Patient Care and COPD: Fine-tuning Current Knowledge and Treatment Outcomes

At an industry-sponsored symposium held in conjunction with CHEST 2002, the annual meeting of the American College of Chest Physicians, four leaders in pulmonary medicine presented new information on better early management and treatment practices, new clinical developments and how to assess quality-of-life outcomes in patients with COPD.

This program was supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

COPD: The Problem

Chronic Obstructive Pulmonary Disease (COPD) has a significant impact. The World Health Organization estimates that there are 2.74 million deaths worldwide attributed to COPD and was the fourth leading cause of death in the United States during 1998 behind only heart disease, cancer and stroke (www.goldcopd.com).

“Although there is higher mortality seen in those three diseases, the changes have been quite significant,” said Mitchell Friedman, MD, FCCP, from Tulane University in New Orleans. “From 1965 to 1998 death rates for coronary diseases dropped while COPD was increasing 163%.” (www.goldcopd.com)

The demographics of COPD are also changing. Age-adjusted death rates for white women in particular have grown to where they might soon catch up with white men. In 1987, 74% of those with COPD were 65 years-of-age or older, by 2001 it was only 50%. Gender differences have reversed with more women than men now having the disease. The only consistent factor was that around 80% of those with COPD smoked (Strassels SA, et al. Chest 2001; 119:344-352).

Host risk factors under study include genetic characteristics such as alpha-1 antitrypsin deficiency, as well as airway hyper-responsiveness and maximum lung growth. While the influence of cigarette smoke is known, occupational dusts, air pollution and infections are being closely scrutinized.

Inflammation of the airway and loss of alveolar attachments are the main pathophysiologic events seen in the development of COPD. Of importance in treatment and prevention are indications the inflammation is different from that seen in asthma (Figure 1).

COPD’s natural history works against the patient. Inflammatory events begin with smoking in the late teens or twenties but the physiologic alterations may not show up until age 40 when FEV₁has already declined.

The natural history of COPD is variable between patients. While the majority are smokers, there are still 10% to 20% who have never smoked. Inflammation may lead to cough and sputum without loss of lung function in some while lung function may be lost in others before a diagnosis is made.

Driving Early Diagnosis and Treatment

“COPD is a 30- to 40-year disease where we have wonderful opportunities to intervene,” said Thomas L. Petty, MD, Master FCCP, from the University of Colorado Health Sciences Center in Denver. “Although we recognize that COPD is a very bad disease with a poor prognosis when diagnosed late, there still is not much interest in early identification and intervention.”

Medical interventions alter the course of the disease and improve the prognosis. For example, oxygen therapy may add 5 years to life expectancy. Pulmonary rehabilitation can improve the quality of life. Little of this progress has been seen in the early stages of COPD.

Very early on, physiological changes begin to occur which could be identified in any primary care doctor’s office. The challenge, according to Dr. Petty, is getting the primary physician and pulmonologist to join forces.

Less than 50 percent of primary care physicians use spirometry in their daily work. Dr. Petty suggests that spirometry has to be taught like blood pressure readings, as a simple expression of a complex process. There are well-established normal values for diastolic and systolic blood pressures. FEV₁ and FVC should do the same for spirometry.

“We have to get rid of all the nonsense numbers from the (spirometer’s) computer printout,” said Dr. Petty. “The important ones are FEV₁, FVC and the ratio between the two.”

He also advocates teaching spirometry lung age (SLA) to physicians and patients. SLA is that age at which measured lung function is considered normal. A patient with an FEV₁ of 2 at age 45 would have a SLA of about 80.

Smoking cessation is the fundamental intervention for patients at all stages. The problem is that patients with COPD have high levels of depression, anxiety and somatic preoccupation mitigated by tobacco. Doctors have to remember that the thing killing the patient is also making their life tolerable.

“The most common cause of death in the Lung Health Study wasn’t COPD at all,” noted Dr. Petty. “It was lung cancer. We need to look at COPD and lung cancer patients as partners in the same disease.”

To address this, the National Lung Health Education Program (NLHEP) has been started to develop a grass roots program to find and treat all patients with COPD. Toward this end pulmonologists should get their primary care colleagues involved in early diagnosis and treatment. Among the recommendations are testing all smokers over 45 or anyone with dyspnea, cough, hypersecretion or wheeze.

“We have the knowledge, technology and ability to implement the NLHEP like the cholesterol, asthma or hypertension education programs,” said Dr. Petty. “With prevention as our goal, we are trying to get patients to save their breath through early identification and intervention.”

