OBJECTIVES : The unmet clinical need for chronic unexplained cough is significantly high due to the lack of effective licensed treatments. The current research aims to conduct a systematic literature review (SLR) and meta-analysis of the efficacy and safety of P2X3-receptor antagonists for the treatment of refractory or unexplained chronic cough.

METHODS : The SLR included randomised controlled trials (RCTs) assessing P2X3 receptor antagonists for the treatment of patients with refractory or unexplained chronic cough. Studies were identified through Embase^®, MEDLINE^®, CENTRAL, and MEDLINE^® In-Process (Database inception to June 2021), relevant conference proceedings, clinical trial registries, and bibliographic searching.

RESULTS : The SLR identified 10 RCTs assessing four different P2X3-antagonists. Among 10, seven trials assessed gefapixant, and one trial each assessed BLU-5937, BAY 1817080, and S-600918. The RCTs varied regarding the trial duration, ranging from two to 24 weeks. The meta-analysis was performed at two-time points, i.e., 2-4 weeks (seven studies) and 12 weeks (two studies). P2X3-antagonists were associated with significantly better efficacy regarding the reduction in awake cough frequency at 12 weeks (mean difference [MD]:-24.50; 95% Confidence Interval [CI]:-34.46 to -14.55) and 2-4 weeks (MD:-26.39; 95%CI:-35.47 to -17.32) vs. placebo. The 24-hours cough frequency was also significantly reduced with P2X3-antagonists vs. placebo at both analysed time points. Among the analysed treatments, gefapixant (MD:-37.54) was associated with the highest reduction in awake cough frequency vs. placebo, followed by S-600918 (MD:-31.60), BAY 1817080 (MD:-26.39), and BLU-5937 (MD:-10.16). Patients treated with P2X3-antagonists experienced higher any cause and taste-related related AEs compared to placebo.

CONCLUSIONS : The SLR and meta-analysis highlight the favourable efficacy of P2X3-antagonists for the treatment of refractory or unexplained chronic cough. The evidence base for gefapixant is well established; however, more studies examining other P2X3-antagonists and the long-term antitussive benefit of this intervention class are warranted for the treatment of chronic cough.