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

BACKGROUND: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality. OBJECTIVES: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions. METHODS: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time. RESULTS: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/µL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses. CONCLUSIONS: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy. TRIAL REGISTRATION: ClinicalTrials.gov number. NCT02135354 .

Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined.Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care.Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality.Measurements and Main Results: A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal.Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.

The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions. METHODS/DESIGN: Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge. DISCUSSION: We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs.

Knowledge of cervix cancer, human papilloma virus (HPV) and HPV vaccination at the moment of introduction of the vaccine in women in Belgium.

AIM: To test the knowledge of women, attending a gynecology clinic, on HPV, cervix cancer awareness and the knowledge and willingness to use HPV vaccine for themselves or their children. SETTING: Routine gynecological and obstetrical care with ambulatory service in a medium-sized general hospital in a small town in Belgium (Heilig Hart Hospital, Tienen). METHODS: Questionnaire to be filled out by 381 consecutive women while in the attendance room for consultation with one of the four gynecologists. Fisher T or Chi(2) were used as statistical methods. RESULTS: Knowledge about HPV as a cause of cervix cancer and the existence of a vaccine was roughly 50%. Women with lower education were more likely to know nothing about the cause of cervix cancer than women with higher education (54 versus 39%, P = 0.016). Half of the women were willing to accept the vaccine, whatever the cost price, and 40% required more information or refunding. Compared to women above 40, young age (25 years or less) was a risk factor for poor knowledge of HPV (P = 0.007), cervix cancer (P = 0.016) and the HPV vaccine (P = 0.07), regardless of a higher degree of education (79% postgraduate degree versus 43.4% in the 40+-year-old women, P = 0.006). Women with a daughter (64.7%) or a son (69.2%) were more inclined to vaccinate their daughter than women without children (46.3%, P < 0.0001). None of the women declined the vaccination because it was meant to protect against a sexually transmitted disease (STD). CONCLUSION: Upon introduction and marketing of the first HPV vaccine, only 50% of women attending a routine gynecology clinic were aware of the role of HPV in cervix cancer and the possibility of getting a vaccination against it. Unexpectedly, despite a high degree of education, young women seem to have a low awareness of cervix cancer, its cause and the preventive measures. Contrary to some women in the USA, Western European women are less likely to decline the HPV vaccine because it will protect them against STD. In Belgium, women who are childless or poorly educated and especially young women should be the targets of campaigns that motivate them to prevent HPV-induced cervix cancer.