Over the years, a number of landmark clinical studies on COPD have been published, shaping how we treat the disease today.
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease, affecting more than 30 million Americans. It is the third leading cause of death in the United States and presents a significant burden on the healthcare system through direct medical costs and reduced productivity.
Over the years, a number of landmark clinical studies on COPD have been published, shaping how we treat the disease today. Here are 5 of those that every pharmacist should know:
1. ISOLDE (2000)1
By the year 2000, COPD was well-established as a leading cause of morbidity and mortality worldwide, with a rising prevalence. Although inhaled corticosteroids (ICS) were widely being prescribed for COPD patients, no published studies had shown pharmacological intervention to modify the progression of disease or the associated decline in health status.
ISOLDE was a 3-year trial conducted to further assess the effect of an ICS, fluticasone propionate, on the rate of decline of FEV1, a measure of lung function, and other relevant clinical outcomes. After an 8-week run-in period, 751 patients with moderate-to-severe COPD were randomly assigned to receive either fluticasone propionate or placebo twice daily.
Throughout the trial, patients used salbutamol, ipratropium, or both for symptomatic relief. Before the double-blind phase, patients received oral prednisolone for 14 days to test whether the acute corticosteroid response could predict those patients who would benefit from long-term ICS therapy. Spirometry measurements were collected up to 36 months from the start date.
Study results showed a non-significant difference in the annual rate of decline in FEV1 between the groups (59 mL/year in placebo and 50 mL/year with fluticasone; P = .16). Significant differences favoring fluticasone were noted in median yearly exacerbation rates (25% reduction), mean FEV1 after bronchodilator throughout the study, health status, and withdrawal rate compared to placebo. No difference was found in the relationship between FEV1 response to oral corticosteroids or fluticasone. Safety measures were similar between treatment groups, except those receiving fluticasone had a small decrease in mean cortisol concentrations.
Fluticasone did not affect the annual rate of decline in FEV1, but did result in fewer exacerbations, a reduced rate of decline in health status, and higher FEV1 values compared to placebo.
2. TRISTAN (2003)2
Several published studies had shown the benefit of ICS and long-acting beta agonists (LABAs) to control symptoms and improve health status in patients with COPD. Whether a LABA and ICS in combination would result in treatment effects that are better than those associated with either drug alone was not clear.
To test this hypothesis, researchers conducted a randomized, double-blind, placebo-controlled trial over 1 year of combination treatment with salmeterol and fluticasone versus each of the components and placebo. One thousand, four hundred and sixty five COPD patients from 196 hospitals in 25 countries were randomized into the study. The primary outcome was FEV1 after patients had abstained from all bronchodilators for at least 6 hours, and from study medication for at least 12 hours.
All three active treatments significantly improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Specifically, by week 52, pretreatment FEV1 in the combination group had increased by 10% compared with 2% in both the salmeterol and fluticasone groups, and had fallen by 3% in the placebo group. The rate of exacerbations fell by 25% in the combination group (p<0·0001) and by 20% (P=.0027) and 19% (P=.0033) in the salmeterol and fluticasone groups, respectively, compared with placebo. All treatments were well tolerated with no differences noted in the frequency of adverse events.
Combination of fluticasone and salmeterol improves symptom control and lung function, with no greater risk of adverse events than with use of either medication alone.
3. TORCH (2007)3
Due to results from ISOLDE, TRISTAN, and several other studies, ICS therapy alone or combination with a LABA, had been shown to improve outcomes in COPD patients. Despite this, however, no pharmacological therapies had been shown to reduce mortality in randomized studies. To test the hypothesis that a LABA and ICS combination would reduce mortality in COPD patients, researchers conducted a double-blind, placebo-controlled, parallel-group study at 444 centers in 42 countries.
