Chronic obstructive pulmonary disease (COPD) has been the fourth leading cause of death in the United
States since at least 1978 (Anthonisen NR, et al, 1994). It is an insidious disease, with a long course of
considerable deterioration of pulmonary function before symptoms develop.
To investigate whether a smoking intervention program and the use of a inhaled bronchodilator could
reduce the rate of decline in pulmonary function among smokers aged 35 to 60 years who have mild
obstructive pulmonary disease, the Lung Health Study (LHS1) was conducted in ten clinical centers
located in the North America from October 1986 to April 1994 as a randomized clinical trial with a total
of 5887 participants. Among them, approximately 63 percent were men. The emphasis of the smoking
intervention program was placed on behavior modification techniques. Nicotine replacement therapy was
used aggressively in the form of nicotine gum provided at no cost to the participants. An intensive
maintenance program was also offered for those who quit (1).
The previous study results showed that the smoking intervention program was successful at slowing down
the rate of decline of pulmonary function, but the use of active bronchodilator did not make much
difference (1). The effect of baseline smoking rate on lung function related to smoking cessation has been
explored and it was reported that the heaviest smokers among continuous smokers had a greater decline
than light smokers, and that the LHS intervention program resulted in a high rate of sustained smoking
cessation among heavy smokers (2). However, few have commented on differences between heavy
smokers and light smokers in the rate of pulmonary function change as they relate to the smoking
intervention program directly.
The present analysis aims to assess the effectiveness of the LHS smoking intervention program in
pulmonary function changes as they related to the smoking rate at baseline. However, from the previous
study results (3) and the preliminary analysis(not shown), gender difference was suspected to
substantially alter the effect of the smoking rate on pulmonary function changes. One of the possible
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explanations is that males have shown much higher the smoking rate than females. Since gender
difference is not the primary concern of this paper, the analysis focuses only on males.
METHODS
The first 318 male participants’ data over a 5-year period from the original “Lung Health Study I” were
obtained. The change in pulmonary function was measured as the cumulative percent change in
postbronchodilator forced expiratory volume in 1 second (FEV1) from baseline to each annual follow-up
visit. The intent-to-treat (treatment) group was formulated into two levels according to their randomized
assignments: smoking intervention (SI), regardless of the use of active or placebo bronchodilator inhalers
in the original study, or usual care (UC). The participants were divided into two levels of smoking-rate,
heavy or light, according to the median (30 cigs/day) of the participants’ self-reported cigarettes per day
smoked at baseline. This grouping criterion is also consistent with other lung health related studies.
In order to analyze the relationship between the baseline smoking rate and the smoking status at the end
of study, smoking status at the study’s final year was categorized as following: sustained quitters (SQ),
intermittent quitters (IQ), and continuous smokers (CS). Participants who did not attend follow-up visits
were assumed to be smokers.
Descriptive statistics were based on counts and percents (for categorical variables) or means and standard
deviations (for quantitative variables). Chi-square test statistics were used to test homogeneity of changes
in smoking status between the two smoking-rate groups within each treatment group. For the continuous
data such as age, F tests were used to test significance of differences among the four combination groups.
For analysis of the relationships between the cumulative percent change in FEV1 and the factors of
interest, a four-way mixed effect analysis of variance (repeated measures model) using PROC MIXED in
the SAS package was used. Factor effects were examined by F test statistics. Time trend in changes in
FEV1 was tested by a polynomial contrast and likelihood ratio test statistics. The annual decline rates of
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FEV1 were estimated using contrasts and presented along with ±2 standard errors. Residual diagnostics
were carried out to assess model assumptions. All analyses were carried out in the SAS Version 8.0 (SAS
Institute, Inc., Cary, NC). Graphics were made in the R Version 1.7.1 (The R Development Core Team,
2003). All tables and figures are presented in the Appendix.
RESULTS
Among 318 participants, 40 participants did not attend the final follow-up visit. A total of 237 missing
values of FEV1 were observed over the 5 year period (14.9%). Detailed analysis for the cause of missing
observations was not carried out.
Baseline characteristics of 318 male participants are shown in table1. The four groups were similar in
weight and baseline FEV1 at the time of entry into the study. However, averaged across the two treatment
groups, the heavy smokers, on average, were younger (50.24±0.52 yrs.) than the light smokers
(52.08±0.52 yrs.), and the difference was significant (F(1,314)=9.36, p-value=0.002).
The cumulative percent change in FEV1 from baseline to the time of annual visits over the 5-year period
is summarized in table 2, classified by the four combination groups. Heavy smokers who participated in
the program had the lowest cumulative percent decline in every year. The effectiveness of the LHS
smoking intervention program on cumulative percent change in FEV1 was significantly different by
smoking rate (F(1,301)=13.81, p-value<0.01). However, averaged across treatment groups, the effect of
the smoking rate was not significant (F(1,301)=0.60, p-value>0.4).
