Early Detection of COPD and Halting the Downward Spiral: Potential for Disease Modification

Faculty disclosures for this summary are provided on page 4 of this publication.

The Social Burden of COPD

Roger Goldstein, MD, Professor of Medicine and Physical Therapy, University of Toronto, Ontario, Canada, began his discussion of the social burden of chronic obstructive pulmonary disease (COPD) by describing a telephone survey conducted in eight countries in North America and Europe.

Respondents were asked if someone in the household was over age 45 and had a diagnosis of COPD or symptoms of chronic bronchitis and a smoking history in excess of 10 years. Of those who answered yes, 44% were women, the mean age was 63, just over half were retired, and just under half were current smokers.

A summary of the data, prepared by Wouters, showed a substantial burden in terms of lost productivity due to COPD (Respir Med. 2003;97 Suppl C:S3-14). Another reflection of disease burden is represented by healthcare resource utilization. “Substantial numbers of individuals in all the countries had inpatient hospitalization and emergency room visits,” said Dr. Goldstein.

Dr. Goldstein continued with an overview of health-related quality of life measures. “The general instruments are health profiles and utility measures, and the specific instruments are function, problem, or disease specific,” he said. He advocated the single-disease specific instruments as being most responsive and useful for outcome measures in COPD trials.

Interventions for COPD

“I don’t think all COPD patients should be treated the same; there is room for variation,” began William Bailey, MD, Professor of Medicine, Director of the Lung Health Center, and Eminent Scholar and Chair in Pulmonary Diseases, University of Alabama.

He noted that the Gold Guidelines provide treatment recommendations based on severity, which aim to improve symptoms and quality of life, but also attempt to change the natural history of the disease, which is “a lot harder.”

“Smoking cessation early in the course of the disease does change the natural history of disease,” remarked Dr. Bailey. He went on to discuss drug treatment that may also have an impact.

“Most COPD patients don’t have any exacerbations, or just one or two a year,” said Dr. Bailey. However, some patients have many exacerbations. “The greatest chance for changing the natural history of the disease is to change the frequency of exacerbations in these patients,” he continued.

He cited a study by Anthonisen and colleagues which showed that antibiotics can shorten exacerbations for patients who have two or three of the following: high volume of sputum, purulent sputum, and shortness of breath (Ann Intern Med. 1987;106:196).

“We know from a number of studies that inhaled steroids don’t change the natural history of FEV₁ decline, but the Lung Health Study showed that frequency of exacerbations was reduced in patients on inhaled steroids versus placebo,” said Dr. Bailey.

Systemic steroids also shorten exacerbations and reduce the frequency of a second exacerbation. But Dr. Bailey cautioned that patients should be tapered off systemic steroids within two weeks, according to a study by Niewoehner and associates (N Engl J Med. 1999;340 (25):1941-1947).

The major treatment for COPD is a long-acting bronchodilator. The anticholinergic tiotropium, which has not yet been FDA approved, has a “tremendous bronchodilatory effect,” said Dr. Bailey. “It not only improves FEV₁ it probably improves hyperinflation.” A major international study of 6,000 patients is underway to test whether tiotropium has an impact on the natural history of the disease.

Barry Make, MD, Director, Emphysema Center, National Jewish Medical and Research Center, and Professor, Division of Pul-monary Sciences and Critical Care, University of Colorado School of Medicine, Denver, took the podium to summarize manage- ment of COPD. He outlined eight steps to improve
outcomes (see box).

Concerning step 3, “consider long-acting anticholinergics,” Dr. Make noted that compared to ipratropium, tiotropium has a much longer duration of action. In addition, tiotropium may have a long-term effect on health status as well as on FEV₁.

On the topic of adding therapies, Dr. Make said “combining agents of different classes, such as anticholinergics and beta-agonists, can improve function.” This is particularly important for patients with the most severe disease.

“The last two therapies we need to make sure to add are pulmonary rehabilitation and oxygen in patients who are appropriate candidates,” said Dr. Make.

Diagnosis and Pharmacotherapy for COPD

Bartolome R. Celli, MD, Professor of Medicine, Tufts University, and Chief of Pulmonary and Critical Care Medicine, St. Elizabeth’s Medical Center, Boston, noted that mortality from COPD increased significantly between 1980 and 2000, particularly among women for whom incidence of deaths increased 185%. In 2000, more women than men died of COPD in the United States for the first time. He also pointed out that unfortunately, COPD remains underdiagnosed.

“One of the biggest problems with COPD is that we have been very negative,” said Dr. Celli, adding that the disease is called “not fully reversible, progressive, and leads to death.” He claimed that it is a myth that the disease is relentless and has no effective treatment. “COPD responds to treatment, patients will get better, and the prognosis has improved,” he said.

