RESEARCH REPORT ABSTRACT

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1 RESEARCH REPORT doi: /j x Does improved access and greater choice of nicotine replacement therapy affect smoking cessation success? Findings from a randomized controlled trialadd_ Natalie Walker 1, Colin Howe 1, Chris Bullen 1, Michele Grigg 2 *, Marewa Glover 3, Hayden McRobbie 4 **, Murray Laugesen 5, Joy Jiang 1, Mei-Hua Chen 6 **, Robyn Whittaker 1 & Anthony Rodgers 7 ** Clinical Trials Research Unit, School of Population Health, The University of Auckland, Auckland, New Zealand, 1 Litmus, Wellington, New Zealand, 2 Centre for Tobacco Control Research, Social and Community Health, School of Population Health, The University of Auckland, Auckland, New Zealand, 3 Queen Mary University of London, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, UK, 4 Health NZ Ltd, Lyttelton, Christchurch, New Zealand, 5 Eli Lilly and Company (New Zealand) Limited, Newmarket, Auckland, New Zealand 6 and The George Institute for International Health, NSW, Australia 7 ABSTRACT Aims To determine the effect of offering smokers who want to quit easy access to nicotine replacement therapy (NRT), a period of familiarization and choice of product on smoking abstinence at 6 months. Design Single-blind, randomized controlled trial. Setting New Zealand. Participants A total of 1410 adult smokers who called the national Quitline for quitting support were randomized to usual Quitline care or a box containing different NRT products (patch, gum, inhaler, sublingual tablet, oral pouch) to try for a week prior to quitting, and then to choose one or two of these products for 8 weeks use. Measurements The primary outcome was 7-day point prevalence smoking abstinence 6 months after quit day. Secondary outcomes included continuous abstinence, cigarette consumption, withdrawal, NRT choice and serious adverse events at 1 and 3 weeks and 3 and 6 months. Findings No differences in 6-month quit rates (7-day point prevalence or continuous abstinence) were observed between the groups. However, smokers allocated to the intervention group were more likely to have quit smoking at 3 months [self-reported point prevalence, relative risk (RR) = 1.17, 95% confidence interval (CI): 1.02, 1.35, P = 0.03], had a longer time to relapse (median 70 days versus 28 days, P < 0.01) and used significantly more NRT. The selection box concept was highly acceptable to users, with the patch and inhaler combination the most popular choice (34%). Conclusions In terms of smoking abstinence at 6 months, offering smokers who want to quit free access to a wide range of nicotine replacement therapy, including a 1-week period of familiarization and choice of up to two products, appears no different to offering reduced cost and choice of nicotine replacement therapy, with no familiarization period. Keywords Access, cessation, choice, clinical trial, nicotine replacement therapy, randomized, smoking. Correspondence to: Natalie Walker, Clinical Trials Research Unit, School of Population Health, The University of Auckland, Private Bag 92019, Auckland, New Zealand. n.walker@ctru.auckland.ac.nz Submitted 2 September 2010; initial review completed 13 October 2010; final version accepted 23 February 2011 INTRODUCTION Despite 65% of smokers making at least one quit attempt in the last 5 years, and 33% in the last year [1], smoking prevalence rates are declining slowly in New Zealand, with 20% of all adults and 38% of indigenous Māori adults still smoking in 2006/7 [1]. Usual cessation practice in many countries involves a single form of nicotine replacement therapy (NRT) for the whole cessation attempt, without any period of familiarization and *Formerly of The Quit Group, PO Box 12605, Wellington, New Zealand. **Formerly of the Clinical Trials Research Unit, School of Population Health, The University of Auckland, Private Bag 92019, Auckland, New Zealand.

