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

Abstract

Background: Although cardiovascular disease is common in patients with chronic obstructive pulmonary disease (COPD), the efficacy and safety of β blockers in reducing cardiac events and mortality is uncertain. This study was designed to assess whether the cardioselective β blocker, bisoprolol, improves cardiorespiratory outcomes when added to usual COPD care.

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. 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. Randomisation was with a concealed, computer-generated sequence, stratified by site, smoking status, and previous diagnosis of cardiovascular disease requiring treatment. 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. Analysis was by intention-to-treat (ITT) in all randomly assigned patients, using a country-stratified win ratio. Adverse events were analysed from the ITT population using all available data. Missing data were not used to determine wins, but regarded as a tie on that level of the hierarchy. 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). The study is complete.

Findings: 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). Mean post-bronchodilator FEV₁ was 45% (SD 11) predicted at baseline. 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. 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. Additionally, no significant differences were seen in FEV₁, COPD symptoms, or quality of life, or adverse events. 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. None of these deaths were attributed to the treatment.

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

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