Highlights of the American Thoracic Society 2005 International Conference

By Lawrence M Prescott, PhD

More than 15,000 physicians, research scientists, and related healthcare professionals from around the world met in San Diego from May 20-24, 2005 at ATS 2005 to hear the latest developments in the control, prevention, and treatment of pulmonary diseases. Listed below are some highlights of presentations concerning chronic obstructive pulmonary disease (COPD), asthma, and pulmonary hypertension.

Chronic Obstructive Pulmonary Disease (COPD)

Public awareness of COPD
While public awareness of COPD has slightly increased due to more intensive efforts to raise the profile of this disease over the past few years, it still remains remarkably low considering that COPD is the fourth leading cause of death in the United States, stated Steven Kesten, M.D., Therapeutic Director of Clinical & Scientific Affairs, Boehringer-Ingelheim Pharmaceuticals.

Previously reported results of a yearly telephone survey indicated no visible change in awareness between 1999 and 2002. In an attempt to examine awareness of COPD in the community and whether changes had occurred since the previous survey, a telephone survey, including questions on COPD, was carried out by Opinion Research Corporation International of 1000 adults in the United States during the same approximate weekend in August for six years, from 1999 to 2004. Respondents were asked if they had heard of chronic obstructive pulmonary disease or COPD (claimed awareness) and how they would describe it (respiratory disease=true awareness).

Key findings of the survey show that while 50% of Americans surveyed in 2004 claimed that they had heard of COPD, only 22%, or one in five, were able to identify COPD as a respiratory disease. The responses actually represent a slight increase from 2003, when 41% of people surveyed claimed awareness of the condition and 17% showed true awareness. Interestingly, the survey findings showed that smokers, although they are most at risk for COPD, were equally lacking in both claimed awareness at 52% and true awareness at 22%.

Tiotropium in general primary care practice
Compared to placebo, tiotropium bromide inhalation powder (Spiriva® Handihaler®, Boehringer Ingelheim/Pfizer) showed a significant morning predose lung function improvement and fewer COPD exacerbations in a broad primary care COPD population on regular treatment with inhaled corticosteroids (ICS) and/or long-acting beta2-agonists (LABA), reported David B. Price, M.D., Professor and General Practice Group Chair of Primary Care Respiratory Medicine, Department of General Practice and Primary Care, University of Aberdeen, United Kingdom.

These conclusions were reached from data collected in a randomized, double-blind, parallel group, 12-week, placebo-controlled study. A total of 374 primary care patients with a diagnosis of COPD were enrolled in the SPRUCE (SPIRiva Usual CarE) study, the first study to evaluate efficacy and safety of once-daily tiotropium, a recently introduced, once-daily, long-acting anticholinergic with prolonged M3-receptor blockage, in a primary care population designed to represent normal clinical practice. These patients were defined by general practitioners as having COPD of a broad severity range and taking a wide variety of other treatments.

Following a two-week run-in period, patients were randomized in a 1:1 fashion to receive either tiotropium 18 µg once daily or placebo via the Handihaler® for 12 weeks. Concomitant use of short-acting beta2-agonists (SABA), LABA, ICAS, and theophylline were allowed. A washout period of 6 hours for SABA and 24 hours for LABA and/or theophylline was required prior to lung function tests on study visits. The primary endpoint was trough forced expiratory volume in one second (FEV1) at days 15 and 43, trough forced vital capacity (FVC) responses at days 15, 43, and 85, and the weekly mean numbers of occasions per day of SABA use. Adverse events were monitored throughout the study.

In all patients and subgroups, significant improvements were seen with tiotropium versus placebo in both trough FEV1 and FVC responses. In addition, tiotropium-treated patients experienced significantly fewer exacerbations than those on placebo, 9.5% versus 17.9%, respectively. Also, the use of rescue medication was significantly lower in patients taking tiotropium compared to those in the placebo group.

With regard to safety, adverse events were reported in 51% of patients treated with tiotropium and 61.5% of patients receiving placebo. Higher incidences of respiratory system disorders were observed in the placebo group compared with the tiotropium group, 30.8% and 23%, respectively.