2 Choice of nicotine therapy for quitting 1177 limited user choice among the different NRT products. In New Zealand, combination NRT therapy is now offered by cessation service providers (such as Quitline), in line with the New Zealand smoking cessation guidelines [2]. However, such services only promote NRT patches, gum and lozenges, as these products are heavily subsidized (NZ$3 6 per item per 4-week course) when issued by registered cessation providers. Nicotine inhalers and sublingual tablets are not subsidized and the inhaler is available only from pharmacies, and thus these products are rarely used in New Zealand [3]. Cost (perceived and real) is a known barrier to the use of NRT [4,5], and reducing cost leads to increased longterm use of NRT and higher quit rates [6 8]. However, evidence regarding the effect of increasing user choice of NRT on quitting success is less clear. Increasing choice could potentially improve quit rates by allowing smokers to gain a sense of control over the quitting process [9,10]. User preferences may vary, as each NRT differs in its ease of use, side effects and nicotine delivery [11,12]. Two [13,14] out of three [13 16] trials investigating user choice of NRT on quit rates demonstrated a positive effect. However, the trials were small ( participants), and had methodological limitations such as short follow-up [13], no familiarization period [14 16] and poor follow-up [14]. We sought to address the above limitations by undertaking a large randomized trial with 6-month follow-up. We hypothesized that by offering smokers who wanted to quit easy access to NRT, and a period of familiarization with a wide range of products, quit rates would be increased. METHODS Setting and participants Between July 2007 and January 2009 all eligible callers to New Zealand s national Quitline were invited into the trial. Participants were eligible if they were 18 years or over, smoked their first cigarette within 30 minutes of waking, wanted to quit within the next 2 weeks, were not pregnant or breastfeeding, were not currently using NRT or other non-cigarette nicotine or tobacco products, had not experienced a stroke or myocardial infarction in the past 3 months, were not using bupropion, clonidine, nortriptyline or varenicline and were able to provide verbal informed consent to participate. Ethics approval for the trial was obtained from the New Zealand Multiregion Ethics Committee (MEC/06/11/150). Randomization, allocation concealment and blinding Participants were allocated randomly by computer, with randomization stratified, using minimization, by ethnicity (Māori versus non-māori), sex and level of nicotine dependence (>5 points, 5 points on the Fagerström score [17]). Participants were not blinded to treatment allocation, but all research staff involved in outcome assessment were blinded and follow-up assessments were identical for all participants. Intervention Participants were randomized to a selection box group or usual care (standard Quitline service). All participants received an average of three support calls from trained Quitline advisors over 8 weeks, with each call lasting about minutes. Participants randomized to the selection box group were mailed a free box of NRT. Each box contained a patch (21 mg), gum (4 mg, fruit and mint), an inhaler (10 mg), sublingual tablets (2 mg) and oral pouches (4 mg). The pouch is a new product designed to be parked under the upper lip for 30 minutes while the nicotine is released. When this trial commenced the pouch was not available for sale in New Zealand or internationally. Each box contained enough NRT for 1 week s use, plus instructions on use and safe storage. Participants were instructed to try each product over 1 week, then choose one or two preferred products for use over an 8-week period after their nominated quit day. A 2-mg gum was offered to those participants who requested a lower-dose gum. A 4-week free supply of their chosen product(s) was mailed out. Participants were offered the option of changing their choice of NRT at a 3-week follow-up call, prior to the second supply of free NRT being mailed out. Participants randomized to the usual care group were supported by Quitline in the usual manner, with NRT provided in the form of patch (7, 14 or 21 mg) and/or gum (2 or 4 mg) issued by post via two quit vouchers (one sent at baseline and one sent at 4 weeks). Participants were instructed to redeem each voucher at a pharmacist for 4 weeks supply of subsidized NRT. The type and strength of NRT was determined by the Quitline adviser, in accordance with national smoking cessation guidelines [2] and in discussion with the participant. Outcome measures Baseline data included demographic characteristics, smoking history, concomitant medication and selfefficacy (belief in ability to give up smoking). The physical signs and symptoms associated with nicotine withdrawal were measured using the Mood and Physical Symptoms Scale (MPSS) [18]. Outcome data were collected by telephone at 1 week (intervention group only), 3 weeks, 3 months and 6 months after quit day. The primary outcome was 7-day point prevalence of smoking abstinence 6 months after

