Benefit-Risk Profile of P2X3 Receptor Antagonists for Treatment of Chronic Cough: Dose-Response Model-Based Network Meta-Analysis.

IF 9.5 1区医学 Q1 CRITICAL CARE MEDICINE Chest Pub Date : 2024-11-01 Epub Date: 2024-06-08 DOI:10.1016/j.chest.2024.05.015

Shota Yamamoto, Nobuyuki Horita, Johsuke Hara, Mao Sasamoto, Yoshihiro Kanemitsu, Yu Hara, Yasushi Obase, Takeshi Kaneko, Akio Niimi, Hiroshi Mukae

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Abstract

Background: Refractory 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 question: How does the benefit-risk profile vary across the five available P2X3 receptor antagonists?

Study design and methods: A 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.

Results: Sixteen 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.

Interpretation: When 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 registration: University Hospital Medical Information Network Center (UMIN-CTR); No. UMIN000050622; URL: https://center6.umin.ac.jp.

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P2X3受体拮抗剂治疗慢性咳嗽的效益-风险概况：基于剂量-反应模型的网络荟萃分析

背景：难治性或原因不明的慢性咳嗽扰乱了人们的生活质量，也给世界各地的医疗保健系统造成了负担。P2X3 受体拮抗剂吉法必申因其止咳作用而在许多国家获得批准，但味觉障碍是一种常见的不良反应。为解决这一问题，已开发出四种更新、选择性更强的 P2X3 受体拮抗剂：研究问题：现有的五种 P2X3 受体拮抗剂的效益-风险特征有何不同？通过系统综述和网络荟萃分析，评估了P2X3受体拮抗剂的疗效，包括吉法必胜、西伏必胜、埃利必胜、坎利必胜和非拉必胜。主要研究结果为 24 小时咳嗽次数减少率和味觉障碍发生率。计算了剂量-反应曲线和中位有效剂量（ED50）。根据 SUCRA 对 ED50 的效应大小进行排序。可信度由 CINeMA 评估：结果：分析了16项随机对照试验，共有4904人参与。吉法匹克治疗方案在减少咳嗽次数方面的ED50为90.7毫克/天。吉法匹克在ED50时显示出最高的止咳效果（24小时咳嗽次数减少率，中位数为28.1%；95%可信区间为21.0%至35.6%；排名1/5；中度确定性），但味觉障碍发生率最高（每100名患者的绝对风险差异，中位数为38；95%CrI为27%至51；排名5/5；高度确定性），停药率最高。康力生有很好的均衡性（24小时咳嗽次数减少率，中位数为14.7%；95%CrI为5.4%至26.0%；排名3/5；低确定性；味觉障碍，每100名患者的绝对风险差异，中位数为2；95%CrI为1%至6%；排名2/5；低确定性）。安慰剂的 24 小时咳嗽次数平均减少 33.1%：在安全剂量下使用时，吉非那潘与其他四种药物相比具有良好的风险收益特征。Camlipixant显示出了初步前景，目前正在进行的III期试验可能会对其进行进一步研究：临床试验注册：UMIN000050622。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chest 医学-呼吸系统

CiteScore

13.70

自引率

3.10%

发文量

3369

审稿时长

15 days

期刊介绍： At CHEST, our mission is to revolutionize patient care through the collaboration of multidisciplinary clinicians in the fields of pulmonary, critical care, and sleep medicine. We achieve this by publishing cutting-edge clinical research that addresses current challenges and brings forth future advancements. To enhance understanding in a rapidly evolving field, CHEST also features review articles, commentaries, and facilitates discussions on emerging controversies. We place great emphasis on scientific rigor, employing a rigorous peer review process, and ensuring all accepted content is published online within two weeks.