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(Chest. 2004;126:150S-158S.)
© 2004 American College of Chest Physicians

Treatment Implications on Morbidity and Mortality in COPD*

Douglas W. Mapel, MD, MPH, FCCP

* From Lovelace Clinic Foundation and University of New Mexico Health Sciences Center, Albuquerque, NM.

Correspondence to: Douglas W. Mapel, MD, MPH, FCCP, Medical Director, Lovelace Clinic Foundation, 2309 Renard Place SE, Suite 103, Albuquerque, NM 87106; dmapel{at}comcast.net


   Abstract
TOP
 Abstract
Introduction
 Patient Heterogeneity in COPD...
 Population Impact: the...
 Conclusions
 References
 
Inhaled corticosteroids (ICSs) remain controversial in COPD, although recent clinical trials have consistently found that they reduce chronic respiratory symptoms and, in some population-based studies, improve survival. Their impact on the general COPD population depends on the variability in clinical response among individuals, the magnitude of treatment benefits, and the prevalence of adverse events in the population. The clinical benefits of ICSs in COPD are less obvious than in asthma; however, even patients with COPD without airway hyperresponsiveness experience significant improvement in baseline lung function and other outcomes after treatment with ICS. Population-based surveys suggest that a majority of patients with COPD have asthma or chronic bronchitis features and, therefore, are predisposed to a stronger treatment benefit from ICS. Clinical data support the use of ICS in patients with moderate-to-severe COPD, and suggest that they have impacts on morbidity and mortality that are as great or greater than those seen among commonly accepted treatments for other chronic diseases.

Key Words: asthma • chronic bronchitis • COPD • epidemiology • inhaled corticosteroids • treatment outcome


   Introduction
TOP
 Abstract
 Introduction
Patient Heterogeneity in COPD...
 Population Impact: the...
 Conclusions
 References
 
The use of inhaled corticosteroids (ICSs) in COPD has been a highly controversial issue among pulmonary specialists.123 Older studies45678910 that examined the effects of ICSs on the airway inflammation associated with COPD had mixed results, and most clinical studies11121314 have found that ICSs do not slow the accelerated decline in lung function associated with COPD. However, more recent randomized clinical trials (RCTs)15161718 have shown that ICSs are associated with improved baseline pulmonary function, reduced chronic respiratory symptoms, reduced COPD exacerbation frequency and severity, and improved quality of life. Population-based cohort studies192021 using longitudinal databases from Canada and the United Kingdom have found that patients with COPD who were prescribed ICSs had a reduced risk of hospitalization and improved survival. However, observational studies are highly susceptible to selection biases and confounding effects, and there is an ongoing debate about how best to analyze and interpret these types of data.22

Estimating the impact of a treatment on morbidity or mortality in a specific condition is similar to conducting a power analysis for a clinical study. In power analysis, we estimate the number of individuals ({eta}) that will need to be enrolled in a study to see a treatment effect. Study power is primarily dependent on two factors: the variability in the treatment response from individual to individual (often described as a SD, or {sigma}), and the effect size, which is the average magnitude of the response seen across the entire study population. This relationship is described by the following formula:

where (Z{alpha} – Zß) is the arbitrarily defined balance between inappropriately accepting a chance association as a true effect ({alpha} or type I error) and inadvertently rejecting a true association (ß or type II error). Note that this is an exponential function, so that slight increases in the variability in treatment response result in large increases in the number of subjects needed to see an effect. The effect size is largely determined by two factors: the absolute change seen in a specific outcome among those treated in the study population, and the background incidence or prevalence of that outcome.

The purpose of this review is to examine the following question: What impact do ICSs have among patients with COPD treated in the general population? We will first focus on the problem of response heterogeneity in this condition or, in other words, the amount of individual-to-individual variability expected. We will approach response heterogeneity with a special emphasis on the overlap between asthma and COPD, and how this overlap is likely to affect the overall benefit of ICSs. Next, we will review several clinical studies that provide data on which to base estimates of effect size in terms of reduction in morbidity and mortality in COPD. Finally, we will examine the interaction between treatment efficacy and outcome incidence, and demonstrate how these factors must be simultaneously considered when examining treatment effect in COPD.


