Detecting Airflow Obstruction in Smoking Cessation Trials

Detecting Airflow Obstruction in Smoking Cessation Trials* A Rationale for Routine Spirometry Abraham Bohadana, MD; Fredrik Nilsson, MSc; and Yves Martinet, MD, PhD

Background: Spirometry is not routinely performed in smoking cessation trials. Smokers with airflow obstruction who are unavailable for follow-up incur the risk of accelerated loss in lung function. We evaluated the prevalence of airflow obstruction among smokers enrolled in smoking cessation trials and the proportion of subjects with obstruction unavailable for follow-up. Design, setting, and participants: The study was performed in a university research laboratory; 598 smokers participating in two smoking cessation trials were included. All subjects underwent spirometry at entry and after 1 year of follow-up. All received nicotine replacement therapy. At completion, they were classified into quitters, reducers, or continuing smokers. Measurements and results: At enrollment, spirometry findings were normal in 493 subjects (82.4%). Airway obstruction (FEV1 < 80% predicted) was found in 105 subjects (17.6%): mild obstruction (FEV1 70 to 80% predicted) in 75 subjects, moderate obstruction (FEV1 50 to 69% predicted) in 22 subjects, and severe obstruction (FEV1 < 50% predicted) in 8 subjects. From these subjects, 75 were unavailable for follow-up: airflow obstruction was mild in 52 subjects (69.3%), moderate in 17 subjects (22.7%), and severe in 6 subjects (8%). Conclusions: Spirometry detected a high prevalence yield of airflow obstruction in participants in smoking cessation trials. Most subjects with airflow obstruction were unavailable for follow-up; they would have remained unaware of their condition if not for spirometry. Smokers with airflow obstruction should be identified and advised to seek further care. (CHEST 2005; 128:1252–1257) Key words: airflow obstruction; FEV1; smokers; smoking cessation; spirometry Abbreviation: FTND ⫽ Fagerstro¨m test for nicotine dependence

smoking has been identified as the most C igarette important risk factor for COPD, and epidemio-

logic surveys1–3 in Europe and the United States have demonstrated a high prevalence and rising mortality of the disease and rising mortality. The condition is insidious, and is usually diagnosed late, when lung function has already deteriorated.4 Since the most effective treatment for COPD is smoking cessation, the early identification of smokers most likely to have COPD develop is important in order to encourage them to stop smoking. *From INSERM ESPRI EP2R (Dr. Bohadana), Vandoeuvre-le`sNancy, France; Service de Pneumologie (Dr. Martinet), EA 3443, CHU de Nancy, Nancy, France; and Pfizer Consumer Healthcare (Mr. Nilsson), Clinical Research, Helsingborg, Sweden. Abraham B. Bohadana had the original ideal, designed the study, recruited the subjects, performed the statistical analysis, and drafted the report. Fredrik Nilsson provided the smoking cessation program and managed the data. Yves Martinet provided critical appraisal and review. All authors approved the final version of this report. This study was supported by Pfizer Consumer Healthcare, Helsingborg, Sweden. 1252

Screening the general population is an effective method for detecting subjects with impaired lung function, but this option is not feasible in the daily routine of general practice.5 In contrast, spirometric screening of populations at risk for COPD might be a more effective method for early detection in primary health care.6 Studies of smokers from a semirural practice in the Netherlands,7 a rural village in Spain,8 and a primary health center in Sweden9 have proven successful; prevalence rates of airflow obstruction ranging from 11.5 to 22% were demonstrated. Incidentally, the Dutch study7 also found The two cessation trials were funded by Pfizer Consumer Healthcare, Helsingborg, Sweden. Manuscript received November 12, 2004; revision accepted January 10, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Abraham B. Bohadana, MD, INSERM, ESPRI EP2R, Faculte´ de Me´decine, B.P. 184 - 9, Av de la Foreˆt de Haye, 54505 Vandoeuvre-le`s-Nancy, France; e-mail: bohadana@ u420.nancy.inserm.fr Clinical Investigations

