The four-year UPLIFT® trial provided data that permitted examination of associations of the magnitude of lung function decline with changes in the clinically relevant health outcomes of exacerbations, HRQoL and survival [4, 5]. In order to examine patterns, the annualised rate of loss of post-bronchodilator FEV1 was divided into quartiles. Other than smoking status, demographics and respiratory medication use appeared to be largely similar among groups; and the most prominent difference at baseline was lung function, which appeared to be least impaired in those with the most rapid loss in FEV1. In longitudinal analyses, the patterns associated with quartiles of increasing rate of decline in FEV1 indicated a relationship to an accelerated loss of HRQoL, increased rate of exacerbations, increased risk of a hospitalised exacerbation and increased risk of death.
COPD is described as a disease of progressive airflow limitation, for which the most described marker remains the serial measurement of FEV1 . The publication by Fletcher and Peto placed FEV1 decline over time at the forefront of biomarkers that illustrate disease progression . However, the utility of any biomarker is somewhat dependent on its predictive value or associations with other clinically important endpoints. In this regard, there are two main analytic approaches to FEV1, regardless of whether it is described as an absolute volume or as a percentage of predicted normal. The first approach is the static single-point measurement. While there is a clear relationship of FEV1 severity to subsequent mortality, the descriptions of which date back several decades [8, 9], composite measures such as the BODE index that have FEV1 as a part of the measure appear to have higher predictive values . Additionally, other parameters such as comorbidities and serum markers should continue to be explored for associations with disease progression. Yet a single measurement of FEV1 is poorly associated with other health outcomes such as exercise tolerance and quality of life. This may relate to issues of a single measurement in a disease that is known to have substantial day-to-day or week-to-week variability. The second analytic approach is serial measurements over time examining the pattern of change (i.e. slope).
Most studies have described FEV1 decline in the context of the effects of cigarette smoking and cessation of exposure to cigarette smoke with minimal data being published on the associations of rate of decline in FEV1 with other health outcomes [3, 11]. The rate of loss of lung function over time was recently described in the Towards a Revolution in COPD Health (TORCH) trial . The authors noted that an increased rate of decline was associated with more frequent exacerbations . A rapid decline in FEV1 has been associated with more frequent exacerbations of COPD in other studies [13, 14] and severe exacerbations have been shown to be associated with premature death . The remaining studies have used FEV1 as an outcome measure but have not described changes in FEV1 over time relative to changes over time in other outcomes [16–19].
Our current population showed that age and gender did not differ significantly among the quartiles of FEV1 decline. Indeed, it appears that physician's treatment patterns, as viewed by concomitant respiratory medication prescription, also did not distinguish patient groups, at least as defined by disease severity at baseline (GOLD stage). Continued smoking did show differences, which is entirely expected and also provides evidence that the subgroups are valid . The most rapid loss was observed in patients who appeared to have somewhat milder disease, either by absolute FEV1, FEV1 percent predicted or FVC. This seems to be somewhat contrary to the 'horse-racing' effect described by Fletcher and Peto, but may highlight the need for earlier and aggressive intervention in patients with COPD . There may be several possible explanations for the differences in our study and that of Fletcher and Peto as follows: (a) different populations (British coal miners vs. well characterized multinational representation), (b) sample size (larger in the UPLIFT trial), (c) survival (more likely to have severe disease in the UPLIFT trial due to advance in health care), and (d) environmental conditions (coal miners and likely higher levels of particulate exposure vs. current air quality standards). A consistency is seen with recent data that show improvements in outcomes with long-term pharmacotherapy in GOLD stage II patients (UPLIFT® and TORCH), as well as significant benefit in patients not previously receiving maintenance respiratory medication [4, 21, 22].
Certain limitations should be noted. The calculation of FEV1 decline was only continued while the patient received study drug and was not assessed following premature discontinuation of study drug. Premature discontinuation of study drug occurred in more control patients (45%) than tiotropium patients (36%). However, there was still substantial exposure to both study drugs during the trial with multiple measurements over years in most patients in the current analysis. Suissa describes the phenomenon of regression to the mean, which certainly could contribute to our findings; however, the inclusion of a data point closely following randomisation (i.e. at 30 days) should limit this . Each treatment group needs to be considered independently since between-treatment comparisons are not valid, given that subgroups are based on outcomes (i.e. rate of decline in FEV1). Furthermore, there is a bias toward the more severe COPD patients preferentially in the tiotropium group continuing to completion, due to the effectiveness of the intervention, which created unequal groups as the trial progressed. Nevertheless, the pattern of association of quartiles to rate of decline in FEV1 can be observed within both treatment groups.
The study's strengths included the large sample size, the rather liberal inclusion criteria, the length of the trial and the rigorous nature of the data collection. The latter is particularly true of spirometry, which pre-specified a stringent protocol and involved standardised equipment, study specific software and a centralised review of all measurements.
The current results provide supportive evidence of the relevance of serial measurements in FEV1 over time. A rapid loss of lung function appears to identify a group at increased risk for more frequent exacerbations, severe exacerbations (i.e. hospitalised events), an accelerated loss of HRQoL and premature mortality. FEV1 measurement is simple, relatively inexpensive, widely available and well standardised with published normative values. COPD is a chronic disease and patients with COPD may be followed clinically for several decades. Identification of rapid decliners could be clinically useful since such patients may represent a unique subset of patients who require aggressive interventions. It is relevant to note that there can be marked heterogeneity between individuals regarding the absolute annual loss of lung function, which will be influenced by their genetic background and environmental factors.
Identification of patients with the most rapid decline in lung function, particularly in the early stages of COPD, would require a study of reproducibility of FEV1 and its decline in individual patients, possibly at short intervals (e.g. 3-6 monthly). Before translating to clinical practice, further research is needed regarding the reproducibility and patterns of rate of decline in individual patients. At a minimum, additional research is required to identify factors, other than continued exposure to noxious fumes and particulate matter (i.e. tobacco smoke), such as biomarkers and genetic patterns that can both predict a rapid decline and lead to novel approaches in treating such patients. Another issue to consider is whether rapid decliners represent a distinct subset of COPD. In an editorial, Rennard and Vestbo described an approach in which COPD can be considered an orphan disease requiring unique approaches to different forms of the disease . Moreover, in another editorial, Reilly wrote about COPD being the sum of many small COPDs . Whether this is the case for rapid or slow decliners remains to be determined.