More than 6000 patients were enrolled in the study and randomized to 1 of 4 groups: salmeterol plus fluticasone propionate, placebo, salmeterol alone, or fluticasone propionate alone. Eligible patients were current or former smokers aged 40 to 80. The study ran for a total of 3 years. The primary outcome of the study was death from any cause for the comparison between the combination regimen and placebo.
After analysis of the data, there was a 17.5% reduction in the risk of death with the combination group compared to placebo, although the results did not reach statistical significance (HR=0.825; 95% CI 0.681-1.002; P=.052). As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<.001 for all comparisons with placebo).
The probability of having pneumonia reported as an adverse event during the study period was significantly greater among patients receiving a medication containing fluticasone (19.6% with combination-therapy, 12.3% placebo, 13.3% salmeterol, and 18.3% fluticasone; P<.001). The authors theorized the primary endpoint did not reach statistical significance as the study was underpowered to detect this effect.
Combination of fluticasone and salmeterol was shown to reduce the rate of COPD exacerbations and improve lung function, but the reduction in all-cause mortality did not reach statistical significance.
4. UPLIFT (2008)4
Tiotropium is a long-acting anticholinergic that has been shown in clinical studies to improve exercise tolerance, health-related quality of life, and rates of dyspnea and exacerbations. As most of these studies were relatively short in duration, researchers sought to conduct a study to evaluate the long-term effects of tiotropium on clinically important outcomes such as rate of decline in FEV1, health-related quality of life, exacerbations, related hospitalizations, and mortality.
UPLIFT was a 4-year randomized, double-blind, placebo-controlled trial involving patients with moderate-to-very severe COPD. Nearly 6000 patients were randomly assigned to receive either tiotropium or placebo. The 2 co-primary end points in the study were the annual rate of decline in the mean FEV1 before the use of a study drug and short-acting bronchodilators in the morning and after the use of a study drug from day 30 until completion of treatment.
Study results showed that after day 30, there were no significant differences between study groups in the rate of decline in mean FEV1 before or after bronchodilation. Significant improvements favoring tiotropium compared to placebo were seen with the increase in FEV1, change in the SGRQ total score, and reduced exacerbations. There was also a numerically lower rate of mortality with tiotropium, although it did not reach statistical significance (HR=0.89; 95% CI 0.79-1.02; P=.09).
Long-term tiotropium was associated with improvements in lung function, quality of life, and exacerbations but did not significantly reduce the rate of decline in FEV1 or decrease mortality.
5. INSPIRE (2008)5
While previous studies had shown reduced COPD exacerbations from LABAs, tiotropium, and ICS (alone or combination with a LABA), no studies had been conducted to directly compare the efficacy of these agents. To address this issue, researchers conducted a randomized, double-blind study to compare the effect of salmeterol plus fluticasone propionate with tiotropium in reducing COPD exacerbations.
Patients aged 40 to 80 years with a history of smoking and previous COPD exacerbations were recruited in 179 centers from 20 countries. After a 2-week run-in period, 1323 patients were randomized to receive salmeterol plus fluticasone propionate or tiotropium bromide. In addition to study medication, patients were allowed SABAs for relief therapy and standardized short courses of oral systemic corticosteroids and/or antibiotics where indicated for treatment of COPD exacerbations. The primary efficacy endpoint was the rate of health care utilization exacerbations.
After the 2 year study was completed, the annual exacerbation rate was found to be 1.28 in the ICS/LABA combination group and 1.32 in the tiotropium group (RR=0.967; 95% CI 0.836—1.119; P=.656). No significant difference was noted in the incidence of exacerbations requiring hospitalization. Statistically significant differences favoring the combination group were seen in reduced SGRQ total score, mortality (3% vs 6%), and withdrawal rates from the study. More cases of pneumonia were reported in the salmeterol/fluticasone group relative to tiotropium (P=0.008).
No difference in exacerbation rates were found between the combination of salmeterol plus fluticasone propionate compared to tiotropium; however, the combination group was associated with better health status, fewer patient withdrawals, and a lower mortality rate.