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EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
0025-7125/96 $0.00
OBSTRUCTIVE LUNG DISEASES, PART I
+
.20
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE A Review of the Lung Health Study Results Richard E. Kanner, MD, for the Lung Health Study Research Group
In 1993, there were an estimated 46 million adult smokers in the United States, representing approximately 25% of the adult population..’ About 15% of one-pack-per-day and 25”/0of two-pack-per-day cigarette smokers go on to develop chronic obstructive pulmonary disease (COPD) if they continue their habit.’ In 1984, the Surgeon General concluded that “cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women.’”h For these reasons, the Lung Division of the National Heart, Lung and Blood Institute organized the Lung Health Study (LHS) to test methods of preventing the debilitating effects of COPD. This article summarizes the medical findings of interest to physicians that have thus far been reported. STUDY DESIGN4
The LHS was a prospective, randomized, multicenter clinical trial designed to: Supported by Contract N01-HR-46014 from the Division of Lung Diseases of the National Heart, Lung and Blood Institute.
From the Division of Respiratory, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah ~~
~
MEDICAL CLINICS OF NORTH AMERICA VOLUME 80 * NUMBER 3 * MAY 1996
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1. Determine whether a program combining smoking interventior and the regular use of a bronchodilator can slow the annua decline in lung function (FEV,) in persons at high risk for COPD 2. Estimate the effects, if any, of bronchodilator therapy, over anc above the effects of smoking intervention, on lung function decline.
Secondary objectives included: 1. Assessment of the effectiveness of the intervention program in producing the desired behavioral changes (i.e., smoking cessation and self-administration of inhalers). 2. Determination of whether the intervention program can reduce the incidence of pulmonary morbidity. 3. Determination of whether airway responsiveness is an important determinant of long-term lung function change and morbidity and whether bronchodilators are more effective in participants with greater responsiveness. 4. Comparison of the effects of study interventions on study outcomes in subgroups selected according to age, sex, degree of obstruction, and extent of smoking habit.4
The LHS recruited 5887 participants between the ages of 35 and 60 who were currently smoking and deemed to be at high risk for clinically significant COPD based on a baseline FEV, between 55% and 90% of predicted and an FEV,/forced vital capacity (FVC) less than 0.70. All were screened on three occasions, with the baseline pulmonary function values being defined as those measured at the second screen. Pulmonary function testing was tightly controlled and of high quality.b Screenees were excluded if they had a disease or condition that might affect participation over the 5-year follow-up period (e.g., cancer, stroke, or heart attack within the past 2 years; alcohol use in excess of 25 drinks per week) or were taking physician-prescribed medications, such as bronchodilators, insulin, nitroglycerin or other nitrate vasodilators, or a beta-adrenergic blocker. The expectation of moving their residence more than 75 miles from the local LHS Center during the subsequent 2 years was also a cause for exclusion. Candidates for the study had to be willing to participate in a behavioral modification program designed to help them to stop smoking. Physicians participating in the LHS could not be the personal physician or participate in the care of any participant. The 5887 participants were recruited at 10 clinical centers in North A m e r i ~ a(See . ~ Appendix for the list of the clinical centers, coordinating center, and participating investigators.) On entry into the study, participants were randomized into one of three groups: smoking intervention including the use of inhaled ipratropium bromide (Atrovent; provided by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) (SIA), smoking intervention with the use of an inhaled placebo that was identical in appearance to the drug canister (provided by Boehringer Ingelheim Pharmaceuticals, Inc.)
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
525
(SIP), and usual care (UC) (no intervention). The inhalers were assigned in a double-blind fashion. In all, there were 1964 participants in the UC group, 1962 in the SIP group, and 1961 participants in SIA. All participants were evaluated annually for 5 years. SIA and SIP had follow-up and maintenance visits (see later) every 4 months in addition to the annual e~aluation.~ The behavioral intervention program was offered to all participants in the SIA and SIP groups. This consisted of 1. A strong physician’s message delivered individually to each SIA and SIP participant. 2. An introductory meeting with a smoking intervention specialist that immediately followed the physician message. 3. A group orientation meeting led by interventionists who explained the program and the use of nicotine gum and the aerosol inhaler. 4. An intensive 12-session group intervention program that took place over a 10-week period. This included the use of general principles of cognitive and social learning theory along with the use of nicotine gum (nicotine polacrilex, [Nicorette; provided by Merrell Dow Pharmaceuticals, Cincinnati, OH]). The gum was used to minimize nicotine withdrawal symptoms. 5. Clinic visits every 4 months for the 5-year period of follow-up, which included individual meetings with intervention staff. These visits were to assess and promote regimen adherence and to look for adverse effects from the nicotine gum or inhaler. New inhalers were distributed every 4 months, and additional nicotine gum was dispensed if necessary to maintain a nonsmoking status. 6. A maintenance program to provide long-term support to prevent smoking relapse and to deal with weight gain and stress associated with smoking cessation. 7. An extended intervention program for those who either were unsuccessful in quitting smoking or relapsed. In these sessions, attempts were made to improve inhaler compliance. These could be in the form of group or individual sessions, physician visits, or restart group^.^
Participants in the SIA and SIP groups were instructed to take two inhalations three times a day from their metered dose inhalers. Proper technique in inhaler usage was explained and demonstrated to them.4 The need to continue to use the inhalers was emphasized repeatedly throughout the study. The primary outcome variable in the study was the annual rate of change of the FEV,. Prebronchodilator and postbronchodilator (inhaled isoproterenol) pulmonary function baseline values were obtained at the second screen, and follow-up values were obtained at each annual visit. Also at the annual visits, information on participants’ health was obtained using questionnaires developed for the study, and permission
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was obtained to review participants’ hospital records if they had been hospitalized since they were last seen at baseline or an annual visit. At all visits, exhaled carbon monoxide was measured, and at annual visits saliva was collected for salivary cotinine levels. These values were used to validate the participants’ self-reported smoking status4 BASELINE CHARACTERISTICS OF THE STUDY POPULATION*
The baseline characteristics are shown in Tables 1 and 2 and Figures 1 through 7. The men and women in the study were of similar age and had a similar FEV, as a percent of predicted. Also, alcohol usage was similar in men and women. There were the expected differences, however, between the genders, including larger body size, higher values for the measured FEV,, and heavier tobacco usage in the men. The women had less exposure to dust and fumes, a greater prevalence of asthma, Table 1. BASELINE CHARACTERISTICS OF LUNG HEALTH STUDY PARTICIPANTS* Men 3702)
Characteristic
(n =
Age at randomization, years FEV,, O h predicted FEV,tFVC, Yo Cigarettestday at screen 1 Salivary cotinine, ng/mL* Age started smoking, years Cigarettes per day over smoking lifetime Pack-years Duration of smoking, years Use of other tobacco products, % Alcohol use, % Drinks per week among alcohol users Height, cm Weight, kg Body mass index5 Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Past exposure to dustifumes, % History of asthma in family, Yo History of emphysema in family, % History of lung cancer in family, %
48.4 74.8 62.8 32.7 377 17.1 27.3
t 7.0 2 9.6 ? 6.2 t 13.2 I 208 2 3.7 t 10.2
43.1 ? 20.1 31.3 t- 7.8 12.2 t 32.7 70.8 t 45.5 6.9 6.0 176.8 ? 6.6 82.5 t 13.0 26.3 f 3.7 122.8 t- 12.9 78.6 ? 9.0 54.9 f 49.8 17.5 ? 38.0 16.6 t 37.2 8.2 r 27.4
Women (n = 2185)
Significance Levelt
6.5 9.3 5.7 11.8 193 3.9 9.2
0.4741
t 16.6 t 7.2 t 9.4 t 46.1 i 4.8
0.0001 0.0001 <0.0001 0.2300 0.0001
163.8 rir 5.9 65.0 t 11.5 24.1 f 4.0 116.4 I 14.8 74.5 t 9.2 22.4 t 41.7 25.5 f 43.6 26.3 r 44.0 12.6 t 33.2
0.0001 0.0001 0.0001 0.0001 0.0001 <0.0001 <0.0001 <0.0001 <0.000 1
48.5 t 74.9 ? 63.5 t 28.9 -t 349 2 18.1 t 24.0 t 36.6 30.4 0.9 69.3 5.0
NS 0.0001 0.0001 0.0001 0.0001 0.0001
‘Values are expressed as mean 2 SD. tBased on t test for difference in means or test for difference in proportions. NS = not significant. *Saliva analysis complete for 2138 women and 3621 men. §Calculated as weighVheighF, where height is measured in meters. From Bust AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.
x2
N
uI
Yes No Yes No Yes No Yes No
No
1029 1080 840 1269 1067 1042 1115 977 166 1943
Yes
0.06
0.0001
0.0001
0.0001
Men 0.0001
P Levelt
0.0008
0.0001
0.0001
0.0001
Women 0.0001
74.2 75.9 74.4 75.6 74.5 75.8 73.5 76.0 74.1 75.2
1708 1849 1586 1971 2022 1535 1284 2232 243 3314
Yes No Yes No Yes No Yes No Yes No 73.9 76.0 73.8 75.7 74.1 75.9 74.1 76.0 72.8 75.2
Mean Yo Predicted
4.34 4.28 4.30 4.32 4.79 3.82 4.36 4.25 7.14 4.07
4.45 4.10 4.26 4.28 4.73 3.67 4.21 4.32 5.07 4.21
Mean#
0.0001
0.63
0.0001
0.92
0.79
0.01
0.50
0.0001
0.91
0.04
P Levelt
51.3 44.3 52.4 44.6 52.9 42.4 49.2 46.2 65.1 46.2
29.3 21.9 28.2 23.2 27.6 22.6 29.6 23.1 39.9 24.4
Mean %
<0.0005
0.16
<0.0005
<0.0005
0.001
<0.0005
<0.0005
0.001
0.001
<0.0005
P Levelt
Methacholine Response to 5 5 mg/mL$
88.5 85.5 89.5 85.3 88.9 85.0 86.9 87.2 91.6 86.6
67.1 51.5 65.8 60.0 65.9 58.2 66.4 60.3 77.0 61.5
Mean %
0.066
0.839
0.009
0.004
0.036
<0.0005
<0.0005
<0.0005
<0.0005
<0.0005
P Levelt
Methacholine Response to 5 2 5 mg/mL$
'Numbers of subjects for same symptom vary slightly depending on number of missing values for different measurements. tBased on t tests for comparisons of means and x2 tests for comparisons of proportions. (post-BD FEV, - pre-BD FEV,) x 100 SBronchdilator response (ED) is defined as pre-BD FEV, SMethacholine response is defines as a drop of 20% or more in FEV, compared to baseline. From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 1033 863-1 872, 1993; with permission.
