Editorial

COPD and Declining FEV₁ — Time to Divide and Conquer?

John J. Reilly, M.D.

N Engl J Med 2008; 359:1616-1618October 9, 2008DOI: 10.1056/NEJMe0807387

Article

In 1976, Fletcher et al. published a monograph summarizing the results of an 8-year observational study of the relationship between cigarette smoking, chronic expectoration, and the development of irreversible airflow obstruction.1 At that time, the nomenclature for chronic obstructive pulmonary disease (COPD) was confusing. COPD was understood to include chronic bronchitis and emphysema, but the definitions of these two entities contained no mention of airflow obstruction. The clinical paradigm described patients as either “blue bloaters,” who had chronic airway inflammation and a propensity for resting hypercapnia, and “pink puffers,” who had airspace destruction and preserved resting arterial oxygenation.

The study by Fletcher et al. showed that a subgroup of smokers had an accelerated rate of decline in rates of maximal forced expiratory flow, represented by the forced expiratory volume in 1 second (FEV₁). This finding shaped subsequent investigative activities in two areas: a search for the factors that underlie an apparent susceptibility to the effects of cigarette smoking and a search for therapies that slow the accelerated rate of decline. Since the introduction of this concept, modification of this trajectory, which is the first-time derivative of FEV₁ during a period of years, d(FEV₁)/dt, has been adopted as a clinical standard for disease-modifying therapy (Figure 1Figure 1Association between the Ratio of FEV₁ to FEV₁ at the Age of 25 Years and Disability or Death.). The acceptance of this concept is reflected by its inclusion as one of five proposed primary efficacy end points in the Guidance to Industry draft document prepared by the Food and Drug Administration on the development of drugs for the treatment of patients with COPD.3

More recently, the Global Initiative for Chronic Obstructive Lung Disease has agreed on a single definition of COPD, which is characterized “by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.”4 This statement reinforced the notion that COPD is a single disease, which is operationally defined by results on spirometry and more specifically by the FEV₁.

In this issue of the Journal, Tashkin and colleagues report the results of a large, randomized trial of the long-acting anticholinergic medication tiotropium in patients with COPD.5 The trial was designed to test the hypothesis that the regular use of tiotropium, in addition to standard therapy for COPD, would favorably alter the rate of decline in FEV₁. This trial, known as the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study (ClinicalTrials.gov number, NCT00144339), illustrates the challenges of using FEV₁ as an end point.

Given the magnitude of the rate of decline in FEV₁, along with its variability among patients and the variability of FEV₁ measures, an adequately powered trial requires the enrollment of a large number of patients who are observed for a period of at least 3 years. This factor creates challenges in recruitment, retention, and expense, all of which are formidable hurdles for clinical investigators. The UPLIFT investigators secured appropriate resources, organized a network of 490 centers in 37 countries, and recruited a total of 5993 patients. Despite their best efforts, about 40% of enrollees dropped out before the study was completed, a rate that is similar to those of other recent, large COPD trials.6 For the coprimary end points — the rates of decline in FEV₁ before and after bronchodilation — there were no significant differences between tiotropium and placebo.

One could argue that this outcome was predictable, since previous trials of a short-acting anticholinergic drug, a number of inhaled corticosteroids, and an antioxidant have all shown no positive effect on the rate of decline in FEV₁.6-11 To date, the only intervention that has met this criterion of disease-modifying therapy is smoking cessation, as shown in the Lung Health Study, sponsored by the National Institutes of Health.8 In retrospect, the accomplishments of the investigators in the Lung Health Study are all the more impressive, since they achieved a 5-year follow-up rate of 94% among 5887 subjects and had the foresight to select smoking cessation among their interventions.

The UPLIFT investigators also noted a trend suggesting a decline in mortality among the tiotropium-treated patients that came tantalizingly close to achieving statistical significance. This is the second large trial to have this result. Last year, the Towards a Revolution in COPD Health (TORCH) trial (NCT00268216) also showed a reduction in mortality in the active-treatment group (in which patients received a combination of fluticasone and salmeterol) that came close to but did not achieve conventional statistical criteria for significance.6 To date, only smoking cessation and, in appropriately selected subgroups of patients, oxygen therapy and surgery for lung-volume reduction have been shown to reduce mortality.

Other than the clinical conclusion that tiotropium should not be prescribed with the goal of disease modification but rather for the alleviation of symptoms, what have we learned from the UPLIFT trial? The pessimistic perspective might be that we have yet to show that any pharmacologic intervention alters the natural history of COPD. A different perspective might be that the issue with this trial, and other recent large trials, is a signal-to-noise problem. In our efforts to simplify and clarify our definition of COPD, we have promulgated an inclusive definition that relies primarily on spirometric measures to establish the diagnosis. There is increasing recognition that FEV₁ alone, while important, does not capture and communicate the heterogeneity of COPD.12

In fact, COPD in the singular is probably a misnomer. It is more appropriate to view COPD as a syndrome that encompasses a variety of obstructive diseases that share a common exposure but differ in terms of mechanism of disease and response to therapy. This concept is expressed in the mathematical notation

in which COPD_n represents subgroups of COPD. As a reflection of this recognized heterogeneity, investigators have developed new classification systems, such as the BODE index, which evaluates the body-mass index, the degree of airflow obstruction and dyspnea, and exercise capacity to create a 10-point scale in which higher scores indicate a higher risk of death. In addition, investigators have attempted to define other homogeneous subgroups of patients with COPD.12

The definition of meaningful subgroups will be crucial to achieving two goals. First, it will help to ensure that therapies that are effective in a subgroup of patients with COPD (such as oxygen therapy and lung-volume reduction) will not be discarded on the basis of results of studies that included patients with various types of COPD. Second, the use of highly refined entry criteria will facilitate genetic and mechanistic studies and should allow for the conduct of meaningful trials with smaller numbers of patients.

This process will be an iterative one, in which the use of post hoc analyses of large data sets, such as those in the UPLIFT trial, will be used to generate proposed definitions of subgroups that can be prospectively tested. Although the characteristics that will define these subgroups remain to be determined and will probably include clinical, physiological, radiologic, and genetic measures, it is clear that the use of FEV₁ alone is not sufficient.

Dr. Reilly reports receiving consulting fees from Indevus Pharmaceuticals and research support from Aeris Therapeutics.No other potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMe0807387) was published at www.nejm.org on October 5, 2008.

Source Information

From the Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh.

References

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