What to do after smoking relapse? A sequential multiple assignment randomized trial of chronic care smoking treatments.

AIM: To compare effects of three post-relapse interventions on smoking abstinence. DESIGN: Sequential three-phase multiple assignment randomized trial (SMART). SETTING: Eighteen Wisconsin, USA, primary care clinics. PARTICIPANTS: A total of 1154 primary care patients (53.6% women, 81.2% White) interested in quitting smoking enrolled from 2015 to 2019; 582 relapsed and were randomized to relapse recovery treatment. INTERVENTIONS: In phase 1, patients received cessation counseling and 8 weeks nicotine patch. Those who relapsed and agreed were randomized to a phase 2 relapse recovery group: (1) reduction counseling + nicotine mini-lozenges + encouragement to quit starting 1 month post-randomization (preparation); (2) repeated encouragement to quit starting immediately post-randomization (recycling); or (3) advice to call the tobacco quitline (control). The first two groups could opt into phase 3 new quit treatment [8 weeks nicotine patch + mini-lozenges plus randomization to two treatment factors (skill training and supportive counseling) in a 2 × 2 design]. Phase 2 and 3 interventions lasted ≤ 15 months. MEASUREMENTS: The study was powered to compare each active phase 2 treatment with the control on the primary outcome: biochemically confirmed 7-day point-prevalence abstinence 14 months post initiating phase 2 relapse recovery treatment. Exploratory analyses tested for phase 3 counseling factor effects. FINDINGS: Neither skill training nor supportive counseling (each on versus off) increased 14-month abstinence rates; skills on versus off 9.3% (14/151) versus 5.2% (8/153), P = 0.19; support on versus off 6.6% (10/152) versus 7.9% (12/152), P = 0.73. Phase 2 preparation did not produce higher 14-month abstinence rates than quitline referral; 3.6% (8/220) versus 2.1% [3/145; risk difference = 1.5%, 95% confidence interval (CI) = -1.8-5.0%, odds ratio (OR) = 1.8, 95% CI = 0.5-6.9]. Recycling, however, produced higher abstinence rates than quitline referral; 6.9% (15/217) versus 2.1% (three of 145; risk difference, 4.8%, 95% CI = 0.7-8.9%, OR = 3.5, 95% CI = 1.0-12.4). Recycling produced greater entry into new quit treatment than preparation: 83.4% (181/217) versus 55.9% (123/220), P < 0.0001. CONCLUSIONS: Among people interested in quitting smoking, immediate encouragement post-relapse to enter a new round of smoking cessation treatment ('recycling') produced higher probability of abstinence than tobacco quitline referral. Recycling produced higher rates of cessation treatment re-engagement than did preparation/cutting down using more intensive counseling and pharmacotherapy.

Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Relations of Current and Past Cancer with Severe Outcomes among 104,590 Hospitalized COVID-19 Patients: The COVID EHR Cohort at the University of Wisconsin.

BACKGROUND: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics. METHODS: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined. RESULTS: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90). CONCLUSIONS: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types. IMPACT: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3.

Understanding contexts of smoking and vaping among dual users: analysis of ecological momentary assessment data.

AIMS: To understand dual users' cigarette and e-cigarette use patterns, including the contexts in which they vape versus smoke and to understand how environmental and internal contexts and smoking patterns differ between dual users and exclusive smokers. DESIGN: Longitudinal observational trial. SETTING: Research center in Wisconsin, USA. PARTICIPANTS: Adult dual users (n = 162) and adults who exclusively smoked (n = 143), with no plans to quit smoking or vaping in the next 30 days. MEASUREMENTS: Participants carried smartphones for 2 weeks at baseline to record each use event for the two products and report on the context of their product use. The percentage of mornings where participants vaped first versus smoked were used to compute e-cigarette dependence. FINDINGS: Hierarchical linear regression models with random slopes and intercepts examined the within- and between-subject effects of context on the likelihood of vaping (versus smoking); significant fixed effects were tested for moderation by e-cigarette dependence. Dual users reported significantly more puffs/cigarette [mean = 13.1, standard deviation (SD) = 10.2] than puffs/vape event (mean = 11.7, SD = 11.5; P = 0.01). E-cigarette dependence moderated the influence of social cues (t-ratio = 2.4, P = 0.02) and smoking restrictions (t-ratio = 3.1, P = 0.003) on the likelihood of vaping versus smoking [odds ratio (OR) = 2.30, P = 0.02]. Context was more related to which product was used in those of low versus higher e-cigarette dependence. Reports of strong cravings to smoke and positive expectancies for cigarettes were associated with a reduced likelihood of vaping, whereas strong cravings to vape and positive vaping expectancies were related to increased likelihood of vaping. CONCLUSIONS: Among dual users of cigarettes and e-cigarettes with no motivation to quit, vaping appears to be related to internal cues and more highly linked with social contexts and smoking restrictions (i.e. under stronger external stimulus control) among those with low to moderate e-cigarette dependence compared with high e-cigarette dependence. These findings illustrate the importance of contextual factors in tobacco product use among dual users with the influence of context being reduced at high levels of e-cigarette dependence.

