An Update on Tiotropium for Chronic Obstructive Pulmonary Disease

Abstract & Commentary

By Rahul Gupta, MD, MPH, FACP, Assistant Professor, Department of Internal Medicine, Meharry Medical College; Assistant Clinical Professor, Division of General Internal Medicine and Public Health, Vanderbilt University Medical School, Nashville, TN. Dr. Gupta reports no financial relationship to this field of study.

Synopsis: Among almost 6000 patients with COPD who were using other classes of respiratory therapies, the addition of tiotropium, compared with placebo, was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period, but did not result in benefits in the rate of decline in FEV1.

Source: Tashkin DP, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States. By the year 2020, it is projected to rank fifth in burden of disease caused worldwide, according to a study published by the World Bank/World Health Organization.1,2 According to the recent COPD Global Initiative for Lung Disease guidelines (GOLD), inhaled tiotropium is indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD.1 The quaternary ammonium structure of inhaled anticholinergic agents limits their systemic bioavailability, and the only commonly recognized adverse effects include the development of anticholinergic effects, such as dry mouth and urinary retention.1

To define the disease and assess its severity, spirometric classification is used, including measuring the FEV1 and the FEV1/FVC ratio. Therefore, the goal of any therapy in COPD is to monitor the disease, reduce risk factors (like smoking), and manage stable disease as well as exacerbations. An ideal drug would attempt to address the underlying disease, which includes benefits in the decline in FEV1. To date, only smoking cessation has been shown to reduce the rate of decline of FEV1.3 All categories of bronchdilators (beta-2 agonists, anticholinergics, and methylxanthines) have been shown to increase exercise capacity in COPD, without necessarily producing significant changes in FEV1. Regular treatment with inhaled glucocorticosteroids does not modify the long-term decline of FEV1 in patients with COPD either.

In their study (Understanding Potential Long-Term Impacts on Function with Tiotropium, or the UPLIFT trial), Tashkin et al conducted a 4-year, randomized, double-blind, placebo-controlled, parallel group trial involving patients with moderate to very severe COPD.4 Patients (n = 5993) with mean age 65 ± 8 years and mean FEV1 of 1.32 ± 0.44 L after bronchodilation (48% of predicted value) were randomly assigned to either the tiotropium or the placebo group. These patients were allowed to use all respiratory medications except inhaled anticholinergic drugs (other than study medications). The co-primary endpoints were the rate of decline in the mean FEV1 before and after bronchodilation beginning on day 30. The secondary endpoints included measures of FVC, changes in response on St. George's Respiratory Questionnaire, exacerbations of COPD, and mortality.

The authors found that there were no significant differences between study groups in the rate of decline in the mean values for FEV1 and FVC either before or after bronchodilation from day 30 to the end of study drug treatment. However, in the tiotropium group, the mean values for FEV1 and FVC before and after bronchodilation showed significant improvements that were maintained at all time points after randomization. The study did find significant differences in favor of tiotropium at all time points during the 4 years for the mean absolute change in the health-related quality-of-life measure, although the differences were small. More convincing was the evidence that tiotropium use was associated with a significant delay in the time to the first exacerbation (about 4 months average) as well as significant delay in the time to first hospitalization for an exacerbation. There was no significant difference in impact on mortality.

The incidence of serious events was lower in the tiotropium group compared to placebo. Patients on tiotropium also had significantly lower incidence of respiratory failure, dyspnea, as well as cardiac events like congestive heart failure and myocardial infarction. It is noteworthy that the overall rate of decline in FEV1 observed in this study was lower than that in other similar studies.5,6 Because patients were allowed to continue all other medications for COPD, the current study was a more "real-life" study even though only 30% of patients were current smokers at baseline, whereas this number was much higher in other studies.

Commentary

Considerable interest in the adverse events profile of inhaled anticholinergics has recently developed. In a recent study published in JAMA, Singh et al performed a systematic review of randomized controlled trials of any inhaled anticholinergics (ipratropium bromide or tiotropium bromide) for treatment of COPD that had at least 30 days of treatment and they reported on cardiovascular events.7 A total of 17 trials enrolling 14,783 patients were analyzed. The authors reached a conclusion that inhaled anticholinergics were associated with a significantly increased risk of cardiovascular death, MI, or stroke. This type of a publication is inherently misleading at best since the trials included in the meta-analysis were never intended to detect differences in all-cause mortality and therefore they were inadequately powered.

In another recent VA study,8 the authors performed a nested case-control study of their database from 1999 to 2003 among COPD patients and found adjusted odds ratios of 1.11 (confidence interval [CI], 1.08-1.15) for ipratropium for all-cause mortality and 1.34 (CI, 1.22-1.47) for cardiovascular death. However, this study also had several limitations including being an observational study that was underpowered for medications use and not accounting for severity of COPD or smoking.

In essence, the global burden of COPD dictates that we must gather more data from good-quality studies such as the one presented above to determine the true benefits and drawbacks of each medication used. The GOLD guidelines remain the "gold criteria" for the treatment of COPD until more evidence becomes clear. In primary care practice, the GOLD guidelines are intended to be simple, clear, and evidence-based.

What would I do? I believe the findings of a well-designed study such as the UPLIFT trial over poor-quality data merely intended to make news as mentioned above. According to the GOLD criteria, in patients with Stage II (moderate) to Stage IV (very severe) COPD, I would consider adding tiotropium or beta-2 agonists or both to those whose dyspnea during daily activities is not relieved despite treatment with as-needed, short-acting bronchodilators. In this population, regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. However, it is noteworthy that some payers are reluctant to advocate utilizing tiotropium as recommended in guidelines due to cost reasons. However, the UPLIFT trial should be evidence that preventing exacerbations, hospitalizations, and respiratory failure is good enough incentive to pay for this drug.

References

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD. Available at: www.goldcopd.org. Accessed Oct. 15, 2008.

2. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-1504.

3. Anthonisen NR, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994;272:1497-1505.

4. Tashkin DP, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1454.

5. Celli BR, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH study. Am J Respir Crit Care Med 2008;178:332-338.

6. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902-1909.

7. Singh S, et al. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis. JAMA 2008;300:1439-1450.

8. Lee TA, et al. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med 2008;149:380-390.