There was some bad news for Boehringer Ingelheim's Spiriva after the mist inhaler formulation, which is co-marketed by Pfizer for chronic obstructive pulmonary disease, was linked with a 52% increase in the risk of death.

According to a meta-analysis of five clinical trials in more than 6,500 patients published in the British Medical Journal, Spiriva (tiotropium) delivered in a mist formulation (as opposed to the alternative powder form) could be significantly increasing the chance of mortality compared with a placebo. 

This is not the first time the product's safety has come into the spotlight, and writing in the BMJ the researchers note that their meta-analysis "explains safety concerns by regulatory agencies".

In addition, in an accompanying editorial, Christopher J Cates, a senior research fellow at the University of London, concluded that "indirect evidence suggests the Respimat [mist] inhaler is riskier than the Handihaler [powder version]" of the drug.

The US Food and Drug Administration, which carried out a two-year investigation into Spiriva's safety, concluded last year that the Handihaler version does not increase the risk of heart attack or stroke in patients with COPD, after a different meta-analysis of studies rang some alarm bells.

And in an online drug safety update in November 2010, the Medicines and Healthcare products Regulatory Agency noted that Respimat had shown a statistically non-inferior increase in all cause mortality compared with the Handihaler form, but no further action was taken.

Review limitations

Talking to PharmaTimes World News, a spokesman for Boehringer Ingelheim was quick to point out the limitations of conclusions drawn from meta-analysis of research. 

Crucially, the researchers do not have access to individual patient data, he said, which could well explain some of the increases in mortality risk.

"A thorough analysis of these data revealed a statistically non-significant, numerical imbalance in number of fatal events with Spiriva Respimat," BI and Pfizer stressed.

Furthermore, BI has assessed Spiriva's safety in a large-scale clinical programme that has already established its safety and efficacy, he said, and noted that the product also already carries a warning on the label that it must be used with caution in patients with underlying cardiac conditions.

Nevertheless, the two forms of Spiriva are currently being assessed in a head-to-head large-scale trial, which has enrolled more than 17,000 patients at 51 sites around the globe, and the results, which are expected in November 2013, should be able to shed further light on the matter.