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Improving the Present Lives and Future Prospects of Patients with COPD

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 19th Annual Congress of the European Respiratory Society

Vienna, Austria / September 12-16, 2009

According to the Global Obstructive Lung Disease (GOLD) initiative, chronic obstructive pulmonary disease (COPD) is considered as an airflow limitation that is not fully reversible. Given that the airflow limitation is associated with an abnormal inflammatory response of the lung to noxious particles or gases such as cigarette smoke, the disease is considered preventable.

Figures for the prevalence of the disease vary, partly because of differences in the definition of the disease used in different studies and partly because the disease is thought to be underreported. Nevertheless, some estimates suggest that 600 million people worldwide suffer from the disease, which has serious consequences for public health and is currently the fourth leading cause of chronic morbidity and mortality in the US. A projection published by the World Bank/World Health Organization suggests that the disease will rank fifth in the burden of disease worldwide in 2020.

COPD Symptoms Fluctuate During Stable Disease

The overall impact, severity and exacerbations of COPD on patient quality of life has been well documented. It has been assumed that the effects of the disease are evenly spread throughout the day; however, symptoms may vary during the day or over the course of a week, even during periods of stable disease.

As presented here at the ERS by Prof. Martyn Partridge, Imperial College London, UK, and colleagues, a substantial impact of COPD on morning activities was reported in a recent Internet survey (Partridge et al. Curr Med Res Opin 2009; 25:2043-8). An analysis based on a pan-European cross-sectional study also presented at the ERS provided further support for this emerging concept. According to the data from the 2441 patients who completed the interview, 60% of patients with severe COPD experience symptom variability outside exacerbations. Prof. Partridge and coworkers concluded that the symptoms of COPD (breathlessness, phlegm, coughing, wheezing and chest tightness) were all more troublesome in the morning, either immediately upon waking or later in the morning. They also found that symptoms had an impact on morning activities such as getting out of bed, washing, drying and dressing. The authors suggested that these findings might have implications on patient management and that treatment could be adjusted to better suit individual patient needs.

In recognition of the potential importance of morning symptoms in COPD, a new questionnaire known as the Capacity of Daily Living during Morning (CDLM) has been developed. The questionnaire contains a number of questions on daily morning activities such as washing, drying, dressing, eating breakfast and walking about, with the following possible answers: “yes, I did it by myself”; “yes, with help”; “no, I was unable to”; or “no, I did not… for other reasons.” The questionnaire has been appropriately validated and was used in two studies presented at the ERS congress, the CLIMB and the SPEED studies.

CLIMB Study

The CLIMB study was designed to investigate whether addition of combination formoterol/budesonide to tiotropium could improve lung function, morning symptoms and activities, and health status in patients with COPD who are eligible for combination therapy with inhaled corticosteroids (ICS)/long-acting ß-agonists (LABAs). On enrolment, patients had to be >40 years of age and to have at least one COPD exacerbation requiring oral steroids and/or antibiotics in the preceding 12 months. Eligible patients entered a two-week run-in phase consisting of tiotropium 18 µg q.d. They were then randomized to receive either formoterol/budesonide or placebo in addition to continued tiotropium therapy for 12 weeks. During the entire study period, terbutaline 0.5 mg/dose was supplied as a reliever in both the run-in and treatment periods.

The primary outcome variable was change in pre-dose forced expiratory volume in 1 second (FEV<sub>1</sub>) in the morning between randomization and the end of therapy, measured in the clinic. At clinic visits, the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) was also administered to provide a measure of health status. Other outcome variables were recorded in an e-diary and included morning bedside spirometry measures, morning and daytime symptoms (Global Chest Symptoms Questionnaire [GCSQ]), morning activities as determined by the CDLM questionnaire, and reliever medication.

In total, 331 patients were randomized to placebo/tiotropium and 329 patients to combination therapy/tiotropium. The groups were well balanced for all demographic variables and disease characteristics. At entry, of the 660 patients randomized, 418 patients used ICS while 503 used LABA. The majority of patients (66% in the placebo/tiotropium group and 62% in the combination/tiotropium group) were GOLD stage III (30% <u><</u>FEV<sub>1</sub> post-bronchodilator <50%). A noteworthy aspect of this study—while recognizing its short-term nature—was that drop-out rates were very low and similar for both groups (7.9% for the combination/tiotropium vs. 8.5% for the placebo/tiotropium group).

According to Dr. Tobias Welte, Head of Respiratory Medicine, University of Hannover, Germany, “There is absolutely no differential drop-out which can influence the interpretation of the study.” This is important, given that differential drop-out rates, particularly in studies of patients with severe disease, have been grounds for criticism of some COPD trials in the past.

Improved Morning Symptom Control

For the CLIMB primary end point, both treatment groups showed improvements in pre-dose FEV<sub>1</sub> measured at the clinic (Figure 1). However, the improvement was more marked for patients on triple combination therapy than those on tiotropium alone (P<0.001 for the group comparison). In view of the increasing emphasis on morning symptoms and disease, morning lung function measured at the bedside was also incorporated into the protocol. “The improvement in lung function was most pronounced in the morning hours and the onset of improvement was very fast, being apparent in the first 16 minutes in patients who used triple therapy,” affirmed Dr. Welte. One implication of this is that there is much more room for improvement for the COPD patient in the morning, providing a rationale for as early administration as possible of the combination therapy.

Figure 1.


Regarding COPD symptom relief, treatment differences were seen for all COPD symptom scores: breathlessness, nighttime awakening, chest tightness and cough. In particular, breathlessness and chest tightness are considered important symptoms that are particularly bothersome for the patient, and these showed a significant improvement for triple combination therapy vs. monotherapy as assessed by the GCSQ.

