Using Post-bronchodilator FEV1 is Better Than Pre-bronchodilator FEV1 in Evaluation of COPD Severity

Abstract

Background: The current standards for the diagnosis and treatment of patients with COPD clearly rely on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria based on post-bronchodilator spirometric values. However, clinical evidence for using the post-bronchodilator FEV1 in the severity classification has not been fully investigated. Methods: Patients with COPD were enrolled and followed up prospectively between October 2006 and January 2011. We compared the observed 3-year risk of all causes and respiratory mortality with the risk predicted by the pre- and post-bronchodilator percent predicted FEV1. Other important phenotypes including BMI, MMRC dyspnea scale, ECOG performance status and severe AECOPD (acute exacerbation) were also compared between the two groups. The different severity classifications of COPD, measured according the GOLD guidelines by post- and pre-bronchodilator percent predicted FEV1 were compared for prediction of mortality. Results: There were 35 deaths among the 300 COPD patients (11.7%). Multivariate analysis showed that the post-bronchodilator percent predicted FEV1 was a significant independent predictor of mortality but pre-bronchodilator percent predicted FEV1 was not (p = 0.008 vs 0.126) and it was more strongly correlated with all studied predictors of outcome than the pre-bronchodilator percent predicted FEV1. Kaplan-Meier analysis showed that the discrimination ability to predict mortality from the GOLD criteria using post bronchodilator percent predicted FEV1 (p = 0.009) was better than using pre-bronchodilator percent predicted FEV1 (p = 0.131). Conclusions: The post-bronchodilator percent predicted FEV1 is better than the pre-bronchodilator percent predicted FEV1 in the evaluation of the severity of disease in COPD patients and is more accurate in predicting the risk of death by the GOLD classification.

Keywords: :

• Cchronic obstructive pulmonary disease
• GOLD criteria
• FEV1
• Ppost-bronchodilator FEV1
• Mmortality.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, and its prevalence and mortality will increase in the coming decades. The World Health Organization has predicted that it will be the third leading cause of death by the year 2020. However, there are still no effective drug therapies for COPD which alter disease progression and improve patient survival (1). Therefore, the accuracy of measurement of disease severity is important for further research on clinical outcomes to predict mortality in patients with COPD.

In clinical practice, the risk of death in patients with COPD is often graded by using spirometric values such as the forced expiratory volume in one minute (FEV1). Both the pre- and post-bronchodilator FEV1 have been reported to predict the health status, rate of exacerbation and risk of death in COPD patients (2–11). The current standards for the diagnosis and measurement of disease severity clearly rely on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria based on post-bronchodilator spirometric values (1).

However, the clinical evidence for replacement of the pre-bronchodilator FEV1 with the post-bronchodilator FEV1 in the classification of the severity of COPD as recommended by GOLD has not been fully established. The aim of this study was to clarify the importance and provide supporting evidence for the use of the post-bronchodilator FEV1 and the GOLD severity classification criteria in the evaluation of the severity of disease, with mortality as the major outcome and other important predictors of outcome.

Methods

We prospectively recruited 305 consecutive outpatients from the pulmonary department at National Cheng Kung University Medical Center between October 2006 and January 2011. They were diagnosed as having COPD, on the basis of their medical history, chest radiographic findings, and spirometric results, according to the diagnosis guidelines and criteria of GOLD (1). Inclusion criteria for COPD included the following: all patients were ≥40 years old, had chronic airway symptoms and signs such as coughing, dyspnea, wheezing, and chronic airway obstruction. The chronic airway obstruction was defined as a ratio of post-bronchodilator FEV1/FVC < 70%. All pulmonary function test were performed according the current standard protocols of the ATS (12) and were performed by experienced and certified pulmonary technologists. Normal reference values were taken as the methods from our previous study (13).

Post-bronchodilator spirometry was measured 20 minutes after the administration of inhaled 400 μg fenoterol in our pulmonary function laboratory. Patients were asked to omit short-acting bronchodilators for 8 hours and long-acting bronchodilators for 12–24 hours before testing. All patients were in clinically stable condition and receiving appropriate therapy. Patients with an illness other than COPD that was likely to result in death within 2 years, such as advanced malignancy and end stage idiopathic pulmonary fibrosis, were excluded from the study. Five patients were lost to follow up during the study period (1.6%).