spirometry to be cost-effective, lasting on average only 4 min at a cost of only 5 to 10€. Smokers participating in cessation trials might be at risk for COPD; they are usually selected because of significant cigarette consumption and are often motivated by health concerns and/or respiratory symptoms. Surprisingly enough, little attention has been paid to the assessment of lung function in cessation trials since the first smoking cessation clinics were started in Stockholm half a century ago.10 Although this is not necessarily a problem for those smokers who are successful in quitting smoking, it may be disastrous for those unavailable for follow-up, typically 70% of participants. Among them, subjects with airflow obstruction who continue to smoke incur the risk of accelerated decline in FEV1.4,8 With the above considerations in mind, we therefore decided to examine the spirometric data obtained during a 1-year follow-up of participants in two cessation trials carried out recently by our team.11,12 The aim of this study was twofold: (1) to evaluate the prevalence of airflow obstruction at enrollment; and (2) to determine the proportion of smokers with airflow obstruction at enrollment who were unavailable for follow-up. In addition, we examined the impact of smoking intervention on lung function in participants who completed the trials. Materials and Methods Subjects Subjects were consecutive volunteers who participated in two cessation trials carried out recently at the Chest Clinic, Centre Hospitalier Universitaire de Nancy-Brabois, France. All were recruited via a local newspaper. The first trial11 enrolled 400 smokers and aimed to investigate the effectiveness of a nicotine inhaler and a nicotine patch as combination therapy for smoking cessation. The second trial12 enrolled 198 smokers and aimed to investigate the impact of smoking cessation or smoking reduction on bronchial hyperresponsiveness. Briefly, inclusion criteria for both trials included active smoking for ⱖ 3 years, an expired carbon monoxide level ⱖ 10 ppm, and motivation to quit smoking. Exclusion criteria included a history of illness/diseases judged by the investigator likely to influence the subject’s participation (eg, myocardial infarction within the past 3 months, unstable angina, and severe cardiac arrhythmia), pregnancy or breast feeding, and use of nicotine replacement therapy products during the previous 6 months. No subjects had asthma, bronchiectasis, acute chest infections, malignancy, or any known chronic pulmonary disease. Subjects with any of these diagnoses were excluded at the entry screening and were referred to our outpatient smoking cessation clinic for further evaluation and treatment. Subjects who fulfilled the entry criteria were given an appointment 1 week later, during which they completed various questionnaires and baseline pulmonary function tests were performed. All subjects were given complete verbal and written instructions regarding the general conduct of the study. At every www.chestjournal.org

visit, only brief support and counseling were provided by the investigator. All subjects gave informed consent, and the study protocols were approved by the local ethics committee. Medication Subjects in the first cessation trial11 were randomly assigned to receive a combination of the nicotine inhaler, 10 mg (4 mg of nicotine available), plus nicotine patch, 15 mg (16 h), or the nicotine inhaler plus a placebo patch. The second cessation trial12 was an open, controlled, exploratory study in which all subjects received nicotine sublingual tablets containing 2 mg nicotine. In both studies, no subjects were receiving regular treatment with bronchodilators, inhaled steroids, or disodium cromoglycate during the study. Several visits were arranged over the 1-year follow-up; however, in this article, we shall refer only to data obtained at the first and last (1-year) visits. Assessments At baseline, the day before quit day, patient characteristics and vital signs were assessed. Subjects were weighed, and questionnaires were used to assess the reasons for stopping smoking and the degree of nicotine dependence (Fagerstro¨m test for nicotine dependence [FTND]).13 A smoking history was obtained, and the carbon monoxide content of expired air was measured using an EC50 Bedfont monitor (Technical Instruments; Sittingbourne, UK). At follow up (1 year), subjects were classified as “quitters” (self-reported complete abstinence at every visit validated by an expired carbon monoxide level ⬍ 10 ppm), “reducers” (a liberal, subjective report of reduction in number of cigarettes compared with baseline and an exhaled carbon monoxide level less than baseline value), or “continuing smokers” (failure to decrease the number of cigarettes compared with baseline). Pulmonary function was measured according to the American Thoracic Society recommended standards.14 Spirometry (Autospiro AS-500; Minato Medical Science; Osaka, Japan) was performed by the same technician by asking the subjects to expire forcefully after a maximal inspiratory maneuver. At least three volume-time and flow-volume curves were obtained from which the FEV1 was taken. The curve with the highest sum of FEV1 and FVC was retained for analysis. Airflow obstruction was considered to be present if FEV1 was ⬍ 80% of the predicted value of the European Respiratory Society.15 The severity of the airway obstruction was categorized as mild (FEV1 ⱖ 70% to ⬍ 80% predicted), moderate (FEV1 ⱖ 50 to 69% of predicted), and severe (FEV1 ⬍ 50% of predicted). Statistical Methods The demographics of the study subjects, the results of the smoking questionnaires, and the spirometric measurements were entered into a database and analyzed using software (Sigma Stat 3.0; SPSS; Chicago, IL). Differences in FEV1 between the first and final two surveys were compared using the paired t test for normally distributed data.