Asthma, physicianconfirmed
Shortness of breath
Wheeze apart from cold
Phlegm
Cough
Asthma, physicianconfirmed
Shortness of breath
Wheeze apart from cold
Phlegm
Cough
Symptom
FEV,
No. of Subjects*
Symptom Present?
Bronchodilator Response
Table 2. RELATIONSHIP OF SYMPTOMS TO LUNG FUNCTION AND BRONCHIAL RESPONSIVENESS IN LUNG HEALTH STUDY PARTICIPANTS
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62%
12%
2o 10 0
13%
~
Less than High School
High School
More than High School
Education Figure 1. Level of education of the Lung Health Study participants. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-I 872,1993;with permission.)
and a stronger family history of lung cancer and emphysema. The men were more educated. There was a tendency in both genders for a decrease in the FEV, percent of predicted and FEV,/FVC with increasing age (see Fig. 3). Women were more apt to react to methacholine with a 20% decline in the FEV,, but a high percentage of all participants had airways hyperresponsiveness (AHR) when concentrations of methacholine up to 25 mg/mL were used (see Fig. 7). AHR was defined as a decline in the FEV, of at least 20% from the baseline established by the inhalation of diluent when increasing concentrations of methacholine (1, 5,10,25 mg/mL) were inhaled from a dosimeter. Respiratory symptoms tended to be related to lung function and AHR; the poorer the lung function and the greater the responsiveness to methacholine, the greater the prevalence of respiratory symptoms (see Table 2).* The three groups (SIA, SIP, UC) were quite similar in most respects except that there was a higher percentage of women in SIA, resulting in a slightly lower measured FEV, in that group. Follow-up rates by group for interviews and lung function measurements for each annual visit are presented in Table 3. Much effort was put into ensuring high follow-up rates, and, as the table demonstrates, this was successful. At the fifth and final annual visit, 94% to 95% of the surviving participants had pulmonary function studies.'
529
EARLY INTERVENTlON IN CHRONIC OBSTRUCTIVE PULMONARY DlSEASE
34
34
34
m" 32
n & a
8 30
5
?? m
28
26 24
I
I
I
I
I
35-39
40-44
45-49
50-54
55-60
Age at randomization (years)
Figure 2. Average number of cigarettes smoked per day at screen 1 by age at randomization and gender. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 1031863-1 872, 1993; with permission.)
Table 3. ANNUAL VISIT FOLLOW-UP RATES ("A) BY STUDY GROUP Annual Visit (AV)
Usual care Interview Lung function Smoking intervention placebo Interview Lung function Smoking intervention ipratropium bromide (Atrovent) Interview Lung Function
+
+
AV1
AV2
AV3
AV4
AV5
95 89
95 90
94 89
93 88
96 94
95 92
94 91
94 89
93 88
97 94
96 92
95 92
95 90
94 88
97 95
From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, 1994; with permission.
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100% 90% 80% 70% 60%
50% 40%
30%
20% 10% 0Yo
0
-
FEVl Yo Pred. FEVl/FVC%
77%
74%
74%
11
35-39 40-44 45-49 50-54 55-60
Men
35-39 40-44 45-49 50-54 55-60 Women
Figure 3. Mean FEV, percent predicted and FEV,/FVC percent at screen 2 by age at randomization and gender. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
SMOKING INTERVENTION PROGRAM: DESIGN AND RESUL T S 2
All participants in the SIA and SIP groups were entered into an intensive group smoking intervention program. There was a common protocol at each of the 10 clinical centers. As noted previously, this consisted of a physician message, behavioral interview, orientation, group intervention sessions, use of nicotine gum, extended intervention sessions, and a maintenance program.I2 Physician Message
All physicians in the study were trained and certified to deliver a strong message to each SIA and SIP participant at the time of randomization into the study. This message provided personalized information about the status of the participant’s respiratory health and risks for clinically significant pulmonary disease. Also, the benefits of the treat-
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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100 Men
901 80
-
c (I)
7 2 % 73%
70-
C
6 1%
m
.8 ._ 60 -
57%
: r
50-
0
c
5 40$2
3020
-
10
-
Ir 0 Women
79%
55-60
035-39
40-44
45-49
50-54
Age at Randomization (years)
Figure 4. Percent of Lung Health Study participants reporting wheezing with a cold by age. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
ment plan in reducing their risks for lung, heart, and other diseases were discussed in detail. The relationship of cigarette smoking to health problems was emphasized. The use of the ipratropium or placebo inhaler and of nicotine gum was explained and prescribed. Behavioral Interview
The behavioral interview was done immediately following the physician message to ensure that the participant understood what the physician explained as well as to obtain a more extensive smoking history and to review the expectations of the smoking intervention program. The interventionist assessed the participant’s motivation to stop smoking and prepared him or her to give up this habit. A stop-smoking date (quit day) was negotiated with the participant. Orientation
The orientation was the first of the group sessions and occurred within 28 days of the physician message. It was led by an intervention
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KANNER
6oB
50
{
40
a 0
r
30 0 c
K
a,
a 20
10 0 35-39
40-44
45-49
50-54
55-60
Age at Randomization (years)
Figure 5. Participants reporting wheezing most days or nights. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
specialist and focused on preparation for stopping smoking on quit day. Family members and support persons were urged to attend with the participant. Other matters covered were a review of the LHS research project, the physician message, information on randomized treatment assignment, blinding, and placebo and bronchodilator assignment. Group Intervention Four group sessions were held on consecutive days during quit week starting with quit day. Quit day, or session 1, was the time all participants were expected to stop smoking. Aerosol inhaler use was explained and demonstrated, and nicotine gum was distributed after its effects, side effects, and proper usage were discussed. The participants were taught to chew the gum slowly and intermittently and to let the nicotine be gradually released while the gum was kept between the cheek and gums. Strategies were introduced for smoking cessation, and daily monitoring of adherence or usage problems of the aerosol inhaler and nicotine gum were discussed. At each session, the participant was weighed and his or her exhaled carbon monoxide level was measured.
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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100
80
1
1M e n Women
30% 30%
<5
5-9
10 - 14
115
Percent Increase in FEVl
Figure 6. Frequency distribution of increase in FEV, (as percentage of baseline) in response to inhaled isoproterenol. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
Seven group sessions between weeks 2 and 12 were held to prevent smoking relapse and to discuss smoking-specific issues, health behavior, and stress management. Additional training was given on relapse prevention skills with a method for tapering nicotine gum usage. Regular 4-month follow-up visits were scheduled once the 12 group sessions were completed. Nicotine Gum Use At the first session, nicotine gum (2 mg/piece) was distributed at no charge to those who desired to use it after the physician had written a prescription for this agent. The nicotine gum distribution continued at individual follow-up visits. If a spouse or support person wished to use the gum at the same time to help break their own smoking habit, first they had to obtain a prescription from their personal physician and then the study would distribute the gum to them at no cost for up to a 6month period of time. Those participants who could not stop using the gum after 6 months met with their interventionist to develop a strategy for reduction in gum usage. A long-term nicotine gum usage protocol
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73.! 60 50 40
30
20 10
0 0.0 (diluent)
1 .o
5.0
10.0
25.0
Methacholine Concentration Figure 7 . Cumulative percentages of males (stippled bars) and females (light bars) responding to increasing doses of methacholine, with a positive response at each concentration being defined as a decline in FEV, of at least 20%. Baseline was the postdiluent value except for the response to diluent, in which case the prediluent value was used. ( f r o m Kanner RE, Connett JE, Altose MD, et al: Gender differences in airway hyperresponsiveness in smokers with mild COPD. Am J Respir Crit Care Med 150:956-961, 1994; with permission.)
was developed for those who could not discontinue the use of the gum. This included the approval of the participant’s personal physician. Pregnant and nursing women were instructed not to use the gum. Also, the presence of active peptic ulcer disease was considered a contraindication for gum usage.
Extended Intervention Extended intervention was made available to those who continued to smoke, to those who relapsed, and to those who did not initially enter the group program. Intervention was offered based on the participant’s readiness to enter a smoking cessation program. At this point, multiple options were offered to the participants, including additional restart and stay-quit support group sessions, individual sessions with an interventionist, and LHS physician visits.
Maintenance Maintenance was considered to have begun when the participant was properly using his or her inhaler and was no longer smoking. The
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
535
goals were to maintain a smoke-free status, facilitate proper inhaler usage, encourage compliance, and maintain good rapport with the participants. At least three maintenance meetings were held annually. There were weight management programs held twice yearly, quarterly newsletters, and frequent telephone and clinic contacts. The minimum contact schedule was monthly for the first 8 months of smoking abstinence.I2
EFFECTIVENESS OF THE SMOKING CESSATION PROGRAM',''
The cotinine and carbon monoxide validated smoking quit rates are shown in Figure 8. At the end of 5 years, 22% of the participants in the SIA and SIP groups had achieved sustained smoking cessation (nonsmokers for the 5-year period) validated by cotinine and/or carbon
' 6 la
50
. I -
II: C
.-0
40
. I -
(d v) v)
6
30
U 0)
c v)
2 20 -0
a
-> .-2
10
E
0)
r 0 .-0
m
0
AV 1
AV2
AV3 Annual Visit
AV4
AV5
Figure 8. Cotinineicarbon monoxide-validated smoking cessation rate (ordinate) as a function of years of follow-up. Usual care (UC) participants (squares) are compared with smoking intervention (SI)participants (circles). Both sustained (closed symbols) and crosssectional (open symbols) cessation rates are shown. Nonattenders of follow-up visits are counted as smokers. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.)
