Long Term Outcomes in COPD Management: Can You Modify the Course of the Disease?

Introduction

According to Bartolome Celli, MD, Tufts University School of Medicine in Brighton, MA, a negative clinical attitude toward COPD exists even among those who treat it. This outlook begins with the definition provided by all of the large international societies.

For example, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines the disease as one characterized by “airflow limitation not fully reversible”. Physicians treating these patients perceive the disease as being “generally progressive” and incorporate this into their overall negative perception of the disease. This occurs even though the physicians are referring to only one aspect of the disease, the physiological decline of FEV1.

“Right in the definition we focus on the negative rather than looking at the positive responses,” said Dr. Celli. “You never hear a cardiologist say that any lesion in the heart is irreversible. We get a picture of negativity translated to the clinical arena so the physician thinks there is nothing he or she can do. I propose to you that this nihilistic approach is wrong.”

Dr. Celli sees this as especially disconcerting given that there are several therapeutic modalities, like rehabilitation, with proven value and new medications nearing release that may be able to alter the course of the disease.

“We have big, heavyweight drugs coming on board,” said Dr. Celli. “Tiotropium will be the 400-pound gorilla of COPD. This will be our Procardia XL, a once-a-day blockbuster.”

The Relevance of Outcome Data in COPD

One of the concerns is a focus on FEV1 as the main determinant of a patient’s condition. While highly valued, according to Marc Decramer, MD, PhD, from the Katholieke Universiteit Leuven in Belgium, there are a number of problems with an overemphasis on just one test.

“I am certainly not going to say that FEV1 isn’t important,” said Professor Decamer. “But there are some other things that are often overlooked.”

To illustrate this concept, he pointed to data obtained in a randomized study of 100 COPD rehabilitation patients his group had recently completed. Fifty were randomized to standard care and a six-month long rehabilitation program. A control group of 50 patients were given standard care (Troosters T et al. Am J Med 2000;109:207-12).

Although there was no change in FEV1 between the groups, there were dramatic changes in other variables. The six-minute walking distance increased in the first six months and stabilized in the experimental group while there was a decline among the controls. This difference met criteria for minimal clinically important difference (MCID), in addition to statistical significance. The MCID of a therapy is defined as the smallest treatment effect that would result in a change in patient management, given its side effects, costs and inconveniences.

Even more pronounced were the changes in quality of life as measured by the Chronic Respiratory Disease Questionnaire (CRDQ). In the first six months of the program there was a clear quality-of-life increase in the rehabilitation group with a small decrease thereafter. In controls, only a steady decline.

“Ten points in the CRDQ is accepted as one minimal clinically important difference,” said Dr. Decramer. “The difference in this instance is two times the MCID. This is a huge change in the quality of life.”

Another endpoint he sees as growing in importance is exacerbations. With each incidence, there is a reduction in peak expiratory flow rate that may never be completely recovered contributing to a decline in health status.

The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) Trial has shown that it is possible to lower exacerbation rates, at least among those taking fluticasone (Burge PS, et al. BMJ 2000;320:1297-1303).

Mortality is another treatment outcome that is often overlooked. Professor Decramer’s group examined this in the previous pulmonary rehabilitation study. The patients who followed the program seemed to live longer, although this was a tendency that did not quite reach significance.

COPD patients are frequently admitted and readmitted to the hospital. Professor Decramer noted that up to 50% of the patients are readmitted within six months after an acute exacerbation. “

We certainly have a sensitive model here,” said Professor Decramer. “Anything that would improve the treatment of exacerbations and reduce the hospital admission frequency would be quickly seen in COPD patients.”

Spirometry in the Diagnosis and Treatment of COPD

The limitations in airflow required for a COPD diagnosis are identified by spirometry. Currently, significant airway limitations exist when the ratio of FEV1 to FVC is < 70% of a patient’s predicted value.

However, there are some clinical limitations in using this definition alone.

“If you look at the National Health and Nutrition Examination Survey (NHANES III) data, the mean predicted ratio for those 35 years or younger is > 80% and < 70% for those 75 or older,” said Dr. Donald Tashkin, MD, UCLA School of Medicine. “Using the fixed cut-off could lead to overdiagnosis in the elderly and underdiagnosis in younger individuals” (Hankinson JL, et al. Am J Respir Crit Care Med 1999; 159:179-87).

