Abstract
Eleven years after Lung Health Study (LHS) entry, we performed spirometry in 77.4% of surviving participants who enrolled in a long-term follow-up study. Those not enrolling tended to be younger male heavy smokers who continued to smoke during the LHS. Their initial LHS lung function, after adjustment for these factors, did not differ from that of enrollees. Smoking habits by original LHS treatment groups (smoking intervention vs. usual care) tended to converge, but 93% of participants who were abstinent throughout the LHS were still abstinent at 11 years. Differences in lung function between treatment groups persisted; smoking intervention participants had less decline in FEV1 than usual care participants. Men who quit at the beginning of the LHS had an FEV1 rate of decline of 30.2 ml/year, whereas women who quit declined at 21.5 ml/year. Men continuing to smoke throughout the 11 years declined by 66.1 ml/year, and women continuing to smoke declined by 54.2 ml/year. When decline in FEV1 was expressed as a percentage of predicted normal value, no significant sex-based difference was apparent among continuing smokers. At 11 years, 38% of continuing smokers had an FEV1 less than 60% of the predicted normal value compared with 10% of sustained quitters.
The original Lung Health Study (LHS 1) was a randomized clinical trial of smoking cessation and regular administration of an inhaled bronchodilator (ipratropium bromide) in 5,887 middle-aged smokers (35–60 years old at study entry) who had airway obstruction, but who did not regard themselves as having lung disease, and who did not have other serious illnesses. The main outcome variables were annual change in lung function in the form of the FEV1, and morbidity and mortality (1). Intent-to-treat analysis showed that smoking cessation reduced the rate of decline of lung function, whereas inhaled bronchodilator did not (2).
Follow-up rates in LHS 1 were unusually high, with more than 90% of participants attending each of five annual visits for assessment of pulmonary function (2). Further, at the end of LHS 1, 5,003 participants were enrolled in a lung cancer substudy designed to ascertain the incidence of cancer. These participants were contacted at 6-month intervals, usually by telephone, and questioned in regard to their health and smoking habits. This follow-up was also successful, with direct contact rates exceeding 94% at all 6-month intervals. Because of this success, an extension of LHS 1 (LHS 3) was thought feasible, asking the original participants to return to the original clinical centers for reassessment approximately 11 years after their enrollment. This report details the results of pulmonary function measurements as related to smoking habits of people who participated in LHS 3. The objectives of LHS 3 were as follows: to ascertain whether differences in lung function between randomly assigned treatment groups persisted, to assess whether differences in smoking habit persist between treatment groups, and to determine whether the profound impact of smoking cessation on lung function decline noted in LHS 1 persisted or increased.
Protocols were approved by the institutional review board for human studies at each clinical center, and written informed consent was obtained from each participant.
All LHS 1 participants who were not known to be deceased were deemed eligible for LHS 3. Those who could be contacted were asked to return for spirometry and to answer smoking questionnaires. Remote participants were visited to obtain data. Some participants refused spirometry, and insofar as lung function is concerned, this report is confined to those who did not.
Questionnaires included the same ones administered as part of LHS 1, including a modified American Thoracic Society–Division of Lung Diseases questionnaire (1). A detailed smoking history was obtained, and smoking status was checked by measuring expired carbon monoxide with a Vitalograph EC50 (Vitalograph, Buckingham, UK), as in LHS 1. Results of 10 ppm or higher were considered indicative of smoking.
Spirometry was performed with a rolling seal spirometer, exactly as it had been in LHS 1 (3). The same spirometers were used (Spirotech 500; Spirotech, Atlanta, GA), and the same quality control program. Measurements of FEV1 and FVC were made before and at least 20 minutes after two puffs (200 μg) of albuterol from a metered dosed inhaler. The largest single FEV1 and FVC were reported, and were converted to percentages of the predicted normal value by using the formulas of Crapo and coworkers (4).
