The association of lung function and St. George's respiratory questionnaire with exacerbations in COPD: a systematic literature review and regression analysis

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway obstruction related to chronic inflammatory responses in the lungs with symptoms including disabling dyspnea, fatigue, and persistent cough with excessive sputum. Exacerbations are characterized by a sustained acute worsening of respiratory symptoms beyond daily fluctuations, which leads to changes in medication use. Due to the disease symptoms, COPD patients often have a reduced capacity for physical activity and this may worsen potential systemic manifestations of the disease, such as cardiovascular and psychiatric comorbidities. The global prevalence of COPD is estimated to be 9.2 % [1] with variable estimates, ranging from 3.9 % [2] in the Netherlands to 20.9 % in the US, [3] when reported by country. Therefore, COPD presents a major clinical and humanistic burden, [4] despite the availability and use of standard treatments, which aim to relieve symptoms and slow disease progression [5].

This heavy disease toll inevitably focuses interest on how patients are treated and the extent to which medications produce meaningful benefits. Assessment of such value in clinical trials has traditionally relied on measures of lung function (such as forced expiratory volume in one second [FEV₁]), symptom control, health status, and rates of exacerbation over a period of up to one year. Exacerbations are a particularly important marker, not least because they are a key driver of health resource use (HRU), such as emergency department visits, antibiotic use and hospitalization. Evidence of this includes the fact that an exacerbation can cost upwards of $7,000 each, depending on its severity and whether the patient is hospitalized [6]. Unsurprisingly, payers tend to focus on this outcome in their formulary considerations, with the expectation that decreased exacerbation rates will likely result in lower costs for their plan.

The clinical and economic importance of exacerbations in COPD invites questions about their inter-relationship with other well-established measures of treatment effect. These include, for example, persistent and/or uncontrolled disease symptoms and health status as measured by the St. George’s Respiratory Questionnaire [SGRQ] – which captures symptoms, impact on patient well-being, and activities of daily living. Additionally, clinically relevant improvements in lung function measures such as FEV₁, are often required by regulators for certain drug approval processes. Of note, previous studies have looked at the link between FEV₁ and SGRQ score [7, 8] but their relationship to longer-term outcomes, such as exacerbations and HRU, is not well-known and/or accepted, and this may account for why they have received comparatively less consideration from clinicians and payers.

Against this background, the current study aimed to investigate the relationship between changes in FEV₁ and SGRQ score and economically significant outcomes of exacerbations and HRU, by conducting a systematic literature review (SLR) and regression analysis of relevant studies of pharmacological interventions for COPD. The results of this analysis will help the interpretation of clinical trial results and provide insights into whether or how the effects of COPD treatment seen in such studies relate to long-term clinical benefits.

Our systematic literature review and regression analysis demonstrated that beneficial mean change in either FEV₁ or SGRQ total score was associated with a lower risk for exacerbations. Specifically, it showed that in randomized trials of COPD drug treatments lasting ≥48 weeks, there was generally a relationship between relative efficacy in improving FEV₁ and SGRQ total score and relative efficacy for lowering exacerbation risk. The majority of analyses showed the same trend towards a relationship between positive changes in FEV₁ and SGRQ score and exacerbation risk, even though results did not always reach statistical significance. Of note, there was no relationship shown between mean change in FEV₁ and annualized exacerbation rate, despite this relationship being moderate and statistically significant when the risk of experiencing at least one exacerbation in patients was analyzed. The mean change in SGRQ total score was not significantly related to the rate of exacerbations across all severities but had a moderate, statistically significant relationship with the rate of moderate-to-severe exacerbations. The relationship between FEV₁ and SGRQ score and hospitalizations was less clear, and further research is needed in this area.

To our knowledge, the literature review and regression analysis we conducted is the first such study to evaluate the inter-relationship that health status and lung function have with exacerbation risk. It provides a more rigorous examination of a relationship between laboratory values and exacerbations than has been done in the past, as, unlike former studies, it correlates relative treatment effects instead of absolute ones, thus lowering the possibility of ecological bias. However, as this analysis used only aggregated patient data from published trials, we cannot assume that any statistical association observed between arm-level variables may be translated to patient-level associations. Therefore, our findings cannot be used to predict any outcome at the patient-level. Additionally, our analysis may be limited by the available data for the surrogate measures given the trials reported FEV₁ in several different ways. Since our analysis was limited to trough or prebronchodilator FEV₁ data, analysis using other measures of FEV₁ could yield different results. Similarly, regarding exacerbation severity, we categorized exacerbations based on the definitions reported by study authors using a standardized approach as defined in our methods section. However, in some cases definitions were not reported so we relied on author-defined groupings of any or moderate-to-severe exacerbations.

Our research may have important implications for regulatory assessment of drugs intended to help reduce the risk of exacerbations in COPD and, in particular, the evidence considered in such deliberations. Currently, to gain marketing approval for this indication, such treatments have to be tested in long-term, parallel trials, which represent a logistic and economic burden on the sponsoring organization. Because of this, few trials of COPD drugs are powered to identify a significant difference in the reduced risk of exacerbations. It is for this reason that to date very few drugs have been approved for reducing exacerbations on the basis of prospective 1–2 year parallel trials, usually in patients with history of acute exacerbations in the prior year. Our study suggests changes in FEV₁ and SGRQ might serve as reliable surrogate markers of patients’ likelihood of experiencing an exacerbation. If so, these measures could allow future trials to be shorter and more manageable while still offering key insights into treatments’ longer-term efficacy. Since exacerbations can be costly to health plans, payers should consider the effect of medications on these surrogate markers, even when long-term RCTs cannot be carried out. Also, confirmation of our results would broaden the application of data already available from published shorter-term studies. This is especially important since the trials used to inform regulatory approval were powered on each specific drug’s expected effect on the acute exacerbation rate and all but one [11] were small and had very selective entry criteria. This contrasts with the trials contributing data for our review and analysis, since these were broader and more inclusive (e.g. with regards to disease duration and reversibility, comorbidities, interventions, and concomitant therapies) and collectively more representative of the general COPD population seen in everyday clinical practice. Therefore, these collated data sources potentially allow more generalizable conclusions to be drawn regarding whether or how standard short-term endpoints assessed in trials relate to effects on exacerbations.

In conclusion, this study demonstrates a significant association between improvements in FEV₁ and SGRQ total score and lower risk for COPD exacerbations. We believe that the results of our study offer providers and payers a more informed picture of the inter-relationship between exacerbations and both FEV₁ and SGRQ score, which will aid clinical and formulary decisions while stimulating research questions for future prospective studies.