Searching for phenotypes in smoking cessation treatment

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1 REIEW ARTICLE Searching for phenotypes in smoking cessation treatment C. A. Jimenez-Ruiz, 1 J. F. Pascual Lledo, 2 A. Cicero Guerrero, 1 M. Mayayo Ulibarri, 1 M. Cristobal Fernandez, 1 L. Perera Lopez 1 1 Smoking Cessation Service, County of Madrid, Spain 2 Pneumology Service, General Hospital of the University of Alicante, Alicante, Spain Correspondence to: Dr Carlos A. Jimenez-Ruiz, Smoking Cessation Service, C/ Santacruz del Marcenado, 9. Piso 2, Madrid 28015, Spain Tel.: Fax: victorina@ctv.es Disclosure C J-R has consulted for most companies with an interest in tobacco dependence treatments. SUMMARY ackground: It is important to define smoking phenotypes according to different variables, such as age, sex and degree of dependence, for which available treatments could have different efficacies. Objective: The main objective of our study was aimed at defining different combinations of these variables to allow the best possible treatment to be chosen in routine clinical practice. Methods: We reviewed the clinical records of smokers who had been treated in our Smoking Cessation Service. In all cases, the treatment programme consisted of a combination of behavioural therapy and optional drug treatment. Results: The group consisted of 3622 subjects, specifically 1757 men (48.5%). The mean age of the participants in the group was years. The mean score of the FTCDquestionnaire was In addition, 78% of the subjects smoked their first cigarette within 30 min after waking. For the total sample, continuous abstinence rate from 9 to 24 weeks was 57.7%. A multivariate analysis using the logistic regression model was implemented, and it showed that: (i) Nicotine Replacement Therapy was less effective in patients with high tobacco dependence, (ii) young subjects can be highly resistant to all treatments and (iii) subjects with low tobacco dependence can be treated with any treatment, but bupropion and varenicline provided the best results. Conclusion: It was possible to identify several smoking phenotypes in which different treatments have different efficacies. Review criteria We have reviewed the clinical records of 3622 smokers who attended a Smoking Cessation Service looking for help to quit. Message for the clinic There are some smoking phenotypes based on gender, age and tobacco dependence. These phenotypes may help us to choice the best treatment. Introduction Nicotine Replacement Therapy (NRT), bupropion and varenicline have proven to be effective and safe to help smokers to quit (1). Each of these treatments has its own advantages and disadvantages. Few clinical studies have directly compared the efficacy and safety among them. A recent meta-analysis comparing the efficacy of varenicline vs. bupropion in two clinical trials found that varenicline was more effective than bupropion at 6 and 12 months of follow-up (2). In the same study, there was no significant difference between the efficacies of varenicline vs. NRT at 6 months follow-up (2). Several studies have found that the efficacy of each of these treatments may vary depending on different variables. Perkins et al. found that nicotine patches were less effective in women than in men (3). Another study examined whether significant differences in the NRT efficacy for smoking cessation exist based on gender. The authors examined 11 randomised clinical trials and found that NRT was effective at all time points. No significant difference was observed between genders (4). Regarding the efficacy of these treatments, there is a unanimous agreement in concluding that their efficacy has not been clearly proven for young smokers. The 2008 update of the Clinical Practice Guideline from the USDHHS does not favour the use of these treatments at an early age (1). Other studies have found that the degree of physical nicotine dependence is crucial in the choice of treatment. An NRT meta-analysis recommends using 4-mg instead of 2-mg gum in people with high dependence or the combination of a prolonged-acting form of NRT (patch) with a short-acting form (gum) (5). Nides et al. found that although varenicline is effective in all types of smokers, regardless of their FTCD-score, it is also true that fewer smokers succeed in treatment as the degree of dependence increases (6). Other studies found no differences in efficacy with varenicline related to neither age nor sex (2) doi: /ijcp.12490