The Predictive Value of Spirometry
Antonio Anzueto, MD, Associate Professor of Medicine, University of Texas Health Science Center, San Antonio, Texas, discussed diagnosis and prognosis of COPD, and the effect of pharmacotherapy. “We have extensive data showing the correlation between FEV1 value and patients’ outcome,” he said.

“The worse the FEV₁, the worse the patient feels,” he continued. “So the main issue is how can we affect this rate of decline in FEV₁?” He noted that smoking cessation is essential and that pharmacotherapy can also have an impact.

Many studies of pharmacotherapy rely on spirometry to measure outcomes, but Dr. Anzueto remarked that it’s important to also identify endpoints that are more relevant to our patients such as quality of life, dyspnea, and frequency of exacerbations.

He presented data from several trials of inhaled corticosteroids, most of which showed no significant changes in FEV₁ compared to placebo.

Dr. Anzueto next presented a study by Casaburi et al. looking at the effect of the long-acting anticholinergic tiotropium (Eur Respir J. 2002; 19: 217-224). Over one year, the decline in FEV₁ from baseline was 58 ml with placebo versus just 12 ml with tiotro-pium, which was statistically significant. A similar statistically significant effect was also seen with tiotropium among the subgroup of patients who were current smokers and those who were former smokers.

He continued by emphasizing that COPD is underdiagnosed; therefore, spirometry has to be used to make an early diagnosis. “Furthermore, the data presented suggest that tiotropium, a long-acting anticholinergic, may decrease the decline of FEV₁,” said Dr. Anzueto. He recommended that primary care physicians use spirometry to identify patients with COPD in order to start therapy early and modify the course of this disease.

Impairment and Disability: Exercise Limitation in COPD

Donald A. Mahler, MD, Professor of Medicine, Dartmouth Medical School, Lebanon, New Hampshire, discussed mechanisms whereby COPD leads to dyspnea and reduced exercise tolerance, and he reviewed the role of bronchodilators in improving these. “Dyspnea and reduced exercise tolerance have a major impact on day-to-day living for COPD patients,” said Dr. Mahler.

Several instruments are available for measuring dyspnea, including the baseline and transition dyspnea indexes and exercise testing using the Borg Scale or Visual Analog Scale. “Studies have shown that a submaximal endurance exercise test is preferable when examining bronchodilator therapy because it is more relevant to day-to-day functioning,” said Dr. Mahler.

He explained that the same mechanisms lead to both dyspnea and exercise limitation. “There is an increased ventilatory demand in large part because of dead space ventilation,” he said, adding that “dynamic hyperinflation is a common occurrence with simple activities such as walking.” Airway hyperreactivity may also be important. In addition, some patients may have muscle weakness involving the diaphragm and other muscles of respiration, and hypoxemia can also play a role.

One approach to addressing these mechanisms is to reduce the ventilatory demand with exercise training or oxygen therapy. “On the other hand, bronchodilators can increase ventilatory capacity,” said Dr. Mahler. Smooth muscle circumferentially surrounds the airway. Bronchodilators relax the smooth muscle, and the diameter of the airway is increased.

How this relates to perception of breathlessness may be explained with Weber’s Law, according to Dr. Mahler. Using this equation, Dr. Mahler computed that about a 20% change in lung volumes is required for someone to detect breathlessness. “If the diameter of the airway is dilated from a bronchodilator, a greater magnitude of change would be required for patients to report breathlessness,” he said.

He cited a study by Casaburi et al. of the bronchodilator tiotropium, which showed a 20% improvement in FEV₁ (Eur Respir J. 2002;19:217). In the same study, the investigators used the transition dyspnea index to measure perception of breathlessness based on activities of daily living. “Over almost one year of the trial, there was a 1 unit difference favoring tiotropium compared to placebo,” said Dr. Mahler.

He next addressed effects of medication on hyperinflation. “If functional residual capacity is reduced, the diaphragm can come up, the vertical muscle fibers can be lengthened and the inward recoil of the outward expanded chest is reduced,” said Dr. Mahler. This reduces the effort placed on respiratory muscles to generate inspiratory airflow, which can reduce the perception of breathlessness.

A study by O’Donnell and colleagues looked at the effects of tiotropium on FEV₁, forced vital capacity (FVC), inspiratory capacity, FRC, and residual volume (Am J Respir Crit Care Med. 2002;165:A265). “There was an FEV₁ improvement of 0.25 liters and even greater changes in lung volumes,” said Dr. Mahler.

In healthy normal people, during exercise there is an increase in end inspiratory lung volume and perhaps a slight decrease in end expiratory lung volume. In patients with COPD, there is a shift to breathe at a higher lung volume, and inspiratory capacity is reduced. “With bronchodilators, we can increase flow and volume,” said Dr. Mahler. “This allows the patient to breathe at a lower lung volume, which provides the same benefit as allowing the diaphragm to move up and the elastic recoil inward to be reduced,” he added.