Effects of Combined Varenicline With Nicotine Patch and of Extended Treatment Duration on Smoking Cessation: A Randomized Clinical Trial.

Importance: Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of varenicline treatment, or both, may increase cessation effectiveness. Objective: To compare combinations of varenicline plus the nicotine or placebo patch vs combinations used for either 12 weeks (standard duration) or 24 weeks (extended duration). Design, Settings, and Participants: Double-blind, 2 × 2 factorial randomized clinical trial conducted from November 11, 2017, to July 9, 2020, at 1 research clinic in Madison, Wisconsin, and at 1 clinic in Milwaukee, Wisconsin. Of the 5836 adults asked to participate in the study, 1251 who smoked 5 cigarettes/d or more were randomized. Interventions: All participants received cessation counseling and were randomized to 1 of 4 medication groups: varenicline monotherapy for 12 weeks (n = 315), varenicline plus nicotine patch for 12 weeks (n = 314), varenicline monotherapy for 24 weeks (n = 311), or varenicline plus nicotine patch for 24 weeks (n = 311). Main Outcomes and Measures: The primary outcome was carbon monoxide-confirmed self-reported 7-day point prevalence abstinence at 52 weeks. Results: Among 1251 patients who were randomized (mean [SD] age, 49.1 [11.9] years; 675 [54.0%] women), 751 (60.0%) completed treatment and 881 (70.4%) provided final follow-up. For the primary outcome, there was no significant interaction between the 2 treatment factors of medication type and medication duration (odds ratio [OR], 1.03 [95% CI, 0.91 to 1.17]; P = .66). For patients randomized to 24-week vs 12-week treatment duration, the primary outcome occurred in 24.8% (154/622) vs 24.3% (153/629), respectively (risk difference, -0.4% [95% CI, -5.2% to 4.3%]; OR, 1.01 [95% CI, 0.89 to 1.15]). For patients randomized to varenicline combination therapy vs varenicline monotherapy, the primary outcome occurred in 24.3% (152/625) vs 24.8% (155/626), respectively (risk difference, 0.4% [95% CI, -4.3% to 5.2%]; OR, 0.99 [95% CI, 0.87 to 1.12]). Nausea occurrence ranged from 24.0% to 30.9% and insomnia occurrence ranged from 24.4% to 30.5% across the 4 groups. Conclusions and Relevance: Among adults smoking 5 cigarettes/d or more, there were no significant differences in 7-day point prevalence abstinence at 52 weeks among those treated with combined varenicline plus nicotine patch therapy vs varenicline monotherapy, or among those treated for 24 weeks vs 12 weeks. These findings do not support the use of combined therapy or of extended treatment duration. Trial Registration: ClinicalTrials.gov Identifier: NCT03176784.

Evaluating four motivation-phase intervention components for use with primary care patients unwilling to quit smoking: a randomized factorial experiment.

