Prof. Arakawa received lecture fees from Otsuka and Eisai and research grants from Otsuka, Eisai, Astellas, Abbott Japan, Takeda, Dainippon Sumitomo, and Daiichi Sankyo. The remaining authors have no conflicts to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: YK YF. Performed the experiments: YK Takanori Watanabe MK YT. Analyzed the data: YK MS. Wrote the paper: YK YF Takanori Watanabe MK YT NK HY TT MS Toshio Watanabe KT TS TA.
Smoking is associated with gastroesophageal reflux disease (GERD). Varenicline, a nicotinic receptor partial agonist, is used to aid smoking cessation. The purpose of this study was to prospectively examine the long-term benefits of smoking cessation on GERD and health-related quality of life (HR-QOL).
Patients treated with varenicline were asked to fill out a self-report questionnaire about their smoking habits, gastrointestinal symptoms, and HR-QOL before and 1 year after smoking cessation. The prevalence of GERD, frequency of symptoms, and HR-QOL scores were compared. We also investigated associations between clinical factors and newly-developed GERD.
A total of 141 patients achieved smoking cessation (success group) and 50 did not (failure group) at 1 year after the treatment. The GERD improvement in the success group (43.9%) was significantly higher than that in the failure group (18.2%). The frequency of reflux symptoms significantly decreased only in the success group. There were no significant associations between newly developed GERD and clinical factors including increased body mass index and successful smoking cessation. HR-QOL significantly improved only in the success group.
Smoking cessation improved both GERD and HR-QOL. Smoking cessation should be recommended for GERD patients.
Gastroesophageal reflux disease (GERD) is the most common gastrointestinal (GI) disease encountered in both Western and Asian countries [
Several epidemiological studies showed a significant association between smoking and GERD or reflux symptoms [
Varenicline (CHANTIX), a nicotinic receptor partial agonist, is used to assist smoking cessation. It is prescribed within Japanese clinics or hospitals when smokers desire to abstain from smoking. The aim of this study was to prospectively examine the long-term clinical benefits of smoking cessation (aided using varenicline) on GERD, reflux symptoms, and HR-QOL.
Patients who visited smoking cessation clinics in Osaka City University Hospital and Uehonmachi-Watanabe Clinic of their own volition, and were treated with varenicline between May 2011 and November 2013 were included in this prospective cohort study. Patients who continuously received acid suppressive drugs including proton pump inhibitors (PPI), had peptic ulcer diseases, or had a history of upper GI surgery were excluded. Patients who had undergone smoking cessation therapy for 12 weeks received a survey through the mail 1 year after the treatment. They were asked whether smoking cessation was achieved, and were subsequently divided into success or failure groups. The study was approved by the Osaka City University Ethics Committee, and written informed consent was obtained from all participants, and procedures conformed to the Declaration of Helsinki.
Patients initiated varenicline treatment 1 week prior to their intended smoking cessation date. Varenicline was taken once or twice daily after eating according to the following treatment regimen: 0.5 mg once daily from day 1 to day 3, 0.5 mg twice daily from day 4 to day 7, and 1 mg twice daily from day 8 to the end of the treatment. Patients took varenicline for a total of 12 weeks.
All participants were asked to complete a questionnaire on their age, gender, height, body weight, smoking habits, alcohol drinking habits, reflux symptoms, and HR-QOL prior to beginning varenicline therapy. BMI was calculated as body weight divided by the square of body height in meters (kg/m2). Respondents with a BMI > 25 kg/m2 were defined as overweight, while those with a BMI ≥ 30 kg/m2 were considered obese. With regard to smoking habits, participants were asked to report the number of cigarettes they smoked per day, the number of years they had been smoking, the amount of tar in their preferred brand of cigarettes, and whether those cigarettes contained menthol. The Brinkman index was calculated by multiplying the number of cigarettes smoked per day by the number of years of smoking. One year after the smoking cessation therapy, the patients were asked to fill out a questionnaire—sent through the mail—regarding their height, body weight, reflux symptoms, HR-QOL, whether they had taken acid-suppressive drugs continuously since completing the therapy, and whether the smoking cessation had remained successful.
The frequency scale for the symptoms of GERD (FSSG) was developed in Japan for screening and evaluating the therapeutic response of GERD patients (
Questionnaire is consist of 12 questions including 7 (light blue lines) with acid reflux symptoms and 5 (dark blue lines) with dysmotility symptoms.