The reduction in reliever use mirrored the improvement in symptoms with the triple combination therapy. Thus, the mean change in morning reliever use was -0.48 with triple therapy compared to -0.08 for monotherapy, corresponding to a mean difference of -0.4 (95% CI: -0.564, -0.236). “Triple therapy in the morning improves patients at a time when symptoms are more pronounced, and so these patients did not use reliever medication as often as in the monotherapy group,” explained Dr. Welte.

The improvements in lung function and symptoms were reflected in an improvement in scores on the CDLM questionnaire. These were apparent from baseline for the triple therapy group, and the between-group comparison at week 12 was significant for all items on the questionnaire (Figure 2). According to the SGRQ-C results, triple therapy also showed significantly greater improvements from baseline compared to monotherapy (3.8 units vs. 1.5 units
;0.05).

Figure 2.

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Future Disease Control

A three-month study cannot provide direct evidence of future disease control, but according to Dr. Welte, “Frequent exacerbations are the key for deterioration in lung function and additional morbidity in COPD patients.” Therefore, exacerbation rate can be used as an indicator of future disease control. “The most surprising result of this study was the dramatic reduction in exacerbation rate in the triple therapy group,” he added. Overall, 7.6% of patients on triple therapy had a severe exacerbation—defined as need for oral steroids, a visit to the emergency room, or hospitalization—compared to 18.5% on monotherapy, and the difference in severe exacerbation rate between the two groups was 62% in favour of triple therapy (P<0.001). The effect in favour of triple therapy was apparent regardless of ICS use at study entry (it could be argued that such usage would reduce the risk of exacerbation). Fewer instances of antibiotic usage for COPD exacerbations were also documented in the triple therapy group compared to the monotherapy group (19 patients [6%] in the triple therapy group vs. 38 patients [12%] in the monotherapy group). “Besides the reliever part, which is focussed on the bronchodilator effects and reduction in symptoms, there is a controller part which may be due to the inhaled steroid treatment that reduces the number of exacerbations and therefore could be able to improve long-term prognosis of these patients,” concluded Dr. Welte.

Further Investigation of Morning Benefit

Another study that focussed on the morning benefit of treatment was the SPEED study carried out by Prof. Partridge and colleagues, where budesonide/formoterol was compared with salmeterol/fluticasone in a crossover design with two one-week periods of active treatment separated by a one- to two-week washout. Patients had to be aged over 40 years with at least one COPD exacerbation in the previous 12 months. In total, 442 patients were recruited, 71% of whom were men and 81% of whom were using ICS at study entry. Most patients were GOLD stage III (59%). Lung function parameters were determined both at the bedside and in the clinic at study visits. In addition the CDLM questionnaire and GCSQ scores, reliever medication use was also recorded.

The primary end point of the SPEED study—peak expiratory flow (PEF) 5 minutes’ post-dose—showed no treatment differences as similar improvements were observed in both cases. However, differences were detected in secondary end points. Thus, morning FEV<sub>1</sub> measured at 15 minutes after dosing showed a significantly greater improvement for budesonide/formoterol than salmeterol/fluticasone (0.140 L vs. 0.100 L, respectively; P<0.05). The bedside measurements for both PEF and FEV<sub>1</sub>, recorded in the eDiaries and expressed relative to pre-dosing levels to give an indication of the speed of onset of effect, showed significant differences in favour of budesonide/formoterol (P<0.001). For the CDLM scores, budesonide/formoterol showed significantly higher scores for eating breakfast and walking about, as were total scores. Taken together, these differences may suggest benefits with the use of budesonide/formoterol. “The rapid onset of effect of budesonide may allow COPD patients to experience a better start to their mornings,” concluded the authors.

CODEX Study

Budesonide/formoterol has been shown to have a fast onset of action when used first thing in the morning. In another trial, longer-term effects were investigated in a study of exercise tolerance in COPD patients eligible for ICS/LABA in a three-way, crossover design with budesonide/formoterol, formoterol or placebo (administered as one inhalation twice daily). The mean age of the 111 patients included in the study was 63.7 years and 39% were using ICS on study entry. Most patients (70%) were GOLD stage III. The primary end point was exercise endurance time (EET) measured at 75% of peak work capacity by cycle ergometry 1 hour after post-morning dose. EET was measured again at 6 hours after dosing, as reported by Dr. Heinrich Worth, Erlangen-Nürnberg University Teaching Hospital, Fürth, Germany.

At 1 hour, EET was significantly prolonged for the combination (517 seconds) vs. formoterol (448 seconds, 14% difference) and placebo (412 seconds, 28% difference). These effects were carried over to 6 hours’ post-dosing. During exercise testing, the authors also assessed inspiratory capacity to give an indication of dynamic hyperinflation. Treatment with the combination gave a 21% higher inspiratory capacity vs. placebo at 1 hour after dosing (P<0.05) and an 8% higher inspiratory capacity at 6 hours after dosing. “These findings suggest that patients with COPD could do more demanding routine activities and for longer, directly and up to 6 hours after the morning dose of budesonide/formoterol compared with formoterol alone,” concluded Dr. Worth.

Summary

There is evidence from studies presented here at the ERS that combination budesonide/formoterol, whether added to tiotropium or alone, can improve lung function and reduce morning symptoms. As Dr. Roland Buhl, Mainz University Hospital, Germany, told delegates, “We have identified the morning as a very crucial time for COPD patients. This is the time of day when they need our help most and when symptoms are particularly problematic for our patients.” He concluded, “Not only can we improve today’s control, but we can also reduce future risk as evidenced by the excellent data on the number of exacerbations.”

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