AIMS: To assess the effectiveness of intervention components designed to increase quit attempts and promote abstinence in patients initially unwilling to quit smoking. DESIGN: A four-factor, randomized factorial experiment. SETTING: Sixteen primary care clinics in southern Wisconsin. PARTICIPANTS: A total of 577 adults who smoke (60% women, 80% White) recruited during primary care visits who were currently willing to reduce their smoking but unwilling to try to quit. Interventions Four factors contrasted intervention components administered over a 1-year period: (i) nicotine mini-lozenge versus none; (ii) reduction counseling versus none; (iii) behavioral activation (BA) counseling versus none; and (iv) motivational 5Rs counseling versus none. Participants could request cessation treatment at any time. MEASUREMENTS: The primary outcome was 7-day point-prevalence abstinence at 52 weeks post enrollment; secondary outcomes were point-prevalence abstinence at 26 weeks and making a quit attempt by weeks 26 and 52. FINDINGS: No abstinence main effects were found but a mini-lozenge × reduction counseling × BA interaction was found at 52 weeks; P = 0.03. Unpacking this interaction showed that the mini-lozenge alone produced the highest abstinence rate (16.7%); combining it with reduction counseling produced an especially low abstinence rate (4.1%). Reduction counseling decreased the likelihood of making a quit attempt by 52 weeks relative to no reduction counseling (P = 0.01). CONCLUSIONS: Nicotine mini-lozenges may increase smoking abstinence in people initially unwilling to quit smoking, but their effectiveness declines when used with smoking reduction counseling or other behavioral interventions. Reduction counseling decreases the likelihood of making a quit attempt in people initially unwilling to quit smoking.

Revision of the Wisconsin Smoking Withdrawal Scale: Development of brief and long forms.

The assessment of tobacco withdrawal is important for both research and clinical purposes. This study describes the psychometric development of a revised version of the 28-item Wisconsin Smoking Withdrawal Scale (WSWS; Welsch et al., Experimental and Clinical Psychopharmacology, 1999, 7, p. 354). Because the different contexts of use sometimes permit only brief assessment, this revision has produced both a brief and longer form using an updated pool of candidate items. For the revised Wisconsin Smoking Withdrawal Scale 2 (WSWS2), a candidate pool of 37 items was developed to measure nine putative withdrawal constructs. The stem and wording of items were revised as was the response scale. Data for psychometric analyses were derived from three smoking cessation randomized clinical trials conducted at the University of Wisconsin Center for Tobacco Research and Intervention. Dimensionality, internal consistency, and item characteristic analyses of the candidate items were conducted in a derivation sample to ascertain the factor structure and to identify items that could be used in the WSWS2 scales. Confirmatory factor analyses (CFAs) of reduced item sets and factor structure were conducted in two validation samples along with reliability and validity analyses. Derivation and validation sample analyses yielded a longer version of the WSWS2 (WSWS2-L) with 19 items and six subscales (Craving, Negative Affect, Hunger, Sleep, Restlessness, and Concentration) and a brief 6-item version (WSWS2-B). In validation sample analyses, both the WSWS2-L and the WSWS2-B demonstrated good reliability and validity as well as good fit in CFAs. The WSWS2-L and WSWS2-B possess improved construct coverage, fewer items, and other enhancements relative to the WSWS. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Barriers to Building More Effective Treatments: Negative Interactions Amongst Smoking Intervention Components.

Meaningfully improved mental and behavioral health treatment is an unrealized dream. Across three factorial experiments, inferential tests in prior studies showed a pattern of negative interactions suggesting that better clinical outcomes are obtained when participants receive fewer rather than more intervention components. Further, relatively few significant main effects were found in these experiments. Modeling suggested that negative interactions amongst components may account for these patterns. This paper evaluates factors that may contribute to such declining benefit: increased attentional or effort burden; components that produce their effects via the same capacity limited mechanisms, making their effects subadditive; and a tipping point phenomenon in which those near a hypothesized "tipping point" for change will benefit markedly from weak intervention while those far from the tipping point will benefit little from even strong intervention. New research should explore factors that cause negative interactions amongst components and constrain the development of more effective treatments.

Electronically Monitored Nicotine Gum Use Before and After Smoking Lapses: Relationship With Lapse and Relapse.