   Patient Heterogeneity in COPD and the Overlap Between COPD and Asthma
TOP
 Abstract
 Introduction
 Patient Heterogeneity in COPD...
Population Impact: the...
 Conclusions
 References
 
One of the major difficulties in COPD research is that COPD is not a disease. It is a clinical syndrome that is usually described as the overlap between two distinct pathoclinical entities: chronic bronchitis and emphysema.23 To complicate the issue, we have the debate over the "Dutch hypothesis," or the overlap between COPD and asthma. The American Thoracic Society 1995 Consensus Statement on COPD and the Global Initiative on Obstructive Lung Diseases guidelines2425 include asthma with fixed airflow obstruction in their definitions of COPD. However, when pulmonologists, primary care physicians, and patients speak of COPD, they most often are not precise in their language, and experts still question whether asthma or airway hyperresponsiveness should even be considered when discussing outcomes in COPD.26

A Venn diagram is commonly used to describe the overlap between emphysema, chronic bronchitis, and asthma in COPD (Fig 1 ).24 The key feature that unites these three diseases is the physiologic phenomenon of obstruction to forced expiratory airflow, represented in this diagram as the area within the rectangle. Patients may have mild or early lung disease without airflow obstruction (areas 1, 2, and 11), indicating persons at risk for acquiring permanent lung damage. Other airways diseases such as cystic fibrosis and some interstitial diseases such as hypersensitivity pneumonitis can also have expiratory airflow obstruction (area 10), but they are not included in the definition of COPD.



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  		Figure 1. The classic Venn diagram used to describe the overlapping disease entities included in the definition of COPD and the potential clinical subcategories (American Thoracic Society 1995 Consensus Statement on COPD). Reprinted with permission of the American Thoracic Society.41

 
This diagram is a useful tool for illustrating the heterogeneity in treatment response that can be expected with ICSs in COPD. Asthma quite clearly has underlying inflammatory characteristics that are improved by ICSs, and clinical studies2728 have confirmed that ICSs reduce chronic respiratory symptoms and improve quality of life. Furthermore, several population-based studies suggest that use of ICSs reduces the risk of death from asthma.29 The inflammatory factors associated with chronic bronchitis are generally less affected by ICSs, although there are some components that do respond.4 The clinical benefits of ICSs in chronic bronchitis are less obvious than those seen in asthma, and chronic bronchitis patients with airway hyperresponsiveness (eg, improved FEV1 after inhaled albuterol) tend to have more clinical improvement than those who do not. There are few data suggesting that the inflammatory mechanisms underlying emphysema, which is still largely thought of as a disease resulting from protease/antiprotease imbalances, are beneficially affected by ICSs. What this conceptual diagram does not do, however, is reflect the relative distribution of these potential subtypes of patients with COPD in the general population.

Recently, Soriano and his colleagues30 conducted an analysis that used data from the Third National Health and Nutrition Examination Survey (NHANES) to develop estimates of the relative proportions of persons represented by these subcategories of obstructive lung disease in the general population. The NHANES was a cross-sectional probability sample (n = 33,994) that was designed to be representative of the total civilian population of the United States. Participants completed a battery of standardized medical history and symptoms questionnaires, which included questions about pulmonary diseases and respiratory symptoms, and spirometry data were obtained on participants aged ≥ 8 years (n = 22,431).

