• Shota Yamamoto, Nobuyuki Horita, Johsuke Hara, Mao Sasamoto, Yoshihiro Kanemitsu, Yu Hara, Yasushi Obase, Takeshi Kaneko, Akio Niimi, and Hiroshi Mukae.
• Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI. Electronic address: yamasho1113x1987@gmail.com.
• Chest. 2024 Nov 1; 166 (5): 112411401124-1140.

BackgroundRefractory or unexplained chronic cough disrupts quality of life and burdens health care systems around the world. The P2X3 receptor antagonist gefapixant is approved in many countries for its antitussive effects, but taste disturbances are a common adverse effect. Four newer, more selective P2X3 receptor antagonists have been developed to address this problem.Research QuestionHow does the benefit-risk profile vary across the five available P2X3 receptor antagonists?Study Design And MethodsA systematic review and network meta-analysis was conducted to evaluate the efficacy of P2X3 receptor antagonists, including gefapixant, sivopixant, eliapixant, camlipixant, and filapixant. Primary outcomes were a reduction rate in 24-hour cough frequency and incidence of taste disturbance. Dose-response curves and median effective dose (ED50) were calculated. Effect size at ED50 was ranked according to the surface under the cumulative ranking curve. The confidence was evaluated by Confidence In Network Meta-Analysis.ResultsSixteen randomized controlled trials involving 4,904 participants were analyzed. The gefapixant regimen demonstrated an ED50 of 90.7 mg/d for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED50 (reduction rate in 24-hour cough frequency: median, 28.1%; 95% credible interval [CrI], 21.0%-35.6%; ranked 1 of 5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients: median, 38; 95% CrI, 27-51; ranked 5 of 5; high certainty) and the highest prevalence of discontinuation. Camlipixant had a well-balanced profile (reduction rate in 24-hour cough frequency: median, 14.7%; 95% CrI, 5.4%-26.0%; ranked 3 of 5; low certainty; and taste disturbance; absolute risk difference per 100 patients; median, 2; 95% CrI, 1-6; ranked 2 of 5; low certainty). Placebo had a mean of 33.1% reduction in 24-hour cough frequency.InterpretationWhen used at safe doses, gefapixant had a favorable risk-benefit profile compared with the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway.Clinical Trial RegistrationUniversity Hospital Medical Information Network Center (UMIN-CTR); No. UMIN000050622; URL: https://center6.umin.ac.jp.Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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