Smoking reduction and the rate of decline in FEV(1): results from the Lung Health Study.

Previous findings from the Lung Health Study have shown that smoking cessation and sustained abstinence substantially reduce the rate of decline in forced expiratory volume (FEV(1)) among smokers with early chronic obstructive pulmonary disease (COPD) when compared with continuing smoking. Intermittent quitters demonstrated rates of FEV(1) decline intermediate between those of sustained quitters and continuing smokers. In this study, data from 1,980 participants were analysed from 10 centres of the Lung Health Study in the USA and Canada. All participants were smokers with mild-to-moderate COPD who were unable to quit smoking at any time during the 1st yr of the study. No linear relationship was found between reduction in cigarettes per day and changes in FEV(1) during the 1st yr of the study. However, examination of the data revealed that this relationship was nonlinear. Further analysis found that smokers who reduced their cigarettes per day to very low amounts had smaller declines in FEV(1) than those who did not. Reduction in cigarettes per day was associated with only minimal changes in the presence of chronic respiratory symptoms. In conclusion, compensatory changes in smoking behaviour may account for the limited and unpredictable impact of smoking reduction on lung function decline and symptom prevalence when compared with smoking cessation.

Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study.

BACKGROUND: Many persons who attempt to quit smoking have made previous unsuccessful attempts to quit with pharmacologic aids. An understanding of the impact of these previous attempts to quit is vital for selecting medications that may be more successful in a future attempt to quit. In particular, the effect of repeated use of bupropion SR (Zyban; INN, amfebutamone) on abstinence rates has not been studied previously. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in 450 smokers who had previously used bupropion in a smoking cessation attempt. The study consisted of a screening phase, a 12-week treatment phase, and a follow-up at month 6. Participants made regular clinic visits throughout the treatment phase during which they received brief counseling sessions to encourage abstinence from smoking. The primary end point was continuous abstinence from smoking from weeks 4 through 7. Secondary efficacy end points were examined throughout the treatment phase and at follow-up after 6 months. RESULTS: In participants receiving bupropion SR, 27% (61 of 226) remained abstinent throughout the period from weeks 4 through 7 compared with 5% (11 of 224) of participants receiving placebo (P <.001). Significantly (P <.001) more participants who received bupropion SR during the treatment phase remained continuously abstinent from the start of week 4 through month 6 (27 of 226; 12%) compared with participants who received placebo (5 of 224; 2%). Eleven participants receiving placebo (5%) and 19 participants receiving bupropion SR (8%) stopped taking the study medication because of an adverse event. CONCLUSIONS: Bupropion SR is an effective medication for retreatment of smokers who have used bupropion SR previously.

Unpredictability of deception in compliance with physician-prescribed bronchodilator inhaler use in a clinical trial.

OBJECTIVE: To identify subject characteristics that may be predictive of intentional dumping of metered-dose inhalers (MDIs) during a clinical trial. DESIGN: Nebulizer Chronologs (NCs; Medtrac Technologies; Lakewood, CO), which record the date and time of each MDI actuation, were attached to the MDIs of participants who were given a prescribed medication schedule to follow in a clinical trial. Participants were not informed of the function of the NC or that their medication use was being monitored. SETTING: The Lung Health Study, a 5-year clinical trial to evaluate the effect of intensive smoking cessation counseling and regular use of an inhaled bronchodilator on the progression of COPD. PARTICIPANTS: One hundred one smokers, 35 to 60 years of age, with mild to moderate airways obstruction enrolled in The Lung Health Study. MEASUREMENTS AND RESULTS: Thirty of these 101 participants (30%) actuated their inhalers > 100 times within a 3-h interval on at least one occasion during the first year of this 5-year trial. Only 1 of an additional 135 participants who had full foreknowledge of the MDI monitoring capability of the NC did so. Most of these dumping episodes occurred shortly before a clinic follow-up visit, suggesting an active attempt to hide noncompliance from the clinic staff. Whereas self-reported inhaler usage and canister weights were similar for the "dumpers" and "nondumpers," NC data indicated significantly lower compliance rates for dumpers (chi(2); p < 0.05). When demographic variables, treatment and clinic assignments, smoking status, pulmonary function test results, respiratory symptoms, and disease history of dumpers and nondumpers were analyzed, no predictors of dumping could be found. CONCLUSIONS: Deception among noncompliers occurs frequently in clinical trials, is often not revealed by the usual methods of monitoring, and cannot be predicted by data readily available in clinical trials.