HR-QOL was assessed using the Japanese version of the 8-item Short-Form Health Survey (SF-8) [
Data were expressed as mean and standard deviation (SD), frequency, or OR with 95% confidence intervals (CI). Factors including age, gender, BMI, alcohol drinking habits (drinker or non-drinker), and smoking habits were compared between patients within the smoking cessation success and failure groups using the student’s t-test or chi square test. The prevalence of GERD symptoms, frequency of symptoms (FSSG score), BMI changes, and HR-QOL score before and 1 year after smoking cessation were compared between patients within the success and failure groups using the chi square test or Wilcoxon signed rank test. We also investigated relationships between clinical characteristics such as age, gender, BMI increase, successful smoking cessation, and alcohol drinking habits and newly-developed GERD 1 year after smoking cessation in patients who had not had GERD at the first visit. A forward stepwise multiple logistic regression model was created to assess independent associations between risk factors and newly-developed GERD. P values <0.05 were considered significant. Statistical analyses were performed using SPSS version 16.0 J (SPSS Japan, Inc., Tokyo, Japan).
A total of 949 patients who visited smoking cessation clinics during the study period were initially enrolled in the study, but 529 patients did not remain in the study after the first visit. Of the remaining 420 patients who had received varenicline for 12 weeks and had ceased smoking short-term, 20 were excluded from the study because of acid-suppressive drug use (n = 11), peptic ulcer disease (n = 6), or a history of surgery in the upper GI tract (n = 3). An additional 209 patients did not complete the survey 1 year later. A total of 191 patients were included in the final analysis, 141 patients who succeeded smoking cessation (success group) and 50 who did not (failure group) (
Among 949 patients who initially visited smoking cessation clinics, 420 underwent smoking cessation therapy using varenicline for 12 weeks; all these patients ceased smoking in the short term. Twenty patients who used acid suppressive drugs, had peptic ulcer disease, or had a history of upper GI surgery were excluded, and 209 patients did not complete the survey 1 year later. Of 191 patients who completed the survey 1 year after attempted smoking cessation, 141 patients achieved smoking cessation (success group) and 50 did not (failure group).
Success group (N = 141) | Failure group (N = 50) | P-value | |
---|---|---|---|
Age (yrs) | 47.0 ± 13.9 | 46.4 ± 12.4 | 0.80 |
Gender (male/female) | 82 / 59 | 32 / 18 | 0.46 |
BMI (kg/m2) | 22.6 ± 3.7 | 22.9 ± 3.5 | 0.60 |
Prevalence of overweightness (%) | 21.9 | 28.0 | 0.38 |
Prevalence of obesity (%) | 3.5 | 4.0 | 0.59 |
Alcohol drinker (%) | 52.5 | 52.0 | 0.95 |
Smoking habits | |||
Number of cigarettes per day | 20.4 ± 9.7 | 23.4 ± 16.7 | 0.13 |
Number of years of smoking (yrs) | 25.0 ± 13.1 | 23.2 ± 13.2 | 0.38 |
Brinkman index | 514.2 ± 370.9 | 528.0 ± 487.3 | 0.83 |
Tar per cigarette (mg) | 5.3 ± 4.0 | 5.2 ± 4.2 | 0.92 |
Menthol (%) | 12.8 | 24.0 | 0.06 |
Prevalence of GERD (%) | 36.2 | 44.0 | 0.33 |
Data presented as mean ± standard deviation (SD) or frequency (%). BMI, body mass index; GERD, gastroesophageal reflux disease.
The BMI of the patients within the success group significantly increased from 22.5 ± 3.6 kg/m2 at baseline to 23.3 ± 3.5 kg/m2 (p<0.01) at 1 year after the treatment, while the BMI of patients within the failure group did not change (22.9 ± 3.4 kg/m2 at baseline versus 22.8 ± 3.4 kg/m2 at 1 year after therapy, p = 0.62). The prevalence of obesity did not change in either the success group (22% at baseline versus 24% at 1 year after the treatment, p = 0.67) or the failure group (28% at baseline versus 26% at 1 year after the treatment, p = 0.82).
The number of patients that experienced improvement in GERD was significantly higher in the success group (43.9%) than in the failure group (18.2%). Seven (7.8%) of the patients within the success group and 2 (7.1%) of the 28 patients within the failure group newly developed GERD at 1 year after the treatment.