Finally, a total of 300 patients were included for analysis. For all included patients, age, gender, body mass index (BMI), modified Medical Research Council (MMRC) dyspnea scale, the degree of co-morbidity as evaluated by the Charlson index and pulmonary function measurements, including pre-bronchodilator and post-bronchodilator spirometric values were assessed. Eastern Co-operative Oncology Group (ECOG) performance status was evaluated for 280 patients. Severe acute exacerbation of COPD (severe AECOPD) was an important outcome for COPD. The definition of a severe AECOPD was based on aggravated cough and dyspnea symptoms which needed hospitalization management.

Severe AECOPD were recorded by research assistants during regular clinical visits or by telephone contact (if patient missed the appointment) every 3 months after their enrollment in 279 patients. The study was approved by the Research Review Board of National Cheng Kung University Medical Center and all participants provided written informed consent.

Evaluation of COPD severity according to GOLD criteria by using pre- and post-bronchodilator FEV1

COPD severity was categorized with the FEV1 according to GOLD (1) criteria. Both post-and pre-bronchodilator FEV1 as a percentage of the predicted value were evaluated and classified for the GOLD criteria. The classification criteria for GOLD staging (1) from spirometry were as follows: Stage I (mild) percent predicted FEV1>80%, Stage II (moderate) >50% percent predicted FEV1 <80%, Stage III (severe) >30% percent predicted FEV1 <50% and Stage IV (very severe) percent predicted FEV1 <30%.

Primary outcome

Patients were observed prospectively for at least 1.5 years. Survival status was the primary outcome evaluated in this study. All patients were contacted during regular clinical visits, or by telephone interview (if they missed the appointment) every 3 months after their enrollment. Most patients who died during the period of study had been regularly followed up and had visited our hospital for treatment before their death; their date and cause of death were recorded and verified by our hospital records. For patients who did not die in our hospital, the date and cause of death were obtained by research assistants by telephone contact with their partners or family to confirm records from the mortality certification provided by physicians for the mortality register.

Statistical analysis

Continuous variables are presented as mean and SD. We used the fit model on the JMP software program (SAS Institute Inc., Cary, NC, USA) for the analysis. Nominal variables were compared using the χ2 test. Comparisons between groups were performed using analysis of variance. To determine independent predictors of mortality for pre- and post-bronchodilator percent predicted FEV1and correlations between pulmonary function variables and predictors of primary outcome (BMI, MMRC dyspnea scale, ECOG performance status and severe AECOPD); we used multivariate analysis after adjustment for age, gender and co-morbidities as measured by the Charlson index.

Age, BMI, MMRC scale, ECOG score, score for Charlson index and percent predicted FEV1 were included as continuous variables in the model, gender and severe AECOPD were included as a categorical variable. A difference with a p-value of <0.05 was accepted as significant. Survival plots for GOLD criteria by pre- and post-bronchodilator percent predicted FEV1 for classification of severity were drawn and analyzed using the Kaplan-Meier method.

Results

There were 300 patients in the study, of whom 283 were men (Table 1). The median survival from entry into the longitudinal study was 31 months (1–51 months), with 35 patients (11.7%) dying during follow-up (median survival 12 months versus 32 months for survivors); the causes of mortality were respiratory disease (20/35; 57.1%), malignancy (7/35; 20.0%), cardiovascular disease (3/35; 8.6%), suicide (1/35; 2.9%) and unknown causes (4/35; 11.4%).