Results were analyzed according to the original LHS 1 treatment assignment: usual care (UC) and smoking intervention (SI). The latter was a combination of groups that were assigned either to active bronchodilator or placebo therapy; both received the smoking cessation program, and were similar, including rates of smoking cessation. Participants were also divided into three groups based on smoking history. Sustained quitters (SQs) were biochemically validated ex-smokers at each of the follow-up visits of LHS 1, who gave a history of abstinence (no month with as much as one cigarette per day) between the end of LHS 1 and enrollment in LHS 3, and who also had a carbon monoxide reading at the LHS 3 visit that was less than 10 ppm. Continuing smokers (CSs) were those who reported smoking at all scheduled follow-up visits, and throughout the time between the end of LHS 1 and LHS 3. Intermittent quitters (IQs) were smoking at some but not all of their LHS 1 and LHS 3 visits, or in the interval of time between the two studies. Because of uncertainties regarding dose of cigarettes, the IQ group was not considered in some analyses.
Comparisons between LHS 3 participants and nonparticipants were performed using t tests for quantitative variables, and χ2 tests for categorical variables. Comparisons adjusted for other covariates were based on analysis of covariance (for quantitative variables) or logistic regression (for dichotomous variables). Comparisons of changes in lung function variables between the SI and UC groups were based on t tests.
The average interval between the baseline visit for LHS 1 and the LHS 3 visit was 10.99 years (SD, 0.63) for SI participants and 11.03 years (SD, 0.62) for UC participants.
Of the original 5,887 participants in LHS 1, 5,413 were eligible for LHS 3 in that they were not known to be dead. Of those eligible, 4,517 (83.4%) were enrolled in LHS 3, whereas 896 did not enter. Enrollment ranged from 77.1 to 91.0% at the various clinical centers. Of those enrolled, 4,194, or 92.8%, underwent spirometry testing. As indicated in Table 1
LHS 3 | Refused | p Value | |
|---|---|---|---|
| Number | 4,517 | 896 | |
| SI, % | 67.3 | 64.6 | 0.119 |
| Age as of LHS 3 | 61.3 (6.8) | 59.7 (6.8) | < 0.001 |
| Sex, % male | 61.9 | 66.0 | 0.021 |
| Cigarettes/d, baseline LHS 1 | 30.9 (12.7) | 32.7 (13.2) | < 0.001 |
| Smoking status at end of LHS 1 | |||
| Sustained quitter, % | 18.8 | 6.6 | < 0.001 |
| Intermittent quitter, % | 29.0 | 21.5 | < 0.001 |
| Continuing smoker, % | 52.2 | 71.9 | < 0.001 |
| Attended last LHS 1 visit, % | 99.2 | 85.6 | 0.001 |
| Symptoms at end of LHS 1, % | |||
| Cough | 32.6 | 39.7 | 0.001 |
| Phlegm | 33.1 | 39.2 | 0.001 |
| Wheeze | 59.5 | 62.9 | 0.053 |
| Dyspnea | 33.6 | 32.5 | 0.532 |
| FEV1 % predicted post-BD, baseline LHS 1 | 78.4 | 78.4 | 0.966 |
| FEV1 % predicted post-BD, end of LHS 1 | 75.3 | 74.9 | 0.362 |
| BD response (%), baseline LHS 1 | 4.3 | 4.3 | 0.844 |
| Change in FEV1% predicted/yr in LHS 1 | −0.62 | −0.81 | 0.005 |
| Methacholine reactivity | |||
| Reaction to ⩽ 5 mg/ml, % | 33.6 | 31.9 | 0.334 |
| No reaction to 25 mg/ml, % | 28.2 | 30.0 | 0.414 |
Table 1 does not show all comparisons between enrollees and those who did not enter LHS 3. The nonenrollees were significantly less likely to have been married at the end of LHS 1 than LHS 3 enrollees, but differences in employment rates, alcohol consumption, and years of education were not significant. Doctor visits or days in bed due to lower respiratory tract illnesses did not differ significantly between these groups. LHS 3 entrants were more likely to have been hospitalized during LHS 1 than those who did not enter, although there were no significant differences in hospitalizations for respiratory illnesses, coronary artery disease, or other cardiovascular disease, the most commonly encountered individual causes of hospitalization. Finally, there were no differences in body mass index or blood pressure measured at the end of LHS 1 between the two groups.