Results Demographic and smoking characteristics and pulmonary function data of the participants are shown in Table 1. The study population consisted of 58.2% men and 41.8% women. Cigarette consumption and nicotine dependence tended to be higher CHEST / 128 / 3 / SEPTEMBER, 2005

1253

Table 1—Demographic and Smoking Data* Parameters

All

Patients, No. Male/female gender, No. Age, yr Height, cm Weight, kg Smoking history Cigarette consumption, pack-yr Carbon monoxide, ppm FTND Pulmonary function tests FEV1, % predicted FVC, % predicted FEV1/FVC, % observed

598 348/250 37.4 (8.6) 170.1 (8.8) 71.5 (14.7) 29.7 (17.6) 30.5 (10.6) 6.2 (2.2) 91.4 (13.8) 99.3 (13.0) 77.4 (8.4)

*Data are presented as mean (SD) unless otherwise indicated.

among men than among women, but the differences were not significant (not shown). On average, pulmonary function test results (percentage of predicted) were within normal limits. The results of spirometry at enrollment and 1-year

follow-up are shown in the flowchart depicted in Figure 1. At enrollment, spirogram results were normal in 493 participants. In this group, the mean (⫾ SD) spirometric variables were as follows: FEV1, 95.9 ⫾ 9.9% predicted; FVC, 102.5 ⫾ 11.6% predicted; and FEV1/FVC ratio, 79.3 ⫾ 6.5% observed. Signs of airway obstruction (FEV1 ⬍ 80% predicted) were found in 105 subjects. The average spirometric values for this group were as follows: FEV1, 70.5 ⫾ 9.8% predicted; FVC, 86.4 ⫾ 11.4% predicted; and FEV1/FVC ratio, 68.5 ⫾ 10.3% observed. Obstruction was mild (FEV1 ⱖ 70 to ⬍ 80% predicted) in 75 subjects, moderate (FEV1 ⱖ 50 to 69% predicted) in 22 subjects, and severe (FEV1 ⬍ 50% predicted) in 8 subjects. The FEV1/FVC ratio (percentage observed) for the three subgroups were 72.2 ⫾ 7.6, 62.7 ⫾ 8.2, and 49.5 ⫾ 10.5, respectively. One hundred forty-one subjects with normal spirometry results (141 of 493 subjects, 28.6%) and 30 subjects with airflow obstruction (30 of 105 subjects, 28.6%) completed the study. In subjects with normal

Figure 1. Flowchart of spirometry at enrollment and follow-up according to the outcome of the smoking intervention. 1254

