By Michael Smith, North American Correspondent, MedPage Today
Published: June 14, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.An inhaled mist formulation of tiotropium, used to treat chronic obstructive pulmonary disease (COPD), is associated with an increased risk of death compared with placebo, researchers reported.Action Points
- Explain that an inhaled mist formulation of tiotropium, used to treat chronic obstructive pulmonary disease (COPD), is associated with an increased risk of death compared with placebo based on a meta-analysis.
Note that the study assessed the mortality using the mist formulation of tiotropium, which is not approved in the U.S., and this formulation may have led to higher serum tiotropium levels than the powder inhaler that is used in the U.S.
In a meta-analysis of five placebo-controlled trials, the mist formulation of the drug was associated with a 52% increase in the mortality rate, according to Sonal Singh, MBBS, of Johns Hopkins University School of Medicine, and colleagues.
The increase varied depending on the dose used, 5 µg or 10 µg a day, Singh and colleagues reported online in BMJ.
Tiotropium, a long-acting anticholinergic drug, is widely used to treat COPD and can be delivered either in a powder form or, more recently, in an inhaled mist. Although the mist formulation is not approved in the U.S., it is licensed in 55 countries.
But patients using the mist inhaler potentially get higher plasma concentrations of the drug, which might raise safety concerns, the researchers noted.
To clarify the issue, they conducted a meta-analysis of double-blind randomized trials that compared the inhaled mist with placebo. All told, they found five such studies, including a total of 6,522 participants.
Of those, 3,686 received tiotropium mist (including 2,839 at the 5 µg dose and 847 at the 10 µg dose) and 2,836 got a placebo. Three of the studies lasted 52 weeks, one went for 24 weeks, and one lasted for 12 weeks.
Overall, Singh and colleagues found that the tiotropium mist was associated with increased mortality compared with placebo -- 90 deaths among 3,686 mist patients and 47 among 2,836 placebo patients.
The relative risk was 1.52, with a 95% confidence interval from 1.06 to 2.16, which was significant at P=0.02.
There was also a suggestion of a dose effect, they reported.
Compared with placebo, the 5 µg dose had a hazard ratio (HR) for death of 1.46, with a 95% confidence interval from 1.01 to 2.10, which was significant at P=0.04.
On the other hand, the 10 µg dose was associated with an HR of 2.15, with a 95% confidence interval from 1.03 to 4.51, also significant at P=0.04.
"What we think is going on is that the mist inhaler is delivering a higher concentration of tiotropium than it should be, and that may be increasing the risk of death," Singh said in a statement.
He and his colleagues noted that a head-to-head trial comparing the two ways of delivering the drug, powder and mist, is now under way, which should clarify the issue.
The researchers cautioned that there were differences in the populations studied in the trials; differences in the doses of tiotropium using the mist inhaler; and differences in length of follow-up. As well, they noted, the estimates were imprecise because of relatively low event rates.
Indeed, while the relative risk of mortality is increased, that by itself is misleading because the baseline risk is small, argued Christopher Cates, FRCGP, of St. George's University of London.
In an accompanying editorial, he noted that in the three year-long trials, the absolute risk of death in patients getting a placebo was 1.8% a year, compared with 2.6% a year for patients using the tiotropium mist inhaler.
The relative increase in risk "therefore represents an absolute difference of 0.8%, because death was a rare event," he noted.
Until a head-to-head trial of the two devices offers definitive results, he argued, the indirect evidence suggests it would be better for patients to use the powder inhaler.
The study was supported by the NIH. Singh and colleagues said they had no conflicts.
Cates said he had no conflicts.
Primary source: BMJ
Source reference:
Singh S, et al "Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials" BMJ 2011; 342: d3215.
Additional source: BMJ
Source reference:
Cates CJ "Safety of tiotropium" BMJ 2011; 342: d2970.
via medpagetoday.com
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