Reports

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.

102nd International Conference of the American Thoracic Society

San Diego, California / May 19-24, 2006

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US, responsible for approximately 119,000 deaths in the year 2000 and is estimated to cost in excess of $20 billion to the healthcare system (Urbano et al. J Manag Care Pharm 2005;11:S2-S13). Because the incidence of COPD is often linked to smoking, it is described as a common but often preventable disease. Worldwide, along with cancer and heart disease, COPD remains one of the top 10 causes of mortality. Unlike many other diseases, however, the rates of COPD have been increasing (Edwards et al. Wisconsin Medical Journal 2005;104:50-4), and new therapies are needed to manage and treat this growing patient population. According to Dr. Bartolome Celli, Division Chief, Pulmonary, Critical Care and Sleep Medicine, Caritas St. Elizabeth’s Medical Center, Boston, Massachusetts, and Professor of Medicine, Tufts University School of Medicine, “COPD prevalence remains a big problem.”

There are global initiatives underway to help combat COPD. One such effort is known as the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines which suggest the following goals:

• Recommend effective COPD management and prevention strategies for use in all countries.

• Increase awareness of COPD among the medical community, public health officials and the general public.

• Decrease morbidity and mortality from COPD.

• Promote study into reasons for increasing prevalence of COPD, including relationship with environment.

• Implement effective programs for prevention.

Combination Therapies

While smoking cessation is vital, long-term home oxygen therapy and reductive lung surgery are strategies that have also been shown to increase survival for COPD patients. Newer, less invasive agents on the horizon show promise as well.

Bronchodilatory long-acting beta2-agonists (LABAs), such as formoterol and salmeterol, and anti-inflammatory inhaled corticosteroids (ICS), such as budesonide and fluticasone propionate, have been recommended as possible therapeutic strategies to reduce symptom exacerbation associated with COPD and also improve health status.

Dr. Peter M. Calverley, School of Clinical Sciences, University Hospital Aintree, Liverpool, UK, presented some of the latest findings of the TORCH (Towards a Revolution in COPD Health) study. In order to investigate the effects of new treatment modalities for COPD, “What was needed was a prospective, double-blind, randomized, controlled trial,” Dr. Calverley told delegates. The primary objective of the study was to “investigate the effects of salmeterol/fluticasone propionate combination [SFC] vs. placebo on all-cause mortality over three years in patients with moderate to severe COPD,” he explained. Safety end points included information on adverse events. Exacerbations of COPD are usually characterized by a deterioration in clinical status due to a worsening of respiratory symptoms such as coughing, wheezing and shortness of breath that may require medical intervention.

The study recruited patients worldwide from 450 centres across 42 countries. A total of 6184 patients were randomized to one of four experimental arms: twice-daily (b.i.d.) treatment with either SFC 50/500 µg (n=1546); FP 500 µg (n=1551); SAL 50 µg (n=1542); or placebo (n=1545) for three years.

Researchers found a 17.5% reduction in risk of death within the three-year study period for those treated with the SFC combination when compared with placebo. The absolute rate in mortality was a 2.6% reduction at three years (SFC vs. placebo). Dr. Calverley also noted that the adjusted significance value for the primary end point of mortality for SFC vs. placebo when taking into account the interim analysis was P=0.052.

In other trials of combination therapies, Dr. Calverley and colleagues have previously reported that lung function in COPD could be improved acutely by oral corticosteroids and bronchodilators. In a study of 1022 patients, the researchers showed that the patients in the budesonide/formoterol (BUD/FORM) combination group had delayed first exacerbation, experienced fewer exacerbations and maintained higher FEV1 measures (Calverley et al. Eur Respir J 2003;22:912-9). This combined therapy was more effective than either component separately in stabilizing lung function.

Dr. Derk Bathoorn, Department of Pulmonary Diseases, University Medical Centre Groningen, The Netherlands, and colleagues examined the effects of BUD/FORM treatment vs. placebo on induced sputum eosinophils during exacerbations in patients suffering from mild to moderate COPD. Secondary end points for the study included FEV1 scores and associated symptoms. The researchers hypothesized that ICS have fewer systemic side effects than oral formulations.

A cohort of 45 patients (37 females, 8 males, 21 smokers, 24 ex-smokers; median age, 65 years) participated in this study. The patients were treated with BUD/FORM (320 µg/9 µg four times daily), prednisone (30 mg/day) or placebo for 14 days in a double-blind, double-dummy, randomized trial. The percentage of eosinophils in induced sputum were compared at baseline and at end of treatment.

The researchers found that significant reductions in sputum eosinophils occurred with BUD/FORM (P=0.01) and prednisone (P=0.01) when compared to placebo (mean changes: -1.5%, -1.1% and -0.2%, respectively). In addition, both BUD/FORM (P£0.01) and prednisone (P£0.05) treatments significantly reduced total symptoms when compared with placebo. The changes in FEV1 measured at two weeks of 125 mL with BUD/FORM and 27 mL on prednisone were not significantly improved when compared to placebo (43 mL).

The researchers summarized their findings, “We found significant improvements in inflammation and symptoms with BUD/FORM treatment, suggesting that mild to moderate COPD exacerbations could be treated with high-dose BUD/FORM.”

