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

Kum E, Patel M, Diab N, Wahab M, Zeraatkar D, Chu DK, O'Byrne PM, Guyatt GH, Satia I. JAMA. 2023 Sep 11. doi: 10.1001/jama.2023.18035.

Key Points

Question  Is the use of gefapixant to treat refractory or unexplained chronic cough associated with greater benefits or harms compared with placebo?

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

Findings  In this dose-response meta-analysis that included 9 randomized clinical trials and 2980 patients, compared with placebo, use of gefapixant (45 mg orally twice daily) reduced cough frequency by 17.6%, decreased cough severity by 6.2 mm on the 100-mm visual analog scale, and improved cough quality of life by 1 point on the Leicester Cough Questionnaire (score range, 3-21). Patients treated with gefapixant (45 mg orally twice daily) had, however, a 32% increase in taste-related adverse events compared with placebo.

Meaning  Gefapixant may provide benefit to some patients with refractory or unexplained chronic cough, but the magnitude is likely small and the risk of adverse events, particularly taste-related, remains substantial.

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.

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

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.

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