Over-the-counter nicotine patch therapy for smoking cessation: results from randomized, double-blind, placebo-controlled, and open label trials.

OBJECTIVES: The purpose of this study was to determine the efficacy and safety of the nicotine patch for smoking cessation in an over-the-counter environment. The years of study were 1994 to 1995. METHODS: Parallel 6-week trials were conducted: a placebo-controlled trial of no-cost 22-mg, 24-hour nicotine patch therapy and an open label trial of the same therapy with patches purchased by subjects. Participants (n = 958) were 18 years or older, had smoked at least 15 cigarettes daily for at least 6 months, and were enrolled at 3 study sites. The main outcome measure was self-reported smoking abstinence confirmed by expired carbon monoxide measurements. RESULTS: Smoking cessation rates in the placebo-controlled trial were 16.8% and 9.6% at week 6 and 8.7% and 4.3% at week 24 for the active patch and placebo groups, respectively. Smoking cessation rates in the open label-pay trial were 19.0% and 10.8% at weeks 6 and 24, respectively. A slight increase in adverse cardiovascular events was noted only in the open label-pay group in comparison with the placebo group. CONCLUSIONS: In an over-the-counter environment, the 22-mg, 24-hour nicotine patch is effective and safe for smoking cessation treatment.

A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.

BACKGROUND AND METHODS: Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. RESULTS: The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. CONCLUSIONS: Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

Validation of the Doser, a new device for monitoring metered-dose inhaler use.

BACKGROUND: Electronic monitoring of medication use has proved valuable in both clinical and research settings. The Doser, a new and inexpensive commercially available device for monitoring metered-dose inhaler (MDI) use, displays 3 measures of daily use of an attached MDI: (1) the daily total of actuations, (2) the number of doses remaining in the MDI, and (3) the number of actuations on each of the preceding 30 days for later recall. OBJECTIVE: We sought to validate the accuracy of the Doser with several commonly prescribed MDIs. METHODS: In the laboratory, clinic personnel actuated an MDI with an attached Doser several times in succession on 3 consecutive days and recorded each of the 3 measures of MDI use (study 1). In study 2 clinic personnel carried an MDI and attached Doser with them for 4 weeks, actuating the MDI according to a prescribed protocol each morning and evening and again recording each of the 3 measures of daily use. In addition, during 2 weeks of study 2, a thermistor-based Nebulizer Chronolog was attached to the MDI to electronically record the date and time of each actuation. In study 3 clinic patients had both a Doser and Nebulizer Chronolog attached to their routinely used inhalers for 2 weeks and a Doser alone during a separate 2-week period. RESULTS: In study 1 agreement was 99% to 100% among the 3 Doser measures, and each measure agreed with actual use by self-report 97% of the time. In study 2 agreement among the 3 Doser measures of use ranged from 98% to 99%. Agreement between each of the 3 Doser measures and the Nebulizer Chronolog ranged from 90% to 93%. Agreement between each of the 3 Doser measures and actual use ranged from 96% to 97%, and the Nebulizer Chronolog agreed with actual use 93% of the time. In study 3 Doser and Nebulizer Chronolog agreement with patient self-report were 85% and 80%, respectively. Agreement between the Doser and Nebulizer Chronolog was 76%. Several failures of the thermistor-based Nebulizer Chronolog occurred, and occasional mechanical problems occurred with the Doser, primarily on particular types of MDI canisters. CONCLUSION: The Doser provides an accurate measure of MDI use with most commonly prescribed medications and may be useful for monitoring MDI use by investigators, clinicians, and patients.

Levels of cotinine associated with long-term ad-libitum nicotine polacrilex use in a clinical trial.