Table 1.  Descriptive data for age, gender, spirometric values, BMI, MMRC dyspnea scale, ECOG performance status, Charlson co-morbidity score for the patients in the study showing mean and standard deviation

	Mean	SD
Age	71.9	10.8
Gender (male)	283/300 (94.3%)*
Pre-bronchodilator	59.5	21.1
FEV1 (% predicted)
Post-bronchodilator	63.4	21.2
FEV1 (% predicted)
BMI (Kg/m2)	23.6	4.1
MMRC dyspnea scale	1.8	0.9
ECOG performance status’ scale	1.1	0.8
Charlson co-morbidity score	2.4	1.8

FEV1 (% predicted): forced expiratory volume in one second (percentage of the predicted value), BMI: body mass index is the weight in kilograms divided by the square of the height in meters, MMRC: modified Medical Research Council dyspnea scale ranges from 0 (no dyspnea) to 4 (indicating that the patient is too breathless to leave home or becomes breathless when dressing or undressing), ECOG: Eastern Co-operative Oncology Group performance status ranges from 0 (fully active, without restriction) to 4 (completely disabled, totally confined to bed or chair). *Gender presented as ratio.

Univariate predictors of mortality were analyzed and their significance values are shown in Table 2. Spirometric values of FEV1, BMI, MMRC dyspnea score, ECOG performance status, Charlson index score and severe AECOPD were predictors of mortality. Multivariate analysis showed that the post-bronchodilator percent predicted FEV1 was a significant independent predictor of all cause and respiratory cause mortality but pre-bronchodilator percent predicted FEV1 was not (p = 0.008 vs 0.126 for all cause mortality, p = 0.016 vs 0.302 for respiratory mortality), and it was more strongly correlated with all the other predictors of mortality (BMI, MMRC dyspnea score, ECOG performance status and severe AECOPD) than the pre-bronchodilator percent predicted FEV1 after adjusting for the influence of other variables (age, gender and co-morbidities) (Table 3).

Table 2.  Univariate predictors of all cause mortality

	Survival	Mortality	P values
Age	71.3 ± 11.2	76.5 ± 5.7	0.007
Gender(male)	250/265(94.3%)	33/35(94.3%)	0.990
Pre-bronchodilator
FEV1 (% predicted)	60.5 ± 21.2	51.5 ± 18.3	0.018
Post-bronchodilator
FEV1 (% predicted)	64.7 ± 21.0	53.7 ± 19.6	0.005
BMI (Kg/m2)	23.9 ± 4.0	21.2 ± 4.3	<0.001
MMRC dyspnea scale	1.7 ± 0.9	2.6 ± 1.0	<0.001
ECOG performance status’ scale	1.0 ± 0.7	1.7 ± 1.0	<0.001
Charlson co-morbidity score	2.3 ± 1.6	3.3 ± 2.3	0.002
Severe AECOPD	26/255(10.2%)	8/24(33.3%)	0.004

FEV1 (% predicted): forced expiratory volume in one second (percentage of the predicted value), BMI: body mass index is the weight in kilograms divided by the square of the height in meters, MMRC: modified Medical Research Council dyspnea scale ranges from 0 (no dyspnea) to 4 (indicating that the patient is too breathless to leave home or becomes breathless when dressing or undressing), ECOG: Eastern Co-operative Oncology Group performance status ranges from 0(fully active, without restriction) to 4 (completely disabled, totally confined to bed or chair). AECOPD: acute exacerbation of COPD.

Table 3.  Multivariate analysis for pre and post-bronchodilator FEV1 associated with mortality, BMI, MMRC dyspnea scale, ECOG performance scale, and severe AECOPD adjusted by age, gender and Charlson co-morbidity score, presented as numbers of regression coefficient (p values)

	All cause mortality	Respiratory mortality	BMI	MMRC dyspnea scale	ECOG performance status’ scale	Severe AECOPD
Pre-bronchodilator FEV1 (% predicted)	0.05 (0.126)	0.04 (0.302)	-0.05 (0.233)	0.01 (0.335)	0.01 (0.151)	0.04 (0.293)
Post-bronchodilator FEV1 (% predicted)	-0.08 (0.008)	-0.10 (0.016)	0.09 (0.020)	-0.03 (<0.001)	-0.02 (<0.001)	-0.08 (0.039)

The GOLD severity classifications evaluated by pre- and post-bronchodilator percent predicted FEV1 were compared for prediction of mortality. The Kaplan-Meier analysis of mortality (Figure 1) showed that each quartile increase in the GOLD staging (pre- and post-bronchodilator percent predicted FEV1) was associated with increased mortality. However, the discrimination ability of the GOLD classification by post-bronchodilator percent predicted FEV1 (p = 0.009) was higher than that by pre- bronchodilator percent predicted FEV1 (p = 0.131) according to the log-rank test.

