Bisoprolol to prevent adverse cardiac events (PACE) in COPD: a multicentre, double-blind, randomised, controlled, phase 3 trial.

This study was designed to assess whether the cardioselective β blocker, bisoprolol, improves cardiorespiratory outcomes when added to usual COPD care.

本研究旨在评估在常规COPD治疗中加入心脏选择性β阻滞剂比索洛尔是否能改善心肺结果。

Methods

This double-blind, randomised, controlled, phase 3 trial was done across 22 hospital and research institute sites selected by research experience and resources to conduct the study in Australia, India, New Zealand, and Sri Lanka.

这是一项双盲、随机、对照的III期试验，在澳大利亚、印度、新西兰和斯里兰卡的22家医院和研究所进行，这些机构是根据研究经验和资源选定的，以进行本研究。

Participants aged 40-85 years with COPD, post-bronchodilator FEV1 30-70% predicted, and at least one COPD exacerbation in the previous 2 years were randomly assigned to receive bisoprolol (1·25-5 mg) or matched placebo, orally, once daily, for 2 years, with both groups continuing to receive usual COPD care.

年龄在40至85岁之间、患有慢性阻塞性肺疾病（COPD）、使用支气管扩张剂后FEV1为预测值的30-70%、并且在过去的2年内至少有一次COPD加重的参与者，被随机分配接受比索洛尔（1.25-5毫克）或匹配安慰剂，每日口服一次，为期2年，两组均继续接受常规COPD治疗。

Randomisation was with a concealed, computer-generated sequence, stratified by site, smoking status, and previous diagnosis of cardiovascular disease requiring treatment.

随机分组采用隐藏的计算机生成序列，按地点、吸烟状况和既往需要治疗的心血管疾病进行分层。

Participants, site personnel, and investigators remained masked to study treatment throughout the trial. The primary outcome was a composite of cardiac and respiratory effects, starting with the most important outcome (death), then cardiac or respiratory hospital admissions, exacerbations, quality-of-life measures, and FEV1.

在整个试验期间，参与者、现场人员和研究人员对研究治疗保持盲态。主要结果是一个包括心脏和呼吸效应的复合结果，首先是最重要的结果（死亡），然后是心脏或呼吸住院、加重、生活质量测量和FEV1。

Analysis was by intention-to-treat(ITT) in all randomly assigned patients, using a country-stratified win ratio.

分析是在所有随机分配的患者中按意向治疗（ITT）进行的，使用了按国家分层的胜率比。

Adverse events were analysed from the ITT population using all available data.

从意向治疗（ITT）人群中使用所有可用数据对不良事件进行了分析。

Missing data were not used to determine wins, but regarded as a tie on that level of the hierarchy.

缺失数据未用于确定胜者，但在该层级被视为平局。

The trial was prospectively registered on ClinicalTrials.gov (NCT03917914), Clinical Trial Registry - India (CTRI/2020/08/027322), and the Sri Lanka Clinical Trials Registry (SLCTR/2021/033).

该试验已在ClinicalTrials.gov (NCT03917914)、Clinical Trial Registry - India (CTRI/2020/08/027322)和斯里兰卡临床试验注册处(SLCTR/2021/033)上进行了前瞻性注册。

The study is complete.

研究已经完成。

Results

Of 360 participants screened for eligibility between June 30, 2020, and March 20, 2023, 280 were randomly assigned to bisoprolol (n=143) or placebo (n=137), with 249 completing 2 years of follow-up. 233 patients (83%) were male and 47 (17%) were female; mean age was 68 years (SD 8).

在2020年6月30日至2023年3月20日期间，共有360名参与者接受了资格筛查，其中280名被随机分配到比索洛尔组（n=143）或安慰剂组（n=137），有249名完成了2年的随访。233名患者（83%）为男性，47名（17%）为女性；平均年龄为68岁（标准差8）。

Mean post-bronchodilator FEV1 was 45% (SD 11) predicted at baseline.

基线时，平均支气管舒张后FEV1为45%（标准差11）预测值。

According to the hierarchy of outcomes, bisoprolol was associated with better cardiorespiratory health for 3041 (45%) of 6763 comparisons and placebo for 3240 (48%), with 482 (7%) showing no difference, giving a win ratio of 0·95 (95% CI 0·72 to 1·25, p=0·72) and a net benefit of -2% (95% CI -15 to 10) with bisoprolol.

根据结果的优先级，对于6763次比较中的3041次（45%），比索洛尔与更好的心肺健康相关，而安慰剂为3240次（48%），有482次（7%）显示无差异，比索洛尔的胜率比为0.95（95%置信区间0.72至1.25，p=0.72），比索洛尔的净效益为-2%（95%置信区间-15至10）。

No significant differences were seen between bisoprolol and placebo in all-cause mortality, cardiorespiratory hospitalisations, major adverse cardiac events, or moderate or severe COPD exacerbations.

在双索洛尔和安慰剂之间，全因死亡率、心肺住院、主要不良心脏事件或中度或重度慢阻肺急性加重方面没有显著差异。

Additionally, no significant differences were seen in FEV1, COPD symptoms, or quality of life, or adverse events.

此外，在第一秒钟用力呼气量（FEV1）、慢阻肺症状、生活质量或不良事件方面也没有显著差异。

The most common adverse events were COPD exacerbations, occuring in 83 (58%) participants in the bisoprolol group and 87 (64%) in the placebo group. 15 (10%) participants in the bisoprolol group and 11 (8%) in the placebo group died.

最常见的不良事件是慢性阻塞性肺疾病（COPD）的急性加重，发生在双索洛尔组的83名（58%）参与者和安慰剂组的87名（64%）参与者中。双索洛尔组中有15名（10%）参与者死亡，而安慰剂组中有11名（8%）参与者死亡。

None of these deaths were attributed to the treatment.

这些死亡均未归因于治疗。

interpretation

In patients with moderately severe COPD, treatment with bisoprolol made no difference to overall cardiorespiratory health, all-cause mortality, or serious cardiorespiratory events.

在中重度慢性阻塞性肺疾病（COPD）患者中，比索洛尔治疗对总体心肺健康、全因死亡率或严重心肺事件没有差异。

funding

National Health and Medical Research Council of Australia and the Health Research Council of New Zealand.

澳大利亚国家卫生与医学研究委员会和新西兰卫生研究委员会。