加重病史对伴有心血管风险增加的慢性阻塞性肺疾病患者使用阿地氯铵的安全性和疗效的影响：ASCENT-COPD 试验。

The Impact of Exacerbation History on the Safety and Efficacy of Aclidinium in Patients with Chronic Obstructive Pulmonary Disease and Increased Cardiovascular Risk: ASCENT-COPD Trial.

机构信息

Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

出版信息

Int J Chron Obstruct Pulmon Dis. 2021 Mar 18;16:689-699. doi: 10.2147/COPD.S285068. eCollection 2021.

DOI:10.2147/COPD.S285068

PMID:33776428

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7987267/

Abstract

PURPOSE

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.

PATIENTS AND METHODS

ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.

RESULTS

Of 3589 patients, 2156 (60.1%) had ≥1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54-1.16; none: HR 1.27, 95% CI: 0.65-2.47; interaction =0.233) or all-cause mortality (≥1: HR 1.08, 95% CI: 0.81-1.43; none: HR 0.66, 95% CI: 0.36-1.22; interaction =0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥1: rate ratio [RR] 0.80, 95% CI: 0.68-0.94; none: RR 0.69, 95% CI: 0.54-0.89; interaction =0.340) and improved FEV (interaction =0.633).

CONCLUSION

In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT01966107.

摘要

目的

慢性阻塞性肺疾病（COPD）加重与主要不良心血管事件（MACE）和死亡率增加相关。在此，我们研究了在伴有心血管风险增加的 COPD 患者中，由于加重史，是否会影响溴化阿地溴铵的安全性和疗效。

患者和方法

ASCENT-COPD 是一项为期 3 年、多中心、双盲、随机、安慰剂对照、平行组的研究，纳入了中度至重度 COPD 且伴有心血管风险增加的患者。患者以 1:1 的比例随机接受阿地溴铵或安慰剂，每日 2 次，最多 3 年。主要终点为 3 年内首次 MACE 和全因死亡率，第 1 年治疗期间的加重率，以及 3 年内基线预剂量用力呼气量（FEV1）的变化。这项预先指定的亚组分析比较了接受阿地溴铵与安慰剂的患者的结局。在方案修正案后增加了主要研究的入组人数，以增加对有加重史和无加重史患者的比较。

结果

在 3589 名患者中，2156 名（60.1%）在过去 1 年中有≥1 次中度或重度加重，而 1433 名（39.9%）无既往加重史。尽管有加重史的患者无论治疗与否，MACE 和死亡率的发生率均较高，但阿地溴铵并未增加 MACE 的风险（≥1：风险比[HR]0.79，95%置信区间[CI]：0.54-1.16；无：HR 1.27，95%CI：0.65-2.47；交互作用=0.233）或全因死亡率（≥1：HR 1.08，95%CI：0.81-1.43；无：HR 0.66，95%CI：0.36-1.22；交互作用=0.154），无论是否有加重史。阿地溴铵降低了加重率，与安慰剂相比，无论是否有加重史（≥1：风险比[RR]0.80，95%CI：0.68-0.94；无：RR 0.69，95%CI：0.54-0.89；交互作用=0.340），并改善了 FEV1（交互作用=0.633）。