INTRODUCTION: Greater use of nicotine replacement therapy (NRT) is related to smoking cessation success, but the causal direction is unclear. This study characterized the relationship between NRT use and smoking lapse and relapse. METHODS: Participants (N = 416 smokers; 57% female, 85% White) were recruited from primary care for a smoking cessation factorial experiment and analyzed if abstaining ≥1 day in the first 2 weeks post-target quit day (TQD). Participants were randomized to counseling and 8 versus 26 weeks of nicotine patch plus nicotine gum post-TQD. Participants carried electronic dispensers that timestamped each gum use. Participants who lapsed (smoked after abstaining) within 6 weeks post-TQD were matched with nonlapsers (n = 146 pairs) on multiple variables. We compared lapsers' versus matched nonlapsers' gum use in the 5 days before and after the lapsers' first lapse. RESULTS: By week 6 post-TQD, 63% of participants lapsed. Compared with nonlapsers, lapsers used less gum 1 and 2 days pre-"lapse" and on the 5 days post-lapse. Lapsers used less gum during the 5 days post-lapse than the 5 days pre-lapse. Univariate survival analyses with lapsers showed greater gum use during both pre- and post-lapse periods predicted longer latency to relapse in the first 6 weeks. CONCLUSIONS: In a smoking cessation attempt using nicotine patch plus gum, lapsers versus matched nonlapsers used less gum immediately preceding and following their first lapse. Lower mean gum use before and after lapses predicted a more rapid escalation to relapse. Decreased nicotine gum use both precedes and follows returns to smoking during cessation attempts. IMPLICATIONS: This research examined electronically monitored nicotine gum use collected in real time and found that among smokers engaged in a quit attempt, lapsers (vs. matched nonlapsers) tended to decrease their gum use 1-2 days prior to lapsing and to further decrease their gum use from pre- to post-lapse. Decreased gum use pre-lapse may signal heightened lapse risk in 1-2 days, with lower level of gum use predicting a more precipitous course of relapse. These results encourage further exploration of objective measures of smoking medication use patterns to examine their signaling properties and to inform understanding of cessation failure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01120704.

Can we increase smokers' adherence to nicotine replacement therapy and does this help them quit?

OBJECTIVE: To examine the effects of five intervention components on smokers' adherence to combined nicotine patch and nicotine gum during a quit attempt and assess whether adherence is related to cessation. METHOD: Smokers interested in quitting (N = 513; 59% female; 87% White) received nicotine patch plus nicotine gum and participated in a 2x2x2x2x2 randomized factorial experiment (i.e., 32 treatment conditions) evaluating five intervention components: (1) medication adherence counseling versus none; (2) automated medication adherence calls versus none; (3) electronic medication monitoring with feedback and counseling versus e-monitoring alone; (4) 26 versus 8 weeks of nicotine patch plus nicotine gum; and (5) maintenance counseling versus none. Adherence was assessed over the first 6 weeks post-target quit day via timeline follow-back (nicotine patch) and electronic medication dispenser (gum). RESULTS: In the first 6 weeks post-quit day, 12% of participants used no patches or gum, and 40% used the patch every day. Only 1.4% used both patch and gum adherently every day in the 6 weeks post-target quit day. E-monitoring counseling increased gum use (from 1.9 to 2.6 pieces/day; p < .001) but did not increase abstinence. More adherent patch and gum use in the first 6 weeks were each associated with higher point-prevalence abstinence rates through 1 year. CONCLUSIONS: This large experiment with electronic monitoring of nicotine gum adherence showed that e-monitoring counseling increased gum use but not abstinence. Adherence to nicotine patch and to gum were each strongly related to abstinence, but it is unclear whether adherence increases abstinence, or relapse causes medication discontinuation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01120704.

Extreme Response Style and the Measurement of Intra-Individual Variability in Affect.

Extreme response style (ERS) has the potential to bias the measurement of intra-individual variability in psychological constructs. This paper explores such bias through a multilevel extension of a latent trait model for modeling response styles applied to repeated measures rating scale data. Modeling responses to multi-item scales of positive and negative affect collected from smokers at clinic visits following a smoking cessation attempt revealed considerable ERS bias in the intra-individual sum score variances. In addition, simulation studies suggest the magnitude and direction of bias due to ERS is heavily dependent on the mean affect level, supporting a model-based approach to the study and control of ERS effects. Application of the proposed model-based adjustment is found to improve intra-individual variability as a predictor of smoking cessation.

Toward precision smoking cessation treatment II: Proximal effects of smoking cessation intervention components on putative mechanisms of action.