2 Looking for the right treatment for each smoker 1531 Another variable that may be involved in the efficacy of these treatments is the nature of the motivation to smoke (7). It has been suggested that some smokers smoke for pleasure (positive reinforcement), while others smoke for not being able to cope with withdrawal (negative reinforcement). It has been reported that NRT works better in smokers with low nicotine dependence and negative reinforcement. In subjects with low nicotine dependence who smoke for positive reinforcement, better results are obtained with the use of varenicline. The combined use of the two variables, nicotine dependence and positive or negative reinforcement, may be useful to choose the type of smoking cessation treatment for a particular subject (7). One of the main problems faced by clinicians when choosing a treatment is that there are no adequate or reliable scientific standards to justify the greater or lesser efficacy of each of these treatments for a specific type of smoker. Hence, it would be highly desirable to define different smoking phenotypes according to different variables, for which each of the available treatments could have better results (8). The main objectives of this research study were, in the first place, to analyse the smoking cessation efficacy of different treatments in a large group of smokers who attended a Smoking Cessation Service, adjusted for confounding variables; secondly, to define combinations of these variables that would allow the selection of the best possible treatment. Methods We reviewed the clinical records of smokers treated in our Smoking Cessation Service between January 1, 2004 and January 1, In all cases, the treatment consisted of a combination of behavioural therapy and optional drug treatment. The therapy comprised 10 individual sessions with an initial visit and nine follow-up visits. On the initial visit, we recorded the clinical and smoking history. The patients received cognitive behavioural therapy and self-help materials and chose a quit date. The cognitive behavioural therapy involved the provision of information on smoking-related disorders and the advantages of quitting. Drug treatment was prescribed and patients learnt its correct use. The follow-up visits took place at 1, 2, 4, 6, 8, 10, 12, 18 and 24 weeks after the quit date. During these visits, the patients received additional behavioural therapy for relapse prevention and to help them deal with high-risk situations. Adverse effects associated with the use of pharmacological treatment were monitored. The main parameter tested was the continuous abstinence rate from weeks 9 to 24. It was defined as the absence of smoking of any type during this period of time, and it was verified by levels of carbon monoxide 10 ppm in exhaled air. This condition was defined as success and the opposite case was defined as treatment failure. The variables included in this study are shown in Table 1. Drug treatment was initiated according to different clinical practice guidelines (1,9) and also taking into account patient preferences, prior experience with previous treatments received by the patient, likely adherence and/or adverse effects that patient had previously with the use of a particular drug treatment, or another clinical aspects of the patient that contraindicated either treatment. Three types of drug treatments were prescribed: NRT, bupropion and varenicline. For NRT, we used nicotine patches and/or nicotine chewing gum. The doses of NRT, bupropion and varenicline followed the guidelines recommended in the manufacturers data sheets, as well as clinical practice guidelines. In some cases, bupropion or varenicline were combined with NRT. In these cases, NRT was rather optional treatment for the patient. All smokers received psychological and pharmacological treatments free of charge, which were administered by Tobacco Treatment Specialists. The drug treatment was offered contingent upon attendance at each of the follow-up visits. Statistical analysis The qualitative variables are represented as percentages and the quantitative variables as the mean value standard deviation. The association between qualitative variables was studied using v 2 analysis. Student s t-test or ANOA was