, characterized by severe congestion, cardiac dysfunction, and sodium avidity, based on the hypothesis that potential benefits of volenrelaxin might be most evident in this group. Ongoing trials evaluating other agents targeting the same pathway are expected to provide further insights into effects across a broader range of HFpEF patients32.
Despite strengths including the novel intervention and robust,multimodal assessment of cardiorenal function and hemodynamics through repeated measurements and complementary biomarkers/echocardiography,the trial ultimately demonstrated a link between volenrelaxin treatment and worsening congestion.
References (as cited in the original text):
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29 Iwanaga, Y. et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J. Am.Coll. Cardiol. 47, 742-748 (2006).
30 Andersen, O. S. et al. Estimating left ventricular filling pressure by echocardiography. J. Am. Coll. Cardiol. 69, 1937-1948 (2017).
31 Obokata, M. et al.Uncoupling between intravascular and distending pressures leads to underestimation of circulatory congestion in obesity. Eur. J. Heart Fail. 24, 353-361 (2022).
32 Du, X.J. Revivifying research on relaxin receptor-targeted therapy for cardiovascular diseases. Cardiovasc. Res. 121, 836-838 (2025).