Using these data, Soriano and colleagues30 developed a Venn diagram that compares the relative proportions of participants reporting a history of lung disease with the number confirmed to have airflow obstruction by spirometry testing (Fig 2 ). The area enclosed by the rectangle represents all adults > 50 years old who participated in the survey, the large circles within the rectangle represent the different subcategories of COPD, and the area enclosed by each circle reflects the relative proportion of the total population that falls within that subcategory. The smaller clear circles within each larger shaded area represent the proportions within each subcategory that were confirmed to have airflow obstruction by spirometry. Among these older adults, 9.3% were found to have airflow obstruction by spirometry but did not report having any respiratory diagnosis. A total of 5.1% reported currently having asthma (vertical shading), 5.8% reported currently having chronic bronchitis (horizontal shading), and 5.0% reported ever having emphysema (diagonal shading). Of those who reported having only one pulmonary diagnosis, only a minority were confirmed to have airflow obstruction (26.5% of those reporting only asthma, 29.6% only chronic bronchitis, and 45.5% only emphysema). Higher proportions of those reporting having two or more diagnoses did have confirmed obstruction (55.8% for asthma and chronic bronchitis, 59.7% for chronic bronchitis and emphysema, 48.7% for emphysema and asthma, and 49.0% for all three).



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  		Figure 2. A proportional Venn diagram comparing self-reports of obstructive lung disease with objective evidence of airflow obstruction among NHANES-III participants aged ≥ 50 years. Airflow obstruction confirmed represents those persons who reported a COPD diagnosis and were confirmed to have an FEV1/FVC ratio < 70% with an FEV1 < 80% of predicted by spirometry. Airflow obstruction undiagnosed represents persons who had significant airflow obstruction by spirometry but who were never told that they had asthma, chronic bronchitis, or emphysema. Reprinted with permission from Soriano et al.30

 
There are three important conclusions that may be drawn from this study. First, the majority of adults with objective airflow obstruction are unaware of having lung disease, so spirometry is an important screening test, especially among older adults who have ever smoked. Second, the majority of those who report having lung disease do not have objective evidence of obstruction, so it is vitally important to use lung function testing to confirm a COPD diagnosis and to assess the severity of disease. Finally, and the point most relevant to this discussion, the majority of COPD patients in the general population fit within disease subcategories that are likely to benefit from ICSs.

As part of another population-based study31 designed to estimate the proportional distribution of the subtypes of COPD, we abstracted the medical records of all patients with COPD who were enrolled in a regional health-maintenance organization during calendar year 1998, and captured the terms that were used to describe each patient’s lung disease. The most common term listed for each patient was designated the primary diagnosis, and all other terms mentioned were designated secondary diagnoses. COPD was the most common primary term listed for 63.0% of this cohort, and asthma (12.0%) was the second most common primary term. Of those patients with a primary diagnosis of asthma, almost all had either severe asthma with fixed airflow obstruction or were current or former cigarette smokers. Another 36.5% of the total group had asthma mentioned as a secondary diagnosis, and asthma was by far the most common secondary diagnosis mentioned. Therefore, almost half of the patients in this COPD population (48.5%) were documented as having asthma as either their primary or secondary lung disease. Chronic bronchitis was not often listed as a primary diagnosis (7.5%), although it was the second most common secondary diagnosis (9.5%). Emphysema was rarely mentioned as either a primary (3.0%) or secondary (7.0%) diagnosis, which is notable since emphysema is still a commonly used self-reported term among patients with COPD participating in population-based surveys.

Although COPD is a heterogeneous condition and some patients stand to benefit more from ICSs than others, these population-based surveys suggest that a majority of patients with COPD have asthma or chronic bronchitis features. Therefore, most patients with COPD are predisposed to having at least some treatment benefit, and variability in treatment response is less of a problem than one might expect when estimating the overall impact of ICSs on all patients with COPD.

