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.

PRIORITY PRESS - 5th International Primary Care Respiratory Group World Conference

Toronto, Ontario / June 2-5, 2010

Prognosis for patients with chronic obstructive pulmonary disease (COPD) is best when they are diagnosed in the earlier stages of the disease when smoking cessation, regular physical activity and nutritional support have the greatest chance of influencing outcomes. A variety of strategies were presented here which may allow health care providers to arrive at an earlier diagnosis, including encouraging general practitioners (GPs) to order spirometry for all patients at potential risk for COPD.

In the Danish TOP study, for example, investigators persuaded a total of 335 GPs to offer spirometry to all patients over the age of 35 with a history or either tobacco use or occupational exposure who presented with at least one respiratory symptom. A total of 3097 patients were recruited. Spirometry results showed that FEV₁/forced vital capacity (FVC) ratio was under 70% in 35% of the cohort, and 79% of those identified with diagnostic FEV₁ had mild to moderate COPD.

Another Danish initiative to screen community residents for early COPD was reported by researcher Peter Bo Poulsen, PhD, Ballerup, Denmark. Smokers and ex-smokers over the age of 35 with at least one respiratory symptom presented to municipal health centres where personnel carried out spirometry testing. Those who had an indication of airway obstruction were requested to visit their GP to confirm the findings and the same individuals were followed up two to three months later to see whether they had in fact visited their physician.

Out of 152 study participants, over half (51%) had airway obstruction of <70% of predicted, Dr. Poulsen reported. Moreover, GPs agreed that it was airway obstruction in 85% of the patients and there was nearly 100% agreement between results obtained on municipal screening and GPs when patients had moderate to severe airway obstruction. Importantly, 39% of those who were diagnosed with COPD embarked on a smoking cessation program and 61% were taking medication as prescribed by their physician.

Earlier Initiation of Therapy

Younger patients with COPD may also respond better to earlier initiation of respiratory medicines treatment including the long-acting anticholinergic tiotropium. In the full UPLIFT cohort, tiotropium did not alter the annual rate of decline in pre- and post-bronchodilator FEV₁ and FVC, the primary end points of the trial. However, an analysis of 356 patients under the age of 50 presented here did show a reduction in the rate of lung function decline over four years among patients receiving additional tiotropium—at a mean decline in post-bronchodilator FEV₁ of 38 mL/year for tiotropium patients vs. 58 mL/year for controls (P<0.05). The rate of exacerbations was also 27% lower in patients receiving additional tiotropium vs. controls. Improvements in health-related quality-of-life scores were seen across all four years, although they did not reach statistical significance between the two groups at year 4.

Adequate Symptom Relief

Bronchodilators remain the cornerstone of COPD treatment but not all patients with COPD achieve adequate symptomatic relief with bronchodilators alone and algorithms typically advise physicians to add on traditional inhaled corticosteroids (ICS) for improved symptom control. Even with optimal pharmacotherapy, however, there are patients who have residual inflammation for which standard doses of ICS do not respond as well as for asthma.

As explained here by Dr. Charles Chan, Professor and Vice-Chair, Department of Medicine, University of Toronto, Ontario, the most predominant inflammatory cells in asthma include eosinophils, mast cells and CD4-positive lymphocytes. “In COPD, there are more neutrophils, CD8-positive cells and macrophages,” he confirmed. This distinction becomes important because of emerging therapies for COPD. “Patients with cough and spit are more likely to have increased airway inflammation, a steeper decline in FEV₁ and increased mortality risk,” Dr. Chan explained.

Patients with chronic cough and sputum also are significantly more likely to experience acute exacerbations than those who do not at 55% vs. 22%, respectively, according to one study (Burgel et al. Chest 2009;135:975-82). Thus, patients with chronic cough and sputum are most likely experiencing ongoing inflammation despite maximal bronchodilator therapy, he added.

As a novel oral phosphodiesterase 4 (PDE-4) inhibitor, roflumilast inhibits the PDE-4 enzyme in inflammatory cells involved in COPD, thereby preventing the breakdown of cyclic adenosine monophosphate (AMP). Since cyclic AMP normally downregulates inflammation, “by building up high levels of cyclic AMP in the cell, it can do its job,” Dr. Chan observed. The agent may also favourably affect smooth muscle cells in the airway and slow down the development of pulmonary hypertension.

Pivotal Trials

Four pivotal trials have now evaluated the safety and efficacy of this novel PDE-4 inhibitor in COPD patients treated concomitantly with either tiotropium or salmeterol. As presented by Dr. Kenneth Chapman, Professor of Medicine, University of Toronto, patients with moderate to severe (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II and III) COPD involved in either study M2-127 (n=933) or M2-128 (n=743) were assigned to roflumilast 500 µg q.d. or placebo. In M2-127, patients were on background salmeterol 50 µg b.i.d., while in M2-128, they were on tiotropium 18 µg q.d. Both trials involved patients with moderate to moderate-to-severe COPD. Neither short-acting anticholinergics, ICS nor other long-acting bronchodilators were allowed in either study.

In the M2-127 study, after 24 weeks of therapy, the combination of roflumilast/salmeterol improved mean pre-bronchodilator FEV₁ by 49 mL over salmeterol alone (P<0.0001), a 39% increase over study entry levels. The concomitant regimen also reduced the mean annual exacerbation rate (moderate or severe) by 36.8% (P=0.0315) and increased median time to first moderate or severe exacerbation by a significant 40% (hazard ratio [HR] 0.6; P=0.0067). In M2-128, the combination of roflumilast and tiotropium improved mean pre-bronchodilator FEV₁ by 80 mL (P<0.0001) vs. tiotropium alone and increased median time to first mild, moderate or severe exacerbation by 30% (HR 0.7; P=0.0264). The same combination also reduced the mean annual rate of moderate and severe exacerbations by 23.2% but not significantly so.The mean rate of moderate to severe exacerbations per patient-year was 0.3 in both combination arms of both trials compared with 0.5 per patient-year with salmeterol in M2-127 (36.8% reduction (P=0.0315) and 0.4 exacerbations-per year with tiotropium in M2-128 (23.2% reduction; ns).

Reviewing two additional studies, M2-124 and M2-125 in GOLD stage III or IV COPD, Dr. Daryl Freeman, Sheringham Medical Practice, UK, noted that roflumilast improved lung function and reduced exacerbations compared with placebo as well. These four studies suggest that the PDE-4 inhibitor improves lung function and reduces exacerbations when added to long-acting beta₂ agonists, short-acting muscarinic antagonists or tiotropium in patients with GOLD stage II, III and IV COPD, although whether it adds to the clinical benefit over ICS alone is not yet known.

As discussed by IPCRG co-chair Dr. Alan Kaplan, family physician, Bedford Park Medical Centre, Richmond Hill, Ontario, on average, patients taking additional roflumilast lost about 2 kg and there were some cases of nausea and diarrhea but no vomiting. “I’m concerned about weight loss but I am reassured that it tends not to occur in thin patients,” Dr. Kaplan observed.

Summary

Current respiratory medicines provide symptomatic relief for many patients, but for certain types of patients such as those with chronic cough and sputum, improved symptom control is often required. A novel oral anti-inflammatory agent has been shown to improve lung function and reduce exacerbations in moderate to severe stages of COPD, suggesting that there will likely be a role for the new agent when it becomes available.

Note: At the time of printing, roflumilast is not authorized for sale in Canada.