Clinical Investigations

spirometry findings, the proportion of quitters (64.5%), reducers (11.3%), and continuing smokers (24.1%) was similar to that observed among their obstructed counterparts (quitters, 66.7%; reducers, 10%; and continuing smokers, 23.3%). The proportions of subjects unavailable for follow-up were equal in both groups: 75 of 105 subjects (71.4%) with obstruction vs 352 of 493 subjects (71.4%) with no obstruction. Airflow obstruction, especially of moderate and severe intensity, was more frequent in subjects ⬎ 35 years of age than in subjects ⬍ 35 years of age (Table 2). The impact of smoking intervention on lung function of participants, irrespective of the presence of airway obstruction, is shown Table 3. Participants who stopped smoking experienced an improvement in FEV1 during the year after quitting (an average of 50 mL, or 1.15% predicted). In contrast, reducers and continuing smokers displayed a decline in FEV1. In quitters with airflow obstruction, the magnitude of improvement of FEV1 was greater than that observed for the group as a whole (Table 4). Discussion Smoking has been labeled the most important preventable cause of death and disease.1 The lack of specific treatment for smoking-related diseases and the recognition of the benefits of smoking cessation justify the dedication of significant scientific and community resources to increase rates of smoking cessation. Among smoking-related diseases, COPD is currently a major cause of morbidity and the fourth leading cause of death in the world. Although cigarette consumption is leveling off and even decreasing in some countries, more people worldwide are smoking, so further increases in the prevalence and mortality of COPD can be predicted in the coming decades.16 Once smoking has caused COPD, the disease is largely irreversible and progressive. Although it does not significantly reverse any loss of FEV1 already incurred, smoking cessation is the only measure that can protect susceptible smokers from

acquiring COPD because it reverses the future rate of decline of FEV1 to that of nonsmokers.4 This study has three main findings. First, it shows that performing spirometry in smokers who participate in smoking cessation trials reveals a high proportion of subjects presenting with signs of airflow obstruction. The observed prevalence of 17.5% was within the range of that reported in primary health care,7–9 and in one cessation trial,17 and three times as great as that reported in a large sample of adult nonsmokers.18 In one third of smokers with obstruction, the airflow obstruction was moderate or severe, an important finding if one considers that they were unaware of their condition and none was receiving medical care. This finding is in line with the third National Health and Nutrition Examination Survey, which showed that 44% of subjects with FEV1 ⬍ 50% predicted did not have a current diagnosis of obstructive lung disease18. Second, this study shows that roughly 30% of the 75 subjects with airflow obstruction unavailable for follow-up (n ⫽ 75) had moderate-to-severe obstruction. Without spirometry at enrollment, these subjects would have remained completely unaware of their condition. Instead, they were presented with the facts about their situation, and all received detailed information about the risk of accelerated decline in FEV1 if they did not quit smoking, as well as instructions to seek medical attention should this happen. The fact that subjects with and without airflow obstruction had similar dropout rates may indicate that the smoking status takes precedence over the health status on the decision to adhere or not to a cessation program. Having airflow obstruction is seemingly less important than becoming abstinent or relapsing, the two main reasons for which smokers quit trials. Third, our data further document the trend toward improvement in lung function in the first year after smoking cessation. The mean 50 mL per year increase in FEV1 we observed was in the range of that documented in the Lung Health Study19,20 and

Table 2—Results of Spirometry Stratified According to Age Groups Bronchial Obstruction* Normal

Mild

Moderate

Severe

All

Groups

No

% Total

No

% Total

No

% Total

No

% Total

No

% Total

Smokers All ⬍ 35 yr old ⱖ 35 yr old

493 202 291

82.4 86.7 79.7

75 26 49

12.5 11.2 13.5

22 04 18

3.7 1.7 4.9

8 1 7

1.3 0.4 1.9

105 31 74

17.6 13.3 20.3

*Mild ⫽ FEV1 ⱖ 70 to ⬍ 80% predicted; moderate ⫽ FEV1 ⱖ 50 to 69% predicted; severe ⫽ FEV1 ⬍ 50% predicted. www.chestjournal.org

CHEST / 128 / 3 / SEPTEMBER, 2005

1255

Table 3—One-Year Change in FEV1 Among Quitters, Reducers, and Continuing Smokers With and Without Airflow Obstruction Who Completed the Study (n ⴝ 171)* Parameters FEV1, L Enrollment One year ⌬, L p Value† FEV1, % predicted Enrollment One year ⌬, % p Value†

Quitters (n ⫽ 111)

Reducers (n ⫽ 19)

Smokers (n ⫽ 41)

Reducers/Smokers (n ⫽ 60)