At the LHS 3 visit, 16.7% of the participants were sustained quitters, 57.4% were intermittent smokers, and 25.9% had smoked continuously since the beginning of LHS 1. There were major differences between treatment groups in smoking habit (p = 0.001), with 21.9% of the SI group being sustained quitters compared with 6.0% of the UC group, and 23.4% of the SI group being continuing smokers, in contrast to 31.3% of the UC group. On the other hand, changes in smoking status between LHS 1 and LHS 3 were not greatly different between groups (Table 2)
% Quit (CO Validated) at LHS 3 | |||||
|---|---|---|---|---|---|
| Status at End of LHS 1 | Total
(n = 4,517) | SI
(n = 3,040) | UC
(n = 1,477) | ||
| Sustained quitter | 92.9 | 92.7 | 94.7 | ||
| Intermittent quitter | |||||
| Not smoking | 79.9 | 76.2 | 87.3 | ||
| Smoking | 43.3 | 42.8 | 45.1 | ||
| Continuous smoker | 24.1 | 22.4 | 26.3 | ||
Figure 1. Loss of lung function among LHS 3 enrollees over the 11 years of study of the SI group (closed symbols) and the UC group (open symbols). Average values of postbronchodilator FEV1 are shown, expressed in absolute terms in (A) and as a percentage of the predicted normal value in (B).
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Figure 2. Loss of lung function over the years of study among sustained quitters (open symbols), continuing smokers (closed symbols), and intermittent smokers (gray symbols). Average values of postbronchodilator FEV1 are shown, expressed in absolute terms in (A) and as a percentage of the predicted normal value in (B).
[More] [Minimize]SI Participants | UC Participants | ||||||
|---|---|---|---|---|---|---|---|
| Status at LHS 3 | n | FEV1/ml/yr | n | FEV1/ml/yr | p Value | ||
| Sustained quitter | 637 | −26.7 (26.5) | 85 | −30.3 (26.5) | 0.250 | ||
| Intermittent quitter | 1,521 | −47.5 (31.7) | 848 | −50.0 (34.5) | 0.079 | ||
| Continuing smoker | 630 | −60.0 (33.7) | 424 | −63.8 (32.2) | 0.070 | ||
| FEV1 % pred/yr | FEV1 % pred/yr | ||||||
| Sustained quitter | 637 | −0.23 (1.03) | 85 | −0.40 (1.11) | 0.109 | ||
| Intermittent quitter | 1,521 | −0.91 (1.21) | 848 | −1.02 (1.28) | 0.041 | ||
| Continuing smoker | 630 | −1.29 (1.16) | 424 | −1.44 (1.26) | 0.043 | ||
Absolute rates of decline of FEV1 differed between men and women. Female SQs lost an average of 21.5 ml/year (SEM, 1.2), whereas male SQs lost an average of 30.2 ml/year (SEM, 1.4). In the CS category, women lost an average of 54.3 ml/year (SEM, 1.3), whereas men lost an average of 66.1 ml/year (SEM, 1.4). When expressed as percentages of the predicted normal value, declines were still less for females among SQs but similar between women and men in the CS category. Among SQ participants, women averaged a loss of 0.11%/year (SEM, 0.06), which was significantly (p < 0.01) less than for the men, who lost an average of 0.31%/year (SEM, 0.05). In the CS category, women averaged a decline of 1.41%/year (SEM, 0.06), and men averaged a decline of 1.31%/year (SEM, 0.04), figures that were not significantly different.
The main findings of this study were that differences in smoking habit established during the first year of LHS 1 were remarkably stable, so that there were significant differences in lung function between randomly assigned treatment groups after 11 years. Further, differences in lung function between participants who quit smoking and those who did not increased progressively over 11 years, resulting in substantial differences in the prevalence of FEV1 values that are associated with disabling illness.
The original Lung Health Study was remarkable for the completeness of its follow-up, and LHS 3 was a similar success; of the original participants who were not known to be dead, more than 77% were enrolled and underwent spirometry 11 years after study entry. There were differences between those who were enrolled in LHS 3 and those who were not (Table 1), and these differences were not surprising. People who did not enter LHS 3 tended to be younger, male, and single at the end of LHS 1. They had been heavier smokers on study entry, were less likely to have quit, and had been less compliant in terms of follow-up than those who were enrolled. Although significant, these differences were relatively small. Although LHS 3 enrollees had less cough and phlegm at the end of LHS 1 than did those who did not enter, the differences were accounted for by differences in smoking habits, and there were no differences in wheeze, dyspnea, body mass index, or blood pressure. During LHS 1, people who did not enroll in LHS 3 lost lung function more rapidly than those who entered, but not more rapidly than enrollees of the same age, sex, and smoking habit. We are unable to explain the increased tendency of LHS 3 participants to have been hospitalized during LHS 1, but this may have related to their greater compliance and concern regarding their health status, indicated by their higher rate of quitting smoking. In summary, LHS 3 participants were a biased sample of the original LHS 1 population, but the biases among surviving participants were relatively minor, and more than 80% of living LHS 1 participants was enrolled.