Another limitation is that this measure may be overestimated if the FVC is reduced by a failure to completely exhale. In addition, the ratio may be exaggerated when dynamic compression and air-trapping diminish the FVC.

Dr. Tashkin suggests that FEV6 may be a more suitable measure than FVC. One reason is that FEV6 is easier to perform. Technical problems with accurately measuring low flows during a prolonged exhalation are less. Finally, the FEV6 is more reproducible in patients with airflow obstructions. NHANES has resulted in reference values becoming available.

Data from The Lung Health Study, found that FEV1/FEV6 was equivalent to FEV1/FVC in predicting decline in FEV1 over five years (Enright RL, et al. Respir Med 2002;96:444-49). A group from New Zealand found FEV6 to be an acceptable surrogate for FVC (Swanney MP, et al. Am J Respir Crit Care Med 2000;162:917-19).

“They had a remarkably good concordance between FEV1/FEV6 and FEV1/FVC numbers with a sensitivity and specificity of 95 % or greater,” said Dr. Tashkin. “Taking into account the expected between-trial variability in FEV1 and FVC, the sensitivity and specificity of the ratio incorporating FEV6 approached 100%.”

Dr. Tashkin then turned his attention to the FEF25-75 . For the most part, FEF25-75 is more sensitive that FEV1 in detecting early disease, but not as sensitive as the FEV1/FVC ratio.

During a study of air pollution in Los Angeles, Dr. Tashkin and others performed field spirometry on individuals over the age of seven residing in enumerated households in four census tracts. They looked at current smokers between 25 and 59 years of age from this cohort. Of those with abnormal FEV1/FVC ratios, only about 60% had an abnormal FEF25-75. They concluded that the FEV1/FVC ratio was more sensitive (Detels R, et al. Chest 1982;82:630-38).
Spirometry is used to stage the severity of COPD. The definition of severity is based entirely on FEV1 percent predicted in the presence of an abnormal FEV1/FVC ratio. The severity, however, may not be accurately reflected by the FEV1 alone.

“Another problem is that the FEV1 is not well correlated with hyperinflation so that an elevated functional reserve capacity (FRC) and total lung capacity (TLC) will actually bring about an increase in FEV1,” noted Dr. Tashkin. “This is because the airways are wider open and there are higher lung volumes.”

Reversibility testing to help distinguish between asthma and COPD is another use for spirometry. However, Dr. Tashkin notes most patients with COPD demonstrate significant acute response to an inhaled bronchodilator, indicating that there is a reversible component to their airflow obstruction. Conversely, the absence of an acute response is not indicative of a long-term response to maintenance bronchodilator therapy. Since reversibility testing may not help with the differential diagnosis between COPD and asthma and does not predict long-term response to these medications, the utility of reversibility testing has been called into question.

One study looked at response to either albuterol or ipratropium given by inhalation and found two of every three patients responded to one or both of the medications (Nisar M, et al. Am Rev Respir Dis 1992;146:555-59). A similar number was seen in more recent studies of short-acting beta agonists (Mahler DA, et al. Chest 1999; 115: 957-65).

FEV1 is an important prognostic indicator, however. Data from the Lung Health Study by Anthonisen and others show that subsequent decline in lung function is tied to the baseline FEV1 (JAMA 1994;272:1497-1505). Tashkin and colleagues also found the greater the airway reactivity to methacholine, the greater the rate of decline in FEV1 (Am J Respir Crit Care Med 1996;153:1802-11).

“The FEV1 is an insensitive indicator of early chronic airflow obstruction, but a good predictor of subsequent decline,” said Dr. Tashkin. “We have learned that the ratio of FEV1 to FVC is a more specific indicator of airflow obstruction and FEV1/FEV6 may be as sensitive an indicator of obstruction as FEV1/FVC and much easier to perform. Finally, changes in lung volume may show greater responses to therapy than changes in FEV1 and may correlate better with other health outcomes.”

Pharmacologic Therapy and Symptom Improvement’s Effect on Symptoms and Cost

Symptom management is an important consideration when discussing modifying the course of a disease. Changing the natural progression of COPD will have profound effects on costs. Currently the bronchodilators and inhaled steroids comprise the entire armamentarium available for treatment.

“You need to look at a number of parameters when trying to evaluate patient improvement,” said Dr. Mitchell Friedman, MD, Tulane University School of Medicine in New Orleans. “It isn’t just FEV1, its not just quality of life and its not just exercise.”

