Tuesday, October 9, 2012

MetaAnalysis - Tiotropium Respimat Soft Mist Inhaler associated wtih increased overall death and CV death compared to Placebo

According to the results of a meta-analysis published early online in Thorax, tiotropium Respimat Soft Mist Inhaler was associated with an increased risk of overall death and CV death compared to placebo and other inhaled medications for COPD. In contrast a long-acting beta-agonist (LABA)-inhaled corticosteroid (ICS) combination, tiotropium HandiHaler and LABAs had relatively safer profiles, with LABA-ICS having the lowest risk of overall death in patients with COPD.


The authors note that tiotropium Handihaler appears to have no excess risk of overall death and cardiovascular (CV) events; however the results of a meta-analysis suggest that tiotropium Soft Mist Inhaler has an increased risk of overall death compared with placebo. The US FDA has continually highlighted the increased risk of death associated with long-acting beta-agonists in patients with asthma; however safety concerns about their use in patients with COPD remain inconclusive.

They conducted both direct comparison and mixed-treatment comparison meta-analyses to compare the risk of overall and CV death for inhaled medications in patients with COPD. A systematic search of the literature was conducted (to July 2012) for any randomised, double-blind, controlled trials of ≥6 months’ duration evaluating any of the treatments of interest (tiotropium Soft Mist Inhaler, tiotropium HandiHaler, LABA, ICS, and LABA-ICS combination) in patients with COPD, and providing data about overall (primary outcome) or CV-related death. Manufacturer’s clinical trial registers were searched to identify any unpublished studies and study authors were contacted when any additional data were required.

A total of 42 eligible trials (n=52,516) reporting on overall death and 31 reporting on CV death were included in the meta-analysis. The main results reported were as follows:

• The results of the MTC meta-analysis with the fixed effect model indicated that patients using tiotropium Respimat Soft Mist Inhaler had an increased risk of overall death compared with placebo (OR 1.51; 95% CI 1.06 to 2.19) and those using tiotropium HandiHaler (OR 1.65; 1.13 to 2.43), LABA (OR 1.63; 1.10 to 2.44) or LABA-ICS (OR 1.90; 1.28 to 2.86).
• In contrast, LABA-ICS were associated with a lower risk of death compared to placebo (OR 0.80; 95% CrI 0.67 to 0.94) or ICS (OR 0.77; 95% CrI 0.64 to 0.93)

• For CV death, the risk increase seen with tiotropium Soft Mist Inhaler versus use of the other comparators was even higher (for example OR 2.07 [95% CrI 1.09 to 4.16] versus placebo and OR 2.38 [1.20 to 4.99] versus tiotropium HandiHaler). In contrast, LABA had a decreased risk versus placebo (OR 0.68; 95% CrI 0.50 to 0.93).


• The results were similar for MTC and direct comparison meta-analyses, with less precision in the random effects model.


• Among all the treatments, tiotropium Soft Mist Inhaler had the highest probability of overall and cardiovascular death (8% and 3.5%, respectively), with an approximate probability of 95% of being ranked as the riskiest treatment. In contrast, LABA-ICS had the lowest probability of overall death (4.5%), with a probability of 0% of being ranked as the riskiest treatment


The authors discuss the strengths and limitations of their study. They comment that until more evidence is available, physicians should use tiotropium Respimat Soft Mist Inhaler with caution; where it is used, the dose should not exceed that recommended. Alternative treatments should be considered in high-risk patients, including those with severe COPD or cardiac dysrhythmias.

Source - Thorax.bmj.com