Richard E. Kanner

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial

Context Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality. Contribution In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking. Implications Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking. The Editors Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1). The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (3, 4). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization. Methods The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention. All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents. When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The other category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS. Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits. Statistical Analysis Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the KaplanMeier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons. Role of the Funding Source This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication. Results Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1FVC ratio 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P= 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers. Table 1. Baseline Characteristics of Lung Health Study Participants There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n= 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n= 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2). Table 2. Causes of Death by Treatment Group Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P= 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except other, death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P= 0.01). Figure 1. All-cause 14.5-year survival. P Figure 2. Mortality rates at 14.5 years by cause. When survival was analyzed according to smoking habit, it differed significantly between groups (P< 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 p

Heart rate variability associated with particulate air pollution

BACKGROUND Epidemiologic studies have linked fine particulate air pollution with cardiopulmonary mortality, yet underlying biologic mechanisms remain unknown. Changes in heart rate variability (HRV) may reflect changes in cardiac autonomic function and risk of sudden cardiac death. This study evaluated changes in mean heart rate and HRV in human beings associated with changes in exposure to particulate air pollution. METHODS Repeated ambulatory electrocardiographic monitoring was conducted on 7 subjects for a total of 29 person-days before, during, and after episodes of elevated pollution. Mean HR, the standard deviation of normal-to-normal (NN) intervals (SDNN), the standard deviation of the averages of NN intervals in all 5-minute segments of the recording (SDANN), and the square root of the mean of squared differences between adjacent NN intervals (r-MSSD) were calculated for 24-hour and 6-hour time segments. Associations of HRV with particulate pollution levels were evaluated with fixed-effects regression models. RESULTS After controlling for differences across patients, elevated particulate levels were associated with (1) increased mean HR, (2) decreased SDNN, a measure of overall HRV, (3) decreased SDANN, a measure that corresponds to ultralow frequency variability, and (4) increased r-MSSD, a measure that corresponds to high-frequency variability. The associations between HRV and particulates were small but persisted even after controlling for mean HR. CONCLUSIONS This study suggests that changes in cardiac autonomic function reflected by changes in mean HR and HRV may be part of the pathophysiologic mechanisms or pathways linking cardiovascular mortality and particulate air pollution.

A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction—measured by the Fagerstrom Test of Nicotine Dependence—in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight α and three β nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0×10−5; odds ratio = 1.82; 95% confidence interval 1.39–2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.

Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease : The Lung Health Study

PURPOSE To evaluate the effects of randomly assigning smokers who have early chronic obstructive pulmonary disease (COPD) to a smoking-cessation intervention on the symptoms of chronic cough, chronic phlegm production, wheezing and shortness of breath, and to determine the effects of quitting smoking on these symptoms. SUBJECTS AND METHODS A total of 5,887 male and female smokers 35 to 60 years of age with early COPD [defined as a forced expiratory volume in the first second (FEV1) of 55% to 90% of predicted and FEV1/forced vital capacity (FVC) <0.70] were enrolled in a 5-year clinical trial. Two-thirds of participants were randomly assigned to smoking-intervention groups and one-third to a usual-care group. The intervention groups attended 12 intensive smoking-cessation sessions that included behavior modification techniques and the use of nicotine chewing gum. One intervention group was treated with ipratropium bromide by inhaler; the other intervention group received placebo inhalers. The usual-care group was advised to stop smoking. All participants were followed annually. Smoking status was biochemically validated by salivary cotinine measurements or exhaled carbon monoxide values. RESULTS Validated 5-year sustained smoking cessation occurred in 22% of participants in the intervention compared with only 5% of participants in the usual-care group. At the end of the study, the prevalence of each of the four symptoms in the two intervention groups was significantly less than in the usual-care group (P <0.0001). For example, among participants who did not report cough at baseline, 15% of those in the intervention groups had cough at least 3 months during the year, compared with 23% of those in usual care. Sustained quitters had the lowest prevalence of all four symptoms, whereas continuous smokers had the greatest prevalence of these symptoms. Changes in symptoms occurred primarily in the first year after smoking cessation. Respiratory symptoms were associated with greater declines in FEV1 during the study (P <0.001). Ipratropium bromide had no long-term effects on respiratory symptoms. CONCLUSIONS In this prospective randomized trial using an intention-to-treat analysis, smokers with early COPD who were assigned to a smoking-cessation intervention had fewer respiratory symptoms after 5 years of follow-up.

Cigarette Smoking: Risk Factor for Premature Facial Wrinkling

OBJECTIVE To determine if cigarette smoking is a risk factor for the development of premature facial wrinkling. DESIGN Cross-sectional study. SETTING Smoking cessation clinic and community. PATIENTS Convenience sample of 132 adult smokers and non-smokers in 1988. MEASUREMENTS A questionnaire was administered to quantify cigarette smoking and to obtain information about possibly confounding factors such as skin pigmentation, sun exposure, age, and sex. Wrinkling was assessed using photographs of the temple region, and a severity score based on predetermined criteria was assigned. A logistic regression model, which controlled for confounding variables, was developed to assess the risk for premature wrinkling in response to pack-years of smoking. MAIN RESULTS The prevalence of premature wrinkling was independently associated with sun exposure and pack-years of smoking. After controlling for age, sex, and sun exposure, premature wrinkling increased with increased pack-years of smoking. Heavy cigarette smokers (greater than 50 pack-years) were 4.7 times more likely to be wrinkled than nonsmokers (95% CI, 1.0 to 22.6; P value for trend = 0.05). Sun exposure of more than 50,000 lifetime hours also increased the risk of being excessively wrinkled 3.1-fold (CI, 1.2 to 7.1). When excessive sun exposure and cigarette smoking occurred together, the risk for developing excessive wrinkling was multiplicative (prevalence ratio of 12.0; CI, 1.5 to 530). CONCLUSION Cigarette smoking is an independent risk factor for the development of premature wrinkling.

Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function

BACKGROUND Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms. METHODS We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest. RESULTS Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids. CONCLUSIONS Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).

Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)

Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) is a multicentre observational study of chronic obstructive pulmonary disease (COPD) designed to guide future development of therapies for COPD by providing robust criteria for subclassifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, and identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials. The goal is to enrol 3200 participants in four strata. Participants undergo a baseline visit and three annual follow-up examinations, with quarterly telephone calls. Adjudication of exacerbations and mortality will be undertaken.

Bronchodilator response in the lung health study over 11 yrs

Long-term changes in bronchodilator response in people with mild chronic obstructive pulmonary disease were assessed in this study. Changes in forced expiratory volume in one second (FEV1) in response to isoproterenol was measured in 4,194 participants in the Lung Health Study annually for 5 yrs, and again 11 yrs after study entry. Responses were quantitated in terms of mL (absolute), as per cent of the pre-bronchodilator value (relative), and as a per cent of the predicted normal value (% predicted). At baseline, the mean pre-bronchodilator FEV1 was 75.4% predicted, and responses were small. Relative and percentage predicted responses were similar in males and females; and correlated positively with methacholine reactivity, and negatively with smoking intensity and age. Baseline bronchodilator responses did not correlate with subsequent decline in FEV1. There was a substantial increase in response over the first year of the study, largely due to smoking cessation, with larger increases in those who stopped smoking. After the first year absolute responses changed little in those who maintained smoking cessation, but increased in those who did not. Mean relative and percentage predicted responses increased in all participants throughout the study. There was substantial annual variability of absolute response, and it was poorly reproducible in individual participants. In conclusion, smoking cessation increased bronchodilator response, and response did not predict the rate of decline of forced expiratory volume in one second.

Predictors of survival in subjects with chronic airflow limitation

In a study of chronic airflow limitation, we followed 140 subjects living in Utah at altitudes of 1,300 to 1,500 meters for seven to 13 years. Twelve-year survival probabilities were determined and compared with an age- and sex-matched Utah population. The lowest 12-year survival probability was 0.40 for those patients with a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of less than or equal to 0.40, indicating that there is much variability in survival. Other indicators of a lower survival probability (and increased death risk ratio) were an FEV1 percent predicted less than or equal to 50, an FEV1 less than or equal to 1.5 liters, male gender, partial pressure of oxygen (PO2) [exercise] less than or equal to 50 mm Hg, partial pressure of carbon dioxide (PCO2) [rest] greater than 39 mm Hg, PCO2 (exercise) greater than 39 mm Hg, FVC percent predicted less than or equal to 80, PO2 (rest) less than or equal to 55 mm Hg, and a carbon monoxide diffusing capacity (DLCO) percent predicted less than or equal to 80. Current smokers had a poorer survival probability than the reference population and an increased death risk when compared with the nonsmokers in the study. Pack/years of smoking also affected survival. Other variables associated with reduced survival were a diagnosis of chronic bronchitis combined with emphysema, more rapid annual declines in the FEV1 and/or FVC, low alpha 1-antitrypsin levels, a 20 percent improvement in FEV1 following the use of a bronchodilator aerosol, and a lower socioeconomic class. Differences between these findings and those noted in other studies are in the main due to differences in the characteristics (such as age, diagnosis, and extent of disease) of the patients in the study populations. The findings have relevance in estimating a patients prognosis and for developing guidelines for disability determination purposes.

Interactions between Viruses and Bacteria in Patients with Chronic Bronchitis

Abstract The possibility that viral infections of the respiratory tract might predispose to bacterial colonization or infection was studied in 120 patients with chronic obstructive pulmonary disease and 30 control subjects; these individuals were observed for seven years. The ratio of the number of observed to the number of expected associations between viruses and bacteria was 2.43 (P = 0.037) for the pair influenza virus and Streptococcus pneumoniae and was 2.06 (P = 0.056) for influenza virus and Haemophilus influenzae. Consistently positive, but not significant, associations were detected between rhinovirus and herpes simplex virus infections and isolations of S. pneumoniae and H. influenzae. In contrast, isolations of the nonpathogenic Haemophilus parainfluenzae could not be related to prior viral infections. Significant rises in titer of antibody to H. iniluenzae were detected on 76 occasions, and 20 (26%) of these antibody rises were associated with viral or mycoplasmal infections during the preceding 120 days. The expected number of such associations was 8.34 (ratio of number observed to number expected, 2.40; P = 0.08). These results suggest that viral infections of the respiratory tract in patients with chronic obstructive pulmonary disease are associated with increased colonization by potentially pathogenic bacteria and may also predispose to infection with H. injluenxae.