Real-life Conditions

The utility of combination therapy of ICS plus LABA was emphasized by other presentations at the conference. Dr. Paul Van den Brande, Division of Respiratory Diseases, Sint-Maarten Hospital, Duffel, Belgium, and colleagues presented findings on their research regarding well-being of COPD patients treated with b.i.d. BUD/FORM combination therapy over three months. Patients were monitored using the InPractice Evaluation Program (iPEP). One of the difficulties of patient monitoring in everyday clinical practice is that patient adherence may be lower than that seen in clinical trials. By using the iPEP instrument, the researchers hypothesized that they would be better able to represent these real-world conditions. In addition, patients were asked to complete a Clinical COPD Questionnaire (CCQ) at baseline and at the conclusion of the study. The CCQ measures symptom severity, functional and mental state, in which a 0 score indicates absence of symptoms, while a score of 6 indicates maximal presence of symptoms.

Of the 161 patients who completed the study, 34% were current smokers. The majority of patients added the BUD/FORM combination therapy to their existing therapies, such as short-acting beta2-agonists (SABAs) (36%), anticholinergics (36%) or theophylline (14%). When compared to baseline, CCQ scores improved significantly among patients subsequent to BUD/FORM therapy. Prior to therapy, baseline median CCQ total was 2.9 (range, 0.8-4.9) in smokers and 2.2 in ex-smokers (range, 0.2-4.4; P=0.002). After BUD/FORM, CCQ scores were 2.1 among smokers (range, 0.5-5.5; P<0.0001) and 1.5 for ex-smokers (range, 0.1-3.6; P<0.0001). A change of ³0.4 in CCQ scores is considered clinically significant.

Dr. Van den Brande and his team concluded that the use of BUD/FORM significantly improved COPD patients’ daily life, independently of whether they were smokers. Noted the researchers, “The use of BUD/FORM in a real-life setting improves the health status of patients with COPD, irrespective of smoking status.”

Asthma Control Critical

According to Dr. Sally Wenzel, Professor, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, there is a need for variable therapeutic options in the management of asthma, and that combination therapy is the most effective overall therapy for asthma. “The availability of formoterol in addition to an ICS has the potential to offer quite impressive flexibility in the dosing. The reason for that is that formoterol is, in fact, a rapid-acting bronchodilator,” noted Dr. Wenzel.

Citing the latest Global Initiative for Asthma (GINA) guidelines, Dr. Paul O’Byrne, Division of Respirology and Chair, Department of Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, emphasized, “the need for regular control of therapy and anti-inflammatory therapy for patients with persistent disease, but I also recommend that for patients in whom low doses of steroids are not sufficient, combination therapy should be the next approach. And that combination preference should be for an ICS and a LABA.”

Similar to the GOLD guidelines in the treatment of COPD, the goals of the GINA program recommend:

• A multinational effort, including increasing awareness of asthma and its public health consequences.

• Promoting identification of reasons for the increased prevalence of asthma.

• Promoting study of the association between asthma and the environment.

• Reducing asthma morbidity and mortality.

• Improving management of asthma and the availability and accessibility of effective asthma therapy.

Dr. O’Byrne indicated findings from pivotal studies that have demonstrated the use of combination therapy in asthma control. One study was the OPTIMA trial on management of mild, persistent asthma. In the study, formoterol, a LABA agent, was added to a low-dose ICS, budesonide. The study included nearly 2000 stratified patients based upon prior corticosteroid use. The study found that for corticosteroid-free patients, low-dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, while for patients already receiving ICS, adding formoterol was found to be more effective than even doubling the corticosteroid dose (O’Byrne et al. Am J Respir Crit Care Med 2001;164:1392-7).

Another study cited by Dr. O’Byrne demonstrated how asthma control could be improved for those on low maintenance dose BUD/FORM by replacing SABA with additional BUD/FORM as needed for rapid symptom relief to reduce exacerbations. In this double-blind, randomized, parallel-group study of 2760 patients, the researchers found that the BUD/FORM combination for maintenance as well as relief prolonged the time to the first, second, and third exacerbation requiring medical intervention (P<0.001), reduced severe exacerbation rate and improved symptoms (O’Byrne et al. Am J Respir Crit Care Med 2005;171:129-36).

“The evidence is very compelling that the most effective treatment approach is combination therapy,” Dr. O’Byrne commented. In fact, the BUD/FORM combination was shown to be more efficacious than its constituent components as rescue therapy among asthma patients.

Study findings were presented by Dr. Mylinh Duong, McMaster University, and colleagues, who examined the effects of using a combination BUD/FORM inhaler therapy to improve asthma control and reduce exacerbations when used as rescue therapy. The combination therapy was compared to its individual components on several variables, including allergen-induced late airway responses. A total of 15 patients were randomized in the double-blind, crossover study, receiving single doses of BUD/FORM (400/12 µg), formoterol (12 µg), budesonide (400 µg) or placebo, that were administered during the acute bronchoconstriction response following allergen inhalation. The researchers found that when compared with placebo, the late airway response was significantly attenuated with the BUD/FORM therapy and was significantly better than either constituent monotherapy (placebo, -21.2 ±3.1%; BUD/FORM, -4.2 ±1.4%; formoterol, -7.5±1.7%; budesonide, -10.4 ±1.6%). The researchers concluded that a single dose of BUD/FORM was more effective than its mono-components in attenuating late airway responses as well as protecting against allergen-induced airway hyper-responsiveness.

Summary

Although COPD remains often under-diagnosed and an under-reported cause of death, this disease may become treatable with global initiatives like the GOLD guidelines. A similar parallel can be seen in the GINA guidelines which were initiated to improve the management of asthma. Dr. Wenzel noted that it has led to the concept of the single inhaler therapy with a combination formulation. This treatment allows for delayed occurrence of symptom exacerbations and improved FEV1 measures, thereby helping to stabilize health status. Looking to the future of respiratory therapy, Dr. Wenzel suggested, “Patient-driven therapies may, in fact, be one of the answers to the compliance and adherence issues.”