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KANNER
monoxide (or both) measurements. Only about 5% of the UC group, however, were able to sustain a nonsmoking status over the 5-year period. The cross-sectional quit rates, which are the validated quit rates at each of the annual visits, were approximately 35% in the SIA and SIP groups with a slight rise to 38% at the fifth annual visit, and in the UC group this rose from 9% at the first annual visit to 21% by the end of the 5-year follow-up period. Predictors of smoking cessation during the initial 4 months of the LHS and relapse during the subsequent 20 months of the study have been published.'" This study demonstrated that the men had higher initial quit rates (40.8%) than the women (35.8%).The relapse rates at the 4- and 12-month visits, however, were similar (men 35%, women 34%). Among the sustained quitters at 12 months, 14% of the men and 18%of the women relapsed by the time of the 24-month visit (differences not significant).Baseline predictors of smoking cessation in women were having more education, being married, having quit for a longer period of time in the past, not having other smokers in the house, not having used nicotine gum in the past, not needing to smoke on awakening in the morning, not having asthma or breathlessness, and consuming fewer alcoholic drinks1" There were some differences in the predictors for the men. Being married, having more education, not having other smokers in the house, and not having used nicotine gum before were also predictors for quitting in the men. In addition, the older men had more success in quitting. Other predictors for the men were having a lower baseline cotinine level, having a higher FEV, percent of predicted, and having a support person with them during the orientation session.1o The most significant predictor of relapse to smoking at the 12month visit after having succeeded in quitting at the 4-month visit for both men and women was the reporting of any episode of smoking between quit day and the 4-month visit.'" For men, additional predictors of relapse during 4- to 12-month visit period were not having a support person at the orientation session9,'" and continuing to use nicotine gum at the 4-month visit. Those who relapsed drank fewer alcoholic drinks than those who remained quitters. There were no other significant predictors for the women.l0The major predictor of relapse between the 12and 24-month visits in both men and women was the continued use of nicotine gum. In women, the presence of another smoker in the house was a strong predictor of relapse during this period of time, whereas other predictors for men were obesity and being aware of missing cigarettes, another measure of nicotine dependence.l0 Weight gain was a problem for sustained quitters. At the 24-month visit, the mean absolute weight gain in the women was 6.2 kg (SD = 6.0 kg) and in the men was 5.4 kg (SD = 6.0 kg). The use of nicotine gum helped to delay the increase in weight, but when the gum was discontinued this effect was lost. Thus, the gum helped the participants to quit smoking and to delay the onset of the weight gain."
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EARLY INTERVENTION IN CHRONIC OBSTIWCTIVE PULMONARY DISEASE
INHALER COMPLIANCE RESULTS
Inhaler compliance over the 5-year period is shown in Figure 9.' As can be noted, the self-reported compliance was better than that determined by weighing the canisters. Compliance tended to decline over the 5-year period.' There is also evidence that compliance with the inhaled medication was poorer than that determined by weighing the canisters. When a microprocessor monitoring device was incorporated into the inhaler unit in a subset of 93 participants at two of the LHS clinical centers, it was noted that even the weighing of the canisters overestimated the number of participants using the inhaler according to the study protoc01.'~ RESULTS OF THE INTENTION-TO-TREAT ANALYSIS
In the intention-to-treat analysis, the three groups were compared for differences in mortality and annual rates of change in lung function.'
I"
I
I
60 50 40
W
I
I
I
I
i
AV 1
AV2
AV3 Annual Visit
AV4
AV5
Figure 9. Inhaler compliance as a function of years of follow-up. Smoking intervention and placebo (circles) and smoking intervention and ipratropium bromide (triangles) are shown, with self-reported compliance indicated by open symbols and compliance as verified by canister weights indicated by closed symbols. Participants not attending the visit were classified as noncompliant, (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.)
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KANNER
There were 149 deaths over the 5-year period, with 54 occurring in the SIA group, 44 in the SIP group, and 51 in the UC group (Table 4). The differences between the groups were not significant except that there were more deaths because of cardiovascular or cerebrovascular disease in the SIA group. This excess number of cardiovascular or cerebrovascular deaths appeared to be unrelated to the use of the inhaler. Only 8 of the 18 SIA participants who died as a result of these disorders reported using the inhaler at the visit before their death, as compared to five of the seven SIP cardiovascular or cerebrovascular deaths.' The changes in the postbronchodilator FEV, over the 5-year period for participants in the SIA, SIP, and UC groups are shown in Figure 10. The mean value for the postbronchodilator FEV, for each group at each annual visit is presented. At baseline, the mean FEV, value was 0.02 L less in the SIA group as a result of the higher percentage of women in this group. In the UC group, there was a linear decline in the FEV, over the 5-year period of follow-up. In the SIA group, and to a lesser extent in the SIP group, there was an initial improvement in the FEV, during the first year, which was followed by a linear decline over the next 4 years that approximately paralleled the decline seen in the UC group. This is also shown in Figure 11 using a best fit model of the changes in FEV,. No changes can be detected in the annual rate of change when comparing the SIA and SIP groups. Because this is an intention-to-treat analysis, the comparisons are made between the three groups regardless of the smoking status of the members of the group or their inhaler usage. This tends to minimize the effects of smoking cessation. In Figure 12, the data are shown according to smoking status for participants in the SIP group who were either sustained quitters or continuous smokers. It can be seen that the annual rate of decline in the sustained quitters is clearly less than what is seen in the continuous smokers. The largest annual gain in FEV, occurs during the first year after smoking cessation, although the curves continue to diverge through year 5.
Table 4. DEATHS WITHIN 5 YEARS OF RANDOMIZATION Treatment Group Cause
SIA
SIP
uc
Cardiovascular disease Lung cancer Other
18 18 18
7 20 17
12 19 20
Total
54
44
51
SIA = Smoking intervention with ipratropium bromide (Atrovent); SIP = smoking intervention with placebo; UC = usual care. From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.
539
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
2.80 2.75 v)
2.70 C .-
5 w
LL C
2.65 2.60
cci
8
2.55 2.50 I
I
I
I
I
I
Screen 2
AV1
AV2
AV3
AV4
AV5
Annuai Visit Figure 10. Mean postbronchodilator FEV, over the course of the study in all participants in whom the measurement was made. Circles and the dotted line represent the smoking intervention and placebo group, triangles and the solid line represent the smoking intervention and ipratropium bromide group, and squares and the dashed line represent the usual care group. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 27214971505, copyright 1994, American Medical Association; with permission.)
Table 5. MEAN CUMULATIVE DECLINES (i- SD) IN PREBRONCHODILATOR FEV, (mL)* ~
~
Time Interval
Entry* to year 5 (first part) Entry* to year 5 (second part) Year 1 to year 5 (first part) Year 1 to year 5 (second part) Year 5, first part to second
Usual Care n = 1380 249 263 196 210 14
?
236
t 248 t 220 2 236
+- 141
Special Intervention Placebo n = 1448 188 196 169 178 9
246 t 257 i 208 -c 217 ? 135
?
Special Intervention Atroventt n = 1470 172 208 178 214 36
263 t 270 t 230 ? 248 ? 173 ?
'Restricted to participants who attended annual visit 1 and both parts of annual visit 5. tlpratropium bromide (Atrovent). SEntry here refers to screen 3. f r o m Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.
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2.80 I 2.75 2.70 2.65 2.60
.. ..
2.55
Y
\
2.50 I
I
I
I
I
I
Screen2
AV1
AV2
AV3
AV4
AV5
Annual Visit Figure 11. Best-fit model of changes in postbronchodilator FEV, over the course of the study. FEV, undergoes a one-time change during the first year of follow-up and then declines linearly, the initial change being independent of the subsequent decline. Circles are observed means for the smoking intervention and placebo group (SIP), triangles for the smoking intervention and ipratropium bromide group (SIA), and squares for the usual care group (UC).Predicted values for the SIA group are represented by a solid line, for the SIP group by a dotted line, and for the UC group by a dashed line. (from Anthonisen NR. Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 27211497-1505, copyright 1994, American Medical Association; with permission.)
Table 5 presents the cumulative declines in FEV, for the three study groups for the 5-year period of the study and for the period from the first to fifth annual visit. This includes the two fifth annual visits, which allowed for the evaluation of the effect of stopping the use of the inhalers at the initial fifth annual visit. It can be seen that in the SIA and SIP groups the cumulative loss over the 5-year period is substantially less than that seen in the UC group. Any benefit from inhaled ipratropium was lost at the second part of the fifth annual visit, when the inhalers were no longer being used.' Thus, the ipratropium bromide has a short-term benefit while it is being used, but it does not have an effect on the long-term decline in FEV,.' The results of the intention-to-treat analysis are consistent with a significant improvement in FEV, from smoking cessation. This improvement occurs primarily in the first year following stopping smoking. Thus, this is the most important intervention that a physician can offer smokers with mild COPD. Also, ipratropium has a beneficial effect on FEV, while it is being used, but this benefit is lost once the drug is
541
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
I
\ - Sustained Quitters
a
-
Y
2.7
3
Continuing S rnokers
2 2.4
I
I
Screen2
AV1
1
I
AV2 AV3 Annual Visit
I
I
AV4
AV5
I
Figure 12. Mean postbronchodilator FEV, for participants in the smoking intervention and placebo groups who were sustained quitters (open circles) and continuous smokers (closed circles). The two curves diverge sharply after baseline. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, 1994; with permission.)
stopped, and it does not affect the annual rate of change of FEV, in this population.' AIRWAY RESPONSIVENESS IN THE LUNG HEALTH STUDY*,l 5
One of the original goals of the LHS was to recruit a cohort of participants with mild COPD of whom at least 20% exhibited AHR. The purpose was to evaluate the Dutch hypothesis5, in a prospective study. This hypothesis states that AHR is a determinant of decline of FEV, in smokers, with those with the greatest degree of AHR having the most rapid declines. The prevalence of AHR in the LHS participant population was considerably higher than expected, as can be seen in Figures 7 and 13. The prevalence of men and women with AHR increased with a decrease in the FEV, as a percent of predicted.15The cumulative percentages of participants responding to increasing doses of methacholine were 87'% of the women and 62% of the men at or before the highest concentration of methacholine used (25 mg/mL); at 5 mg/mL (a level at which most patients with asthma would respond), a quarter of the men and almost
542
KANNER
100
:80 S
0
a
a
40
c
0 1
C a,
p
a
20
o !