applied to study the association between qualitative and quantitative variables. Non-parametric Mann Whitney U-test or Kuskal Wallis test was used when assumptions of normal distribution (tested by the Kolmogorov Smirnov test) and homogeneity of variances (measured using the Levene s test) were not met. The analysis of the association between the outcome variable and the treatment variable, which was adjusted for the effect of other variables that were considered as cofactors or confounding, was performed using a binary logistic regression procedure, where the dependent variable was the outcome, with failure category as reference, and using the methodology proposed by Domenech and Navarro (10). To evaluate the effect of various treatments on the outcome variable as a function of combinations of remaining variables, we calculated the odds ratio of each type of treatment from the logistic regression model obtained, for all possible combinations of the

3 1532 Looking for the right treatment for each smoker Table 1 ariables included in this study Gender Age Fagerstrom test for cigarette dependence (FTCD) Short version of the FTCD Time to first cigarette Type of reinforcement Type of treatment Male or female Expressed in years Measuring cigarette dependence A shortened version of the FTCD which includes only the first two questions of the FTCD and is scored as low degree of dependence when the score is 0 3 points and high degree of dependence when the score is 4 6 points The time from which the subject is raised until smoke the first cigarette was recorded and coded as less than 5 min (0 points), from 5 to 30 min (1 point) and more than 30 min (2 points) It was assessed by asking the subject: If you have tried to stop smoking what was the most difficult, choose A,. A. The permanent state of something missing and that you did not function well.. That you could not smoke at those special moments when it really taste well and makes you feel good. If the smoker answers A the type of reinforcement was negative, if the answer was, the type was positive Was coded as without treatment, NRT, bupropion, and varenicline (see text) predictor or confounders variables, with confidence interval at 95% (CI 95% ). For quantitative variables, in the case of age were chosen ages 20, 40, 60 and 80 years, and for FTCD-score were chosen values 3, 6 and 9 points. For these calculations, we used the method proposed by Figueiras et al. (11). The combinations of the variables can be used to identify potential phenotypes that allow discover the best treatment for each combination. A value of a < 0.05 was considered for statistical significance. Statistical analysis was performed using SPSS v (IM SPSS Software, IM Corporation, Armond, New York, United States), and an Excel 2003 spreadsheet. Results The group comprised of 3622 subjects (48.5% males). The mean age was years, with mean age difference statistically significant (p < 0.001) between males ( years) and females ( years). The mean value of the FTCD-score was There was a statistically significant difference (p < 0.001) between the mean value of FTCD-score for men ( ) and for women ( ). A 32.3% of the subjects smoked their first cigarette within 5 min after waking, 45.7% smoked between 5 and 30 min, 22.0% smoked after 30 min or more and, finally, 64.1% smoked for negative reinforcement. All these subjects wanted to make a serious attempt to quit. Most of them (65%) had made more than two previous attempts to quit, 35% had made two or less and 5% had never made any attempt. In average, the mean number of years of smoking was 25.6 (13.5). A 43% of the subjects were suffering from psychiatric comorbidity (25% major depression, 19% schizophrenia, 23% bipolar disorder and 37% anxiety-depression syndrome). Table 2 shows the different types of treatments received by the smokers. For the purposes of statistical analysis, all subjects who received only NRT, in any of their forms, were grouped into a single category. Since the number of subjects who received bupropion + NRT or varenicline + NRT was quite low, they were grouped into bupropion and varenicline categories, respectively. Table 3 shows the distribution of treatments between the different categories of variables. The age of the subjects who received varenicline was significantly higher than the age of the subjects who Table 2 Type of treatment and continuous abstinence rates at 6 months follow-up Type of treatment Continuous abstinence Frequency rate at 6 months N (%) Number abstainers (%) Without treatment 88 (2.4) 59 (67) Patches 914 (25.2) 493 (53.9) Gum 108 (3) 153 (49) Patches plus gum 598 (16.5) 277 (46.3) upropion 628 (17.3) 385 (61.3) upropion plus gum 124 (3.4) 73 (58.8) upropion plus 13 (0.4) 8 (61.5) patches arenicline 1093 (30.2) 715 (65.4) arenicline plus gum 56 (1.5) 27 (48.2)

