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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.

PRIORITY PRESS - Better Breathing Conference 2011

Toronto, Ontario / January 27-29, 2011

In Canada, the economic burden of exacerbations of chronic obstructive pulmonary disease (COPD) is estimated at over $1.5 billion/year (Mittman et al. Respir Med 2008;102:413-21). According to Public Health Agency of Canada 2007 data, by the year 2020, COPD mortality will surpass stroke and become the third leading cause of death.

Importance of Reducing Exacerbations

Dr. Charles Chan, Professor of Medicine, Division of Respirology, UHN-Toronto General Hospital, Ontario, presented new data from a practice assessment of 58 respirologists and 931 COPD patients conducted regionally across Canada from June to October 2010.

Dr. Chan reported that based on the spirometry values from the most current visit, 83% of 476 patients referred had either moderate or severe disease. Moreover, 57% of patients in the practice assessment experienced an exacerbation in the past 12 months, 67% of which were either severe or very severe. Dr. Chan emphasized the need to target the exacerbations because they are the biggest cost driver of the disease.

The Role of Inflammation

Scientific committee member Dr. Alan Kaplan, Chair, Family Physician Airways Group of Canada, Richmond Hill, Ontario, reported the initial results of a 14-country on-line survey which included 150 patients and 100 physicians from Canada. The average patient aged 53 years experienced at least 2 symptoms of breathlessness on exertion, mucus/sputum/phlegm production, chronic or troublesome cough, or chest discomfort on walking and regular chest infections, especially in winter. Data showed that 60% of patients experienced an exacerbation in the last year and 40% experienced =2.

Dr. Kaplan reported that COPD patients were unclear about the role of chronic inflammation, exacerbations and their long-term consequences. Regarding exacerbations, 57% of the Canadian physicians surveyed indicated it had either a major or very major long-term impact. Dr. Kaplan stated, “Earlier identification of these patients and more effective management and prevention of ‘lung attacks’ would help ease the burden of COPD.”

The Inflammatory Process in COPD

Dr. Ken Chapman, Asthma and Airway Centre, UHN-Toronto Western Hospital, indicated that in asthma, airway inflammation is primarily related to allergens/sensitizing agents implicating CD4-positive T-lymphocytes, eosinophils, macrophages and mast cells and is mostly reversible with corticosteroids. In COPD, airway inflammation is primarily related to cigarette smoke/noxious agents activating CD8-positive T-lymphocytes, neutrophils and macrophages. With increasing severity of COPD, the inflammation becomes mostly irreversible despite corticosteroids (Figure 1).

Figure 1.

In the ISOLDE study, a reduction in annual exacerbation rate of 25% (P=0.026) was observed after 3 years of treatment with inhaled fluticasone 500 µg b.i.d. compared to placebo in moderate to severe COPD patients (Burge et al. BMJ 2000;320:1297-303). However, in COPD, increasing inhaled corticosteroid dose has been recently shown to be associated with a greater risk of developing new-onset diabetes. In addition, a meta-analysis has shown inhaled corticosteroids to increase the risk of non-fatal pneumonia in COPD.

While up to now, corticosteroids were the only anti-inflammatory agents known to help in COPD and asthma, a new understanding of the underlying pathways involved has advanced the need for a new class of agents specific to inflammation in COPD.

Previously, Giembycz (Monaldi Arch Chest Dis 2002;57(1): 48-64) demonstrated that T-lymphocytes, eosinophils, neutrophils, monocytes, mast cells and macrophages express a phosphodiesterase subtype 4 (PDE-4). Moreover, in both in vivo and in vitro studies, compounds that inhibit PDE-4 suppress these pro-inflammatory and immune cells. The PDE family of enzymes is known to catalyze the degradation of cAMP and cGMP to the 5’ nucleotide monophosphates. Thus, inhibiting PDE results in an increase in cAMP and cGMP. However, inhibition of PDE-4 subtype is specific for an increase in cAMP only, modulating the inflammatory process.

The novel PDE-4 inhibitor roflumilast is indicated as add-on therapy to a bronchodilator for maintenance treatment of patients with severe COPD. Dr. Chapman demonstrated that the available data on this compound showed a statistically significant reduction in sputum leukocyte counts (total, eosinophils and neutrophils) relative to placebo.

Study Findings

According to a multicentre, placebo-controlled, double-blind trial in 1411 COPD patients in an outpatient setting, a 34% decrease in COPD exacerbations was observed with roflumilast 500 µg relative to placebo-treated patients (Rabe et al. Lancet 2005; 366:563-71). The PDE-4 inhibitor also showed a statistically significant increase in FEV₁ of 97 mL at the end of 24 weeks of treatment with the 500-µg dose. In this study, patients were allowed salbutamol as a rescue medication and short-acting anticholinergics as concomitant medications at a constant daily dose. Patients also could receive oral corticosteroids during an acute exacerbation but inhaled corticosteroids were withdrawn 4 weeks before randomization.

In the 2 large, multicentre double-blind trials, M2-127 and M2-128, patients with moderate to severe COPD were randomly assigned to roflumilast 500 µg or placebo for 24 weeks in addition to either salmeterol or tiotropium (Fabbri et al. Lancet 2009;374:695-703). The addition of the PDE-4 inhibitor to either salmeterol or tiotropium resulted in a 49-mL and 80-mL increase in prebronchodilator FEV₁, respectively (both P<0.0001). While the proportion of patients experiencing a moderate or severe exacerbation decreased in both studies, addition of the PDE-4 inhibitor to salmeterol achieved significance in the M2-127 (P=0.0015) but not in the M2-128 when added to tiotropium (P=0.0867).

Dr. Chapman also reported the results of a post-hoc, pooled analysis of the M2-111 and M2-112 studies in COPD patients. Added to inhaled corticosteroid, roflumilast treatment resulted in an additional 18.8% reduction (P=0.0137) in mean rate of moderate and severe exacerbations/patient/year (Rennard et al. Respir Res 2011;12:18).

Dr. Chapman stated that PDE-4 inhibition in COPD improves lung function and reduces the exacerbation rate with or without background bronchodilators. He added, “Patients with chronic cough—if you will, patients with airway inflammation, as evidenced by that cough—are patients that appear to be the most ideal phenotype for PDE-4 inhibition.”

COPD and Comorbidities

A recent prospective study (Crisafulli et al. Eur Resp J 2010;36:1042-8) determined that 62% of patients with COPD had comorbidities. In this study, it was noted that 45% of patients improved on a standard pulmonary rehabilitation program. In the Canadian survey reported by Dr. Chan, the specific comorbidity prevalence was 45% for hypertension, 36% for ischemic heart disease, 17% for diabetes and between 7% and 10% for coronary heart failure; 63% of the patients have not participated in a pulmonary rehabilitation program. However, there appears to be a positive relationship with severity of disease in Canada and participation in a pulmonary rehabilitation program.

Additionally, Dr. Peter Selby, Clinical Director, Addictions Program and Head, Nicotine Dependence Clinic, Centre for Addiction and Mental Health, Toronto, suggested to the audience, “We need to do a better job so that people make a greater link and awareness about smoking and COPD.” He stressed that there is a relationship with the amount of time a physician spends counselling patients on smoking cessation and their quit rates.

Summary

COPD exacerbations continue to be a driver of patient hospitalizations, decrease in lung function and overall deterioration of the patient. Both treatment and education gaps exist. An improvement in patient and physician communication on defining, reporting and managing exacerbations would benefit patients with COPD. Inhibition of PDE-4 presents a new treatment option for managing COPD exacerbations and the underlying inflammation.