I
I
I
I
I
1
5 59
60-64
65-69
70-74
75-79
> 79
1
Baseline FEV, Percent of Predicted
Figure 13. Percentages of men and women in the Lung Health Study responding to concentrations of methacholine 5 5 mg/mL and 5 25 rng/mL with a 2 20% decline in FEV, from baseline, by baseline FEV, as percent of predicted. (Closed circles = women, 25 mg/mL; open squares = men, 25 mg/mL; dotted circles = women, 5 mg/mL; dotted squares = men, 5 mg/mL.) ( f r o m Tashkin DP, Altose MD, Bleecker ER, et al, and the Lung Health Study Research Group: The Lung Health Study: Airways responsiveness to inhaled metacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 145:301-310, 1992; with permission.)
half of the women demonstrated AHR as defined by a decline in the FEV, of 20% from baseline.8Thus, a marked gender difference was seen. The higher prevalence in women is thought to be due to the women having smaller airways because when the data are adjusted for the measured FEV, the differences are no longer seen.8 Thus, AHR was much more prevalent in this population of smokers with mild COPD than was anticipated, and AHR was inversely related to the level of pulmonary function. Analysis of the predictive consequences of this finding is currently in progress.
SUMMARY The major findings of the LHS that have been reported thus far are that an effective smoking cessation program can be developed that can
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
543
produce more than a 20% success rate in getting smokers to give up the habit permanently, and that by stopping smoking, individuals with early COPD benefit by having an initial improvement in lung function and a slowing of the annual loss of their FEV,. The use of a bronchodilator has a short-term effect in improving the FEV1, but it does not affect long-term changes in lung function. AHR is common in patients with mild-to-moderate COPD. The reward for a smoker to give up the habit is an initial gain in FEV, and a subsequent close to normal annual rate of decline of this pulmonary function parameter. These results should provide a positive incentive for smokers to quit and thereby decrease the morbidity and mortality caused by the use of tobacco.
References 1. Anthonisen NR, Connett JE, Kiley JP, et a1 for the Lung Health Study Research Group: Effects of smoking intervention and the use pf an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:14971505, 1994 2. Buist AS, Connett JE, Miller RD, et a1 for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993 3. Centers for Disease Control: Cigarette smoking among adults-United States, 1993. MMWR 43:925-930, 1994 4. Connett JE, Kusek JW, Bailey WC, et a1 for the Lung Health Study Research Group: Design of the Lung Health Study: A randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Controlled Clin Trials 14:3%19S, 1993 5. de Vries K, Booij-Noord H, Goei JT, et al: Hyperreactivity of the bronchial tree to drugs, chemical and physical agents. In Orie NGM, Sluiter HJ (eds): Bronchitis 11. Assen, the Netherlands, Royal Van Gorcum, 1964, pp 167-180 6. Enright PL, Johnson LR, Connett JE, et al: Spirometry in the Lung Health Study: 1. Methods and quality control. Am Rev Respir Dis 143:1215-1223, 1991 7. Fletcher C, Peto R, Tinker C, et a1 The Natural History of Chronic Bronchitis and Emphysema. Oxford, Oxford University Press, 1976 8. Kanner RE, Connett JE, Altose MD, et a1 for the Lung Health Study Research Group: Gender differences in airway hyperresponsiveness in smokers with mild COPD. Am J Respir Crit Care Med 150:956-961, 1994 9. Murray RP, Johnston JJ, Dolce JJ, et al: Social support for smoking cessation and abstinence: The Lung Health Study. Addict Behav 20:159-170, 1995 10. Nides MA, Rakos RF, Gonzales D, et a1 for the Lung Health Study Research Group: Predictors of initial smoking cessation and relapse through the first 2 years of the Lung Health Study. J Consult Clin Psychol 63:60-69, 1995 11. Nides M, Rand C, Dolce J, et al: Weight gain as a function of smoking cessation and 2-mg nicotine gum use among middle aged smokers with mild lung impairment in the first 2 years of the Lung Health Study. Health Psychol 13:354-361, 1994 12. O’Hara P, Grill J, Rigdon MA, et a1 for the Lung Health Study Research Group: Design and results of the initial intervention prograin for the Lung Health Study. Prev Med 22~304-315,1993 13. Orie NGM, Sluiter HJ, De Vries K, et al: The host factor in bronchitis. In Orie NGM, Sluiter HJ (eds): Bronchitis. Assen, the Netherlands, Royal Van Gorcum, 1961; pp 43-59 14. Rand CS, Wise RA, Nides M, et al: Metered-dose inhaler adherence in a clinical trial. Am Rev Respir Dis 146:1559-1564, 1992 15. Tashkin DP, Altose MD, Bleecker ER, et a1 and the Lung Health Study Research
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Group: The Lung Health Study: Airways responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 145:301-310, 1992 16. U.S. Public Health Service: The health consequences of smoking: Chronic obstructive lung disease. A report of the surgeon general. Office of Smoking and Health, DHHS Publication No. (PHS) 84-50205, 1984
Address wprint rrqitests to John E. Connett, PhD LHS Data and Coordinating Center 2221 University Avenue SE Suite 200 Minneapolis, MN 55414-3080
APPENDIX
The principal investigators and senior staff of the clinical and coordinating centers, the NHLBI, members of the Safety and Data Monitoring Board, and the Morbidity and Mortality Review Board are as follows: Case Western Reserve University, Cleveland, OH M. D. Altose, MD (Principal Investigator) A. F. Comers, MD (Co-Principal Investigator) S. Redline, MD (Co-Principal Investigator) C. D. Deitz, PhD R. F. Rakos, PhD Henry Ford Hospital, Detroit, MI W. A. Conway, Jr., MD (Principal Investigator) A. DeHorn, PhD (Co-Principal Investigator) J. C. Ward, MD (former Co-Principal Investigator) C. S. Hoppe-Ryan, CSW R. L. Jentons, MA J. A. Reddick, RN C. Sawicki, RN, MPH Johns Hopkins University School of Medicine, Baltimore, MD R. A. Wise, MD (Principal Investigator) S. Permutt, MD (Co-Principal Investigator) C. S. Rand, PhD (Co-Principal Investigator)
Mayo Clinic, Rochester, MN P. D. Scanlon, MD (Principal Investigator) L. J. Davis, PhD (Co-Principal Investigator) R. D. Hurt, MD (Co-Principal Investigator) R. D. Miller, MD (Co-Principal Investigator) D. E. Williams, MD (Co-Principal Investigator) G. M. Caron G. G. Lauger, MS S. M. Toogood (Pulmonary Function Quality Control Manager) Oregon Health Sciences University, Portland, OR A. S. Buist, MD (Principal Investigator) W. M. Bjornson, MPH (Co-Principal Investigator) L. R. Johnson, PhD (LHS Pulmonary Function Coordinator) 545
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University of Alabama at Birmingham, Birmingham, AL W. C. Bailey, MD (Principal Investigator and Associate Chief of Staff for Education, Department of Veterans Affairs Medical Center, Birmingham) C. M. Brooks, EdD (Co-Principal Investigator) J. J. Dolce, PhD D. M. Higgins M. A. Johnson B. A. Martin University of California, Los Angeles, CA D. P. Tashkin, MD (Principal Investigator) A. H. Coulson (Co-Principal Investigator) H. Gong, MD (former Co-Principal Investigator) P. I. Harber, MD (Co-Principal Investigator) V. C. Li, PhD, MPH (Co-Principal Investigator) M. Roth, MD (Co-Principal Investigator) M. A. Nides, PhD M. S. Simmons I. P. Zuniga University of Manitoba, Winnipeg, Canada N. R. Anthonisen, MD (Principal Investigator) J. Manfreda, MD (Co-Principal Investigator) R. P. Murray, PhD (Co-Principal Investigator) S. C. Rempel-Rossum J. M. Stoyko University of Minnesota Coordinating Center, Minneapolis, MN J. E. Connett, PhD (Principal Investigator) M. 0. Kjelsberg, PhD (Co-Principal Investigator) M. K. Cowles, PhD D. A. Durkin P. L. Enright, MD K. J. Kurnow, MS W. W. Lee, MS P. G. Lindgren, MS S. Mongin, MS P. O’Hara, PhD (LHS Intervention Coordinator) H. T. Voelker L. Waller, PhD University of Pittsburgh, Pittsburgh, PA G. R. Owens, MD (Principal Investigator) R. M. Rogers, MD (Co-Principal Investigator) J. J. Johnston, PhD F. P. Pope, MSW F. M. Vitale, MA
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
547
University of Utah, Salt Lake City, UT* I<. E. Kanner, MD (Principal Investigator) M. A. Rigdon, PhD (Co-Principal Investigator) K. C. Benton 1'. M. Grant Safety and Data Monitoring Board M. Becklake, MD B. Burrows, MD P. Cleary, PhD P. Kimbel, MD (Chairperson; deceased October 27, 1990) L. Nett, RN (former member) J. K. Ockene, PhD R. M. Senior, MD (Chairperson) G. L. Snider, MD W. Spitzer, MD (former member) 0. D. Williams, PhD National Heart, Lung and Blood Institute Staff, Bethesda, MD S. S. Hurd, PhD (Director, Division of Lung Diseases) J. P. Kiley, PhD (Project Officer) M. C. Wu, PhD (Div. of Epidemiology & Clinical Applications) Mortality and Morbidity Review Board S. M. Ayres, MD R. E. Hyatt, MD B. A. Mason, MD *The Salt Lake City Center has been assisted by the Clinical Research Center, Public Health Research Grant M01-RR00064 from the National Center for Research Resources.