3.30 (0.70) 3.35 (0.73) ⫹ 0.05 (0.27) 0.106

3.15 (0.79) 3.03 (0.77) ⫺ 0.12 (0.27) 0.076

3.17 (0.60) 3.11 (0.63) ⫺ 0.06 (0.21) 0.084

3.16 (0.65) 3.09 (0.67) ⫺ 0.07 (0.23) 0.012

91.8 (13.5) 92.9 (14.3) ⫹ 1.1 (7.3) 0.102

87.3 (13.2) 84.1 (14.2) ⫺ 3.2 (8.0) 0.105

92.7 (13.5) 90.9 (13.7) ⫺ 1.8 (6.3) 0.075

91.0 (13.5) 88.8 (14.1) ⫺ 2.2 (6.8) 0.015

*Data are presented as mean (SD). †Paired t test.

in line with a cessation trial17 showing that smokers who succeeded in quitting had a trend toward a lower ⌬FEV1 over the 1-year study period when compared with continuing smokers. In contrast, reducers and continuing smokers showed further deterioration in lung function. We speculate that the more marked deterioration among reducers as compared with smokers might have resulted from some kind of compensatory smoking behavior similar to the smokers’ observed tendency to self-regulate nicotine intake.21 Overall, these observations emphasize the importance of smoking cessation as a measure contributing to slowing down the rate of decline in lung function in smokers. A detailed review22 of the impact of smoking cessation on lung function and other pulmonary parameters has been published. There are reasons for not performing spirometry routinely in smoking cessation trials. For instance, it may be argued that the procedure is time consuming. However, as already stated in the introduction, studies7 in primary care showed that a good spirom-

Table 4 —One-Year Change in FEV1 Among Quitters, Reducers, and Continuing Smokers With Airway Obstruction at Enrollment Who Completed the Study* Parameters FEV1, L Enrollment One year ⌬, L p Value† FEV1, % predicted Enrollment One year ⌬, % p Value†

Quitters (n ⫽ 20)

Reducers/Smokers (n ⫽ 10)

2.52 (0.60) 2.61 (0.68) ⫹ 0.09 (0.18) 0.035

2.61 (0.54) 2.54 (0.46) ⫺ 0.07 (0.20) 0.309

73.0 (10.1) 75.5 (13.0) ⫹ 2.50 (5.3) 0.047

72.9 (13.6) 70.8 (8.9) ⫺ 2.1 (5.7) 0.260

*Data are presented as mean (SD). †Paired t test. 1256

etry measure can be obtained in ⬍ 5 min. Additionally, one may argue that providing information about spirometry in cessation trials might introduce a bias toward good results. However, in double-blind, controlled trials, it is sufficient to provide the same advice to both the active- and placebo-treatment groups. Incidentally, as in another cessation trial,17 our study failed to document a positive effect of spirometry as a tool to improve quit rates, but this might have been due to a lack of more structured information. As noted in the Spanish study,8 the results are probably influenced by how strongly the advice to stop smoking is given to the different groups. In summary, the present study demonstrates the following: (1) spirometry detected airflow obstruction in a high proportion of smokers who participated in smoking cessation trials; (2) the majority of smokers with airflow obstruction at entry were unavailable for follow-up and, if not for spirometry, the functional abnormality would have gone undetected in these subjects; and (3) smokers who were able to stop smoking had improved lung function during the first year after cessation, while those who failed to stop smoking showed deterioration. In view of the current results, we suggest that spirometry be included in smoking cessation trials as well as in smoking cessation in ordinary clinical practice in smokers ⬎ 35 years old, in order to detect airflow obstruction at an early stage when the natural course of the disease can be reversed. Participants with airflow obstruction should be informed of their condition, which might increase their motivation to quit, and those who fail to quit should be advised to seek further medical attention. ACKNOWLEDGMENT: The authors thank Mr. J-P Michaely, research engineer, for preparing customized programs for data management, and the subjects for their kind participation. Clinical Investigations

