A one-year trial of tiotropium Respimat® plus usual therapy in COPD patients

Abstract

In this randomised double-blind study, patients >or=40 years old with COPD, a smoking history of >or=10 pack-years, a pre-bronchodilator FEV(1) of <or=60% predicted and an FEV(1)/FVC of <or=70% received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks. Other medications were permitted except inhaled anticholinergics. Co-primary endpoints were trough FEV(1) and the time to first exacerbation. Adverse events were followed and vital status regularly assessed. In all, 3991 patients (mean age, 65 years [SD, 9 years]) were evaluable. Mean baseline FEV(1) was 1.11 L (0.40 L) or 40% (12%) of predicted normal. Adjusted mean differences in trough FEV(1) and trough FVC at Week 48 (tiotropium minus placebo) were 102 and 168 ml respectively (p < 0.0001, both). Tiotropium delayed time to first exacerbation relative to placebo (hazard ratio [HR], 0.69 [95% CI, 0.63-0.77]) and time to first hospital-treated exacerbation (HR, 0.73 [0.59-0.90]). SGRQ score at Week 48 was 2.9 units lower with tiotropium (p < 0.0001). Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials. The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 (0.67-1.86). By the end of planned treatment (Day 337) 52 patients on tiotropium (incidence rate per 100 years, 2.94) and 38 on placebo (2.13) had died (HR = 1.38 [0.91-2.10]; p = 0.13). Lung function, exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality. The protocol is registered on the European Clinical Trials Database as trial number 2006-001009-27 and in the ClinicalTrials.gov database as NCT00387088.

Tiotropium Respimat increases the risk of mortality: pro

“…For example, in the largest 1-year study the vital status was known for o99% of randomised patients for the primary analysis of death by the end of the planned treatment period (day 337) [10]; in the combined analysis of the other two 1-year studies, vital status was known for 97.7% of randomised patients for the primary analysis of death by the end of the planned treatment and 30-day follow-up observation period (day 366) [9,20].…”

“…In this BATEMAN [9] BATEMAN [9] Total (95% CI) regard, the exclusion criteria in the largest tiotropium Respimat study included a recent history of unstable arrhythmias, myocardial infarction or heart failure requiring hospital admission [10], thereby specifically ensuring the exclusion of patients at highest risk of cardiovascular mortality. The importance of cardiovascular comorbidity in determining this risk is illustrated in the Food and Drug Administration (FDA) review of this study, in which even after exclusion of such high-risk patients, those with a baseline history of cardiac disease or cardiac rhythm disorder had a markedly increased risk of cardiac death with 5 mg of tiotropium Respimat, RR 4.03 (95% CI 1.15-14.13) and 8.61 (95% CI 1.10-67.23), respectively [20].…”

“…Furthermore, COPD populations screened for inclusion in the studies are likely to vary between centres, and overarching exclusion criteria such as ''patients who had a disease that might put them at risk because of study participation'' are sensitive to investigator interpretation, resulting in selection biases that may be very difficult to ascertain post hoc, making it difficult to determine which patients were excluded [7]. However, in support of this possibility, data submitted to the FDA [25] indicates that patients with a history of cardiac rhythm disorders were more likely to be enrolled in the major tiotropium Respimat study [10], than in the major tiotropium Handihaler study [26], (11.8% versus 6.8%, respectively, RR 1.72 (1.54-1.96)).…”

“…These analyses provide substantive evidence that tiotropium Respimat increases mortality in the treatment of COPD [6,7]. It is informative to review each of the systematic reviews and the issues that have been raised relevant to their interpretation.In 2011 the British Medical Journal (BMJ) published the first systematic review and meta-analysis, which included all parallel-group, randomised, placebo-controlled trials of tiotropium Respimat in the treatment of COPD that had reported data on mortality and were of a minimum 30-day duration [3] (table 1 [ [8][9][10]). Five trials were included in the analysis, two 12-week trials and three 12-month trials, studying 6522 participants.…”

“…In 2011 the British Medical Journal (BMJ) published the first systematic review and meta-analysis, which included all parallel-group, randomised, placebo-controlled trials of tiotropium Respimat in the treatment of COPD that had reported data on mortality and were of a minimum 30-day duration [3] (table 1 [8][9][10]). Five trials were included in the analysis, two 12-week trials and three 12-month trials, studying 6522 participants.…”