3 1178 Natalie Walker et al. quit day (defined as no cigarettes, not a single puff, in the previous 7 days). Verification of quitting status was sought, with participants informed at the outset of the study that their levels of smoking and quitting may be verified, in order to improve the veracity of self-reported data [19]. Participants who reported having quit smoking at 6 months were mailed a NicAlert salivary cotinine kit for verification [20], and asked to post (postage paid) back their test-strips once tested. Two researchers recorded the results from each strip independently, with differences resolved by discussion. Participants who reported having quit smoking at 6 months, self-reported not using NRT at 6 months and had a NicAlert result of 0 (i.e. 10 ng/ml of salivary cotinine) were considered to be non-smokers. One reminder telephone call was made to encourage strip return. Secondary outcomes included self-reported 7-day point prevalence abstinence at 3 weeks and 3 months, continuous abstinence at 3 weeks, 3 months and 6 months (defined as self-report of smoking not more than five cigarettes since quit date), date of returning to regular (daily) smoking (data collected at 3 weeks, 3 months and 6 months), NRT use, cigarettes smoked per day (CPD) and serious adverse events. Withdrawal symptoms were recorded at 1 and 3 weeks using the MPSS [18]. Participants in the intervention group were also asked at 1 week about self-efficacy and their choice of NRT, reasons for selection, product concerns; adequacy of product information; and the importance of having product choice and delivery to the door (measured on a scale of 1 5, where 1 was not very important and 5 was extremely important). Sample size A sample size of 1410 people (705 in each group, 25% Māori) was calculated assuming a quit rate in the usual care group of 15% and a loss to follow-up rate of 20%. This number provided 90% power at P = 0.05 to detect a difference in point prevalence abstinence of 7.5%. This sample size also allowed the consistency of effects for prespecified subgroups to be assessed. Analysis Analysis was undertaken on an intention-to-treat (ITT) basis, according to a pre-specified plan using SAS version (SPSS Inc., Chicago, IL, USA). Participants with missing smoking status data were considered to be still smoking. c 2 analyses compared the proportion quit by treatment group, and incidence rates, relative risks (RRs), risk differences, 95% confidence intervals (CI) and two-sided P values were calculated. Logistic regression analyses were utilized to adjust for important prognostic factors. Continuous outcome data were analysed using multiple linear regression modelling. Both the number of CPD and withdrawal symptoms over time were compared using analysis of covariance (ANCOVA). Pre-specified subgroup analyses using tests for heterogeneity were undertaken for ethnicity (Māori, non-māori) age (<40 years, 40 years), sex and socio-economic status (dichotomized as those who left school below year 12 or with no school qualification, and those who completed year 12 and above). Adverse events were coded using ICD-10 AM codes. Separate post hoc analyses were undertaken to examine time-to-first-lapse using Kaplan Meier analysis and self-reported 7-day point prevalence of smoking abstinence at 6 months in those with complete smoking status data. RESULTS Figure 1 illustrates participant flow through the trial and Table 1 shows participant baseline characteristics. Final loss to follow-up for the trial was modest at 19%. NRT access and choice At 1 week follow-up, 14 participants in the intervention group could not be contacted and 99% (685) of the remaining 692 had tried the NRT in the box. Delivery of the box to the door was considered very or extremely important by 92% (636) of these participants, and 89% (618) felt it very or extremely important that they could choose their own NRT. Ninety-nine per cent (683) of participants stated that they had been given sufficient information about the NRT. Furthermore, the majority (91%, 631) had no concerns about the safety of using the products. At the 3-week follow-up call, 93% (628) of the 672 remaining participants considered delivery of NRT to the door as very or extremely important, compared to 49% (327) of the 674 remaining participants in the control group. Table 2 shows details of participants choice of NRT in the intervention group. The patch and inhaler combination was the most popular at both 1 (34%) and 3 (24%) weeks follow-up. A patch and 4-mg gum combination and patches alone were the next most popular choices at 1 and 3 weeks. Fewer participants chose to use the sublingual tablet (Table 2) or the oral pouch (2% of participants selected the pouch as their first choice and 4% as their second choice at weeks 1 and 3). NRT choice at both 1 and 3 weeks did not differ significantly by age, sex, ethnicity, socio-economic status or level of nicotine dependence. The NRT used in previous quit attempts was not associated significantly with NRT choice at 1 week. The main reason people made their choice of NRT was ease of use, few side effects and taste (for oral products). Table 2 also provides details on NRT allocation to