BACKGROUND: Understanding how smoking cessation treatments exert their effects can inform treatment development and use. Factorial designs allow researchers to examine whether multiple intervention components affect hypothesized change mechanisms, and whether the affected mechanisms are related to cessation. METHODS: This is a secondary data analysis of smokers recruited during primary care visits (N=637, 55% women, 87% white) who were motivated to quit. Participants in this fractional factorial experiment were randomized to one level of each of six intervention factors: Prequit Nicotine Patch vs None, Prequit Nicotine Gum vs None, Preparation Counseling vs None, Intensive In-Person Counseling vs Minimal, Intensive Phone Counseling vs Minimal, and 16 vs 8 Weeks of Combination Nicotine Replacement (nicotine patch+nicotine gum). Data on putative mechanisms (e.g., medication use, withdrawal, self-efficacy) and smoking status were gathered using daily assessments and during follow-up assessment calls. RESULTS: Some intervention components influenced hypothesized mechanisms. Prequit Gum and Patch each reduced prequit smoking and enhanced prequit coping and self-efficacy. In-Person Counseling increased prequit motivation to quit, postquit self-efficacy, and postquit perceived intratreatment support. Withdrawal reduction and reduced prequit smoking produced the strongest effects on cessation. The significant effect of combining Prequit Gum and In-Person Counseling on 26-week abstinence was mediated by increased prequit self-efficacy. CONCLUSIONS: This factorial experiment identified which putative treatment mechanisms were influenced by discrete intervention components and which mechanisms influenced cessation. Such information supports the combined use of prequit nicotine gum and intensive in-person counseling as cessation interventions that operate via increased prequit self-efficacy.

Toward precision smoking cessation treatment I: Moderator results from a factorial experiment.

BACKGROUND: The development of tobacco use treatments that are effective for all smokers is critical to improving clinical and public health. The Multiphase Optimization Strategy (MOST) uses highly efficient factorial experiments to evaluate multiple intervention components for possible inclusion in an optimized tobacco use treatment. Factorial experiments permit analyses of the influence of patient characteristics on main and interaction effects of multiple, relatively discrete, intervention components. This study examined whether person-factor and smoking characteristics moderated the main or interactive effects of intervention components on 26-week self-reported abstinence rates. METHODS: This fractional factorial experiment evaluated six smoking cessation intervention components among primary care patients (N=637): Prequit Nicotine Patch vs. None, Prequit Nicotine Gum vs. None, Preparation Counseling vs. None, Intensive Cessation In-Person Counseling vs. Minimal, Intensive Cessation Telephone Counseling vs. Minimal, and 16 vs. 8 Weeks of Combination Nicotine Replacement Therapy (NRT; nicotine patch+nicotine gum). RESULTS: Both psychiatric history and smoking heaviness moderated intervention component effects. In comparison with participants with no self-reported history of a psychiatric disorder, those with a positive history showed better response to 16- vs. 8-weeks of combination NRT, but a poorer response to counseling interventions. Also, in contrast to light smokers, heavier smokers showed a poorer response to counseling interventions. CONCLUSIONS: Heavy smokers and those with psychiatric histories demonstrated a differential response to intervention components. This research illustrates the use of factorial designs to examine the interactions between person characteristics and relatively discrete intervention components. Future research is needed to replicate these findings.

Effects of Nicotine Patch vs Varenicline vs Combination Nicotine Replacement Therapy on Smoking Cessation at 26 Weeks: A Randomized Clinical Trial.

