Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo – a post-hoc analysis of the BACE randomized controlled trial

In the field of chronic obstructive pulmonary disease (COPD), acute exacerbations (AECOPD) are considered the most important determinants of a patient’s health status [1‐3]. They are characterized by an acute worsening of respiratory symptoms that necessitate additional therapy, based on which they are classified as mild (treated with short-acting bronchodilators only), moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization) [4]. Hospital readmissions after an initial hospitalization for an exacerbation (‘index event’) are associated with significant morbidity, mortality and high resource utilization [5], especially within the first 3 months after hospital discharge [6].

We recently reported the results of the Belgian trial with Azithromycin for acute COPD Exacerbations requiring hospitalization (BACE, NCT02135354) [7]. The BACE trial was an investigator-initiated randomized placebo-controlled trial (RCT) comparing azithromycin (500 mg once a day for 3 days and subsequently administered for 3 months at 250 mg every 2 days) with placebo on a novel composite primary endpoint, treatment failure (TF). Though formally negative on the primary endpoint (p = 0.0526), the applied time-to-first event analyses of its 3 subcomponents revealed that the reduction in TF rate within 3 months of hospital admission was mainly driven by a significant decrease of treatment intensification with systemic corticosteroids and/or antibiotics (TI), as well as step-up in hospital care (SH) for respiratory reasons, while no difference was observed for all-cause mortality. The main analyses, however, limit our understanding to ‘whether’ and ‘when’ a first TF, or one of its subcomponents, occurred [8].

In the present study, we aimed to investigate the intervention’s effect on recurrent events, with a particular focus on hospital readmissions. Based on a number of pre-specified baseline patient characteristics, we additionally aimed to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions.

The study protocol [9] and primary findings [7] have been published previously.

The BACE trial was an investigator-initiated, randomized, double-blind, placebo-controlled trial evaluating a 3-month intervention with low-dose azithromycin, initiated at the onset of a severe infectious AECOPD requiring hospitalization. Although formally negative on the composite primary endpoint (TF rate within 3 months, p = 0.0526), secondary time-to-first event analyses demonstrated a significant 21 and 52% reduction in the rate of TI and SH for respiratory reasons, respectively [7]. The present post-hoc analyses were performed to further elucidate the intervention’s effect on recurrent events, in particular hospital readmissions, and demonstrate that azithromycin reduces the TF rate within 3 months of a severe AECOPD by preventing subsequent hospital readmissions with more than 50%.

COPD is a chronic disease, typically characterized by recurrent exacerbations as the patient’s condition progressively deteriorates [11]. Severe exacerbations requiring hospitalization are the number one contributor to the overall burden and cost of the disease [5], warranting targeted interventions to reduce these readmissions. In the BACE trial, first events accounted for only 63% of the total number of TFs within 3 months. Though conventionally applied, restricting the efficacy analyses to first events would therefore incompletely represent the intervention’s effect on the patient’s overall burden of disease. Moreover, as time-to- first TF was defined as a composite endpoint, with no hierarchy among the different subcomponents, 98% of TFs were first captured by TI even though they were subsequently accompanied by SH or mortality. To provide insight into the true components of TF, the present analyses focus on the exclusive hierarchical subcomponents ranked by severity (mortality > transfer to ICU > hospital readmission > TI with systemic corticosteroids and/or antibiotics). In doing so, we demonstrated that azithromycin reduces the incidence rate of TF at 3 months mainly by reducing subsequent hospital readmissions with 53%, while a clinically relevant though statistically not significant 32% reduction in the transfers to the ICU was also observed. Conversely, we found that azithromycin did not affect the overall incidence rate of moderate events (i.e., treatment intensification not resulting in hospital admission, transfer to ICU or mortality), which – in part – could account for the lack of statistically significant differences in quality of life and symptom assessment scores observed in the BACE trial [7]. When compiled, the BACE trial results substantiate previous findings suggesting azithromycin may be most effective in preventing severe AECOPD requiring hospitalization [12‐14]. Azithromycin appears to modify the severity of new exacerbations, so that this high risk subgroup may be less likely to require hospitalization when they do experience new exacerbations. The BACE trial is the first macrolide study in COPD to identify this affordable therapeutic option as a much desired intervention to safely reduce hospital readmissions. Potential adverse effects related to the intervention were discussed previously [7]. No group differences were observed in the number of SH, its exclusive subcomponents (transfer to the ICU and hospital readmissions) or mortality between treatment withdrawal (day 90) and 6 months of follow-up (day 270), supporting earlier time-to-first event analysis findings that prolongation of intake is needed to maintain azithromycin’s clinical benefits. Notably, an increased number of TI in the azithromycin group compared to the placebo group underlies an increase in the number of TF when withdrawing azithromycin.