4 Choice of nicotine therapy for quitting 1179 Enrolment Assessed for eligibility (n=9771) Contacted Ineligible (n=158) Declined (n=299) Eligible (n=1410) Allocation Allocated to Intervention (n=706) Received intervention (n=706) Randomised (n=1410) Not contactable in time available (n=7904) Allocated to usual care (n=704) Received usual care (n=704) One week follow-up Lost to follow-up (n=14, 2%) Participants withdrawn (n=5) Follow-up Three weeks follow-up Lost to follow-up (n=34, 5%) Participants withdrawn (n=11) Three months follow-up Lost to follow-up (n=87, 12%) Participants withdrawn (n=15) Three weeks follow-up Lost to follow-up (n=30, 4%) Participants withdrawn (n=6) Three months follow-up Lost to follow-up (n=81, 12%) Participants withdrawn (n=12) Six months follow-up Lost to follow-up (n=144, 20%) Participants withdrawn (n=16) Six months follow-up Lost to follow-up (n=127, 18%) Participants withdrawn (n=17) Analysis Analysed (n=706) Protocol violations (n=6) Became pregnant (n=6) Used clonidine (n=0) Used nortriptyline (n=0) Used varenicline (n=0) Analysed (n=704) Protocol violations (n=12) Became pregnant (n=6) Used clonidine (n=1) Used nortriptyline (n=3) Used varenicline (n=2) Figure 1 Flowchart of recruitment and retention of participants throughout the trial participants in the usual care group. Patches were the most common product allocated at baseline and 3 weeks, followed by the patch and 2-mg gum combination at baseline. Twice as many participants in the usual care group were not using NRT at 3 weeks (16%), compared to the intervention group (8%) (c 2 = 19.6, P < 0.001). Compared to the usual care group, the average amount of NRT used in abstainers (in terms of milligrams of nicotine used per day) was significantly higher in the intervention group at all time-points, with this difference highest at 3 weeks (Table 3). Cessation rates Table 4 shows that smoking cessation rates at 6 months were high, but similar between the groups. A greater proportion of participants in the intervention group (215, 30%) compared to the usual care group (202, 29%) reported not having smoked in the previous 7 days, but the difference was not statistically significant (crude RR 1.06, 95% CI: 0.90, 1.25, P = 0.47; risk difference 1.76, 95% CI: -3.00, 6.52). A similar finding was found when sensitivity analyses were undertaken on those partici-

5 1180 Natalie Walker et al. Table 1 Baseline characteristics of participants. Variables Intervention group n = 706 (%) Usual care group n = 704 (%) Sex Female 426 (60) 426 (61) Male 280 (40) 278 (39) Age (years) Mean SD Ethnicity Māori 175 (25) 173 (25) Non-Māori 531 (75) 531 (75) Education Below year 12/no qualification 396 (56) 391 (56) Year 12 and above 309 (44) 313 (44) Refused to answer 1 0 Cigarettes smoked per day Mean SD Fagerström Test for Nicotine Dependence (1 10). Mean SD Type of cigarettes smoked Factory made only 316 (45) 308 (44) Roll your own only 289 (41) 311 (44) Both 101 (14) 85 (12) At least one quit attempt in last 12 months 204 (29) 197 (28) NRT used in last quit attempt Yes patch 23 (11) 34 (17) Yes gum 11 (5) 8 (4) Yes other NRT 19 (9) 10 (5) No 151 (74) 145 (74) Partner is a current smoker 193 (27) 230 (33) Self-efficacy a Mean SD a Measured on a scale of one to five, where one was very low and five was very high. NRT: nicotine replacement therapy; SD: standard deviation. Table 2 Nicotine replacement therapy (NRT) combinations. Intervention group Usual care group b Product One week n = 692 (%) Three weeks n = 672 (%) Baseline n = 704 (%) Three weeks n = 674 (%) Patch and inhaler 235 (34) 160 (24) NA NA Patch and gum (4 mg) 159 (23) 133 (20) 3 (0.4) 3 (0.4) Patch alone 83 (12) 148 (22) 414 (59) 495 (73) Patch and sublingual tablets 53 (8) 26 (4) NA NA Gum alone (2 or 4 mg) 19 (3) 23 (3) 59 (8) 50 (7) Patch and gum (2 mg) 8 (1) 15 (2) 145 (21) 5 (0.7) Lozenge only a NA NA 11 (2) 12 (2) Patch and lozenge a NA NA 72 (10) 2 (0.3) Other 115 (17) 113 (17) NA NA Did not use NRT 20 (3) 54 (8) 0 (0) 107 (16) a In September 2008 (5 months before the end of recruitment), the NRT lozenge was added to the Quitline-subsidized NRT options but was not available in New Zealand at the start of the trial for inclusion in the selection box. Thus, some participants in the usual care group had access to NRT lozenges. b Allocation of NRT to participants in the usual care group was driven primarily by the Quitline adviser, although participant input regarding product preference was allowable (based on their prior use of NRT). NA: option not available.

