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FDA: safety of Spiriva HandiHaler

Chronic obstructive pulmonary disease ( COPD ) is a leading cause of death worldwide, and the rate of COPD-related death is increasing. No current drug therapy alters the progressive decline in lung function that characterizes this disease.

In 2004, the Food and Drug Administration ( FDA ) approved the use of Tiotropium delivered by the HandiHaler device ( Spiriva HandiHaler ), the first long-acting anticholinergic bronchodilator for treatment of COPD.
Trials supporting Tiotropium's approval demonstrated sustained bronchodilation over a 24-hour period.
More recent studies have shown that treatment with the Tiotropium HandiHaler reduces COPD exacerbations. Concerns have been raised, however, about Tiotropium's safety. In particular, disparate sources have identified stroke, cardiovascular events, and death, which have been studied as individual or composite end points, as possible adverse outcomes.

The potential for a drug-related increase in the risk of stroke was first reported to the FDA in November 2007 by Boehringer Ingelheim, Tiotropium's manufacturer. Pooled data from 29 placebo-controlled Tiotropium trials, stratified by study, demonstrated an increase in the rate of stroke ( Safety Data from Pooled Analysis of Tiotropium Trials and UPLIFT ).

This analysis, like most pooled analyses of adverse events, explored a large number of adverse events and was not corrected for analysis of multiple safety end points. Rather, it was performed to detect any potential safety signals warranting further investigation.
However, because of the severity of the type of event and the FDA's commitment to informing the public early about investigations of potentially serious safety concerns, it issued a communication in March 2008 while continuing to investigate this finding.

In September 2008, Singh et al. published a meta-analysis of 17 randomized clinical trials evaluating the cardiovascular risk associated with inhaled anticholinergic agents. After correcting for double counting of trials, the authors reported a relative risk of cardiovascular events of 1.60 ( 95% confidence interval [ CI ], 1.22 to 2.10 ) for inhaled anticholinergics ( a combination of Tiotropium HandiHaler and Ipratropium ) as compared with a combination of placebo and active controls.
They concluded that the use of inhaled anticholinergics was associated with a significantly increased risk of major adverse cardiovascular events, including death from cardiovascular causes, myocardial infarction, and stroke.

Boehringer Ingelheim also reported a potential increase in the rate of death from any cause in association with an alternative formulation of Tiotropium delivered by the Respimat device ( which has not been approved for marketing in the United States ). Each of three 1-year, placebo-controlled clinical trials of Tiotropium Respimat ( Spiriva Respimat ) showed a numerical imbalance in mortality, favoring placebo, without a consistent cause of death.
In the combined trials, the risk ratio for death during treatment with 5 mcg of Tiotropium Respimat once daily as compared with placebo was 1.7 ( 95% CI, 1.1 to 2.8 ).
Vital status information was collected for patients who discontinued the trial prematurely to assess the effects of differential discontinuation and a potential healthy-survivor effect. With the inclusion of this vital status information, the risk ratio decreased to 1.4 ( 95% CI, 0.9 to 2.0 ).

In contrast with these trials, the Understanding Potential Long-Term Impacts on Function with Tiotropium ( UPLIFT ) trial did not show an increased risk of myocardial infarction, death from cardiovascular causes, or death from any cause in its comparison of Tiotropium HandiHaler with placebo.
UPLIFT was a large, 4-year, randomized, controlled trial whose results became available in late 2008. In this study, data on deaths, including the vital status of patients who withdrew from the study, were collected prospectively, and the cause of death was adjudicated by an independent Committee.
With 17,721 patient-years of exposure, the UPLIFT study quadrupled the safety database for patients with COPD participating in placebo-controlled trials of Tiotropium HandiHaler and doubled the size of the overall safety database for Tiotropium.

Because of the disparate results between the UPLIFT trial and the meta-analysis conducted by Singh et al., the FDA convened a meeting of the Pulmonary - Allergy Drugs Advisory Committee ( PADAC ) on November 19, 2009, to discuss the data on cardiovascular risk and mortality.
In a vote that was nearly unanimous, the PADAC decided that the data from UPLIFT adequately addressed the potential stroke signal ( 11 yes votes, 1 no vote ) and cardiovascular signal ( 11 yes votes, 1 abstention ).
Participants noted certain methodologic limitations in the Singh meta-analysis that may explain the disparities between the studies. These included potentially biased study selection, which was limited to trials reporting cardiovascular events; lack of assessment of patient follow-up time, with no accounting for differential discontinuation rates, which were significantly higher among patients given placebo ( patients who continue to take placebo may be generally healthier than those who stop taking it, and potential differences in baseline cardiovascular risk factors were not accounted for in the analysis ); lack of information on occurrence of adverse events in patients who withdrew from many of the included trials; lack of patient-level data; and the fact that trials on short-acting and long-acting anticholinergics were combined in the main analysis.

In contrast, the UPLIFT trial had a large sample size, a long follow-up period, and prespecified safety end points, including all adverse events, serious adverse events, and death from any cause. Information on vital status was collected for 97% of treated patients until the end of treatment day 1440, and for 75% of treated patients until off-treatment follow-up day 1470.
Findings regarding stroke, cardiovascular events, and death were consistent across a variety of analyses.

Although the reported potential risk of death seen in trials of Tiotropium Respimat remains unresolved, Committee members noted that delivery devices are important components of locally acting drugs such as inhaled bronchodilators.
Differences between the products in terms of lung deposition and other factors may result in differential risk.
They also noted that the causes of death were diverse and that Boehringer Ingelheim was performing a large safety study to further evaluate the finding.

Because of the strength of the UPLIFT data, the absence of a strong signal related to stroke or cardiovascular events with Tiotropium, and the potential methodologic limitations of the Singh meta-analysis, the FDA concluded that current data do not support the conclusion that there is an increased risk of stroke, heart attack, or death associated with Tiotropium HandiHaler.
FDA placed significant emphasis on UPLIFT because it was the largest and longest randomized trial of Tiotropium to date, mortality-related end points were prespecified, information on vital status was systematically collected and adjudicated, and mortality results were robust across different analyses. ( Xagena )

Michele TM et al, N Engl J Med 2010; 363:1097-1099