Figure 1: Kaplan-Meier survival curves for the four quartiles of the GOLD staging with post-bronchodilator percent predicted FEV1 (Panel A), and GOLD staging with pre-bronchodilator percent predicted FEV1 (Panel B). Survival differed significantly among the 4 stages for the GOLD with post-bronchodilator percent predicted FEV1 (p = 0.009), but not for the GOLD staging with pre-bronchodilator percent predicted FEV1 different staging criteria (p = 0.131) by the log-rank test.

Discussion

FEV1 has long been used as the principal variable to diagnose COPD, measure its severity, and predict its mortality and the response to different treatments (1–11, 14, and 15). Our study supports previous findings that dyspnea (16 and 17), BMI (8, 9, 11, 18), the presence of co-morbidity (19), ECOG performance status (20), severe AECOPD (21) and FEV1 (2, 8–11) are significant predictors of COPD mortality.

The post-bronchodilator percent predicted FEV1 value was the independent predictor of mortality and associated with important phenotypes in the 300 patients with COPD in this study while the pre-bronchodilator percent predicted FEV1 value was not. Meanwhile, the post-bronchodilator percent predicted FEV1 value was more accurate in predicting the risk of death than the pre-bronchodilator percent predicted FEV1 value according the GOLD severity classification.

The GOLD guidelines for diagnosis and severity, which have been updated yearly since 2001, have become the gold standard in clinical practice (1). GOLD strongly recommends post-bronchodilator spirometric values to define COPD and measure its severity (1). The use of post-bronchodilator values is essential, mainly because the airflow limitation in COPD is not fully reversible and the prevalence of COPD is overestimated when using pre-bronchodilator values (22, 23).

However, in contrast to the GOLD recommendations, the usefulness of pre-bronchodilator spirometry to predict mortality and classify disease severity has long been established (24) and a number of studies on COPD have used the GOLD criteria with pre-bronchodilator spirometry values (25, 26, and 27). Therefore, it is not unexpected that the application of GOLD criteria does not seem to be uniform and is not really the gold standard among researchers in COPD, as the evidence base for comparison of pre-bronchodilator and post-bronchodilator FEV1 in severity classification has not yet been established.

The effect of replacement of the pre-bronchodilator with the post-bronchodilator FEV1 in mortality prediction for COPD patients, as in the GOLD recommendations, is unknown. Meanwhile, the replacement of the pre-bronchodilator with the post-bronchodilator FEV1 in measurement of the severity of COPD by GOLD criteria has not been evidence-based (28). However, as far as we know, no one has compared the GOLD severity classification using post- and pre- bronchodilator FEV1.

The limitations of the present study were the relatively small number of recruited and including relatively old-aged population. Using the fixed FEV1/FVC ratio to define obstructive spirometry is potentially over-diagnosis for COPD in milder patients who are elderly as the normal process of aging-related lung function change. Although our study patients are relatively old, most of our patients were moderate to severe and very severe stages according to GOLD severity classification (224/300; 72.8%).

Besides, all of our patients were diagnosed as having COPD not only according to their pulmonary function test, but also had typical clinical symptoms and signs of COPD to avoid potential over-diagnosis. Nonetheless, a study of large group subjects including various aged population may be needed in the future

In conclusion, we found that the post-bronchodilator percent predicted FEV1 was better than the pre-bronchodilator percent predicted FEV1 in the evaluation of the severity of COPD. This study clarifies the importance and provides evidence to support the use of the post-bronchodilator FEV1 as recommended by GOLD in the evaluation of the severity of disease among patients with COPD.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

This study was supported by grants NSC 97-2314-B-006-056 from the National Science Council and NCKUH 9903016 from National Cheng Kung University Hospital. We are grateful to Jia-Ling Wu and Dr. Liang-Yi Wang for providing the statistical consulting services from the Biostatistics Consulting Center, National Cheng Kung University Hospital. All authors have no financial interests related to the material in the manuscript.