6 Choice of nicotine therapy for quitting 1181 Table 3 Mean amount of nicotine replacement therapy (NRT) used over time. Time-period Mean NRT used in mg/day (SD) Difference 95% CI P-value Three weeks Intervention 47.6 (45.2) <0.001 Control 18.2 (21.5) Three months Intervention 12.3 (27.2) <0.001 Control 5.4 (12.9) Six months Intervention 4.6 (14.2) Control 2.9 (10.9) SD: standard deviation; CI: confidence interval. Table 4 Treatment effects on number of participants achieving smoking cessation (Intention to treat analysis). Intervention n = 706 (%) Usual care n = 704 (%) Relative risk (95% CI) P value Seven-day point prevalence abstinence Three-week quit rate a 313 (44) 282 (40) 1.11 ( ) 0.10 Three-month quit rate a 269 (38) 229 (33) 1.17 ( ) 0.03 Six-month quit rate a 215 (30) 202 (29) 1.06 ( ) 0.47 Sensitivity analyses for 6-month quit data Complete cases only b 215/562 (38) 202/577 (35) 1.09 ( ) 0.26 Adjustment for salivary cotinine verification c 161 (23) 136 (19) 1.19 ( ) 0.10 Continuous abstinence Three-week quit rate a 368 (52) 343 (49) 1.07 ( ) 0.20 Three-month quit rate a 208 (29) 184 (26) 1.13 ( ) 0.16 Six-month quit rate a 143 (20) 133 (19) 1.07 ( ) 0.52 a Assumes all participants with missing smoking status were smoking. b Only includes participants for whom data on smoking status was complete at 6 months. c Of the 471 eligible participants, 467 (99%) were sent a NicAlert test strip for verification of quit status; 157 (34%) returned their strips (84 intervention, 73 usual care). Seventy-five per cent (63 of 84) of those who returned the strips in the intervention group and 67% (49 of 73) in the usual care group had a test result of 0 for cotinine. The validated rate presented here is based on extrapolation of these proportions to the trial population. CI: confidence interval. pants with complete smoking data and those with validated 7-day point prevalence data. Using continuous abstinence as the measure of outcome at 6 months shows that 143 (20%) participants from the intervention group and 133 (19%) in the usual care group had smoked fewer than five cigarettes since quit day. This result gives a crude RR of 1.07 (95% CI: 0.87, 1.33), with a P value of 0.52 and an absolute risk difference of 1.36% (95% CI: -2.78%, 5.50%). Subgroup analyses showed no clear difference in the primary outcome according to age, sex, ethnicity, socioeconomic status or type of cigarette smoked. In the intervention group 6-month quit rates were similar, irrespective of choice of NRT (for the three most popular choices). In the usual care group, self-reported point prevalence abstinence rates at 6 months were slightly higher after the introduction of the lozenge, but not significantly so (28% versus 32%, c 2 = 1.12, P = 0.3). Self-reported point prevalence abstinence rates did not differ at 3 weeks, but participants in the intervention group were more likely to have quit smoking at 3 months than those in the usual care group (RR = 1.17, 95% CI: , P = 0.03) (Table 4). There was no difference between the groups for self-reported continuous abstinence rates at 3 weeks or 3 months (Table 4). Other outcomes Participants in both groups reduced their daily cigarette consumption significantly and progressively from baseline to 3 months. Participants in the intervention group who were still smoking smoked on average two (95% CI: 0.91, 3.1) fewer cigarettes per day at 3 weeks and 1.3 (95% CI: 0.3, 2.4) fewer cigarettes at 3 months, compared to the usual care group. For abstainers only, symptoms associated with nicotine withdrawal and urges to smoke did not differ significantly between each group from baseline to 3 weeks. Results of the time-to-first-lapse Kaplan Meier analysis showed a significant difference between groups in

7 1182 Natalie Walker et al. Figure 2 Kaplan Meier curve for time to relapse (days) favour of the intervention group (394 versus 450 participants reported relapse within 6 months, P value for logrank test ) (Fig. 2). Furthermore, participants were significantly more likely to relapse within 6 months if they: were female [hazard ratio (HR) = 1.32, 95% CI: 1.10, 1.61], had left school below year 12 or with no school qualification (HR = 1.22, 95% CI: 1.01, 1.47), had low self-efficacy (self-efficacy 3, HR = 1.55, 95% CI: 1.25, 1.92) or had a higher level of nicotine dependence (Fagerström score [17] of >5: HR = 1.28, 95% CI: 1.05, 1.55). NRT choice (for the three most popular choices) was not associated significantly with time-tofirst-lapse. There was no significant difference in the occurrence of serious adverse events between the intervention group (53 events in 53 participants, 7.5%) and usual care group (55 events in 51 participants, 7.3%, incidence rate ratio = 0.98 P = 0.9). Cancer, surgical