Neprilysin Inhibitors May Provide Additive Hemodynamic Effects in PAH

A phase 2 study found racecadotril, a neprilysin inhibitor, to be effective for increasing plasma atrial natriuretic peptide (ANP) concentrations and plasma cyclic guanosine-3’,5’-monophosphate (GMP) levels and reducing pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH). Findings from this study were published in the British Journal of Pharmacology.

A total of 21 patients with PAH who were stable on phosphodiesterase 5 inhibitor therapy were randomly assigned to receive 100 mg racecadotril (n=9) or matching placebo (n=4). Investigators determined posttreatment acute hemodynamic and biochemical changes by evaluating venous blood samples and assessed 14-day safety and efficacy of the treatment.

During the study, the researchers looked for changes in circulating ANP concentration (Δ_max). Additionally, changes in pulmonary and systemic hemodynamics plus mechanistic biomarkers were also examined.

Patients who received racecadotril had a 79% (95% CI, 6-203) increase in plasma ANP concentration. Acute administration of racecadotril was also associated with a 106% (95% CI, 28-229) increase in levels of plasma cyclic GMP.

The researchers observed a 14% (95% CI, -24 to -3) reduction in pulmonary vascular resistance in racecadotril-treated patients. Racecadotril 100 mg 3 times daily for 14 days was also associated with a 19% (95% CI, -18-72) increase in concentration of plasma ANP.

No noticeable reduction in mean arterial blood pressure or increase in serious adverse events were observed with either acute (-16%; 95% CI, -28-1) or chronic (-4%; 95% CI, -21-16) racecadotril treatment.

Limitations of the study include its small sample size as well as its relatively short duration of follow-up.

According to the researchers, a larger-scale, prospective study is warranted “to determine if efficacy, selectivity, and safety are maintained over a longer period with respect to pulmonary hemodynamics, right ventricular function, exercise capacity, and quality of life.”

Disclosures: Multiple study authors have disclosed financial relationships with pharmaceutical companies. Please refer to original manuscript for full list of author disclosures.

Reference

Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial [published online February 13, 2019]. Br J Pharmacol. doi: 10.1111/bph.14621

This article originally appeared on The Cardiology Advisor