Cross-sectional smoking quit rates tended to converge when treatment groups were compared (see Figure E1 in the online data supplement); quitting was more common in the UC group than in the SI group in the interval between LHS 1 and LHS 3. This tendency has been noted in other follow-up studies of clinical trials involving smoking cessation (5), and indeed a similar trend was observed during LHS 1 in that cross-sectional quit rates in the UC group after the first year increased faster than in the SI group (2). This was presumably due to the much higher quit rate being obtained in the SI group at the onset of LHS 1, so that relapse occurred in this group more often than in the UC group. However, the convergence of cross-sectional quit rates was in some ways misleading, in that changes in smoking habit occurred largely among intermittent smokers and not among either sustained quitters or continuing smokers (Table 2). Indeed, some 93% of those who quit for the 5 years of LHS 1 were able to maintain abstinence in the subsequent 6 years. Five years of abstinence would seem to be a “cure” of the smoking habit.
The stability of smoking habit, especially among those who quit at the onset of LHS 1, was the major reason that differences in lung function between the SI and UC groups established during LHS 1 persisted essentially unchanged for the additional 6 years between LHS 1 and LHS 3. This is supported by the data of Table 3, which shows that SI–UC differences in rate of decline of FEV1 were small in groups with similar smoking histories. The major SI–UC difference was that the SI group was composed of a larger fraction of SQs and a smaller fraction of CSs than was the UC group. When lung function was examined as a function of smoking history, LHS 3 results were essentially a linear extrapolation of the LHS 1 data, showing a continuing sharp divergence between the SQ and CS groups.
The cumulative impacts of smoking cessation are illustrated in Figure 3
Figure 3. Distribution of values of postbronchodilator FEV1 among enrollees in LHS 3 who were sustained quitters and continuing smokers. The ordinate represents the percentage of either sustained quitters or continuing smokers; the abscissa shows categories of FEV1, expressed as a percentage of the predicted normal value.
[More] [Minimize]The LHS was one of a limited number of studies with a group of female smokers large enough to examine sex differences in the effects of smoking on lung function. Rates of decline of FEV1 were assessed in terms of change expressed as a percentage of the predicted normal value, which should account for sex differences in stature and lung size. There was a small sex difference among SQs favoring the women, but none among CSs, apparently indicating that the effects of smoking and smoking cessation were similar for the two sexes. Two previous cross-sectional studies of smokers in Beijing and Copenhagen (6, 7) indicated that lung function in women might be more affected by smoking than in men, but longitudinal data from the Tucson group (8) showed that women smokers lost lung function more slowly than did men, and an Australian longitudinal study showed a similar rate of loss between the sexes (9). At LHS 3 enrollment, male continuing smokers consumed 25.2 cigarettes per day as compared with 22.1 per day by female continuing smokers. It could therefore be argued that the women were slightly more sensitive than the men, but the important point is probably that among people with mild to moderate airway obstruction, loss of lung function in continuing smokers is similar between the sexes.
There have been many other studies comparing decline in FEV1 between smokers and ex-smokers (8–19). All found, like the LHS, that smoking cessation was associated with a rate of decline that did not differ from that noted in never smokers and was considerably less than that of continuing smokers. Quantitative comparisons among studies are difficult because of varying age of the subjects and differing classifications of smoking habit. Nevertheless, for ex-smokers, our SQ group, figures of 21.5 ml/year for women and 30.2 ml/year for men agree well with those of most others (8–11, 14, 15). However, the mean rate of loss observed in our female continuing smokers was substantially higher at 54.2 ml/year than in other studies of women (8, 9, 14, 15, 18, 19), and the mean decline of 66.1 ml/year among our male continuing smokers was higher than most comparable data (8–10, 13, 15, 19), and most of the studies that showed rates of decline similar to ours among male smokers also had relatively high rates of decline among nonsmokers (12, 16–18). Thus, loss of lung function among the continuing smokers of the LHS was more rapid compared with most previous observations. This is likely due to the original selection criteria for the LHS, which sought to identify smokers at high risk for the development of clinical chronic obstructive pulmonary disease and therefore recruited people with evidence of airway obstruction, defined as having FEV1/FVC less than 0.70. Burrows and coworkers (20) had previously found that obstruction defined in this way was a predictor of rapid decline in a group of 13 men, and argued that spirometry might identify high-risk smokers. The LHS data support this argument. The data also indicate the crucial and sustained benefit of smoking cessation by high-risk smokers.