In the BACE trial, azithromycin was uploaded within 48 h post emergency admission, as potential benefits during the index event were hypothesized to contribute to the overall effect on the primary endpoint. Prior to hospital discharge, azithromycin tended to reduce the incidence rate of TF within 6 days compared to placebo (25% reduction, with a 17 and 45% reduction in TI and all-cause mortality, respectively). These observations were not statistically significant as the study remained largely underpowered for any conclusions on potential benefits during the index event. Several studies, however, have demonstrated that bacterial eradication in the acute phase may result in better long-term outcomes, including readmission rates [15‐17]. Future prospective randomized placebo-controlled trials with azithromycin are therefore highly encouraged to evaluate the added value of azithromycin in the acute setting of a severe AECOPD, in addition to a limited prolonged administration to prevent relapse. At this stage, it is up to the clinician to decide when prolonged therapy with macrolides is indicated. Based on the BACE trial findings, patients with COPD suffering from severe infectious exacerbations are at least a target subgroup that needs proper consideration.

The treatment effect of azithromycin appeared to differ according to baseline CRP levels at hospital admission for the index event. Serum CRP has been identified as a relatively sensitive and specific biomarker to distinguish patients who require antibiotics [18, 19], with previous studies showing that a cut-off value of 50 mg/L for high CRP is most optimal to determine antibiotic needs [20‐22]. We observed a large and statistically significant effect of azithromycin on hospital readmissions within 3 months in patients with high CRP at baseline (31% of the studied population). This may suggest that the antibacterial effect of azithromycin is the dominant mechanism, although one may argue that all patients were already treated with an effective antibiotic as part of the standardized treatment during the index event. These findings complement the observed 23% significant reduction in the total days of antibiotic use within 3 months in the azithromycin group when compared to placebo (a pre-specified secondary endpoint of the main analysis, p < 0.0001) [7]. Similarly, however, azithromycin was found to be more effective in patients with absence of blood eosinophilia at baseline, which corroborates previous findings that high eosinophilia is a good marker for the need of systemic corticosteroids [23]. This observation is biologically plausible, since macrolides have been shown to be effective in neutrophilic chronic airway diseases and might be due to anti-inflammatory and immunomodulatory effects in addition to azithromycin’s antibiotic properties. Although it is tempting to speculate that in AECOPD with high blood eosinophilia azithromycin has no added value, such biomarker guided treatment is needing prospective studies before broad implementation can be recommended. It is currently unknown to what degree azithromycin’s antimicrobial and anti-inflammatory properties contribute to the compiled BACE trial findings. As long as we have no macrolides available that are completely stripped of their antibiotic properties, any further understanding of the mechanism leading to its clinical benefits will be influenced by this dual mode of action.

Through continuous spline modelling, neither age, FEV1, CRP nor blood eosinophil count could be identified as possible predictors of azithromycin response, determined from the incidence rate of TF and hospital readmissions within 3 months. However, we did observe a trend for a negative association between blood eosinophil count at hospital admission for a severe AECOPD and the incidence rate of hospital readmissions within 3 months in patients treated with azithromycin.

In conclusion, a 3-month intervention with low-dose azithromycin for severe infectious AECOPD requiring hospitalization appears to reduce the rate of treatment failure within 3 months mainly by preventing subsequent hospital readmissions. This complements the BACE trial’s main finding that azithromycin may be a promising and cost-saving therapy for a subgroup of patients with the highest unmet needs. Although rigorous prospective studies are required, the present findings also suggest a potential role for CRP and blood eosinophil count at admission in guiding azithromycin therapy in patients with a severe AECOPD.