4 Looking for the right treatment for each smoker 1533 Table 3 Distribution of treatments among different variables Without treatment NRT upropion arenicline p* Age (years) 47.3 (12.5) 48.1 (11.7) 46.0 (10.0) 49.0 (10.8) < Gender Male 35 (2.0) 785 (44.7) 299 (17.0) 638 (36.3) < Female 53 (2.8) 835 (44.8) 466 (25.0) 511 (27.4) p NS NS < < FTCD score 5.6 (2.7) 6.5 (2.4) 6.2 (2.4) 7.2 (2.1) < Short version of FTCD Low grade (5 or less points) 38 (3.7) 478 (47.0) 269 (26.5) 232 (22.8) < High grade (more than 5 points) 50 (1.9) 1142 (43.8) 496 (19.0) 917 (35.2) p < < 0.1 < < Time to first cigarette (min) < 5 13 (1.1) 517 (44.2) 201 (17.2) 438 (37.5) < (2.8) 717 (43.3) 361 (21.8) 532 (32.1) > (3.6) 386 (48.4) 203 (25.2) 179 (25.5) Type of reinforcement Positive 34 (2.6) 500 (38.5) 415 (31.9) 351 (27.0) < Negative 54 (2.3) 1120 (48.2) 350 (15.1) 798 (34.4) p NS < < < NRT, nicotine replacement therapy; FTCD, Fagerstr om test for cigarette dependence; NS, not significant. *Degree of significance between the two variables. Mean and standard deviation. Categories with statistically significant differences. Number of patients (%). Degree of significance between the two previously categories. received bupropion or NRT; the age of the subjects who received bupropion was significantly lower than that of those receiving NRT; there was no statistically significant difference in the age of subjects without treatment and other kinds of treatment. We found no significant differences in the percentage of males and females who received no treatment or who received NRT; bupropion was administered more frequently in females, while varenicline was administered more often in males. Subjects receiving varenicline had significantly higher mean score of the FTCD than subjects who received other treatments. Subjects receiving NRT had significantly higher mean score of FTCD than untreated subjects. When considering the shorter version of the FTCD, varenicline was more frequently administered to subjects with high degree of dependence, while other treatments were more frequent in subjects with low degree of dependence. arenicline was prescribed more frequently in individuals who smoke within 5 min after waking up, whereas it was prescribed less in those who smoked after 30 min. upropion was more frequently prescribed in subjects who smoked their first cigarette after 30 min and it was less prescribed in subjects who smoked their first cigarette within the first 5 min. Subjects who reported smoking for positive reinforcement more frequently received bupropion, whereas those who smoked for negative reinforcement received more frequently NRT or varenicline. A total of 3622 subjects were studied. The followup was completed for 6 months by 2780 subjects, while 842 abandoned the study. Continuous abstinence rate from weeks 9 to 24 was 57.7% (2090 out of 3622). Table 4 shows the comparison between the treatment outcome and the other variables. Males were more successful than women in quitting smoking. Subjects who failed had higher values in the FTCD and higher degree of dependence on the short version of the FTCD. When subjects smoked their first cigarette within 5 min after waking, the percentage of failures to stop smoking was 37.5%, higher (p < 0.001) than the percentage of success (28.5%); on the other hand, those who smoked their first cigarette more than 30 min after waking had 25.1% of success rate and it was higher (p < 0.001) than the failure rate of 17.8%. There were no differences in the percentages of the outcome among those who smoked their first cigarette between 5 and 30 min after waking. The failure rate was higher among those who received NRT. Treatment with bupropion or varenicline provided greater percentage of success. There were no differences in the percentages of success or failure among those who received no drug treatment. Age or type of reinforcement showed no relation to treatment outcome.