Asthma

Omalizumab in severe persistent asthma
Add-on therapy with omalizumab (Xolair®, Genentech/Novartis), the first IgE blocker developed to treat the symptoms of allergy-related asthma, significantly reduces the rate of asthma exacerbations in patients with severe persistent asthma requiring oral corticosteroids, according to Sally E. Wenzel, M.D., Professor/Co-Director, Clinical Research Unit, Medicine, National Jewish Medical and Research Center, and Professor of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado.

To reach this conclusion, data from seven controlled trials of omalizumab in patients with severe IgE-mediated asthma were pooled and analyzed. Omalizumab was added to current asthma therapy and compared with placebo in five double-blind studies or added to current therapy alone in two open-label studies. Maintenance oral corticosteroids were allowed in four of the seven studies. The pooled analysis evaluated the efficacy of add-on omalizumab therapy in a subgroup of patients requiring oral corticosteroids, the rate of asthma exacerbation according to baseline oral corticosteroid use being assessed.

A total of 4,273 patients were enrolled in the seven studies. Of these, 444 patients were receiving maintenance oral corticosteroids and 3,829 patients were not. Add-on omalizumab therapy significantly reduced the annualized asthma exacerbation rate by 37% in patients requiring oral corticosteroids. This reduction was similar to the 39% reduction reported in patients not taking oral corticosteroids. In absolute terms, however, the results in patients on oral corticosteroids were greater because the exacerbation rates in patients requiring oral corticosteroids due to their persistent severe asthma were higher at baseline.

Pulmonary Arterial Hypertension (PAH)

Sidenafil in all functional classes of PAH
Sidenafil citrate (Viagra®, Pfizer), a drug well known for enhancing nitric oxide-mediated vasodilation, shows promise in the treatment of patients with pulmonary arterial hypertension (PAH) as it is the first oral therapy to show a significant improvement in exercise capacity in PAH patients in functional class (FC) I/II, in addition to its effect in FC III and FC IV patients, reported David E. Badesch, M.D., Professor of Medicine, Division of Pulmonary Sciences and Critical Care Medicine/Clinical Director of the Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colorado.

PAH, defined as mean pulmonary arterial pressure of greater than 25 mmHg and pulmonary capillary wedge pressure of less than 15 mmHg at rest, is a progressive disease that leads to right ventricular failure and premature death. Nitric oxide (NO) pathway changes have been detected in patients with PAH. The pulmonary vasodilator effects of NO are mediated by cyclic guanosine monophosphate (CGMP), which is rapidly degraded by phosphodiesterase type 5 (PDE5). Studies have shown that sildenafil inhibits PDE5, promoting the accumulation of intracellular CGMP and consequently enhancing NO-mediated vasodilation.

To date, most PAH clinical trials have studied patients in World Health Organization (WHO) function class (FC) III and IV, and relatively few studies have included patients in FC II. Since treatment options for PAH patients in FC II are limited, a 12-week, double-blind, placebo-controlled clinical trial designed to assess the efficacy and safety of oral sildenafil included not only PAH patients in FC III/IV but also patients in FC I/II. Patients were randomized to receive placebo or sildenafil 20 mg, 40 mg, or 80 mg orally, three times daily (tid). Study medication was added to the patients' background medication. Randomization was stratified with respect to baseline walk distance (less than 325 meters and more than 325 meters) and etiology. The 6 minute walk distance (6MWD) test was performed at predicted trough plasma concentration of study drug, at a minimum four hours post-dose. Patients who completed the 12-week study period were eligible for entry into a long-term, open-label study with an initial blinded phase.

The primary endpoint of the randomized study was change in exercise capacity from baseline to week 12, measured by 6MWD. Patients were analyzed by FC, divided into FC I/II or FC III/IV. Safety and tolerability also were assessed.

Improvements in 6MWD from baseline at 12 weeks treatment was seen overall for almost all sildenafil doses in FC I/II and FC III/IV patients compared to placebo. In FC I/II patients, the 6MWD increased significantly by 50 meters on sildenafil 20 mg tid and 49 meters on 80 mg tid. In FC III/IV patients, the 6MWD increased significantly by 48 meters, 71 meters, and 54 meters in those on 20 mg tid, 40 mg tid, and 80 mg tid, respectively. After 12 weeks, placebo-treated patients in FC I/II showed no decline in 6MWD, but, in contrast, those in FC III/IV showed an overall decrease of 15 meters, suggesting that deterioration in exercise capacity occurred faster in patients with a high FC.

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