David Brill
Doctors can be reassured about prescribing inhaled tiotropium as a treatment for chronic obstructive pulmonary disease (COPD), one of Singapore’s leading respiratory experts has advised in light of a recent trial publication.
The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study found that tiotropium was safe and significantly reduced the risk of cardiac adverse events among patients with moderate to very severe COPD.
The safety of inhaled anticholinergics had been called into question following the publication of two separate studies in September which linked the class of drugs to an increased risk of cardiovascular mortality.
One of the papers – a meta-analysis published in the Journal of the American Medical Association (JAMA) – reported a 58 percent increase in the risk of cardiovascular death, myocardial infarction or stroke among COPD patients taking either tiotropium or ipratropium. [2008 Sep 24;300(12):1439-50]
The US Food and Drug Administration (FDA) is conducting a thorough review of the findings from UPLIFT and expects to receive the full data set in November. However, the complete analysis could take several months, according to a statement on the FDA website.
The 4-year UPLIFT study, published in The New England Journal of Medicine, involved 5,993 patients from 37 countries who were randomized to tiotropium (18 μg once daily) or placebo. [2008 Oct 9;359(15):1543-54]
Dr. Ong Kian Chung, president of the Singapore COPD Association, said that he was happy with the safety data from UPLIFT and would continue to prescribe tiotropium as normal.
“I’m personally not too convinced that there is any significant complication from using these medications,” he said.
“The data from the meta-analysis isn’t enough to deny the patient the effectiveness of a long-acting anticholinergic. I think it’s more likely that it is a statistical fluke than a truly increased risk,” said Ong, who is currently a private practitioner at Mount Elizabeth Medical Centre, and was a co-investigator for the UPLIFT trial.
Patients in UPLIFT were allowed to continue their usual respiratory care with the exception of other inhaled anticholinergics, such as ipratropium, a shorter-acting formulation than the study
drug tiotropium. The use of these drugs was permitted, however, in the event of a serious exacerbation of COPD.
Dr. Sonal Singh, lead authorof the JAMA meta-analysis, questioned this aspect of the UPLIFT design and said that the trial does not invalidate the findings of the meta-analysis since the usage of ipratropium for exacerbations has not been reported.
“There might be differences in the risk between the long-acting and the short-acting, but UPLIFT is not going to answer that question because it was not designed that way,” he said.
“In one arm you have the long-acting and in the other arm you have people using the short-acting, so it’s not a valid comparison,” he said, adding that the meta-analysis demonstrated a higher cardiovascular risk with short-acting ipratropium than with long-acting tiotropium (risk ratios 1.70 and 1.43, respectively).
The meta-analysis incorporated 17 trials involving 14,783 patients.
A second paper, a nested case-control study including 32,130 cases and 320,501 controls, found an odds ratio of 1.34 for cardiovascular death associated with ipratropium. [Ann Intern Med 2008 Sep 16;149(6):380-90]
Tiotropium in UPLIFT was delivered with the HandiHaler inhalation device manufactured by Boehringer Ingelheim, which co-sponsored the trial with Pfizer.
Dr. Iylen Benedict, regional medical affairs director for Boehringer Ingelheim, said that the study by Singh et al. is methodologically flawed and pointed out that the majority of the evidence on ipratropium comes from a single study, the Lung Health Study. [Am J Respir Crit Care Med 2002;166(3):333-9]
“In this study, most of the cardiovascular deaths occurred among patients who were not using their medication,” she said.
“Other limitations [of the metaanalysis] include the inability to adjust for treatment duration and accounting for patients who discontinue the trial early, apparent double-counting of trials and combining placebo and active comparator drugs in the control group.”
Benedict also reiterated that the use of other anticholinergics such as ipratropium was not allowed in UPLIFT, and that the decision to allow any intervention in the face of a life-threatening exacerbation, as deemed necessary by a physician, was an ethical position.
She added that there are currently no plans for a trial looking specifically at cardiovascular outcomes with tiotropium, but confirmed that the full UPLIFT data will be provided to the FDA for the safety analysis.
UPLIFT did not reach its primary endpoint of significantly reducing the decline in forced expiratory volume 1, but did demonstrate significant improvements in lung function, exacerbations and quality of life with tiotropium therapy.
The trial included patients from seven Asian countries, including Singapore, Hong Kong, Malaysia and the Philippines. The results were first presented at the annual meeting of the European Respiratory Society, held recently in Berlin, Germany.
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