OBSTRUCTIVE LUNG DISEASES, PART I
+
.20
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE A Review of the Lung Health Study Results Richard E. Kanner, MD, for the Lung Health Study Research Group
In 1993, there were an estimated 46 million adult smokers in the United States, representing approximately 25% of the adult population..’ About 15% of one-pack-per-day and 25”/0of two-pack-per-day cigarette smokers go on to develop chronic obstructive pulmonary disease (COPD) if they continue their habit.’ In 1984, the Surgeon General concluded that “cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women.’”h For these reasons, the Lung Division of the National Heart, Lung and Blood Institute organized the Lung Health Study (LHS) to test methods of preventing the debilitating effects of COPD. This article summarizes the medical findings of interest to physicians that have thus far been reported. STUDY DESIGN4
The LHS was a prospective, randomized, multicenter clinical trial designed to: Supported by Contract N01-HR-46014 from the Division of Lung Diseases of the National Heart, Lung and Blood Institute.
From the Division of Respiratory, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah ~~
~
MEDICAL CLINICS OF NORTH AMERICA VOLUME 80 * NUMBER 3 * MAY 1996
523
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KANNER
1. Determine whether a program combining smoking interventior and the regular use of a bronchodilator can slow the annua decline in lung function (FEV,) in persons at high risk for COPD 2. Estimate the effects, if any, of bronchodilator therapy, over anc above the effects of smoking intervention, on lung function decline.
Secondary objectives included: 1. Assessment of the effectiveness of the intervention program in producing the desired behavioral changes (i.e., smoking cessation and self-administration of inhalers). 2. Determination of whether the intervention program can reduce the incidence of pulmonary morbidity. 3. Determination of whether airway responsiveness is an important determinant of long-term lung function change and morbidity and whether bronchodilators are more effective in participants with greater responsiveness. 4. Comparison of the effects of study interventions on study outcomes in subgroups selected according to age, sex, degree of obstruction, and extent of smoking habit.4
The LHS recruited 5887 participants between the ages of 35 and 60 who were currently smoking and deemed to be at high risk for clinically significant COPD based on a baseline FEV, between 55% and 90% of predicted and an FEV,/forced vital capacity (FVC) less than 0.70. All were screened on three occasions, with the baseline pulmonary function values being defined as those measured at the second screen. Pulmonary function testing was tightly controlled and of high quality.b Screenees were excluded if they had a disease or condition that might affect participation over the 5-year follow-up period (e.g., cancer, stroke, or heart attack within the past 2 years; alcohol use in excess of 25 drinks per week) or were taking physician-prescribed medications, such as bronchodilators, insulin, nitroglycerin or other nitrate vasodilators, or a beta-adrenergic blocker. The expectation of moving their residence more than 75 miles from the local LHS Center during the subsequent 2 years was also a cause for exclusion. Candidates for the study had to be willing to participate in a behavioral modification program designed to help them to stop smoking. Physicians participating in the LHS could not be the personal physician or participate in the care of any participant. The 5887 participants were recruited at 10 clinical centers in North A m e r i ~ a(See . ~ Appendix for the list of the clinical centers, coordinating center, and participating investigators.) On entry into the study, participants were randomized into one of three groups: smoking intervention including the use of inhaled ipratropium bromide (Atrovent; provided by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) (SIA), smoking intervention with the use of an inhaled placebo that was identical in appearance to the drug canister (provided by Boehringer Ingelheim Pharmaceuticals, Inc.)
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
525
(SIP), and usual care (UC) (no intervention). The inhalers were assigned in a double-blind fashion. In all, there were 1964 participants in the UC group, 1962 in the SIP group, and 1961 participants in SIA. All participants were evaluated annually for 5 years. SIA and SIP had follow-up and maintenance visits (see later) every 4 months in addition to the annual e~aluation.~ The behavioral intervention program was offered to all participants in the SIA and SIP groups. This consisted of 1. A strong physician’s message delivered individually to each SIA and SIP participant. 2. An introductory meeting with a smoking intervention specialist that immediately followed the physician message. 3. A group orientation meeting led by interventionists who explained the program and the use of nicotine gum and the aerosol inhaler. 4. An intensive 12-session group intervention program that took place over a 10-week period. This included the use of general principles of cognitive and social learning theory along with the use of nicotine gum (nicotine polacrilex, [Nicorette; provided by Merrell Dow Pharmaceuticals, Cincinnati, OH]). The gum was used to minimize nicotine withdrawal symptoms. 5. Clinic visits every 4 months for the 5-year period of follow-up, which included individual meetings with intervention staff. These visits were to assess and promote regimen adherence and to look for adverse effects from the nicotine gum or inhaler. New inhalers were distributed every 4 months, and additional nicotine gum was dispensed if necessary to maintain a nonsmoking status. 6. A maintenance program to provide long-term support to prevent smoking relapse and to deal with weight gain and stress associated with smoking cessation. 7. An extended intervention program for those who either were unsuccessful in quitting smoking or relapsed. In these sessions, attempts were made to improve inhaler compliance. These could be in the form of group or individual sessions, physician visits, or restart group^.^
Participants in the SIA and SIP groups were instructed to take two inhalations three times a day from their metered dose inhalers. Proper technique in inhaler usage was explained and demonstrated to them.4 The need to continue to use the inhalers was emphasized repeatedly throughout the study. The primary outcome variable in the study was the annual rate of change of the FEV,. Prebronchodilator and postbronchodilator (inhaled isoproterenol) pulmonary function baseline values were obtained at the second screen, and follow-up values were obtained at each annual visit. Also at the annual visits, information on participants’ health was obtained using questionnaires developed for the study, and permission
526
KANNER
was obtained to review participants’ hospital records if they had been hospitalized since they were last seen at baseline or an annual visit. At all visits, exhaled carbon monoxide was measured, and at annual visits saliva was collected for salivary cotinine levels. These values were used to validate the participants’ self-reported smoking status4 BASELINE CHARACTERISTICS OF THE STUDY POPULATION*
The baseline characteristics are shown in Tables 1 and 2 and Figures 1 through 7. The men and women in the study were of similar age and had a similar FEV, as a percent of predicted. Also, alcohol usage was similar in men and women. There were the expected differences, however, between the genders, including larger body size, higher values for the measured FEV,, and heavier tobacco usage in the men. The women had less exposure to dust and fumes, a greater prevalence of asthma, Table 1. BASELINE CHARACTERISTICS OF LUNG HEALTH STUDY PARTICIPANTS* Men 3702)
Characteristic
(n =
Age at randomization, years FEV,, O h predicted FEV,tFVC, Yo Cigarettestday at screen 1 Salivary cotinine, ng/mL* Age started smoking, years Cigarettes per day over smoking lifetime Pack-years Duration of smoking, years Use of other tobacco products, % Alcohol use, % Drinks per week among alcohol users Height, cm Weight, kg Body mass index5 Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Past exposure to dustifumes, % History of asthma in family, Yo History of emphysema in family, % History of lung cancer in family, %
48.4 74.8 62.8 32.7 377 17.1 27.3
t 7.0 2 9.6 ? 6.2 t 13.2 I 208 2 3.7 t 10.2
43.1 ? 20.1 31.3 t- 7.8 12.2 t 32.7 70.8 t 45.5 6.9 6.0 176.8 ? 6.6 82.5 t 13.0 26.3 f 3.7 122.8 t- 12.9 78.6 ? 9.0 54.9 f 49.8 17.5 ? 38.0 16.6 t 37.2 8.2 r 27.4
Women (n = 2185)
Significance Levelt
6.5 9.3 5.7 11.8 193 3.9 9.2
0.4741
t 16.6 t 7.2 t 9.4 t 46.1 i 4.8
0.0001 0.0001 <0.0001 0.2300 0.0001
163.8 rir 5.9 65.0 t 11.5 24.1 f 4.0 116.4 I 14.8 74.5 t 9.2 22.4 t 41.7 25.5 f 43.6 26.3 r 44.0 12.6 t 33.2
0.0001 0.0001 0.0001 0.0001 0.0001 <0.0001 <0.0001 <0.0001 <0.000 1
48.5 t 74.9 ? 63.5 t 28.9 -t 349 2 18.1 t 24.0 t 36.6 30.4 0.9 69.3 5.0
NS 0.0001 0.0001 0.0001 0.0001 0.0001
‘Values are expressed as mean 2 SD. tBased on t test for difference in means or test for difference in proportions. NS = not significant. *Saliva analysis complete for 2138 women and 3621 men. §Calculated as weighVheighF, where height is measured in meters. From Bust AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.
x2
N
uI
Yes No Yes No Yes No Yes No
No
1029 1080 840 1269 1067 1042 1115 977 166 1943
Yes
0.06
0.0001
0.0001
0.0001
Men 0.0001
P Levelt
0.0008
0.0001
0.0001
0.0001
Women 0.0001
74.2 75.9 74.4 75.6 74.5 75.8 73.5 76.0 74.1 75.2
1708 1849 1586 1971 2022 1535 1284 2232 243 3314
Yes No Yes No Yes No Yes No Yes No 73.9 76.0 73.8 75.7 74.1 75.9 74.1 76.0 72.8 75.2
Mean Yo Predicted
4.34 4.28 4.30 4.32 4.79 3.82 4.36 4.25 7.14 4.07
4.45 4.10 4.26 4.28 4.73 3.67 4.21 4.32 5.07 4.21
Mean#
0.0001
0.63
0.0001
0.92
0.79
0.01
0.50
0.0001
0.91
0.04
P Levelt
51.3 44.3 52.4 44.6 52.9 42.4 49.2 46.2 65.1 46.2
29.3 21.9 28.2 23.2 27.6 22.6 29.6 23.1 39.9 24.4
Mean %
<0.0005
0.16
<0.0005
<0.0005
0.001
<0.0005
<0.0005
0.001
0.001
<0.0005
P Levelt
Methacholine Response to 5 5 mg/mL$
88.5 85.5 89.5 85.3 88.9 85.0 86.9 87.2 91.6 86.6
67.1 51.5 65.8 60.0 65.9 58.2 66.4 60.3 77.0 61.5
Mean %
0.066
0.839
0.009
0.004
0.036
<0.0005
<0.0005
<0.0005
<0.0005
<0.0005
P Levelt
Methacholine Response to 5 2 5 mg/mL$
'Numbers of subjects for same symptom vary slightly depending on number of missing values for different measurements. tBased on t tests for comparisons of means and x2 tests for comparisons of proportions. (post-BD FEV, - pre-BD FEV,) x 100 SBronchdilator response (ED) is defined as pre-BD FEV, SMethacholine response is defines as a drop of 20% or more in FEV, compared to baseline. From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 1033 863-1 872, 1993; with permission.