He presented results of trials which looked at whether this makes a difference clinically. A study of tiotropium showed that exercise endurance increased and “there was reduction in dyspnea and prolongation of exercise endurance,” said Dr. Mahler.

Dr. Mahler concluded: “Bronchodilators can increase exercise endurance and reduce dyspnea by increasing ventilatory capacity and reducing hyperinflation at rest and during exercise.”

The Link Between Exacerbations and Health Status

Paul Jones, PhD, FRCP, Professor of Respiratory Medicine, St George’s Hospital Medical School, London, England, began his talk on exacerbations and health status by citing a study which showed that 63% of patients with moderate to severe COPD and 43% of patients with mild disease had at least one exacerbation per year.

“Exacerbations occur with all degrees of COPD severity, but they are more common with severe obstruction,” said Dr. Jones. He cited a study by Seemungal et al. which found that patients who had numerous exacerbations had a health status score that was statistically and clinically greater than those with only a few exacerbations (Am J Respir Crit Care Med. 1998;157:1418-1422).

Dr. Jones explained that several factors go into health status measurement of COPD, and the only way to take them all into account is with health status questionnaires. “There is evidence that health status measurements, using different questionnaires, are valid measures of the effect of the disease on patients’ lives,” he said.

He described a study he conducted that followed COPD patients for three years. Patients who had no exacerbations during that time had started off with a health status score of 45 on the St. George’s Respiratory Questionnaire (SGRQ) Score. Those who subsequently had one exacerbation per year started with a SGRQ score of 50 (i.e., worse than those who had no exacerbations); those who had over two exacerbations per year had an even higher score at the beginning. “This tells us that patients’ current health status is a predictor of exacerbations over the next year or two,” said Dr. Jones.

He presented findings from a study by Spencer and Jones showing that one exacerbation of COPD has a long-lasting effect with the result that “if the patient has more than one exacerbation per year much of the rest of the year is spent recovering” (Thorax. 2003;58: 589-593).

He next addressed the effect of long-acting bronchodilators on FEV1, health status, and exacerbations. He presented results of a trial of tiotropium versus placebo by Casaburi et al. (Eur Respir J. 2002;19:209-216). “All of the improvement in FEV₁ was present by the eighth day of treatment,” he said. In terms of health status, the tiotropium-treated patients got better and continued to improve for six months and then they remained stable. “Many of the improvements in health status occurred a long time after the benefit in FEV₁,” he said. Tiotropium also resulted in a 20% reduction in exacerbations.

“There is now evidence for the hypothesis that exacerbations progressively worsen health and FEV₁,”said Dr. Jones. He also theorized that reducing the exacerbation rate can lead to a sustained improvement in COPD.

“There may be a vicious cycle where patients with poor health have more frequent exacerbations and health status declines faster with frequent exacerbations,” he summarized, adding that “there is now evidence that therapies that prevent exacerbations may have major benefits on overall disease
progression.”

Improving Patient Outcomes

Dr. Celli returned to the podium to summarize the session and make the argument that it is possible to improve outcomes for patients with COPD. He advocated looking at COPD and spirometry in the same way that cardiologists look at cardiovascular disease and hypertension.

Hypertension is a surrogate marker predicting possible heart disease. Studies of antihypertensives look not only at how well they lower blood pressure but also how that change reduces stroke, congestive heart failure, and myocardial infarctions.

“I think we have to use the forced vital capacity and FEV₁ as surrogate markers predicting possible exacerbations and respiratory failure,” said Dr. Celli. “The studies presented by the previous speakers have shown that improving FEV₁ with medications has a positive impact on dyspnea, health status, and exacerbations.”

“In the study by Casaburi et al., of 900 COPD patients, tiopropium produced an 18% improvement on trough FEV₁ and a 16% improvement on peak FEV₁,” said Dr. Celli (Eur Respir J. 2002;19:217-224). Tiotropium also improves outcomes in dyspnea and health status. “The drug also results in a decrease in exacerbations, including the re-incidence of exacerbations,” he added.

“While pure bronchodilation is good enough to alter outcomes, adding inhaled corticosteroids may further improve survival,” Dr. Celli continued.

Dr. Celli also discussed the effectiveness of pulmonary rehabilitation. In a study by Cote et al. (presented at the ATS meeting in 2003), patients were given the option to enter a 24-session rehabilitation program, which could be extended. Those who opted out completely had a drop in the 6-minute walking distance test, while those who continued the program long-term (8%) were still at baseline level, and some slightly higher, after three years.

Additionally, FEV₁ levels improved in patients in the rehabilitation program, with those who maintained the program having a higher volume.

In conclusion, Dr. Celli pointed out that in 1980, a person with COPD had a 60% chance of surviving 30 months; the odds are now 90% with treatment. “We are at a stage where we can go from nihilism to being optimistic, and we can present patients with treatment options that have shown positive results.”