What is Spiriva? Tiotropium bromide is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium bromide capsules for inhalation are co-promoted by Boehringer-Ingelheim and Pfizer under the trade name Spiriva. It is also manufactured and marketed by Cipla under trade name Tiova. Source.
The study is titled, "Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials."
Objective To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.
Data sources Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.
Study selection Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I2 statistic.
Results Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P=0.02; I2=0%). Both 10 µg (2.15, 1.03 to 4.51; P=0.04; I2=9%) and 5 µg (1.46, 1.01 to 2.10; P=0.04; I2=0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P=0.04), limiting the analysis to three trials of one year’s duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.
Conclusions This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.
From the FDA in 2008:
Update 10/07/2008: FDA’s Early Communication About an Ongoing Safety Review issued on March 18, 2008 stated that Boehringer Ingelheim, the maker of Spiriva HandiHaler (tiotropium bromide), had conducted a pooled analysis of 29 trials that suggested a small excess risk of stroke (2 cases per 1000) with tiotropium bromide over placebo. FDA has now received preliminary data from UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium), a large, 4-year, placebo controlled clinical trial with Spiriva HandiHaler in approximately 6000 patients with chronic obstructive pulmonary disease (COPD). The preliminary results of UPLIFT reported by Boehringer Ingelheim to the FDA showed that there was no increased risk of stroke with tiotropium bromide (Spiriva HandiHaler) compared to placebo.
Two recent publications1, 2 reported increased risk for mortality and/or cardiovascular events in patients who received tiotropium or inhaled anticholinergics. Both studies examined cardiovascular outcomes. Singh et al.1 performed a systematic review and meta-analysis of 17 clinical trials enrolling 14,783 patients treated with inhaled anticholinergic drugs used for the treatment of chronic obstructive lung disease. Lee et al.2 performed a case-control study of 32,130 patients (320,501 controls) treated with inhaled medications, including an anticholinergic, for the treatment of chronic obstructive lung disease.
FDA expects to receive the complete report for UPLIFT in November 2008. Results from this trial will also help to address some issues raised about tiotropium in the two recent publications. Due to the amount of data collected in UPLIFT, a complete review of the results could take several months, at which time FDA will update this communication with the final results of the UPLIFT analysis, as well as all the available data regarding tiotropium and stroke risk.
1. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease. JAMA 2008; 300 (12): 1439-1450.
2. Lee TA, Pickard S, et al. Risk of Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease. Annals of Internal Medicine 2008; 149: 380-39