Patient Care and Quality of Life

According to Barry Make, MD, FCCP, from National Jewish Medical and Research Center in Denver, there are many patient factors clinicians should consider when treating COPD patients. For example, FEV₁ is used as a marker for severity of the disease. However, there are only rough correlations with symptoms, such as shortness of breath, that patients actually complain about. A more appropriate focus for the clinician would be on a variety of treatment outcomes.

“It is not just one outcome that is important,” said Dr. Make. “We need to look at multiple outcomes in order to really assess our individual patients, what kinds of therapy they need and how they as individuals respond to the therapies we prescribe.”

Such outcomes include not only physiologic parameters such as FEV₁, but also patient symptoms such as shortness of breath and health status (also termed health-related quality of life). Other outcomes may be useful in the future as our understanding of this disease improves.

The response to medication and therapies is another important outcome to measure. Although FEVv is the traditional outcome, it does not provide a precise indication of the total impact of the disease individual patients.

“Multiple random trials with bronchodilators have shown that FEV₁ does improve (with bronchodilator administration),” said Dr. Make. “Unfortunately, pulmonologists are jaded by the much better response to bronchodilators that we see in asthma.”

“Benefits to the patient with COPD are not only seen in peak bronchodilator response, but also in duration of effect,” he continued. “The effects of short-acting medications wane quickly which does not occur with longer-acting medications.”

For example, a study by Matera, et al., evaluated improvement of FEV₁ over time with formoterol, salmeterol and salbutamol. The effects of salbutamol (albuterol) returned to baseline within 5 or 6 hours while the other two demonstrated more prolonged bronchodilation (Matera MG, et al. Pulm Pharmacol. 1995;8:267).

Research by Mahler and others compared salmeterol and ipratropium. The two medications had similar peak improvement in FEV₁. However, the duration of improvement was longer with salmeterol (Mahler DA. Chest. 1999; 115:957-965).

Combination bronchodilator therapy is becoming important in successful COPD treatment. In a recent paper from ZuWallack, a combination of salmeterol and theophylline was more effective than either one alone in the overall group as well as in who responded to short-acting beta-agonists and those who did not (ZuWallack, RL, et al. Chest 2001; 119:1661).

Another way to assess bronchodilator efficacy is to determine if fewer prn medications are needed to control dyspnea. Van Noord and his group compared mean puffs of rescue albuterol used per day in patients receiving either tiotropium (a longer-acting anticholinergic bronchodilator not yet approved for use in the United States) or ipratropium. Patients receiving tiotropium needed fewer puffs of albuterol (van Noord JA, et al. Thorax. 2000;55:289-294).

“Functional capacity is important because quality of life is affected by what patients can actually do,” said Dr. Make. “Six-minute walking tests (SMW) are a surrogate for formal exercise tests as a measure of functional capacity.”

The theory is that if a person can walk farther, there is probably less functional impairment. Dr Make says measuring functional capacity directly overcomes the fact that there is only a rough correlation between exercise and FEV₁.

One of the therapies that can be used to increase walking distance and functional capacity is pulmonary rehabilitation (PR). A paper by Griffiths found a significant increase in walking distance at 6 weeks in those undergoing PR when compared to controls. The increase was still significant (P=0.002) at one year (Griffiths TL, et al. Lancet 2000;355: 362).

Respiratory symptoms can be measured in a number of ways. Another tool to consider using is the Traditional Dyspnea Index (TDI).

Vicken’s recent paper in the European Respiratory Journal shows that TDI can be used to measure medication response. Patients taking tiotropium showed improvement in dyspnea using this measure when compared with placebo (Vicken W, et al. Eur Respir J. 2002;19:209-216).

Treatments for COPD can profoundly influence mortality, another important outcome to patients and physicians. The NOTT Group concluded that 24-hour-a-day oxygen therapy improves survival when compared to nocturnal oxygen alone (NOTT Group. Ann Intern Med. 1980;93:391).

“Exacerbation is an important issue which has only recently been recognized as an important outcome, “ noted Dr. Make. “We will see a lot more in the next several years about different therapies that can reduce the frequency and severity of exacerbations.”

The Inhaled Steroids in Chronic Obstructive Lung Disease in Europe (ISOLDE) compared placebo and inhaled fluticasone in a randomized, controlled trial.

The median number of exacerbations was decreased by 25 percent from 1.3 a year in the placebo group to less than one in the inhaled steroid arm. There was also less decline over time in quality of life in those administered fluticasone (Burge et al. Brit Med J. 2002;320:1297).