5 1534 Looking for the right treatment for each smoker Table 4 Comparison between the variable treatment outcome (success or failure) and the other variables Treatment outcome Success Failure p* Gender Male 1047 (50.1) 710 (46.3) Female 1043 (49.9) 822 (53.7) p Age (years) 48.2 (11.3) 47.9 (11.1) FTCD score 6.4 (2.4) 7.0 (2.3) < Short version of FTCD Low grade (5 or less points) 647 (31.0) 370 (24.2) < High grade (more than 5 points) 1443 (69.0) 1162 (75.8) < p < Time to first cigarette (min) < (28.5) (50.9) 574 (37.5) (49.1) < (46.4) (58.6) 685 (44.7) (41.4) > (25.1) (65.7) 273 (17.8) (34.3) < p < Type of reinforcement** Positive 760 (36.4) (58.5) 540 (35.2) (41.5) Negative 1330 (63.6) (57.3) 992 (64.8) (42.7) p Treatment Without treatment 59 (2.8) 29 (1.9) NRT 823 (39.4) 797 (52.0) < upropion 466 (22.3) 299 (19.5) arenicline 742 (35.5) 407 (26.6) < p < FTCD, Fagerstr om test for cigarette dependence. *Degree of significance between the two categories of the variable. Number of cases; the bracket is the % within Treatment outcome variable. Degree of significance between the two variables. Mean and standard deviation. Number of cases; the first bracket is the % within Treatment outcome variable; the second bracket is the % within Time to first cigarette variable. **Number of cases; the first bracket is the % within Treatment outcome variable; the second bracket is the % within Type of reinforcement variable. To evaluate the relationship between variables such as type of treatment and outcome, logistic regression models were constructed with the outcome variable as the dependent variable and the type of treatment as a predictor, controlling for the other variables. Three models were built. The first model included the variable FTCD score, the second model included the variable short version of FTCD and the third model included the variable time to first cigarette ; these three variables were not included together in any of the models to avoid phenomena of collinearity. Table 5 shows the results. The variable type of reinforcement was only significant in model 1; when variables; short version of FTCD or time to first cigarette were considered, the variable type of reinforcement was not significant. To equal the remaining variables, being male increases the odds of success for smoking cessation by 20% (CI 95% :5 37%). The chances of success are reduced with the higher the score on the FTCD score and smoking by positive reinforcement. For every point increase in FTCD score, the odds of failure to quit are multiplied by 1.15 (CI 95% : ). The same is seen in model 2, in which subjects with higher degree of nicotine dependence multiply the OR of smoking cessation failure by 1.48 (CI 95% : ) compared to subjects with a lower degree of nicotine dependence. Smoking for positive reinforcement multiplied by 1.17 the OR of failure in quitting smoking (CI 95% : ). Subjects who smoked their first cigarette within 5 min or between 5 and 30 min after waking, compared with those who smoked their first cigarette more than 30 min after waking, showed a reduced chance of successfully quitting smoking, and the OR of failure was multiplied by 1.99 (CI 95% : ) and 1.42 (CI 95% : ), respectively.

6 Looking for the right treatment for each smoker 1535 Table 5 Parameters of logistic regression models between the outcome variable (success vs. failure; the last is the reference category) and the variable type of treatment, controlling for the other variables OR (CI 95% ) (p) ariable Model 1 Model 2 Model 3 Type of treatment* Typtx(1) NRT vs. NoTx (ref.) 0.34 ( ) (0.276) 0.35 ( ) (0.278) 0.30 ( ) (0.212) Typtx(2) upropion vs. NoTx (ref.) 0.21 ( ) (0.126) 0.22 ( ) (0.131) 0.19 ( ) (0.095) Typtx(3) arenicline vs. NoTx (ref.) 0.27 ( ) (0.188) 0.26 ( ) (0.170) 0.23 ( ) (0.139) Gender Male vs. female (ref.) 1.20 ( ) (0.009) 1.15 ( ) (0.037) 1.14 ( ) (0.056) Age 0.99 ( ) (0.453) 0.99 ( ) (0.468) 0.98 ( ) (0.388) Typtx 3 Age Typtx(1) 9 Age 1.01 ( ) (0.621) 1.01 ( ) (0.668) 1.01 ( ) (0.523) Typtx(2) 9 Age 1.03 ( ) (0.150) 1.03 ( ) (0.181) 1.03 ( ) (0.124) Typtx(3) 9 Age 1.03 ( ) (0.158) 1.03 ( ) (0.173) 1.03 ( ) (0.127) FTCD score 