IMPORTANCE: Smoking cessation medications are routinely used in health care; it is vital to identify medications that most effectively treat this leading cause of preventable mortality. OBJECTIVE: To compare the efficacies of varenicline, combination nicotine replacement therapy (C-NRT), and the nicotine patch for 26-week quit rates. DESIGN, SETTING, AND PARTICIPANTS: Three-group randomized intention-to-treat clinical trial occurring from May 2012 to November 2015 among smokers recruited in the Madison, Wisconsin, and Milwaukee, Wisconsin, communities; 65.5% of smokers offered the study (2687/4102) refused participation prior to randomization. INTERVENTIONS: Participants were randomized to one of three 12-week open-label smoking cessation pharmacotherapy groups: (1) nicotine patch only (n = 241); (2) varenicline only (including 1 prequit week; n = 424); and (3) C-NRT (nicotine patch + nicotine lozenge; n = 421). Six counseling sessions were offered. MAIN OUTCOMES AND MEASURES: The primary outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence at 26 weeks. Secondary outcomes were carbon monoxide-confirmed self-reported initial abstinence, prolonged abstinence at 26 weeks, and point-prevalence abstinence at weeks 4, 12, and 52. RESULTS: Among 1086 smokers randomized (52% women; 67% white; mean age, 48 years; mean of 17 cigarettes smoked per day), 917 (84%) provided 12-month follow-up data. Treatments did not differ on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 22.8% [55/241]; varenicline, 23.6% [100/424]; and C-NRT, 26.8% [113/421]) or at 52 weeks (nicotine patch, 20.8% [50/241]; varenicline, 19.1% [81/424]; and C-NRT, 20.2% [85/421]). At 26 weeks, the risk differences for abstinence were, for patch vs varenicline, -0.76% (95% CI, -7.4% to 5.9%); for patch vs C-NRT, -4.0% (95% CI, -10.8% to 2.8%); and for varenicline vs C-NRT, -3.3% (95% CI, -9.1% to 2.6%). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness, and indigestion. CONCLUSIONS AND RELEVANCE: Among adults motivated to quit smoking, 12 weeks of open-label treatment with nicotine patch, varenicline, or C-NRT produced no significant differences in biochemically confirmed rates of smoking abstinence at 26 weeks. The results raise questions about the relative effectiveness of intense smoking pharmacotherapies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01553084.

Comparative effectiveness of intervention components for producing long-term abstinence from smoking: a factorial screening experiment.

AIMS: To identify promising intervention components that help smokers attain and maintain abstinence during a quit attempt. DESIGN: A 2 × 2 × 2 × 2 × 2 randomized factorial experiment. SETTING: Eleven primary care clinics in Wisconsin, USA. PARTICIPANTS: A total of 544 smokers (59% women, 86% white) recruited during primary care visits and motivated to quit. INTERVENTIONS: Five intervention components designed to help smokers attain and maintain abstinence: (1) extended medication (26 versus 8 weeks of nicotine patch + nicotine gum); (2) maintenance (phone) counseling versus none; (3) medication adherence counseling versus none; (4) automated (medication) adherence calls versus none; and (5) electronic medication monitoring with feedback and counseling versus electronic medication monitoring alone. MEASUREMENTS: The primary outcome was 7-day self-reported point-prevalence abstinence 1 year after the target quit day. FINDINGS: Only extended medication produced a main effect. Twenty-six versus 8 weeks of medication improved point-prevalence abstinence rates (43 versus 34% at 6 months; 34 versus 27% at 1 year; P = 0.01 for both). There were four interaction effects at 1 year, showing that an intervention component's effectiveness depended upon the components with which it was combined. CONCLUSIONS: Twenty-six weeks of nicotine patch + nicotine gum (versus 8 weeks) and maintenance counseling provided by phone are promising intervention components for the cessation and maintenance phases of smoking treatment.

Enhancing the effectiveness of smoking treatment research: conceptual bases and progress.

BACKGROUND AND AIMS: A chronic care strategy could potentially enhance the reach and effectiveness of smoking treatment by providing effective interventions for all smokers, including those who are initially unwilling to quit. This paper describes the conceptual bases of a National Cancer Institute-funded research program designed to develop an optimized, comprehensive, chronic care smoking treatment. METHODS: This research is grounded in three methodological approaches: (1) the Phase-Based Model, which guides the selection of intervention components to be experimentally evaluated for the different phases of smoking treatment (motivation, preparation, cessation, and maintenance); (2) the Multiphase Optimization Strategy (MOST), which guides the screening of intervention components via efficient experimental designs and, ultimately, the assembly of promising components into an optimized treatment package; and (3) pragmatic research methods, such as electronic health record recruitment, that facilitate the efficient translation of research findings into clinical practice. Using this foundation and working in primary care clinics, we conducted three factorial experiments (reported in three accompanying papers) to screen 15 motivation, preparation, cessation and maintenance phase intervention components for possible inclusion in a chronic care smoking treatment program. RESULTS: This research identified intervention components with relatively strong evidence of effectiveness at particular phases of smoking treatment and it demonstrated the efficiency of the MOST approach in terms both of the number of intervention components tested and of the richness of the information yielded. CONCLUSIONS: A new, synthesized research approach efficiently evaluates multiple intervention components to identify promising components for every phase of smoking treatment. Many intervention components interact with one another, supporting the use of factorial experiments in smoking treatment development.

