Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis

Abstract

Importance: Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough.

Objective: To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough.

Data sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023.

Study selection: Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo.

Data extraction and synthesis: Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID).

Main outcomes and measures: Cough frequency (measured using the VitaloJAK cough monitor; 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.

Results: Nine RCTs including 2980 patients were included in the primary analysis. 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). 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]).

Conclusions and relevance: Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

Figure 1.. Literature Search Flow Diagram: Study of Gefapixant for Chronic Cough

EMA indicates European Medicines Agency; FDA, US Food and Drug Administration.

Figure 2.. Dose-Response Relationship Between Gefapixant Dose and 24-Hour, Awake, and Sleep Cough Frequency

A and B, Percent reductions are in comparison with placebo (dose = 0). Circles represent percent reductions observed in individual trials, and the diameters are proportional to the inverse variance of the study. Randomized clinical trials (RCTs) evaluating different doses may have contributed more than 1 circle in the graph. Doses are truncated at the largest dose for use in clinical practice (60 mg twice daily). C, Effects for sleep cough frequency are represented as mean differences in log-transformed coughs/h. Percent reduction compared with placebo is calculated as 100*(e^diff – 1), where diff is the mean difference in log-transformed coughs/h. Size of data markers indicates the weight of each study in the analysis.

Figure 3.. Effects of Gefapixant by Approximate Dose Compared With Placebo Estimated by a Study-Level Meta-Analysis

Model estimates are listed at clinically relevant doses from 0 to 60 mg twice daily at equal intervals (every 15 mg twice daily). Cells in the last 4 columns show effect estimates and 95% CIs in parentheses. Shading corresponds to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) certainty rating in whether patients would perceive effects to be important (ie, greater than the minimal important difference [MID]) or not importantly different (less than the MID). MIDs were considered as a 20% reduction in cough frequency, a 30-mm reduction on the 100-mm cough severity visual analog scale (VAS), a 1.3-point increase on the Leicester Cough Questionnaire (LCQ), a 15% increase for treatment-related adverse events, a 10% increase for adverse events leading to discontinuation, and a 10% increase for taste-related adverse events. Outcomes are ordered by the frequency with which studies consider the outcome as a primary, secondary, or safety outcome. eTable 2 in Supplement 1 reports the GRADE evidence profiles for each outcome and dose. ^aExpected risk or change from baseline with placebo. ^bNo evidence was found of a dose-response relationship for sleep cough frequency. Estimate is based on a pairwise meta-analysis treating all doses as having the same effect. ^cHigher score is worse; score range, 0 (no cough) to 100 mm (worst possible cough). ^dHigher score is better; score range, 3 (maximal impairment) to 21 (no impairment). ^eTaste-related adverse events include ageusia, dysgeusia, and/or hypogeusia.

Figure 4.. Dose-Response Relationship Between Gefapixant Dose and Cough Severity, Cough-Specific Quality of Life, Taste-Related Adverse Events, and Adverse Events Leading to Gefapixant Discontinuation

Mean differences or relative risks are in comparison with placebo (dose = 0). Shaded regions represent 95% CIs. Circles represent mean differences or relative risks observed in individual trials, and the diameters are proportional to the inverse variance of the study. Trials evaluating different doses may have contributed more than 1 circle in the graph. Doses are truncated at the largest dose for use in clinical practice (60 mg twice daily). For panels B through D, outcomes were analyzed using a 1-stage dose-response model using restricted cubic splines. Heterogeneity was examined through visual inspection of the dose-response plots and the variance partition coefficient (eFigures 1, 3, and 4 in Supplement 1). A, Assessed using visual analog scale (VAS). Higher score is worse; score range, 0 (no cough) to 100 mm (worst possible cough); minimum important difference (MID), 30 mm. B, Assessed using the Leicester Cough Questionnaire (LCQ). Higher score is better; score range, 3 (maximal impairment) to 21 (no impairment); MID, 1.3 points. C, Taste-related adverse events include ageusia, dysgeusia, and/or hypogeusia.