0.87 ( ) (< 0.001) Type of reinforcement Positive vs. Negative (ref.) 0.85 ( ) (0.036) Short version of FTCD High vs. low grade (ref.) 0.67 ( ) (< 0.001) Time to first cigarette** (min) < 5 vs. > 30 (ref.) 0.50 ( ) (< 0.001) 5 30 vs. > 30 (ref.) 0.70 ( ) (< 0.001) ref., reference category; OR, odds ratio; CI 95%, Confidence interval at 95% for the odds ratio; p, degree of significance; FTCD, Fagerstr om test for cigarette dependence. *Typtx: Type of treatment. NoTx: without treatment; no treatment is the reference category. Female is the reference category. Degree of significance for interaction type of treatment with age: Model 1, p = Model 2, p = Model 3, p = Negative reinforcement is the reference category. Low grade (5 or less points) is the reference category. **Time to first cigarette > 30 min is the reference category; degree of significance for the variable time to first cigarette in the model 3: p < We estimated the OR of each type of treatment on the outcome variable, with failure as the reference category, with CI 95%, and for all possible combinations of the predictor variables, obtained from the three logistic regression models, respectively. Table 6 shows a summary of the treatments where the CI 95% for the odds ratio is greater than 1. We could observe that the odds ratio decreased with age for treatment categories no treatment and NRT, while increase with age for treatments upropion and arenicline in all other combinations of variables. The CI 95% was less than 1 in some combinations, indicating that treatment success rate worsens, increasing the likelihood of failure to quit. This applies to NRT in subjects with high nicotine dependence, such as: FTCD scores of around 9 in women who smoke for negative reinforcement or in the same people with age 40 years who smoke for negative reinforcement, and in males with the same age; high-grade level in the short version of FTCD in relatively older women (age 60 years); or in subjects who smoke their first cigarette within 5 min after waking and age 40 years. Young subjects, around age 20, with high levels of tobacco dependence, are highly resistant to treatment. No treatment showed an odds ratio with CI 95% above one in females of that age with FTCD score 6 points, males with FTCD score about 9 points who smoke for negative reinforcement, or 6 points FTCD score and smoking for positive reinforcement. No treatment showed a CI 95% that included one in subjects aged around 20 years with high grade dependence in the short version of FTCD or who smoke their first cigarette within 30 min (except in the category of without treatment in males who smoke their first cigarette between 5 and 30 min). Subjects with low tobacco dependence (FTCD score about 3, low grade in the short version of FTCD, or who smoke their first cigarette more than 30 min after waking) were able to succeed in quitting virtually with any treatment modality, although at relatively advanced ages (from age 60 onwards) the best results were obtained with bupropion and varenicline.

7 1536 Looking for the right treatment for each smoker Table 6 Treatments whose estimate of CI 95% of the OR of the variable outcome (success vs. failure) is greater than 1 (in italics indicate processing whose estimate of the OR of the variable result success vs. failure is less than 1) Model 1 Age (years) Gender FTCD score Type of reinforcement Females 3 WT WT WT Negative 6 WT 9 Males 3 WT WT WT WT NRT 6 WT WT WT 9 NRT NRT Females 3 WT WT WT Positive 6 WT 9 NRT Males 3 WT WT WT NRT 6 WT 9

8 Looking for the right treatment for each smoker 1537 Table 6 Continued Model 2 Gender Age (years) Short version of FTCD Female WT WT WT WT Low grade (5 or less points) WT High grade (more than 5 points) NRT NRT Male WT WT WT Low grade (5 or less points) WT High grade (more than 5 points) Model 3 Gender Age (years) Time to first cigarette Females < 5 min WT 5 30 min Males WT WT WT > 30 min < 5 min WT WT 5 30 min WT WT WT > 30 min NRT CI 95%, confidence interval at 95%; OR, odds ratio; FTCD: Fagerstr om test for cigarette dependence; WT, without treatment; NRT, nicotine replacement therapy;, upropion;, arenicline.