Studies of nicotine replacement by 2 mg nicotine polacrilex gum (NG) have typically found that one half to one third of plasma nicotine in recent smokers is replaced. This 5-year study sought to find the extent of nicotine replacement among ex-smokers in the longer term and to identify a mechanism for this relationship. The sample was the special intervention group (N = 3923) in the Lung Health Study, a controlled clinical trial involving smoking cessation. The extent of nicotine replacement was assessed by levels of salivary cotinine. Cotinine levels of ex-smokers using NG after 1 year (219 +/- 149 ng/ml) were similar to those in continuing smokers (290 +/- 159 ng/ml). After 5 years, cotinine levels were the same for NG-using ex-smokers (316 +/- 276 ng/ml), NG-using smokers (309 +/- 240 ng/ml), and NG-non-using smokers (311 +/- 198 ng/ml). Salivary cotinine among NG users at 1 year was only weakly correlated with baseline cotinine levels prior to smoking cessation. Although NG users appear to re-establish cotinine levels characteristic of their smoking, the mechanism by which this occurs remains unclear.

Effects of multiple attempts to quit smoking and relapses to smoking on pulmonary function. Lung Health Study Research Group.

The effect of intermittent smoking on pulmonary function was assessed among participants in the Lung Health Study, 5887 adult smokers with evidence of early chronic obstructive pulmonary disease (COPD), followed up for 5 years. The mean annual rate of loss in FEV1% of predicted after year 1 was smallest for those who quit at some point during the first year of the study and stayed quit (-0.33%/year, +/-0.05%), intermediate for those who smoked intermittently during the study (-0.58%/year, +/-0.05%) and greatest for those who continued to smoke throughout the study (-1.18%/year, +/-0.03%). Surprisingly, those who made several attempts to quit smoking had less loss of lung function at comparable cumulative doses of cigarettes than those who continued to smoke. Quitting smoking for an interval followed by relapse to smoking appeared to provide a measurable and lasting benefit in comparison to continuous smoking. In this early COPD population, not only quitting smoking but attempts to quit smoking can prevent some loss of lung function. These results provide some encouragement to exsmokers who relapse on their way to complete cessation.

Intervention for relapse to smoking: the Lung Health Study restart programs.

The Lung Health Study enrolled 3,923 participants in a smoking cessation intervention program, and followed them for 5 years. The study provided intensive group interventions for participants who had relapsed. The purpose of this analysis was to describe and evaluate these Restart programs. Among 1,004 relapsed participants, the percent not smoking at 5th year was higher for men who had used Restart (47) compared to those who had not (28), but not for women (42 vs. 33). Overall, there was equivocal evidence of the impact of the Restart programs due to limitations in the evaluation design. Because relapse is a common feature of efforts to quit smoking, relapse intervention programs need further study and more rigorous evaluation.

Trends in compliance with bronchodilator inhaler use between follow-up visits in a clinical trial.

STUDY OBJECTIVE: To assess objectively measured, long-term trends in compliance with physician-prescribed metered-dose inhaler (MDI) use during a clinical trial. DESIGN: A prospective study. SETTING: The Lung Health Study, a 5-year clinical trial to determine the effect of special intervention with an intensive smoking cessation program and bronchodilator therapy in cigarette smokers 35 to 60 years of age with minimal to moderate airflow limitation due to COPD. PARTICIPANTS: Two hundred thirty-one participants who were issued an MDI with an attached Nebulizer Chronolog (NC) (Forefront Technologies Inc; Lakewood, Colo) which electronically records the date and time of each MDI actuation. One hundred two participants were not informed of the recording capabilities of the attached NC, while 129 participants were aware of the NC's monitoring function. INTERVENTION: Following an initial 12-week period of counseling, participants returned to the clinic every 4 months. MEASUREMENTS AND RESULTS: Analysis of the data from the NC collected over a period of 2 years indicates that compliance with the prescribed medication regimen was best immediately following each follow-up visit and gradually declined during the interval between follow-up visits. The level of compliance after each visit was lower for each successive follow-up. These trends could not be observed from self-report or weighting the medication canisters at follow-up visits. The participants who were informed of the NC's function and who were provided with detailed feedback about their inhaler use generally showed better compliance.

Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study. Lung Health Study Research Group.