Principal investigators and senior staff of the clinical and coordinating centers, the NHLBI, and members of the Data Monitoring Board and the Morbidity and Mortality Review Board:
Case Western Reserve University, Cleveland, OH: M. D. Altose, M.D. (Principal Investigator), S. Redline, M.D. (Co-Principal Investigator), C. D. Deitz, Ph.D.; Henry Ford Hospital, Detroit, MI: M. S. Eichenhorn, M.D. (Principal Investigator), W. A. Conway, M.D. (Co-Principal Investigator), R. L. Jentons, M.A., K. Braden; Johns Hopkins University School of Medicine, Baltimore, MD: R. A. Wise, M.D. (Principal Investigator), S. Permutt, M.D. (Co-Principal Investigator), C. S. Rand, Ph.D. (Co-Principal Investigator), M. Daniel, V. Santopietro, K. A. Schiller; Mayo Clinic, Rochester, MN: P. D. Scanlon, M.D. (Principal Investigator), J. P. Utz, M.D. (Co-Principal Investigator), G. M. Caron, K. S. Mieras, L. Walters; Oregon Health Sciences University, Portland: A. S. Buist, M.D. (Principal Investigator), V. J. Bortz, D. J. Youtsey; University of Alabama at Birmingham: W. C. Bailey, M.D. (Principal Investigator), C. M. Brooks, Ed.D. (Co-Principal Investigator), L. B. Gerald, Ph.D., M.S.P.H. (Co-Principal Investigator), S. Erwin, D. Gardner, M. Johnson, J. Mangan; University of California, Los Angeles: D. P. Tashkin, M.D. (Principal Investigator), A. H. Coulson, Ph.D. (Co-Principal Investigator), E. C. Kleerup, M.D. (Co-Principal Investigator), I. P. Zuniga; University of Manitoba, Winnipeg: N. R. Anthonisen, M.D. (Principal Investigator), J. Manfreda, M.D. (Co-Principal Investigator), R. P. Murray, Ph.D. (Co-Principal Investigator), S. C. Rempel-Rossum; University of Minnesota Coordinating Center, Minneapolis: J. E. Connett, Ph.D. (Principal Investigator), P. G. Lindgren, M.S., M. A. Skeans, M.S., H. T. Voelker; University of Pittsburgh, Pittsburgh, PA: R. M. Rogers, M.D. (Principal Investigator), G. R. Owens, M.D. (Co-Principal Investigator), M. E. Pusateri; University of Utah, Salt Lake City: R. E. Kanner, M.D. (Principal Investigator), G. M. Villegas, A. Sharp; Safety and Data Monitoring Board: C. Furberg, M.D., Ph.D., J. R. Landis, Ph.D., E. Mauger, Ph.D., J. R. Maurer, M.D., Y. Phillips, M.D., J. K. Stoller, M.D., I. Tager, M.D., A. Thomas, Jr., M.D.; Morbidity and Mortality Review Board: T. Cuddy, M.D., R. Fontana, M.D., R. E. Hyatt, M.D., C. T. Lambrew, M.D., B. A. Mason, M.D., D. Mintzer, M.D., R. Wray, M.D.; National Heart, Lung, and Blood Institute, Bethesda, MD: S. S. Hurd, Ph.D. (Former Director, Division of Lung Diseases), J. P. Kiley, Ph.D. (Director, Division of Lung Diseases), G. Weinmann, M.D. (Project Officer, Director, Airway Biology and Disease Program), T. Croxton, Ph.D. (Project Officer), M. C. Wu, Ph.D. (Division of Epidemiology and Clinical Applications).
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