Since its registration in 2002, a dry-powder formulation of tiotropium delivered by a HandiHaler inhalation device has consistently been recommended in clinical-practice guidelines as first-line maintenance bronchodilator therapy for chronic obstructive pulmonary disease (COPD). This recommendation is based on the efficacy of tiotropium in improving lung function, exercise capacity, and quality of life and in reducing moderate and severe COPD exacerbations.

The safety reputation of tiotropium as delivered by dry-powder inhalation remained relatively unblemished until its successor, tiotropium delivered by a soft-mist Respimat inhaler, underwent clinical trials. Despite the clear efficacy of the Respimat formulation, post hoc pooled safety analyses showed an increased rate of death from any cause in patients treated with the Respimat inhaler at a dose of 5 μg of tiotropium, as compared with placebo, an effect that was particularly evident in patients with a history of cardiac arrhythmias.1 All of a sudden, the previous hints at the possibility of cardiovascular risk for ipratropium and tiotropium held more water and needed to be addressed, especially given the widespread use of this drug, the increasing global prevalence of COPD, the guideline recommendations for tiotropium as a first-line COPD treatment, and the high burden of coexisting cardiac conditions and deaths in the COPD population.

Multiple meta-analyses and observational database studies did not resolve the issue, and regulators issued warnings.2 In a systematic review of pooled data from 17 trials (enrolling a total of 13,645 participants), patients with COPD who received inhaled anticholinergic medications had higher rates of myocardial infarction, stroke, and death from cardiovascular causes or a composite of all three outcomes than those receiving placebo or an active control, with a relative risk of 1.60 (95% confidence interval [CI], 1.22 to 2.10; P<0.001) for cardiovascular events and 1.29 (95% CI, 1.00 to 1.65; P=0.05) for death from any cause.3 However, several other meta-analyses showed no evidence of increased rates of cardiovascular events or death.4,5 Most important, data from the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial6 were consistent with a reduction in all-cause mortality in patients with COPD who were receiving tiotropium, as compared with those receiving placebo, during a 4-year period, with a protective effect for cardiac mortality. A subsequent meta-analysis of 30 trials including UPLIFT (enrolling a total of 19,545 participants) showed that tiotropium was associated with reduced rates of death from any cause and from cardiac causes and of cardiovascular events.5However, the soft-mist Respimat inhaler remained under a cloud, with a systematic review reporting a 50% increased risk of death in 2011.1 Although a Cochrane review of 22 studies (enrolling a total of 23,309 participants) did not show an increased risk of death from any cause associated with dry-powder tiotropium HandiHaler, it showed significantly more deaths associated with the soft-mist Respimat inhaler (Peto odds ratio, 1.47; 95% CI, 1.04 to 2.08), with placebo used as the control in the two comparisons.7

Large randomized, controlled trials are usually designed and powered to meet statistical certainty for efficacy end points that have clinical significance for clinicians, patients, or regulators. But when efficacy has been established and safety is then questioned, it is sadly not the rule that rigorous, well-powered studies are conducted to address these concerns. Most studies are grossly underpowered for safety outcomes, and adverse events are listed with small numbers to which only an eyeball test can be applied. The reporting of “no difference” between adverse events in an intervention group and those in a control group is hardly ever questioned, even though it rarely has statistical validity.

In the Tiotropium Safety and Performance in Respimat (TIOSPIR) study,8 Wise et al. turn this tradition on its head by seriously addressing the widely expressed concern about the safety of tiotropium Respimat. In this large clinical trial, now reported in the Journal, involving 17,135 patients with COPD for a median duration of 835 days, the investigators compared the safety and efficacy of once-daily tiotropium doses of 2.5 μg and 5 μg delivered by Respimat with a once-daily dose of 18 μg of tiotropium delivered by HandiHaler. Primary end points were the rate of death (noninferiority study for both doses of Respimat vs. HandiHaler) and the rate of the first COPD exacerbation (superiority study for Respimat 5 μg vs. HandiHaler). There was no significant difference among the three study groups with respect to death (hazard ratio for Respimat 5 μg vs. Handihaler, 0.96; 95% CI, 0.84 to 1.09; hazard ratio for Respimat 2.5 μg vs. Handihaler, 1.0; 95% CI, 0.87 to 1.14) or the first exacerbation (hazard ratio for Respimat 5 μg vs. HandiHaler, 0.98; 95% CI, 0.93 to 1.03). Patients with stable cardiac disease were included in the study, and there was no significant difference in mortality for those with a history of arrhythmia. The incidences of major cardiovascular adverse events were similar in the three study groups.

These results address several previous criticisms leveled against randomized, controlled trials and meta-analyses that did not identify an increased risk of death (or that showed a risk reduction) associated with tiotropium. A major concern was the possibility that the failure to identify a risk of death in some meta-analyses was due to the exclusion of patients with a cardiac history, especially arrhythmia or recent myocardial infarction, or those with other serious coexisting illnesses who might be at risk because of participation in the trial. In the TIOSPIR study, the clinical characteristics, coexisting illnesses, and coprescribed medications of the recruited patients suggest they do represent typical patients with symptomatic COPD, and the rate of follow-up was 99.7%. However, it is important to note that the absence of a placebo group in this study has implications for its interpretation and that it cannot be concluded from these results that tiotropium reduces mortality in patients with COPD.

The rigor, careful conduct, scrupulous follow-up of patients, and use of clinically appropriate entry criteria in this study will reassure many clinicians who may have had concerns about the narrow focus of some COPD trials. The global recruitment, fast completion, and clear outcomes of the trial should also encourage all those who fear that real-world studies enrolling patients who truly reflect typically heterogeneous populations and phenotypes will produce messy, uninterpretable results. This study clears the air regarding the safety of tiotropium delivered by Respimat and at the same time establishes a high standard for clinical trials involving patients with COPD, particularly studies that focus on patient safety.

Source: NEJM