9 1538 Looking for the right treatment for each smoker Discussion We have conducted a retrospective analysis of the results obtained in 3622 smokers who were treated in a Smoking Cessation Service. Our main objective was to analyse the effect of the type of treatment on the outcome, adjusted by gender, age, FTCD score, type of reinforcement and time to first cigarette in the morning. We have tried to find combinations of variables (phenotypes) that can predict the result of quitting smoking. Our main results were: (i) continuous abstinence rate at 24 weeks was 56.7%; (ii) the higher the nicotine dependence score or smoking for positive reinforcement, the higher was the rate of smoking cessation failure and (iii) we could identify different smoking phenotypes for which the efficacy of different treatments varies. In this sense, (i) NRT may not be recommended in subjects of any age with high levels of nicotine dependence (FTCD-score about 9 points, high grade in the short version of FTCD, or < 5 min in time to first cigarette after waking) because it can increase the likelihood of failure; (ii) in subjects with high levels of tobacco dependence and with increasing age, the treatments that worked better were bupropion or varenicline, (iii) young subjects (< 20 years) with moderate-tohigh levels of tobacco dependence (FTND-score 6 points, high grade in the short version of FTND, or time to first cigarette before 30 min after waking) are resistant to any type of treatment; finally, (iv) subjects with low nicotine dependence can be treated with any of the treatments tested, although bupropion and varenicline provided the best results. Different studies have shown that smokers with the highest scores on the FTCD are less likely to success when they are treated with different drugs for smoking cessation. Nides et al. found that varenicline was effective regardless of the baseline nicotine dependence, baseline cigarette consumption or time elapsed to first cigarette of the day, although the absolute efficacy of varenicline tended to decline with increased nicotine dependence (6). These studies support our data regarding the increased possibility of failure in those who smoke their first cigarette immediately after waking. A striking finding of our analysis is that those smokers with positive reinforcement have less possibilities for quitting than those with negative one. This finding can be explained by taking into account that smoking cessation treatments are more effective in controlling nicotine withdrawal syndrome than in giving pleasure to those who use them. Our finding on the lack of efficacy of different treatments for people about 20 years old with high degree of physical dependence on nicotine could be supported by the contraindication that the 2008 Update Clinical Practice Guideline of USDHHS makes regarding the use of this type of medication in these subjects. However, it should be noted that the number of subjects in this age group in our series was low and that any conclusion in this regard should be taken with caution. Nevertheless, a recent meta-analysis examined six randomised clinical trials involving 816 smokers, who were years of age, and found no significant increase in abstinence rates with pharmacological therapy. Similarly, no significant increase in abstinence rates was found in subgroup meta-analyses of studies with both shortterm ( 12 weeks) and mid-term (26 weeks) followup periods (12). Several authors have found that nicotine patches are not effective in women (13). We found that NRT had worse outcomes in the phenotype corresponding to women of any age with high degree of nicotine dependence. This result can be explained by the low efficacy of NRT in the group of smokers with high nicotine dependence that was found in our study. Another striking finding of our study is that smoking cessation seems to be more difficult in women. There are several reasons that can explain this finding: (i) in our sample NRT was less effective in women than in men, (ii) women smoke for positive reinforcement more than men and it must be kept in mind that the efficacy of smoking cessation treatments in those who smoke for positive reinforcement is lower than in those who smoke for negative reinforcement and (iii) depression and anxiety are more frequent among women and these disorders diminish the chances of quitting. It is interesting to note that a high proportion of those who did not receive pharmacological treatment were successful in quitting. Two reasons can explain this: (i) most of these subjects had low grade of nicotine dependence and (ii) although they did not receive pharmacological treatment, they received a strong psychological support and had ten appointments in 6 months with tobacco treatment specialists. This research has several limitations. The main is that the treatments were not randomly assigned, but based on clinical practice guidelines, therapist experience, patient preference and previous experience of success or failure with either treatment, as well as other clinical considerations. Moreover, varenicline was introduced in Spain in January This study included patients from January 2004, which may have influenced the treatment allocation. However, its use in our study was only 31.7%. Other studies have also used retrospective samples to compare