Estimating the Impact of ICSs on Morbidity and Mortality in COPD
Data on the effects of ICSs on COPD morbidity, and the difference in impact that ICSs have on COPD patients with and without airway hyperresponsiveness, can be derived from recently published RCTs. In a study15 comparing patients with COPD randomized to a combined fluticasone/salmeterol inhaler, inhaled fluticasone or salmeterol individually, and placebo, patients who had a reversible component to their airflow obstruction (≥ 12% and 200-mL improvement in lung function after treatment with albuterol) were compared with those who did not (Table 1 ). All who received fluticasone or the combined fluticasone/salmeterol product had significant improvement in their baseline lung function, with those having partially reversible obstruction showing slightly better improvement. The same pattern was also seen when the dyspnea measures were compared, although the improvement among those with fixed obstruction who were randomized to fluticasone alone did not reach statistical significance (Table 1). Similar results were seen in the study conducted by Hanania et al,18 who examined the effects of the 250-µg dose of fluticasone in a similarly designed RCT. The Trial of Inhaled Steroids and Long-Acting ß2 Agonists16 was another RCT that compared fluticasone, salmeterol, and the combined product with placebo; but, importantly, this study excluded patients with COPD who had any history of asthma or who had improvement in baseline FEV1 with albuterol. Despite the exclusion of patients with COPD who were predisposed to a favorable response, the fluticasone-treated patients still had clinically relevant improvements in baseline lung function and quality-of-life scores, and reductions in chronic symptoms and exacerbation rates. These RCTs confirm that ICSs effectively reduce morbidity in COPD, that the magnitude of the response is clinically relevant, and that patients with COPD without asthma features still experience significant benefits.


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  		Table 1. Response to Salmeterol, Fluticasone, and the Combination by Reversibility to Albuterol (≥ 12% and 200 mL) Among Patients With Moderate-to-Severe COPD*

 
RCTs are considered to be the best way to prove the benefits of a specific treatment, also known as treatment efficacy. In COPD, there are no currently available RCTs of ICSs that were designed with improvement in COPD survival as their primary study aim, although a large one is underway. However, a post hoc analysis of the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)13 study did find a trend toward improved survival among COPD patients treated with fluticasone.32 The ISOLDE randomized 751 patients with moderate-to-severe COPD to fluticasone or placebo, with the primary study aims of treatment effects on lung function, symptoms, quality of life, and exacerbations. In the initial analysis that excluded persons who dropped out of the study, there was no survival difference between the treated and placebo groups. Later, the data were reanalyzed using an intent-to-treat approach, identifying deaths among the dropouts by matching them to UK vital statistics registries. Although this is a post hoc analysis and the survival difference did not quite reach statistical significance (p = 0.069), it was impressive given the small size of the study population and limited follow-up interval.

Population-based cohort studies are limited by their susceptibility to selection biases and confounding factors, although their results are usually consistent with those of RCTs.3334 Because they capture the natural history of the treated and untreated disease, they provide insights into how well treatments actually work among persons in the general population, which is also known as treatment effectiveness. Three population-based cohort studies have suggested that ICSs are effective in reducing mortality and the risk of rehospitalization, and that the risk reduction is relatively large. Using the provincial health database for Ontario, Sin and Tu19 examined all patients aged ≥ 65 years who were discharged after their first hospitalization for COPD (n = 22,620), comparing survival among those who received ICSs within 90 days of discharge (n = 11,481) with those who did not.19 Persons who died within 30 days of discharge from the hospital were excluded. Survival was significantly better among those prescribed ICSs compared with those who were not (Fig 3 ). After adjustment for differences in age, gender, other respiratory treatments, other prognostically important conditions, and COPD severity as indicated by the number of emergency department visits, the relative risk for hospitalization and for death were each reduced by 24%. Twelve-month survival among those meeting enrollment criteria was 29% and 22% in the ICS-treated and ICS-untreated groups, respectively, which illustrates how seriously ill this population was and what a difficult prognosis those hospitalized with COPD face.