Sin and Tu’s study of Canadian COPD patients showed that medications could positively impact on hospitalizations and mortality. They evaluated over 20,000 patients who filled prescriptions for inhaled steroids within 90 days following hospitalization. They were compared with a group discharged from the hospital that had no inhaled steroids prescribed. The endpoint was hospitalization-free survival. Those on inhaled steroids had reduced mortality and fewer rehospitalizations following the index hospitalization compared to patients who were not receiving inhaled steroids (Sin DD, Tu JV. Am J Respir Care Med. 2001;164:580-584).

There are a number of tools to measure quality of life. Some, such as the SF-36 from the Rand Health Study or the Index of Well-Being, are general in nature. Others, including the St. George’s Respiratory Questionnaire (SGRQ), are specific to COPD populations.

Casaburi and colleagues used the SGRQ to assess changes in persons prescribed tiotropium or a placebo. With tiotropium, the quality-of-life scores improved and were maintained over a year. The placebo arm’s quality of life, as measured by the SGRQ, declined (Casaburi, et al. Eur Respir J. 2002;19:217).

Understanding the pathophysiology of the disease will lead to a better understanding of the cellular and molecular features causing the disease. Although current practice does not call for a biopsy to see if a particular therapy may be potentially useful or is working, Dr. Make predicted bronchoscopies, bronchial lavage and biopsies may eventually find a roll in assessing pathophysiology and response to treatment.

“Radiology is also a tool we will see more of in the next several years,” said Dr. Make. “We have new quantitative methods for assessing chest CT scans with computer algorithms that can ascertain the degree of emphysema and give us a numerical picture of the severity.”

“We should evaluate multiple outcomes in COPD,” said Dr. Make. “With our therapeutic armamentarium we can affect most of them.”

New Developments in the Management of COPD

There is a widespread negative attitude toward COPD, according to Bartolome Celli, MD, FCCP, from St. Elizabeth’s Medical Center and Tufts University School of Medicine in Boston. This negativity starts with the current definition of COPD as a “disease characterized by airflow limitation, not fully reversible that is generally progressive”.

Contrast this with the approach to coronary artery disease, which is also largely reversible.

“Coronary artery disease is defined by cardiologists as a disease that can always be reversed,” said Dr. Celli. “They do catheterizations of every vessel, put in stents, and do bypasses because it can be reversed. We should define COPD as a disease that is partially reversible and take the positive outlook.”

COPD should be looked upon as the pulmonologist’s equivalent to hypertension. Both have surrogate numbers such as blood pressure and FEV₁/FVC that can easily be understood. Both have outcomes that can be impacted by treatments currently available.

Simplification of the measures is important. Spirometry tests are usually corrected for age, height and many other factors confusing both the public and many primary care physicians. “A simple number would take us into a new dimension where we can easily check outcomes,” said Dr. Celli. “Dyspnea would become our angina, exacerbations the same as a myocardial infarction and respiratory failure is similar to cardiogenic shock. If we accept those outcomes as being important, then we can provide therapies that can be shown to be effective.”

Data from a study by Schols looked at COPD patient survival rates stratified by body mass index (BMI). They found that weight loss, specifically protein from the muscles, resulted in a worsening prognosis. Those with very low BMI measurements had a prognosis similar to small cell carcinoma of the lung (Schols A. AJRCCM. 1998;157: 1791).

Dr. Celli sees COPD as existing in three different domains. There is a respiratory domain measured by tests such as FEV1 or blood gases. A systemic domain that encompasses aspects of the patient such as BMI and exercise capacity. Finally, there is a perception domain including shortness of breath.

There is also a heterogeneity to these patients that needs to be taken into account.

To illustrate, Celli discussed an article currently under revision. Taking such variables as PA02, results of the SMW, BMI and dyspnea, they developed a composite score. He then followed a cohort of 600 for 40 months. The index score predicted mortality much better than any other individual variable.
There are other treatments that can have a positive impact on the disease.

Dr. Celli points to noninvasive inhalation machines that can sense how a person wants to breathe. In just a few years they have become the standard of care in the emergency department for those with acutely compensated COPD and CO₂ retention.

“This is our equivalent of the intraaortic balloon pump,” said Dr. Celli. “I would challenge any area other than COPD to show that you can put someone on noninvasive inhalation, decrease the rate of intubation, decrease the length-of-stay and improve mortality.”

Surgery is another treatment that may be on the horizon. Indeed, a recent article by Geddes indicates that those undergoing volume reduction surgery walked longer and had a better quality of life when compared to those that did not. (Geddes D, et al. NEJM. 2000;343:239)

“Before, many have told us that we should change the way in which we think about the disease,” said Dr. Celli. “I propose that we push even more and change the framework in which we work. We should drop the nihilistic attitude we have had to our patients with COPD and realize that, given the evidence that has accumulated, we can improve the outcome of the patients we treat. We have every reason to be optimistic.”