Therapy for Early-Stage COPD: What is the GOLDen Regimen?

Nearly 16 million adults in the United States have chronic obstructive pulmonary disease (COPD) but this is probably a woeful underestimate as many adults are asymptomatic in early stages.^1,2 The United States Preventative Services Task Force recommends against screening in asymptomatic adults due to a lack of evidence that regular screening improves morbidity, mortality, or quality of life. Screening is only recommended if patients exhibit symptoms and have risk factors.³  However, the most rapid decline in lung function occurs during GOLD stage 1.⁴ As COPD progresses, mortality, morbidity, and the economic burden increase very significantly.⁵ These facts suggest a need to detect and treat early-stage disease to slow its progression. While studies have shown that pharmacologic treatments reduce symptoms, reduce frequency and severity of exacerbations, and improve quality of life in patients with COPD, there is relatively little evidence medications can slow disease progression.^6-8

The Tie-COPD study was a multicenter, randomized, double-blind, placebo-controlled, phase 4 trial conducted in China.  The study was designed to evaluate the effect of tiotropium on progression of lung dysfunction in adult patients with mild to moderate COPD (GOLD stage 1 or 2). Patients were excluded if they had a COPD exacerbation within 4 weeks prior to screening or concurrent large-airway disease (such as asthma). Patients were randomized in a 1:1 ratio to receive usual care plus either tiotropium 18 mcg once daily using the proprietary HandiHaler or matching placebo.

The primary efficacy outcome was the change in pre-bronchodilator FEV₁ from baseline to month 24. Key secondary outcomes included change in post-bronchodilator FEV₁, forced vital capacity (FVC) before and after bronchodilator use, annual decline in lung function, change in symptom scores, time to first exacerbation, exacerbation rate, and rescue medication use. Follow-up was scheduled at 1 month and subsequently every 3 months. Spirometry was conducted at baseline and months 1, 6, 12, 18, 24, and 25. Investigators calculated 400 participants were needed in each group to detect a clinically significant difference in FEV₁ (100 mL) with a two-sided significance level of 5%, power of 90%, and estimated withdrawal rate of 35%. Secondary and subgroup analyses were exploratory.

The final analysis included 383 patients in the placebo and 388 in the tiotropium group. Baseline characteristics and study withdrawal was similar in both groups. The mean age of enrolled patients was approximately 65 years and the majority were men. The mean baseline FEV₁:FVC ratio after bronchodilator use was approximately 0.60 and the mean post-bronchodilator FEV₁ at baseline was approximately 78% of predicted. The majority of patients had a baseline COPD Assessment Test (CAT) score <10 with a mean score of approximately 7.

At month 24, tiotropium-treated group had a significantly higher pre-bronchodilator FEV₁ with compared to placebo (difference = 157 mL [95% CI 123-192; p<0.001]). Results were similar after adjusting for smoking, baseline FEV₁, age, gender, and GOLD stage. In addition, there was significantly higher mean pre- and post-bronchodilator FEV₁ and FVC with tiotropium (p<0.001 for all comparisons of FEV₁; p<0.05 for all comparisons of FVC). Adherence, measured by capsule counts at each visit, was significantly higher with tiotropium (93.3%) compared to placebo (90.5%; p=0.004). There was significantly more rescue medication use in the placebo-treated group (p<0.05). Placebo-treated patients (39.2%) were more likely to experience an exacerbations when compared to tiotropium (28.9%; p<0.001). Treatment with tiotropium cut the exacerbation risk per patient-year by nearly 50% (RR= 0.53; 95% CI 0.39-0.73; p<0.001). The time to first exacerbation was significantly longer with tiotropium, 522 versus 236 days (p<0.001). See Tables 1 and 2.

Table 1. Difference in FEV₁ between groups at select time points.

Table 2. Annual declines in FEV₁ before and after bronchodilator use.

In those patients with fewer symptoms (CAT <10) there was a non-significant difference in mean annual decline of pre-bronchodilator FEV₁ (95% CI -1-35; p=0.07). However, there was a slower annual decline noted with post-bronchodilator FEV₁ with tiotropium. For patients with more symptoms (CAT >10) at baseline, the difference between groups in annual decline of pre- and post-bronchodilator FEV₁ was not significant. However, the CAT score for these patients improved from 15.5 to 9.2 by month 24. Analyses stratified by GOLD stage and category were similar to results in the overall analysis. While there was a higher incidence of oropharyngeal discomfort with tiotropium (p<0.001), the incidence of serious adverse events and death were similar in the two groups.

It is notable that the primary endpoint was change in pre-bronchodilator FEV₁. Guidelines recommend staging patients based on post-bronchodilator FEV₁, symptoms, and exacerbation history.⁶ Both pre- and post-bronchodilator FEV₁ values predict mortality.⁹ The duration of follow-up was only 24 months – thus the results from this trial can’t be extrapolated beyond two years.  Given the pathophysiology of COPD and disease progression over time, we’d really need longer studies to understand the impact of early tiotropium use on long-term outcomes. The dropout rate was relatively high (30.4%) with most patients withdrawing due to adverse effects, withdrawing consent, or being lost to follow-up. Investigators did not meet pre-designated power.

Over 70% of the patients enrolled in Tie-COPD had a baseline CAT <10, indicating minimal symptoms. Patients were allowed to continue maintenance medications initiated before recruitment, which included combination inhalers, β2 agonists, and inhaled corticosteroids. Approximately 40% of patients were current smokers. Investigators did not address smoking cessation, which is pertinent as smoking cessation is the only intervention that is known to alter the decline in lung function.¹⁰ Previous trials have reported the rate of FEV₁ decline with continued smoking (approximately 55 mL/year) is substantially greater than the decline observed in patients who quit (30 mL/year) – a difference in the rate of change comparable to this study.¹¹ It is unknown if the combination of smoking cessation plus early tiotropium treatment is more effective at slowing lung function decline than either intervention alone.

Evidence supporting pharmacotherapy to slow lung function decline is limited. A subgroup analysis of the UPLIFT trial, which included GOLD stage 2 patients, showed significant but modest reduction in the rate of post-bronchodilator FEV₁ decline (43 mL/year vs. 49 mL/year; p=0.024).  More importantly, the risk of exacerbations with tiotropium over the 4-year study period was significantly lower.¹² However, the correlation between FEV₁ decline and exacerbation rate has not been firmly established.¹³

This study provides promising evidence that early use of tiotropium in COPD may be beneficial. Tiotropium appears to reduce exacerbations, decrease symptoms, and slow lung function decline. However, we are left with several questions.  Since we don’t routinely screen for COPD, how would we identify candidates for this therapy? Do the benefits from early use of tiotropium multiply over time with long-term use?  Or is there diminishing returns with a regression to the mean? Would you recommend initiation of tiotropium for patients with GOLD stage 1 COPD? What factors would persuade you to consider early therapy with tiotropium? What factors would dissuade you?