The reflux and total scores significantly decreased 1 year after smoking cessation in the success group, but not in the failure group. *p<0.05 versus baseline.
Nine (7.6%) of the 118 patients without GERD at baseline newly developed GERD 1 year after smoking cessation therapy, which included 7 (7.8%) of the 90 patients within the success group and 2 (7.1%) of the 28 patients within the failure group. By multivariate analysis there was no significant association between newly-developed GERD and clinical factors including age, gender, BMI increase, successful smoking cessation, or alcohol drinking habits (
Crude OR | Multiple-adjusted OR | |
---|---|---|
Age (per 1 year) | 0.96 (0.91–1.12) | 0.94 (0.89–1.01) |
Male gender | 0.26 (0.06–1.09) | 0.39 (0.08–1.96) |
BMI increase (per kg/m2) | 0.73 (0.17–3.09) | 0.54 (0.09–3.14) |
Successful smoking cessation | 1.10 (0.21–5.61) | 1.25 (0.20–7.70) |
Alcohol drinker | 0.12 (0.01–0.98) | 0.12 (0.01–1.11) |
Data presented as crude odds ratio (OR) (95% confidence interval, CI) and multiple-adjusted ORs (95% CI) after adjustment for age, gender, body mass index (BMI), successful smoking cessation, and alcohol drinker.
HR-QOL was evaluated using the SF-8 survey before and after attempted smoking cessation in each group. Several SF-8 domains significantly improved after smoking cessation in the success group, including general health, vitality, and mental health, whereas there were no significant changes in any domains in the failure group. The mental component summary score also improved only in the success group, but the physical component summary score did not (
General health (GH), vitality (VT), and mental health (MH) significantly improved after smoking cessation in the success group, whereas there were no significant changes in the failure group. PF, physical functioning; RO, role physical; BP, bodily pain; SF, social functioning; RE, role emotional; PCS, physical component summary; MCS, mental component summary. *p<0.05 versus baseline.
To our knowledge, this is the first study which prospectively investigated the long-term effects of varenicline-induced smoking cessation on GERD, reflux symptoms, and HR-QOL. The present study showed that successful smoking cessation by varenicline associated with decreased prevalence of GERD, reduced frequency of reflux symptoms, and improved HR-QOL. Approximately 7% of patients who had not previously had GERD newly developed GERD after varenicline therapy, but there was no association with age, gender, BMI increase, successful smoking cessation, or alcohol drinking habits.
Recently, the HUNT study reported that quitting smoking improved reflux symptoms, but only in individuals of normal weight [
The HUNT study also reported risk factors for new onset of reflux symptoms[
Early studies demonstrated that smoking reduced lower esophageal sphincter (LES) pressure and prolonged acid clearance through a decrease in saliva bicarbonate secretion [
Since varenicline is associated with several GI side effects such as nausea, epigastralgia, and indigestion, we could not judge the exact effect of smoking cessation on GERD symptoms during or just after the varenicline therapy. Instead, we conducted the survey 1 year after completion of varenicline treatment since these side effects subside before 1 year after treatment.
Our study showed successful smoking cessation improved HR-QOL. Several other studies showed that successful smoking cessation resulted in improved well-being using subjective methods of evaluation [
There are some limitations of this study. First, the number of subjects was relatively small, especially considering that approximately half of the patients did not complete the survey 1 year after smoking cessation. However, we posit that there was no bias, as the group that provided the follow-up questionnaire did not differ significantly in terms of baseline characteristics from the group that did not. Second, GERD was diagnosed based on a specific questionnaire but endoscopy or esophageal pH-metry was not utilized to confirm the presence of the disease. Third, it is possible that some patients had GERD with relatively mild symptoms because they did not seek medications such as PPI during the study period. Fourth, we assessed smoking status 1 year after the treatment by using a self-report questionnaire alone. Future studies that employ biochemical verification by measuring exhaled carbon monoxide, cotinine, or thiocyanate levels should be conducted. Finally, we found no significant association between BMI increase and new development of GERD. Recent studies emphasized that waist circumference and visceral obesity are more important risk factors for GERD than BMI (27). Future studies including changes in waist size rather than just looking at BMI would be useful.
In summary, smoking cessation reduced the prevalence of GERD, reduced the severity of reflux symptoms, and improved HR-QOL. However, neither success nor failure of smoking cessation influenced new development of GERD during the first year after attempted smoking cessation. Smoking cessation should be recommended for GERD patients.
(XLSX)