procedures and neuropsychiatric events were more common in the intervention group (seven, 10 and five events, respectively) than the usual care group (five, six and no events, respectively), while more skin and subcutaneous events occurred in the usual care group (three versus no events). All other events were similar in both groups. There were three deaths during the trial, two among participants in the intervention group (heart disease and car crash) and one in the usual care group (pancreatic cancer). DISCUSSION This is the largest trial conducted to date to explore whether smokers who have better access to NRT, more product choice and no financial barriers to NRT are more likely to stop smoking at 6 months than smokers without these options. No increase in long-term quit rates over usual care was found, despite a significant impact on short-term quit rates, time to relapse, high participant acceptability and greater use of NRT. There was no evidence of any excess adverse events in the intervention group. Ease of product use, side effects and taste (for oral products) were key factors for participants when choosing NRT. As this trial tested a package of care, we are unable to say which of the factors within the package had the most impact on the study findings. This trial has highlighted the fact that personal choice of NRT is important but variable among smokers trying to quit, and that smokers appear to use NRT for long periods (as evidenced by the quantity of NRT still being used at 6 months in both groups). The latter finding suggests that smokers in this trial either did not use their initial supply of NRT according to the recommended dosing regimen and/or they purchased additional NRT during the study period. A previous Quitline-based cessation trial run in New Zealand also noted that participants were still using NRT at 6 months (either trial product or

8 Choice of nicotine therapy for quitting 1183 purchased product) [21]. The reasons for this finding should be elucidated further, as they may have implications for treatment effectiveness and/or policy. Results from the previous trials of NRT choice and quitting [13 16] cannot be pooled with data from this trial due to substantial differences in the interventions and outcome measures. However, the cessation results are broadly consistent with those found in this trial. Furthermore, this trial provides some of the first data on smoker preference when offered combination NRT therapy. The findings in this paper support those of West et al. (2001), that choice of NRT does not necessarily improve cessation outcome, suggesting that there is nothing to be lost by restricting patients choice of products due to issues such as cost or practicability [16]. Although cost analyses were not undertaken in this trial, the direct costs of providing the selection box of NRT used in this trial were clearly more expensive than providing the vouchers used in the usual care group. Research has demonstrated that a wide range of NRT choices are made by smokers [11,12,16]. In New Zealand combination therapy is recommended [2], given that trial evidence supports improved quit rates over and above single therapy [22]. Patches and gum are the most common combination in New Zealand, possibly because they have been available the longest, they are relatively affordable (via the quit voucher scheme) and are the most heavily promoted by smoking cessation providers [3]. This trial was not powered to detect differences in quit rates according to specific products combinations, but smokers wanting to quit will certainly take full advantage of choice if it is offered, with combination NRT therapy popular and without any apparent added risk. The popularity of the NRT patch and inhaler combination in this trial is of interest, as traditionally fewer than 5% of New Zealand smokers trying to quit have used the inhaler [3]. The cost of the inhaler and its classification as a pharmacy-only medicine may have contributed to its limited uptake in the past. Subsidizing this form of NRT and/or reclassifying it to make it more widely available may help to increase its uptake. The low uptake of the oral pouch was surprising, given that a cross-over trial among 30 adult smokers in New Zealand showed that the pouch was as effective as 4-mg gum at relieving cravings, and was more acceptable to participants [23]. A second cross-over trial (n = 63) found that the pouch had a greater (although non-significant) effect on withdrawal symptoms and urge to smoke and less side effects, compared to 4-mg gum [24]. Smokers in New Zealand have had no access to or previous use of the pouch, or other similarly packaged products (such as smokeless tobacco). This lack of product