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  		Figure 3. Adjusted probability of hospitalization-free survival among patients treated with ICSs within 90 days of initial hospital discharge for COPD. Reproduced with permission from Sin et al.19

 
Soriano and his colleagues20 examined the use of ICSs in the General Practice Research Database, which is a longitudinal sample of approximately 5% of all patients treated in primary care clinics in the United Kingdom. This study focused on only one ICS, fluticasone, and examined whether the combined use of fluticasone and a long-acting ß-adrenergic (LABA) inhaler was associated with a greater survival benefit than that seen with either agent alone. This study captured all patients with a new diagnosis of COPD made between 1990 and 1999, and set a minimum exposure requirement of 90 days worth of fluticasone, LABA, or another respiratory drug prescribed within a 6-month period to define the comparison groups and establish a start date for follow-up. After adjustment for confounding factors, the relative risk reduction (RRR) for the 3 years beyond the index date was 25% in the LABA group, 33% in the fluticasone group, and 50% in the combined group, compared with those who only used bronchodilators.

The analytic methods used by these studies were recently criticized in a two other articles3536 that used population-based longitudinal data. Suissa35 suggested that the because the Ontario study required that patients in the treatment group had to survive long enough to receive the ICSs within the 90 days beyond discharge needed for inclusion in the study, an immortal time bias was introduced that spuriously enhanced the beneficial outcomes of ICSs. However, ICSs were still beneficial in both the Ontario and Saskatchewan provincial databases even after adjustment for the immortal time period.3537 These beneficial effects are eliminated only after performing a "time-dependent" analysis, which is a statistical method that attempts to adjust for variation in treatment compliance during the study period. However, there are major differences in treatment populations and enrollment criteria that limit comparison of these four studies. For example, the total Saskatchewan COPD population (n = 979) was < 5% of the size of the Ontario population (n = 22,620), and the demographic and utilization characteristics of the two groups were substantially different. Although time-dependent analyses might allow for a better accounting of lifetime exposure to treatment, they have a number of limitations in themselves. Most importantly, they unable to fully adjust for disease severity, and patients with COPD who receive ICSs in the general population are more likely to have advanced disease and thus be at higher risk of poor outcomes. Also, time-dependent analysis assumes that decisions about starting and stopping treatment are independent of other clinical factors that affect the outcomes of interest, which is unlikely to be the case in this situation.38 This debate is an excellent illustration of the difficulties of analyzing and interpreting population-based data, and why RCTs are still necessary to prove effectiveness even when observational data suggest that ICSs have strong treatment efficacy.


   Population Impact: the Relationship Between Efficacy and Outcome Incidence
TOP
 Abstract
 Introduction
 Patient Heterogeneity in COPD...
 Population Impact: the...
Conclusions
 References
 
The impact of a treatment on a specific population is dependent on two factors: its effectiveness in improving a specific outcome, and how common that outcome is in the population of interest. For example, an intervention may be highly effective in reducing the risk of death in a specific situation (eg, closing beaches during shark season), but if the overall incidence of that event is rare (less than one death due to shark attack per million swimmers per year), then the impact on overall public health will be very small. However, interventions with limited effectiveness (eg, smoking cessation and prevention) applied to problems that lead to a very high incidence of adverse events (> 400,000 smoking-related deaths in the United States per year) can have a very large impact on public health.

Treatment efficacy is often expressed in RRR, which is calculated by dividing the difference in the event rate between treated and untreated groups, usually in the number of events per the number of persons at risk, by the baseline risk during the specified study interval (Table 2 ). While RRR provides useful information about how well a treatment works, it does not provide information about how commonly that problem occurs. Note that the two example treatments in Table 2 have identical efficacy in RRR (50%, or a reduction in the mortality rate by half). However, the first intervention is for a very common disease that occurs in 1 in 5 at-risk persons during the specified time interval, while the second intervention is for a relatively rare disease, occurring in only 1 in 50,000.


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  		Table 2. Comparison of RRR With the NNT as Measures of Treatment Effectiveness in the General Population

 
A more useful concept that incorporates not only treatment efficacy but how commonly an outcome occurs among persons at risk is the number needed to treat (NNT), or the number of persons at risk who have to be treated to prevent one outcome event during a specified time interval. The NNT may be estimated by taking the reciprocal of the absolute difference in outcome rates between the treated and untreated groups (Table 2). The NNT gives a useful indication of the potential impact of an intervention on public health, and it is a more intuitive concept for clinicians who apply these treatments in their everyday practice.