Asthma, physicianconfirmed
Shortness of breath
Wheeze apart from cold
Phlegm
Cough
Asthma, physicianconfirmed
Shortness of breath
Wheeze apart from cold
Phlegm
Cough
Symptom
FEV,
No. of Subjects*
Symptom Present?
Bronchodilator Response
Table 2. RELATIONSHIP OF SYMPTOMS TO LUNG FUNCTION AND BRONCHIAL RESPONSIVENESS IN LUNG HEALTH STUDY PARTICIPANTS
528
KANNER
62%
12%
2o 10 0
13%
~
Less than High School
High School
More than High School
Education Figure 1. Level of education of the Lung Health Study participants. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-I 872,1993;with permission.)
and a stronger family history of lung cancer and emphysema. The men were more educated. There was a tendency in both genders for a decrease in the FEV, percent of predicted and FEV,/FVC with increasing age (see Fig. 3). Women were more apt to react to methacholine with a 20% decline in the FEV,, but a high percentage of all participants had airways hyperresponsiveness (AHR) when concentrations of methacholine up to 25 mg/mL were used (see Fig. 7). AHR was defined as a decline in the FEV, of at least 20% from the baseline established by the inhalation of diluent when increasing concentrations of methacholine (1, 5,10,25 mg/mL) were inhaled from a dosimeter. Respiratory symptoms tended to be related to lung function and AHR; the poorer the lung function and the greater the responsiveness to methacholine, the greater the prevalence of respiratory symptoms (see Table 2).* The three groups (SIA, SIP, UC) were quite similar in most respects except that there was a higher percentage of women in SIA, resulting in a slightly lower measured FEV, in that group. Follow-up rates by group for interviews and lung function measurements for each annual visit are presented in Table 3. Much effort was put into ensuring high follow-up rates, and, as the table demonstrates, this was successful. At the fifth and final annual visit, 94% to 95% of the surviving participants had pulmonary function studies.'
529
EARLY INTERVENTlON IN CHRONIC OBSTRUCTIVE PULMONARY DlSEASE
34
34
34
m" 32
n & a
8 30
5
?? m
28
26 24
I
I
I
I
I
35-39
40-44
45-49
50-54
55-60
Age at randomization (years)
Figure 2. Average number of cigarettes smoked per day at screen 1 by age at randomization and gender. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 1031863-1 872, 1993; with permission.)
Table 3. ANNUAL VISIT FOLLOW-UP RATES ("A) BY STUDY GROUP Annual Visit (AV)
Usual care Interview Lung function Smoking intervention placebo Interview Lung function Smoking intervention ipratropium bromide (Atrovent) Interview Lung Function
+
+
AV1
AV2
AV3
AV4
AV5
95 89
95 90
94 89
93 88
96 94
95 92
94 91
94 89
93 88
97 94
96 92
95 92
95 90
94 88
97 95
From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, 1994; with permission.
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100% 90% 80% 70% 60%
50% 40%
30%
20% 10% 0Yo
0
-
FEVl Yo Pred. FEVl/FVC%
77%
74%
74%
11
35-39 40-44 45-49 50-54 55-60
Men
35-39 40-44 45-49 50-54 55-60 Women
Figure 3. Mean FEV, percent predicted and FEV,/FVC percent at screen 2 by age at randomization and gender. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
SMOKING INTERVENTION PROGRAM: DESIGN AND RESUL T S 2
All participants in the SIA and SIP groups were entered into an intensive group smoking intervention program. There was a common protocol at each of the 10 clinical centers. As noted previously, this consisted of a physician message, behavioral interview, orientation, group intervention sessions, use of nicotine gum, extended intervention sessions, and a maintenance program.I2 Physician Message
All physicians in the study were trained and certified to deliver a strong message to each SIA and SIP participant at the time of randomization into the study. This message provided personalized information about the status of the participant’s respiratory health and risks for clinically significant pulmonary disease. Also, the benefits of the treat-
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
531
100 Men
901 80
-
c (I)
7 2 % 73%
70-
C
6 1%
m
.8 ._ 60 -
57%
: r
50-
0
c
5 40$2
3020
-
10
-
Ir 0 Women
79%
55-60
035-39
40-44
45-49
50-54
Age at Randomization (years)
Figure 4. Percent of Lung Health Study participants reporting wheezing with a cold by age. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
ment plan in reducing their risks for lung, heart, and other diseases were discussed in detail. The relationship of cigarette smoking to health problems was emphasized. The use of the ipratropium or placebo inhaler and of nicotine gum was explained and prescribed. Behavioral Interview
The behavioral interview was done immediately following the physician message to ensure that the participant understood what the physician explained as well as to obtain a more extensive smoking history and to review the expectations of the smoking intervention program. The interventionist assessed the participant’s motivation to stop smoking and prepared him or her to give up this habit. A stop-smoking date (quit day) was negotiated with the participant. Orientation
The orientation was the first of the group sessions and occurred within 28 days of the physician message. It was led by an intervention
532
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6oB
50
{
40
a 0
r
30 0 c
K
a,
a 20
10 0 35-39
40-44
45-49
50-54
55-60
Age at Randomization (years)
Figure 5. Participants reporting wheezing most days or nights. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
specialist and focused on preparation for stopping smoking on quit day. Family members and support persons were urged to attend with the participant. Other matters covered were a review of the LHS research project, the physician message, information on randomized treatment assignment, blinding, and placebo and bronchodilator assignment. Group Intervention Four group sessions were held on consecutive days during quit week starting with quit day. Quit day, or session 1, was the time all participants were expected to stop smoking. Aerosol inhaler use was explained and demonstrated, and nicotine gum was distributed after its effects, side effects, and proper usage were discussed. The participants were taught to chew the gum slowly and intermittently and to let the nicotine be gradually released while the gum was kept between the cheek and gums. Strategies were introduced for smoking cessation, and daily monitoring of adherence or usage problems of the aerosol inhaler and nicotine gum were discussed. At each session, the participant was weighed and his or her exhaled carbon monoxide level was measured.
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
533
100
80
1
1M e n Women
30% 30%
<5
5-9
10 - 14
115
Percent Increase in FEVl
Figure 6. Frequency distribution of increase in FEV, (as percentage of baseline) in response to inhaled isoproterenol. (From Buist AS, Connett JE, Miller RD, et al, for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial [Lung Health Study]: Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993; with permission.)
Seven group sessions between weeks 2 and 12 were held to prevent smoking relapse and to discuss smoking-specific issues, health behavior, and stress management. Additional training was given on relapse prevention skills with a method for tapering nicotine gum usage. Regular 4-month follow-up visits were scheduled once the 12 group sessions were completed. Nicotine Gum Use At the first session, nicotine gum (2 mg/piece) was distributed at no charge to those who desired to use it after the physician had written a prescription for this agent. The nicotine gum distribution continued at individual follow-up visits. If a spouse or support person wished to use the gum at the same time to help break their own smoking habit, first they had to obtain a prescription from their personal physician and then the study would distribute the gum to them at no cost for up to a 6month period of time. Those participants who could not stop using the gum after 6 months met with their interventionist to develop a strategy for reduction in gum usage. A long-term nicotine gum usage protocol
534
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73.! 60 50 40
30
20 10
0 0.0 (diluent)
1 .o
5.0
10.0
25.0
Methacholine Concentration Figure 7 . Cumulative percentages of males (stippled bars) and females (light bars) responding to increasing doses of methacholine, with a positive response at each concentration being defined as a decline in FEV, of at least 20%. Baseline was the postdiluent value except for the response to diluent, in which case the prediluent value was used. ( f r o m Kanner RE, Connett JE, Altose MD, et al: Gender differences in airway hyperresponsiveness in smokers with mild COPD. Am J Respir Crit Care Med 150:956-961, 1994; with permission.)
was developed for those who could not discontinue the use of the gum. This included the approval of the participant’s personal physician. Pregnant and nursing women were instructed not to use the gum. Also, the presence of active peptic ulcer disease was considered a contraindication for gum usage.
Extended Intervention Extended intervention was made available to those who continued to smoke, to those who relapsed, and to those who did not initially enter the group program. Intervention was offered based on the participant’s readiness to enter a smoking cessation program. At this point, multiple options were offered to the participants, including additional restart and stay-quit support group sessions, individual sessions with an interventionist, and LHS physician visits.
Maintenance Maintenance was considered to have begun when the participant was properly using his or her inhaler and was no longer smoking. The
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
535
goals were to maintain a smoke-free status, facilitate proper inhaler usage, encourage compliance, and maintain good rapport with the participants. At least three maintenance meetings were held annually. There were weight management programs held twice yearly, quarterly newsletters, and frequent telephone and clinic contacts. The minimum contact schedule was monthly for the first 8 months of smoking abstinence.I2
EFFECTIVENESS OF THE SMOKING CESSATION PROGRAM',''
The cotinine and carbon monoxide validated smoking quit rates are shown in Figure 8. At the end of 5 years, 22% of the participants in the SIA and SIP groups had achieved sustained smoking cessation (nonsmokers for the 5-year period) validated by cotinine and/or carbon
' 6 la
50
. I -
II: C
.-0
40
. I -
(d v) v)
6
30
U 0)
c v)
2 20 -0
a
-> .-2
10
E
0)
r 0 .-0
m
0
AV 1
AV2
AV3 Annual Visit
AV4
AV5
Figure 8. Cotinineicarbon monoxide-validated smoking cessation rate (ordinate) as a function of years of follow-up. Usual care (UC) participants (squares) are compared with smoking intervention (SI)participants (circles). Both sustained (closed symbols) and crosssectional (open symbols) cessation rates are shown. Nonattenders of follow-up visits are counted as smokers. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.)