Overall, there was no evidence that the decline of FEV1 occurred in quadratic pattern across the 5 years
(LRT(4)=5.7, p-value>0.22). Figure 1 indicates a linear trend of decline in FEV1 for each group along the
years, and substantial difference in the decline rate between the two treatment groups. The decline rate
(percent per year) was estimated as -0.43±1.62 for the heavy smokers in the program; -1.70±1.14 for the
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light smokers in the program; -2.69±1.00 for the light smokers under the usual care. The most rapid
decline was observed among the heavy smokers under the usual care (-3.07±1.44% per year).
As shown in table 3, slightly more sustained quitters and slightly fewer intermittent quitters were
observed for the heavy smokers compared to the light smokers in both treatment groups. However, the
distribution of smoking status at the study’s end was not significantly different between baseline
smoking-rate groups in either treatment group (both p-values > 0.1). Among sustained quitters, on
average, the participants in the program started quitting in earlier years than the participants under the
usual care (0.92±0.34 vs. 2.25±0.77). However, no substantial difference between former heavy smokers
and former light smokers was observed (1.10±0.45 vs.1.23±0.48).
The cumulative percent changes in weight and in the smoking rate, from baseline to the final year of the
study, were explored to see if they were related to the findings. No substantial differences were observed
between smoking-rate groups either in the percent change in weight (5.22±1.32 vs. 5.19±1.24) or in the
percent change in smoking rate (-60.24 ±6.52 vs. -54.82±7.61).
Since a significant age difference was observed between the two smoking-rate groups at baseline and
since FEV1 is known to be associated with age, the age group with two levels, young and old, divided by
the median of age at the randomization time (51 years of age) was added to the model and the
significance of its association with the cumulative percent change in FEV1 in the presence of the two
primary factors was tested. No significant effects were found for either main effect (F(1, 297)=1.17, pvalue=0.28) or interaction effects (all p-value > 0.08).
Independence between subjects and the compound symmetry of variance-covariance matrix were
assumed. Checked by summary statistics and diagnostic plots (not shown), other repeated measures
model assumptions, normality and common variance, were reasonably satisfied.
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DISCUSSION
Although distribution of smoking status at the study end was not significantly different between the
baseline heavy smokers and the light smokers among male participants in the LHS smoking intervention
program, the heavy smokers achieved a larger reduction in the cumulative percent decline of FEV1 unlike
what we observed in the participants under the usual care. However, it was not true for females.
Preliminary analysis (not shown) indicated that, for females, the effectiveness of smoking intervention
program on the cumulative percent change in FEV1 was more likely related to age differences rather than
baseline smoking rate. Among males, why heavy smokers had more benefit from the LHS smoking
intervention program is still unanswered. One possible explanation is that participants showed similar
FEV1 at baseline despite of different rates of smoking, so that the difference might be related to airway
hyper-responsiveness (2).
This analysis has several shortcomings. First, it was a post-hoc analysis of clinical trial data. Second, the
participants in lung health study were recruited in voluntary bases. The generalization of results would not
be appropriate without further investigation. The evaluated smoking intervention program was specific to
the one used in the Lung Health Study. The quality and length of smoking intervention program would
substantially alter the results. In addition, there are questions on the reliability of how primary outcome
and smoking rate were measured. The percent FEV1 predicted for other risk factors such as age and
gender would be a more appropriate outcome measure rather than raw FEV1. The smoking rate could be
biased since it was based on the self-report.
In summary, greater benefit of the LHS smoking intervention program on reducing the decline of
pulmonary function was observed among male heavy smokers. The result is promising that an intensive
and effectively organized smoking intervention program could help male heavy smokers prevent or delay
the advance of severe chronic obstructive pulmonary diseases.
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Reference:
1. Anthonisen NR, Connett JE, Kiley JP et al. Effects of smoking intervention and the use of an inhaled
anticholinergic bronchodilator on the rate of decline of FEV1: The Lung Health Study. JAMA 1994,
272(19):1497-1505
2. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS, and Tashkin DP, for the Lung
Health Study Research Group. Smoking cessation and lung function in mild-to-moderate COPD: The
Lung Health Study. Am J Respir Crit Care Med 2000, 161:381-390.
3. Connett JE, Murray RP, Buist AS, Wise RA, Bailey WC, Lindgren PG, Owens GR, for the Lung
Health Study Research Group. Changes in smokeing status affect women more than men: Results of
the Lung Health Study. Am J Epidemiol 2003, 157:973-797.
4. Bjornson W, Rand C, Connett JE, Lindgren P, Nides M, Pope F, Buist A, Hoppe Ryan C, O'Hara P,
for the Lung Health Study Research Group. Gender differences in smoking cessation after 3 years in
the Lung Health Study. Am J Public Health 1995, 85:223-230.
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