10 Looking for the right treatment for each smoker 1539 treatments for smoking cessation, including patients prior to 2007, before varenicline was available (8,14,15). In some of these studies, the choice of treatment was made by the smokers themselves (14,16). The non-random distribution of treatments causes an unequal distribution of other predictive variables between them, which may influence the associations found between them and the outcome variable. The method used in this study to construct regression models permit to control for differences in the distributions of the variables in non-randomized studies (10). In fact, the discovery of the interaction between the type of treatment and age should not be considered a true interaction, but as an adjustment term introduced by the construction method of the regression models. Another limitation of the study is that it describes the results of a series of smokers without a control group. However, the aim of this study was to try to define characteristics of smokers or combinations of them to help predict the likelihood of success or failure. Our study was made in a real clinical setting, without the inherent limitations of clinical trials. Our results can serve to advise the most appropriate treatment for patients with similar characteristics, or to help plan future studies to corroborate the findings observed. In conclusion, we have analysed the results of a smoking cessation treatment in a group of 3622 smokers attending a smoking cessation clinic and found that some smoking phenotypes based on gender, age and tobacco dependence could be identified. The identification of these phenotypes may assist decision making regarding the choice of treatment. Funding None. References 1 Fiore MC, Jaen CR, aker T, ailey WC, enowitz N, Curry S. Treating Tobacco Use and Dependence: 2008 Update Clinical Practice Guideline. Rockville, MD: Department of Health and Human Service, Public Health Service, Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev, 4(1), CD Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A. Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. Psychopharmacology 2006; 184: Munafo M, radburn M, owes L, David S. Are there sex differences in transdermal nicotine replacement therapy patch efficacy? A meta-analysis. Nicotine Tob Res 2004; 6: Stead LF, Perera R, ullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008, 23(1): CD DOI: / CD pub3. 6 Nides M, Glover ED, Reus I et al. arenicline versus bupropion SR or placebo for smoking cessation: a pooled analysis. Am J Health ehav 2008; 2008(32): Fagerstr om K, Jimenez-Ruiz CA, Mochales JA, Gilljam H. Can smoking for positive or negative reinforcement together with dependence help us better diagnose smokers? J Smoking Cessation 2007; 2: Minas M, Apostolidou E, Goudouva I, Markris E, Gourgoulianis KI, Hatzoglou C. Clinical phenotypes related to smoking cessation. J Subst Abuse Treat 2013; 44: Jimenez-Ruiz CA, Riesco JA, Ramos A et al. Recommendations for pharmacological tobacco cessation treatments: proposals for financing. Arch ronconeumol 2008; 2008(44): Domenech JM, Navarro J. Regresion logıstica binaria, multinomial, de Poisson y binomial negativa [inary Logistic Regression, Multinomial, Poisson and Negative inomial]. arcelona: Signo, Figueiras A, Domenech JM, Cadarso C. Regression models: calculating the confidence interval of effects in the presence of interactions. Stat Med 1998; 17: Kim Y, Myung SK, Jeon YJ et al. Efficacy of pharmacologic therapy for smoking cessation in adolescent smokers: meta-analysis of randomized controlled trials. Am J Health-Syst Ph 2011; 2011 (68): Rahmanian SD, Diaz P, Wewers ME. Tobacco use and cessation among women: research and treatment-related issues. J Womens Health 2011; 20: Kralitkova E, Kmetova A, Stepankova L, Zvolska K, Davis R, West R. Fifty-two-week continous abstinence rates of smokers being treated with varenicline versus nicotine replacement therapy. Addiction 2013; 108: Marqueta A, Nerın I, Jimenez-Muro A,, eamonte A. Predictors of outcome of a smoking cessation treatment by gender. Gac Sanit 2013; 27: Nerin I, Novella P, eamonte A, Gargallo P, Jimenez-Muro A, Marqueta A. Results of smoking cessation therapy in a specialist unit. Arch ronconeumol 2007; 43: Paper received January 2014, accepted June 2014