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monoxide (or both) measurements. Only about 5% of the UC group, however, were able to sustain a nonsmoking status over the 5-year period. The cross-sectional quit rates, which are the validated quit rates at each of the annual visits, were approximately 35% in the SIA and SIP groups with a slight rise to 38% at the fifth annual visit, and in the UC group this rose from 9% at the first annual visit to 21% by the end of the 5-year follow-up period. Predictors of smoking cessation during the initial 4 months of the LHS and relapse during the subsequent 20 months of the study have been published.'" This study demonstrated that the men had higher initial quit rates (40.8%) than the women (35.8%).The relapse rates at the 4- and 12-month visits, however, were similar (men 35%, women 34%). Among the sustained quitters at 12 months, 14% of the men and 18%of the women relapsed by the time of the 24-month visit (differences not significant).Baseline predictors of smoking cessation in women were having more education, being married, having quit for a longer period of time in the past, not having other smokers in the house, not having used nicotine gum in the past, not needing to smoke on awakening in the morning, not having asthma or breathlessness, and consuming fewer alcoholic drinks1" There were some differences in the predictors for the men. Being married, having more education, not having other smokers in the house, and not having used nicotine gum before were also predictors for quitting in the men. In addition, the older men had more success in quitting. Other predictors for the men were having a lower baseline cotinine level, having a higher FEV, percent of predicted, and having a support person with them during the orientation session.1o The most significant predictor of relapse to smoking at the 12month visit after having succeeded in quitting at the 4-month visit for both men and women was the reporting of any episode of smoking between quit day and the 4-month visit.'" For men, additional predictors of relapse during 4- to 12-month visit period were not having a support person at the orientation session9,'" and continuing to use nicotine gum at the 4-month visit. Those who relapsed drank fewer alcoholic drinks than those who remained quitters. There were no other significant predictors for the women.l0The major predictor of relapse between the 12and 24-month visits in both men and women was the continued use of nicotine gum. In women, the presence of another smoker in the house was a strong predictor of relapse during this period of time, whereas other predictors for men were obesity and being aware of missing cigarettes, another measure of nicotine dependence.l0 Weight gain was a problem for sustained quitters. At the 24-month visit, the mean absolute weight gain in the women was 6.2 kg (SD = 6.0 kg) and in the men was 5.4 kg (SD = 6.0 kg). The use of nicotine gum helped to delay the increase in weight, but when the gum was discontinued this effect was lost. Thus, the gum helped the participants to quit smoking and to delay the onset of the weight gain."
537
EARLY INTERVENTION IN CHRONIC OBSTIWCTIVE PULMONARY DISEASE
INHALER COMPLIANCE RESULTS
Inhaler compliance over the 5-year period is shown in Figure 9.' As can be noted, the self-reported compliance was better than that determined by weighing the canisters. Compliance tended to decline over the 5-year period.' There is also evidence that compliance with the inhaled medication was poorer than that determined by weighing the canisters. When a microprocessor monitoring device was incorporated into the inhaler unit in a subset of 93 participants at two of the LHS clinical centers, it was noted that even the weighing of the canisters overestimated the number of participants using the inhaler according to the study protoc01.'~ RESULTS OF THE INTENTION-TO-TREAT ANALYSIS
In the intention-to-treat analysis, the three groups were compared for differences in mortality and annual rates of change in lung function.'
I"
I
I
60 50 40
W
I
I
I
I
i
AV 1
AV2
AV3 Annual Visit
AV4
AV5
Figure 9. Inhaler compliance as a function of years of follow-up. Smoking intervention and placebo (circles) and smoking intervention and ipratropium bromide (triangles) are shown, with self-reported compliance indicated by open symbols and compliance as verified by canister weights indicated by closed symbols. Participants not attending the visit were classified as noncompliant, (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.)
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There were 149 deaths over the 5-year period, with 54 occurring in the SIA group, 44 in the SIP group, and 51 in the UC group (Table 4). The differences between the groups were not significant except that there were more deaths because of cardiovascular or cerebrovascular disease in the SIA group. This excess number of cardiovascular or cerebrovascular deaths appeared to be unrelated to the use of the inhaler. Only 8 of the 18 SIA participants who died as a result of these disorders reported using the inhaler at the visit before their death, as compared to five of the seven SIP cardiovascular or cerebrovascular deaths.' The changes in the postbronchodilator FEV, over the 5-year period for participants in the SIA, SIP, and UC groups are shown in Figure 10. The mean value for the postbronchodilator FEV, for each group at each annual visit is presented. At baseline, the mean FEV, value was 0.02 L less in the SIA group as a result of the higher percentage of women in this group. In the UC group, there was a linear decline in the FEV, over the 5-year period of follow-up. In the SIA group, and to a lesser extent in the SIP group, there was an initial improvement in the FEV, during the first year, which was followed by a linear decline over the next 4 years that approximately paralleled the decline seen in the UC group. This is also shown in Figure 11 using a best fit model of the changes in FEV,. No changes can be detected in the annual rate of change when comparing the SIA and SIP groups. Because this is an intention-to-treat analysis, the comparisons are made between the three groups regardless of the smoking status of the members of the group or their inhaler usage. This tends to minimize the effects of smoking cessation. In Figure 12, the data are shown according to smoking status for participants in the SIP group who were either sustained quitters or continuous smokers. It can be seen that the annual rate of decline in the sustained quitters is clearly less than what is seen in the continuous smokers. The largest annual gain in FEV, occurs during the first year after smoking cessation, although the curves continue to diverge through year 5.
Table 4. DEATHS WITHIN 5 YEARS OF RANDOMIZATION Treatment Group Cause
SIA
SIP
uc
Cardiovascular disease Lung cancer Other
18 18 18
7 20 17
12 19 20
Total
54
44
51
SIA = Smoking intervention with ipratropium bromide (Atrovent); SIP = smoking intervention with placebo; UC = usual care. From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.
539
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
2.80 2.75 v)
2.70 C .-
5 w
LL C
2.65 2.60
cci
8
2.55 2.50 I
I
I
I
I
I
Screen 2
AV1
AV2
AV3
AV4
AV5
Annuai Visit Figure 10. Mean postbronchodilator FEV, over the course of the study in all participants in whom the measurement was made. Circles and the dotted line represent the smoking intervention and placebo group, triangles and the solid line represent the smoking intervention and ipratropium bromide group, and squares and the dashed line represent the usual care group. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 27214971505, copyright 1994, American Medical Association; with permission.)
Table 5. MEAN CUMULATIVE DECLINES (i- SD) IN PREBRONCHODILATOR FEV, (mL)* ~
~
Time Interval
Entry* to year 5 (first part) Entry* to year 5 (second part) Year 1 to year 5 (first part) Year 1 to year 5 (second part) Year 5, first part to second
Usual Care n = 1380 249 263 196 210 14
?
236
t 248 t 220 2 236
+- 141
Special Intervention Placebo n = 1448 188 196 169 178 9
246 t 257 i 208 -c 217 ? 135
?
Special Intervention Atroventt n = 1470 172 208 178 214 36
263 t 270 t 230 ? 248 ? 173 ?
'Restricted to participants who attended annual visit 1 and both parts of annual visit 5. tlpratropium bromide (Atrovent). SEntry here refers to screen 3. f r o m Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, copyright 1994, American Medical Association; with permission.
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2.80 I 2.75 2.70 2.65 2.60
.. ..
2.55
Y
\
2.50 I
I
I
I
I
I
Screen2
AV1
AV2
AV3
AV4
AV5
Annual Visit Figure 11. Best-fit model of changes in postbronchodilator FEV, over the course of the study. FEV, undergoes a one-time change during the first year of follow-up and then declines linearly, the initial change being independent of the subsequent decline. Circles are observed means for the smoking intervention and placebo group (SIP), triangles for the smoking intervention and ipratropium bromide group (SIA), and squares for the usual care group (UC).Predicted values for the SIA group are represented by a solid line, for the SIP group by a dotted line, and for the UC group by a dashed line. (from Anthonisen NR. Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 27211497-1505, copyright 1994, American Medical Association; with permission.)
Table 5 presents the cumulative declines in FEV, for the three study groups for the 5-year period of the study and for the period from the first to fifth annual visit. This includes the two fifth annual visits, which allowed for the evaluation of the effect of stopping the use of the inhalers at the initial fifth annual visit. It can be seen that in the SIA and SIP groups the cumulative loss over the 5-year period is substantially less than that seen in the UC group. Any benefit from inhaled ipratropium was lost at the second part of the fifth annual visit, when the inhalers were no longer being used.' Thus, the ipratropium bromide has a short-term benefit while it is being used, but it does not have an effect on the long-term decline in FEV,.' The results of the intention-to-treat analysis are consistent with a significant improvement in FEV, from smoking cessation. This improvement occurs primarily in the first year following stopping smoking. Thus, this is the most important intervention that a physician can offer smokers with mild COPD. Also, ipratropium has a beneficial effect on FEV, while it is being used, but this benefit is lost once the drug is
541
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
I
\ - Sustained Quitters
a
-
Y
2.7
3
Continuing S rnokers
2 2.4
I
I
Screen2
AV1
1
I
AV2 AV3 Annual Visit
I
I
AV4
AV5
I
Figure 12. Mean postbronchodilator FEV, for participants in the smoking intervention and placebo groups who were sustained quitters (open circles) and continuous smokers (closed circles). The two curves diverge sharply after baseline. (From Anthonisen NR, Connett JE, Kiley JP, et al, for the Lung Health Study Research Group: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:1497-1505, 1994; with permission.)
stopped, and it does not affect the annual rate of change of FEV, in this population.' AIRWAY RESPONSIVENESS IN THE LUNG HEALTH STUDY*,l 5
One of the original goals of the LHS was to recruit a cohort of participants with mild COPD of whom at least 20% exhibited AHR. The purpose was to evaluate the Dutch hypothesis5, in a prospective study. This hypothesis states that AHR is a determinant of decline of FEV, in smokers, with those with the greatest degree of AHR having the most rapid declines. The prevalence of AHR in the LHS participant population was considerably higher than expected, as can be seen in Figures 7 and 13. The prevalence of men and women with AHR increased with a decrease in the FEV, as a percent of predicted.15The cumulative percentages of participants responding to increasing doses of methacholine were 87'% of the women and 62% of the men at or before the highest concentration of methacholine used (25 mg/mL); at 5 mg/mL (a level at which most patients with asthma would respond), a quarter of the men and almost
542
KANNER
100
:80 S
0
a
a
40
c
0 1
C a,
p
a
20
o !