Using data derived from the Ontario study,19 we can calculate the NNT for ICSs in COPD in the post-hospital discharge situation, compared with ICSs in asthma29 and gemfibrozil therapy for hypercholesterolemia in coronary artery disease (CAD)39 (Table 3 ). These estimates are derived from studies that have very different designs and are, thus, subject to a variety of systematic biases. Nevertheless, this Table 3 helps illustrate how great an impact ICSs may already be having in COPD, and that the magnitude of this effect is favorable when compared with other commonly accepted treatments. It is important to note that in COPD, much of the benefit is attributable to the very high incidence of morbidity and mortality, especially among persons with moderate-to-severe airflow obstruction or those hospitalized for COPD.


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  		Table 3. Impact of ICSs on COPD Survival Compared With ICSs Treatment in Asthma and Cholesterol Therapy in CAD

 

   Conclusions
TOP
 Abstract
 Introduction
 Patient Heterogeneity in COPD...
 Population Impact: the...
 Conclusions
References
 
Available data from surveys, RCTs, and population-based longitudinal databases suggest that ICSs are already having an important impact on morbidity and mortality in COPD. Although the treatment response can be expected to be highly variable from patient to patient, it appears that most persons with COPD have a subtype of lung disease that is likely to benefit from treatment. Comparison of untreated and ICS-treated patients with COPD in RCTs suggests that the reductions in lung disease-related morbidity are large and clinically relevant, even among those without asthma. Longitudinal follow-up of patients enrolled in the ISOLDE study13 has shown that the great majority of COPD patients have reversible airflow obstruction at some point during the progression of their disease, so the old concept of reversible and nonreversible COPD is becoming obsolete. Observational data also suggest that ICSs are having a significant impact on mortality, although this debate will not be settled until RCTs designed specifically to examine survival are completed.

These findings seem to directly contradict the consistent finding that ICSs do not slow the accelerated decline in lung function seen in COPD. However, this situation illustrates why physiologic outcomes are often not reliable surrogate markers for survival. As an analogy, it is helpful to think of the definition and outcomes of another common syndrome—CAD. Paraphrasing the Global Initiative on Obstructive Lung Diseases definition of COPD,2425 CAD is described as a disease state characterized by (blood) flow limitation that is not fully reversible. The (blood) flow limitation is usually both progressive and associated with an abnormal inflammatory response of the (coronary arteries) to noxious (agents), then we might falsely conclude that such interventions as cholesterol reduction therapy and daily aspirin are of no benefit, because they do not slow the accelerated decline in cardiac output seen over time. Fortunately, for > 50 years the primary outcomes of interest in heart disease have been reductions in ischemic events and death, and a variety of useful interventions have been discovered that have substantially reduced mortality from CAD. Until recently, RCTs of ICSs in COPD have focused on a physiologic measure, change in FEV1, even though it is well recognized that the correlation between FEV1 and survival is weak and inconsistent.26 New treatments for COPD including ICSs clearly affect the outcomes of most interest to patients: exacerbation rates, symptoms, and quality of life, and it appears likely that they will also improve survival. While spirometry is in invaluable diagnostic and screening tool for COPD, the end point of long-term change in FEV1 should be relegated to its more appropriate place as a secondary outcome measure.


   Footnotes
 
Abbreviations: CAD = coronary artery disease; ICS = inhaled corticosteroids; ISOLDE = Inhaled Steroids in Obstructive Lung Disease in Europe; LABA = long-acting ß-adrenergic; NHANES = National Health And Nutrition Examination Survey; NNT = number needed to treat; RCT = randomized clinical trial; RRR = relative risk reduction

Dr. Mapel has received research grants were provided by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., and Pfizer Inc. He has also been a consultant to AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer Inc.


   References
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 Abstract
 Introduction
 Patient Heterogeneity in COPD...
 Population Impact: the...
 Conclusions
 References
 

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