STUDY OBJECTIVE: To assess cardiovascular conditions and other side effects associated with the use of nicotine polacrilex (NP), 2 mg. DESIGN: A multicentered randomized control trial of early intervention for the prevention of COPD. SETTING: Ten university medical centers in the United States and Canada. PARTICIPANTS: Adult smoking volunteers with evidence of early COPD; 3,923 in intervention and 1,964 controls. INTERVENTION: Smoking cessation program, including NP. MEASUREMENTS: Data on hospitalizations were collected annually. Data on reported NP side effects were collected at 4-month intervals for intervention participants. RESULTS: The rates of hospitalization for cardiovascular conditions and cardiovascular deaths during the 5 years of the study were not related to use of NP, to dose of NP, or to concomitant use of NP and cigarettes. About 25% of NP users reported at least one side effect, but most were very minor and transient. Side effects associated with discontinuance of NP in 5% or more of users included headache, indigestion, mouth irritation, mouth ulcers, and nausea. There was no evidence that concomitant use of NP and cigarettes was associated with elevated rates of reported side effects. Participants in the smoking cessation intervention who received intensive levels of instruction and monitoring of NP use (initially at 12 meetings during 3 months) appeared to report significantly lower rates of side effects (dizziness, headache, and throat irritation) than control participants, presumed to have less instruction and monitoring. CONCLUSIONS: NP, as used in the Lung Health Study, appears to be safe and unrelated to any cardiovascular illnesses or other serous side effects.

Predictors of initial smoking cessation and relapse through the first 2 years of the Lung Health Study.

Analyses were made separately for men and women of the predictors of end-of-treatment (4 months) smoking cessation and subsequent relapse at 12 and 24 months among 3,923 participants enrolled in the Lung Health Study's 12-week cognitive-behavioral group smoking cessation program. Nicotine gum (2 mg) was available to all participants. Men were more likely than women to quit smoking initially, but relapse rates were similar for both genders. Baseline variables associated with initial quitting for both genders included greater education, lower nicotine dependence, and fewer respiratory symptoms. The best predictor of relapse between 4 and 12 months was smoking at least 1 cigarette between quit day and 4 months. Nicotine gum use at 12 months predicted relapse by 24 months for both genders. Greater social and environmental support for quitting smoking were the only factors that predicted both initial quitting and relapse for both genders. Clinical implications are discussed.

Salivary cotinine, frequency of cigarette smoking, and body mass index: findings at baseline in the Lung Health Study.

This study investigates the relation of salivary cotinine and of the reported number of cigarettes smoked per day to body mass index among middle-aged male (n = 3,538) and female (n = 2,096) cigarette smokers participating in screening for entry to a clinical trial of early intervention in chronic obstructive pulmonary disease (Lung Health Study) from 1986 to 1989. Both before and after controlling for age, education, and alcohol intake, the number of cigarettes smoked per day was positively related to body mass index among both men and women, whereas salivary cotinine levels were negatively related to body mass index among both men and women. The opposite relation of salivary cotinine and of reported number of cigarettes smoked per day to body mass index is discussed with regard to nicotine metabolism, energy intake, and measurement issues in the assessment of cigarette smoke exposure.

Improving inhaler adherence in a clinical trial through the use of the nebulizer chronolog.

This study examined whether utilizing an electronic medication monitor (Nebulizer Chronolog) to provide participants with detailed feedback on their metered-dose inhaler (ipratropium bromide or placebo) usage patterns would result in closer adherence to the prescribed regimen of two inhalations three times daily compared to a control group not receiving feedback. Adherence was also measured by canister weighing and self-report. Two-hundred fifty-one consecutive special intervention participants from the University of California, Los Angeles, and Johns Hopkins University centers of a National Heart, Lung, and Blood Institute-sponsored clinical trial were enrolled in this ancillary study. Compared to controls, feedback participants at the 4-month follow-up adhered more closely to the prescribed three sets per day (mean 1.95 vs 1.65) and used the prescribed two actuations in a greater percentage of sets (80 percent vs 60.3 percent). These results indicate that electronic monitoring of metered-dose inhaler use with a Nebulizer Chronolog in a clinical trial not only provides a more accurate assessment of adherence to prescribed inhaler use, but also enhances adherence when participants are given feedback of the monitoring results.