I
I
I
I
I
1
5 59
60-64
65-69
70-74
75-79
> 79
1
Baseline FEV, Percent of Predicted
Figure 13. Percentages of men and women in the Lung Health Study responding to concentrations of methacholine 5 5 mg/mL and 5 25 rng/mL with a 2 20% decline in FEV, from baseline, by baseline FEV, as percent of predicted. (Closed circles = women, 25 mg/mL; open squares = men, 25 mg/mL; dotted circles = women, 5 mg/mL; dotted squares = men, 5 mg/mL.) ( f r o m Tashkin DP, Altose MD, Bleecker ER, et al, and the Lung Health Study Research Group: The Lung Health Study: Airways responsiveness to inhaled metacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 145:301-310, 1992; with permission.)
half of the women demonstrated AHR as defined by a decline in the FEV, of 20% from baseline.8Thus, a marked gender difference was seen. The higher prevalence in women is thought to be due to the women having smaller airways because when the data are adjusted for the measured FEV, the differences are no longer seen.8 Thus, AHR was much more prevalent in this population of smokers with mild COPD than was anticipated, and AHR was inversely related to the level of pulmonary function. Analysis of the predictive consequences of this finding is currently in progress.
SUMMARY The major findings of the LHS that have been reported thus far are that an effective smoking cessation program can be developed that can
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
543
produce more than a 20% success rate in getting smokers to give up the habit permanently, and that by stopping smoking, individuals with early COPD benefit by having an initial improvement in lung function and a slowing of the annual loss of their FEV,. The use of a bronchodilator has a short-term effect in improving the FEV1, but it does not affect long-term changes in lung function. AHR is common in patients with mild-to-moderate COPD. The reward for a smoker to give up the habit is an initial gain in FEV, and a subsequent close to normal annual rate of decline of this pulmonary function parameter. These results should provide a positive incentive for smokers to quit and thereby decrease the morbidity and mortality caused by the use of tobacco.
References 1. Anthonisen NR, Connett JE, Kiley JP, et a1 for the Lung Health Study Research Group: Effects of smoking intervention and the use pf an inhaled anticholinergic bronchodilator on the rate of decline of FEV,: The Lung Health Study. JAMA 272:14971505, 1994 2. Buist AS, Connett JE, Miller RD, et a1 for the Lung Health Study Research Group: Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study): Baseline characteristics of randomized participants. Chest 103:1863-1872, 1993 3. Centers for Disease Control: Cigarette smoking among adults-United States, 1993. MMWR 43:925-930, 1994 4. Connett JE, Kusek JW, Bailey WC, et a1 for the Lung Health Study Research Group: Design of the Lung Health Study: A randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Controlled Clin Trials 14:3%19S, 1993 5. de Vries K, Booij-Noord H, Goei JT, et al: Hyperreactivity of the bronchial tree to drugs, chemical and physical agents. In Orie NGM, Sluiter HJ (eds): Bronchitis 11. Assen, the Netherlands, Royal Van Gorcum, 1964, pp 167-180 6. Enright PL, Johnson LR, Connett JE, et al: Spirometry in the Lung Health Study: 1. Methods and quality control. Am Rev Respir Dis 143:1215-1223, 1991 7. Fletcher C, Peto R, Tinker C, et a1 The Natural History of Chronic Bronchitis and Emphysema. Oxford, Oxford University Press, 1976 8. Kanner RE, Connett JE, Altose MD, et a1 for the Lung Health Study Research Group: Gender differences in airway hyperresponsiveness in smokers with mild COPD. Am J Respir Crit Care Med 150:956-961, 1994 9. Murray RP, Johnston JJ, Dolce JJ, et al: Social support for smoking cessation and abstinence: The Lung Health Study. Addict Behav 20:159-170, 1995 10. Nides MA, Rakos RF, Gonzales D, et a1 for the Lung Health Study Research Group: Predictors of initial smoking cessation and relapse through the first 2 years of the Lung Health Study. J Consult Clin Psychol 63:60-69, 1995 11. Nides M, Rand C, Dolce J, et al: Weight gain as a function of smoking cessation and 2-mg nicotine gum use among middle aged smokers with mild lung impairment in the first 2 years of the Lung Health Study. Health Psychol 13:354-361, 1994 12. O’Hara P, Grill J, Rigdon MA, et a1 for the Lung Health Study Research Group: Design and results of the initial intervention prograin for the Lung Health Study. Prev Med 22~304-315,1993 13. Orie NGM, Sluiter HJ, De Vries K, et al: The host factor in bronchitis. In Orie NGM, Sluiter HJ (eds): Bronchitis. Assen, the Netherlands, Royal Van Gorcum, 1961; pp 43-59 14. Rand CS, Wise RA, Nides M, et al: Metered-dose inhaler adherence in a clinical trial. Am Rev Respir Dis 146:1559-1564, 1992 15. Tashkin DP, Altose MD, Bleecker ER, et a1 and the Lung Health Study Research
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Group: The Lung Health Study: Airways responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 145:301-310, 1992 16. U.S. Public Health Service: The health consequences of smoking: Chronic obstructive lung disease. A report of the surgeon general. Office of Smoking and Health, DHHS Publication No. (PHS) 84-50205, 1984
Address wprint rrqitests to John E. Connett, PhD LHS Data and Coordinating Center 2221 University Avenue SE Suite 200 Minneapolis, MN 55414-3080
APPENDIX
The principal investigators and senior staff of the clinical and coordinating centers, the NHLBI, members of the Safety and Data Monitoring Board, and the Morbidity and Mortality Review Board are as follows: Case Western Reserve University, Cleveland, OH M. D. Altose, MD (Principal Investigator) A. F. Comers, MD (Co-Principal Investigator) S. Redline, MD (Co-Principal Investigator) C. D. Deitz, PhD R. F. Rakos, PhD Henry Ford Hospital, Detroit, MI W. A. Conway, Jr., MD (Principal Investigator) A. DeHorn, PhD (Co-Principal Investigator) J. C. Ward, MD (former Co-Principal Investigator) C. S. Hoppe-Ryan, CSW R. L. Jentons, MA J. A. Reddick, RN C. Sawicki, RN, MPH Johns Hopkins University School of Medicine, Baltimore, MD R. A. Wise, MD (Principal Investigator) S. Permutt, MD (Co-Principal Investigator) C. S. Rand, PhD (Co-Principal Investigator)
Mayo Clinic, Rochester, MN P. D. Scanlon, MD (Principal Investigator) L. J. Davis, PhD (Co-Principal Investigator) R. D. Hurt, MD (Co-Principal Investigator) R. D. Miller, MD (Co-Principal Investigator) D. E. Williams, MD (Co-Principal Investigator) G. M. Caron G. G. Lauger, MS S. M. Toogood (Pulmonary Function Quality Control Manager) Oregon Health Sciences University, Portland, OR A. S. Buist, MD (Principal Investigator) W. M. Bjornson, MPH (Co-Principal Investigator) L. R. Johnson, PhD (LHS Pulmonary Function Coordinator) 545
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University of Alabama at Birmingham, Birmingham, AL W. C. Bailey, MD (Principal Investigator and Associate Chief of Staff for Education, Department of Veterans Affairs Medical Center, Birmingham) C. M. Brooks, EdD (Co-Principal Investigator) J. J. Dolce, PhD D. M. Higgins M. A. Johnson B. A. Martin University of California, Los Angeles, CA D. P. Tashkin, MD (Principal Investigator) A. H. Coulson (Co-Principal Investigator) H. Gong, MD (former Co-Principal Investigator) P. I. Harber, MD (Co-Principal Investigator) V. C. Li, PhD, MPH (Co-Principal Investigator) M. Roth, MD (Co-Principal Investigator) M. A. Nides, PhD M. S. Simmons I. P. Zuniga University of Manitoba, Winnipeg, Canada N. R. Anthonisen, MD (Principal Investigator) J. Manfreda, MD (Co-Principal Investigator) R. P. Murray, PhD (Co-Principal Investigator) S. C. Rempel-Rossum J. M. Stoyko University of Minnesota Coordinating Center, Minneapolis, MN J. E. Connett, PhD (Principal Investigator) M. 0. Kjelsberg, PhD (Co-Principal Investigator) M. K. Cowles, PhD D. A. Durkin P. L. Enright, MD K. J. Kurnow, MS W. W. Lee, MS P. G. Lindgren, MS S. Mongin, MS P. O’Hara, PhD (LHS Intervention Coordinator) H. T. Voelker L. Waller, PhD University of Pittsburgh, Pittsburgh, PA G. R. Owens, MD (Principal Investigator) R. M. Rogers, MD (Co-Principal Investigator) J. J. Johnston, PhD F. P. Pope, MSW F. M. Vitale, MA
EARLY INTERVENTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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University of Utah, Salt Lake City, UT* I<. E. Kanner, MD (Principal Investigator) M. A. Rigdon, PhD (Co-Principal Investigator) K. C. Benton 1'. M. Grant Safety and Data Monitoring Board M. Becklake, MD B. Burrows, MD P. Cleary, PhD P. Kimbel, MD (Chairperson; deceased October 27, 1990) L. Nett, RN (former member) J. K. Ockene, PhD R. M. Senior, MD (Chairperson) G. L. Snider, MD W. Spitzer, MD (former member) 0. D. Williams, PhD National Heart, Lung and Blood Institute Staff, Bethesda, MD S. S. Hurd, PhD (Director, Division of Lung Diseases) J. P. Kiley, PhD (Project Officer) M. C. Wu, PhD (Div. of Epidemiology & Clinical Applications) Mortality and Morbidity Review Board S. M. Ayres, MD R. E. Hyatt, MD B. A. Mason, MD *The Salt Lake City Center has been assisted by the Clinical Research Center, Public Health Research Grant M01-RR00064 from the National Center for Research Resources.