recognition could explain the limited interest in the pouch among New Zealand smokers. Despite being available for general sale in New Zealand since March 2005, few participants chose to use the sublingual tablets, a finding supported by New Zealand survey data showing <5% of smokers trying to quit had used this product [3]. Unlike previous trials investigating the effect of NRT choice on quit rates [13 16], this study had adequate statistical power to detect a difference in treatment effect. Loss to follow-up at 6 months was modest, and similar in both groups. A further strength was the rigorous conduct of the trial, in line with Consolidated Standards of Reporting Trials (CONSORT) guidelines [25,26]. The study population was similar to Quitline callers and the wider population of New Zealand smokers as a whole [3,27], although we acknowledge the limitations associated with recruiting through Quitline [28]. Although blinded treatment allocation was not possible in this trial, outcome assessments were undertaken by researchers blind to treatment allocation, as was validation of quitting status. Verification of self-reported abstinence was difficult, with low return rates for the NicAlert strips. Nevertheless, the verified 6-month abstinence rate in the usual care group was consistent with that seen in previous New Zealand Quitline research [21,29]. Although the effect of this package of care on longterm quit rates was no different to offering a limited selection of NRT at reduced cost to people wishing to stop smoking, the package clearly stimulated greater reported use of NRT. It is possible that despite reporting greater use of NRT, participants (particularly highly dependent smokers) in the intervention group may still have been under-dosed, which is why no effect was seen on quit rates. Traditionally, a one size fits all approach has been taken regarding NRT dosing, despite NRT delivering less than half the nicotine a smoker receives from a cigarette [30], different NRT products delivering different amounts of nicotine and there being significant inter-person variability in how fast nicotine is metabolized [31]. By using the principle of therapeutic drug monitoring it is possible to achieve almost 100% replacement of nicotine using NRT, with resulting high quit rates [32]. Perhaps if smokers wanting to quit are given product choice and are taught how to self-regulate their dosing of NRT to manage their withdrawal symptoms, their belief in their ability to quit and overall quit rates may improve. Trial registration This trial is registered with the Australasian Clinical Trials Network Number: ACTRN Declarations of interest All authors declare that no authors have received support from any companies for the submitted work. C.B. and H.M. have previously undertaken research on behalf of

9 1184 Natalie Walker et al. NicoNovum, but prior to the purchase of the company by R.J. Reynolds. H.M. has received honoraria for speaking at research symposia and received benefits in kind and travel support from, and has provided consultancy to the manufacturers of smoking cessation medications. N.W. has provided consultancy to the manufacturers of smoking cessation medications, received honoraria for speaking at a research meeting and received benefits in kind and travel support from a manufacturer of smoking cessation medications. M.G. has provided consultancy to the manufacturers of smoking cessation medications. Their spouses, partners or children have no financial relationships that may be relevant to the submitted work; and all authors have no non-financial interests that may be relevant to the submitted work. All authors are currently involved in a trial looking at the effect of reduced nicotine cigarettes on smoking cessation. This trial involves the use of cigarettes which have been purchased from Vector Group Ltd. Acknowledgements The trial was funded by the Health Research Council of New Zealand and the Heart Foundation of New Zealand. NRT was purchased for the intervention arm of the study from Novartis Consumer Health Australasia Pty Ltd (patch and gum), and provided free by Johnson and Johnson Pacific (inhaler and sublingual tablet) and Niconovum (oral pouch). Note that the inclusion of Niconovum product in this study was prior to the purchase of the company by R.J. Reynolds. We thank the research assistants (Rose Silcock, Elspeth Chell, Stella McGough, Janneke Van t Klooster) at The Quit Group, CTRU study-related staff (Nathan Cowie, John Fa atui, Marissa Russell, Stephen Boswell, Micheal Ng, Joy Jiang, Johan Strydom, Terry Holloway, Lyn Cummings, Karen Carter, Mary Cosson, Denise Miller and Sheila Fisher) and the trial participants. 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