Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial. (22nd May 2020) - Giannoni, Alberto
Abstract : Aims: Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF. Methods and results: The BREATH study was a randomized, double‐blind, placebo‐controlled, crossover study (EudraCT‐code 2015‐005383‐42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate‐severe CA [nocturnal apnoea‐hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash‐out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention‐to‐treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14–73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity ( P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone‐related serious adverse events. Conclusions: Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF. Abstract : The increased chemoreflex gain (CG), which causes central apnoeas in heart failure ( A ), is blunted by buspirone, which increases the difference between CO2 at the equilibrium setpoint (ES) and at apnoeic threshold (AT) and stabilizes breathing ( B ). Buspirone acts on the serotonergic system ( C ), linking to pre‐synaptic 5‐HT1A autoreceptors and decreasing the release of serotonin in the synaptic cleft ( D ). ETCO2, end‐tidal pressure of carbon dioxide; ETO2, end‐tidal pressure of oxygen; VENT, ventilation.