Mahler studied the effects of salmeterol versus ipratropium versus placebo on the transitional dyspnea index. Use of these pharmacological agents improved shortness of breath compared to no medication at all (Chest 1999; 115: 957-65).

The same things happen when health status is the outcome of interest. Vincken’s group noted that ipratropium lead to improved status as measured by the St. George’s Respiratory Questionnaire (SGRQ) when compared to no medication. Tiotropium was superior to ipratropium with more patients showing improvement in their quality of life with the more effective bronchodilator (Eur Respir J 2002;19:209-16).

Dr. Friedman then asked if medications could have an impact on the prevention and control of exacerbations.

“The answer is ‘yes’,” he said. “Ipratropium by itself and in combination with albuterol significantly decreases exacerbations when compared with the short-acting beta agonists. Salmeterol and formoterol have also been shown to be effective in preventing relapses.”

Another study by Casaburi and others found a 24% decrease in exacerbations in those taking tiotropium when compared to patients given ipratropium (Eur Respir J 2002;18:217-224). The ISOLDE Study showed a 25% reduction in exacerbations in users of inhaled steroids.

In addition to the areas already discussed, health care costs can be lowered with treatment.

Friedman and others published data from a group of 400 patients with a range of COPD severity. The median costs for mild disease was $2,000 a year, $5,000 for moderate and almost $11,000 in those with severe disease. Regardless of the severity, two thirds of the health care utilization and costs were related to exacerbations (Hilleman DE et al. Chest 2000;118:1278-85).

According to information from the ipratropium/albuterol study discussed earlier, using these agents to decrease exacerbations can save about $400 a year per patient. The use of tiotropium increases those savings to $1,043 per patient per year (Friedman M et al. Eur Respir J 2001 [abstract]).

“Patients have their symptoms for a very long time, but we have agents available to improve them,” said Dr. Friedman. “We can also improve their quality of life and decrease their exacerbations with the end result of lowering health care costs.”

Summary and Future

According to Dr. Celli, physicians treating COPD are being confronted by a new paradigm.

To maximize the benefits of the new medications, he feels that pulmonologists need to think more like cardiologists.

To illustrate this point, he mentioned results from the Intervention with Nifedipine SI as a Goal in Hypertension Treatment (INSIGHT) study (Brown MJ, et al. Lancet 2000; 356:366-372). They compared two antihypertensive medications and found a mean reduction in blood pressure of around 19% for the systolic and 8% for the diastolic value. The authors called it a “significant result”. “

Yet when we talk about changes in the FEV1 (equivalent to the BP values) that are similar or larger that those reported in INSIGHT, we call them negative,” said Dr. Celli. He also sees a need to start looking for the positive aspects of treatment. He points to the first paper on lung volume reduction surgery published as part of the National Emphysema Treatment Trial Research Group (NETT) trial (NETT NEJM 2001;345:1075-83). The journal article focused on the people who died and ignored those where the surgery was successful. Instead, the first study should highlight those whose surgery lead to an improvement, what he calls “the positive trial.”

Another concern is the need to simplify the measures being used. Many of the predictive indicators used do more harm than good by confusing the practitioner with large sheets of paper containing many numbers. This may serve to obscure the positive outcomes that do occur. “Most of us want to correct (the spirometry results) by height, age, and ethnicity,” said Dr. Celli. “We’ve got to teach simplicity and begin looking at outcomes different from the FEV1, our equivalent of angina, heart attack and strokes. They do exist and they are dyspnea, exacerbations and respiratory failure.”

He called for improvements in the clinical phenotyping of these patients. He sees COPD being broken out by domains. They would include a respiratory domain expressed by the FEV1, a perceptive domain measured as shortness of breath, and a systemic domain including body mass index and exercise capacity. He also suggested that doctors rely less on FEV1 and other threshold numbers to make clinical decisions, especially as they relate to treatment.

“As a doctor you have in your hands the power to move (available treatments and medications) around,” he noted. “You are a clinician, not a robot, and which medication to put a patient on should be made after looking how their needs relate to all therapies available.” More importantly, to Dr. Celli, these treatments have been proven to work. “I believe we should change our framework to reinforce that patients with COPD can lead a fruitful life. COPD is preventable, and when it develops, it responds to treatment as we have shown today.”