References 1 Cigarette smoking: attributable mortality and years of potential life lost, United States, 1990. MMWR Morb Mortal Wkly Rep 1993; 42:645– 648 2 Strachan DP. Epidemiology: a British perspective. In: Calverley PMA, Pride NB, eds. Chronic obstructive pulmonary disease. New York, NY: Chapman and Hall, 1995; 47– 67 3 Racineux JC, Vidal JF, Meslier N. Les maladies respiratoires chroniques lie´es au tabagisme. Rev Prat 1993; 43:1223–1226 4 Fletcher CM, Peto R, Tinker CM, et al. Natural history of chronic bronchitis and emphysema. Oxford, UK: Oxford University Press, 1976 5 van den Boom G, van Schayck CP, van Rutten-Mo¨lken MPMH, et al. Active detection of COPD and asthma in the general population: results and economic consequences of the DIMCA programme. Am J Respir Crit Care Med 1998; 158:1730 –1738 6 Zielinski J, Bednarek M, and the Know the Age of Your Lung Study Group. Early detection of COPD in a high-risk population using spirometric screening. Chest 2001; 119:731–736 7 Van Schayack CP, Loozen JMC, Wagena E, et al. Detecting patients at a high risk of developing chronic obstructive pulmonary disease: a prospective case-finding study of smokers in general practice. BMJ 2002; 324:1370 –1373 8 Clotet J, Gomez-Arbone´s X, Ciria C, et al. Spirometry is a good method for detecting and monitoring chronic obstructive pulmonary disease in high-risk smokers in primary health care. Arch Bronconeumol 2004; 40:155–159 9 Nihlen U, Montenemry P, Lindholm LH, et al. Detection of chronic obstructive pulmonary disease in primary health care: role of spirometry and respiratory symptoms. Scand J Prim Health Care 1999; 17:232–237 10 Schwartz JL. Methods of cessation smoking. Med Clin North Am 1992; 76: 451– 476 11 Bohadana AB, Nilsson F, Rasmussen T, et al. Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: a randomized, double-blind, placebo-controlled trial. Arch Intern Med 2000; 160:3128 –3134 12 Bohadana A, Nilsson F, Westin A, et al. Smoking cessation and smoking reduction: effects on symptoms, spirometry and bronchial responsiveness; a longitudinal study in occupationally-exposed workers. Presented at The Society for Research on Nicotine and Tobacco, Fifth European Conference,

www.chestjournal.org

Padua, Italy, November 20 to 22, 2003 13 Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerstro¨m test for nicotine dependence: a revision of the Fagerstro¨m tolerance questionnaire. Br J Addict 1991; 86: 1119 –1127 14 Standardisation of spirometry, 1994 update. Statement of the American Thoracic Society. Am J Respir Crit Care Med 1995; 152:1107–1136 15 Quanjer PH, Tammeling JE, Cotes JE, et al. Lung volumes and forced ventilatory flows: Report Working Party; standardization of lung function tests. European Community for Steel and Coal. Eur Respir J 1993; 6(Suppl):5– 40 16 Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990, and projected to 2020. Cambridge, MA: Harvard University Press, 1996. 17 Paoletti P, Fornai E, Maggiorelli F, et al. Importance of baseline cotinine plasma values in smoking cessation: results from a double blind study with nicotine patch. Eur Respir J 1996; 9:643– 651 18 Mannino DM, Gagnon RC, Petty TL, et al. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988 –1994. Arch Intern Med 2000; 160:1683–1689 19 Anthonisen NR, Connet 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 FEV1: The Lung Health Study. JAMA 1994; 272:1497–1505 20 Scanlon PD, Connett JE, Waller LA, et al, for the Lung Health Study Research Group. Smoking cessation and lung function in mild-to-moderate chronic obstructive disease: The Lung Health Study. Am J Respir Crit Care Med 2000; 161:381–390 21 Jarvis MJ, Boreharn R, Primatesta B, et al. Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey. J Natl Cancer Inst 2001; 193:134 –138 22 Willemse BWM, Postma DS, Timens W, et al. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J 2004; 23:464 – 476

CHEST / 128 / 3 / SEPTEMBER, 2005

1257