The P2X3 antagonist gefapixant 45 mg orally twice daily produced modest improvements in cough frequency, cough severity, and cough-specific quality of life in patients with refractory or unexplained chronic cough, according to a systematic review and dose-response meta-analysis. Patients on the drug had increased taste-related adverse events.
Included in the analysis were randomized controlled trials of patients with refractory or unexplained chronic cough who received either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. The main outcome measures were cough frequency (measured using the VitaloJAK cough monitor; minimal important difference [MID], 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events.
“Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, −6.2 mm [95% CI, −4.1 to −8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty),” the authors report. “Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]).”
Editorial: “[This meta-analysis] is compelling and highlights the difficulties of managing chronic cough, a condition with severe effects on quality of life and one for which effective treatment has unmet needs,” editorialists write. “If a seemingly large placebo effect is partially attributable to unknown or untreated comorbidities such as GERD leading to chronic cough in a larger proportion of the [phase 3] COUGH-1 and COUGH-2 participants receiving placebo compared with those receiving gefapixant, it might be premature to conclude that P2X3 antagonists have only modest effects on refractory or unexplained cough until there are new studies that selectively enroll only patients with truly refractory and truly unexplained chronic cough.”