Comparative effectiveness of motivation phase intervention components for use with smokers unwilling to quit: a factorial screening experiment.

AIMS: To screen promising intervention components designed to reduce smoking and promote abstinence in smokers initially unwilling to quit. DESIGN: A balanced, four-factor, randomized factorial experiment. SETTING: Eleven primary care clinics in southern Wisconsin, USA. PARTICIPANTS: A total of 517 adult smokers (63.4% women, 91.1% white) recruited during primary care visits who were willing to reduce their smoking but not quit. INTERVENTIONS: Four factors contrasted intervention components designed to reduce smoking and promote abstinence: (1) nicotine patch versus none; (2) nicotine gum versus none; (3) motivational interviewing (MI) versus none; and (4) behavioral reduction counseling (BR) versus none. Participants could request cessation treatment at any point during the study. MEASUREMENTS: The primary outcome was percentage change in cigarettes smoked per day at 26 weeks post-study enrollment; the secondary outcomes were percentage change at 12 weeks and point-prevalence abstinence at 12 and 26 weeks post-study enrollment. FINDINGS: There were few main effects, but a significant four-way interaction at 26 weeks post-study enrollment (P = 0.01, ß = 0.12) revealed relatively large smoking reductions by two component combinations: nicotine gum combined with BR and BR combined with MI. Further, BR improved 12-week abstinence rates (P = 0.04), and nicotine gum, when used without MI, increased 26-week abstinence after a subsequent aided quit attempt (P = 0.01). CONCLUSIONS: Motivation-phase nicotine gum and behavioral reduction counseling are promising intervention components for smokers who are initially unwilling to quit.

Identifying effective intervention components for smoking cessation: a factorial screening experiment.

AIMS: To identify promising intervention components intended to help smokers to attain and maintain abstinence in their quit smoking attempts. DESIGN: A fully crossed, six-factor randomized fractional factorial experiment. SETTING: Eleven primary care clinics in southern Wisconsin, USA. PARTICIPANTS: A total of 637 adult smokers (55% women, 88% white) motivated to quit smoking who visited primary care clinics. INTERVENTIONS: Six intervention components designed to prepare smokers to quit, and achieve and maintain abstinence (i.e. for the preparation, cessation and maintenance phases of smoking treatment): (1) preparation nicotine patch versus none; (2) preparation nicotine gum versus none; (3) preparation counseling versus none; (4) intensive cessation in-person counseling versus minimal; (5) intensive cessation telephone counseling versus minimal; and (6) 16 versus 8 weeks of combination nicotine replacement therapy (nicotine patch + nicotine gum). MEASUREMENTS: Seven-day self-reported point-prevalence abstinence at 16 weeks. FINDINGS: Preparation counseling significantly improved week 16 abstinence rates (P = .04), while both forms of preparation nicotine replacement therapy interacted synergistically with intensive cessation in-person counseling (P < 0.05). Conversely, intensive cessation phone counseling and intensive cessation in-person counseling interacted antagonistically (P < 0.05)-these components produced higher abstinence rates by themselves than in combination. CONCLUSIONS: Preparation counseling and the combination of intensive cessation in-person counseling with preparation nicotine gum or patch are promising intervention components for smoking and should be evaluated as an integrated treatment package.

Disparities in chronic myeloid leukemia survival by age, gender, and ethnicity in pre- and post-imatinib eras in the US.

BACKGROUND: Since May 2001, imatinib mesylate has become the first-line therapy for chronic myeloid leukemia (CML) but the survival pattern by age, sex, and ethnicity is not clear. MATERIAL AND METHODS: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database to compare survival rates in CML among Caucasians, African-Americans (AA), and other races, and also within each race to see survival differences from the pre-imatinib (1973-2000) to post-imatinib eras (2002-2008). We used Z-tests in SEER*Stat to compare relative survival rates categorized by race, gender, and age groups (all ages, < 50, 50+ years). RESULTS: The three-year relative survival rates among Caucasians, AA, and other races in the pre-imatinib era were 44.9 ± 0.6%, 46.8 ± 1.8%, and 48.0 ± 2.2%, respectively, and in the post-imatinib era 64.4 ± 0.8%, 67.3 ± 2.4%, and 69.6 ± 1.6%, respectively. The relative survival increased from the pre-to post-imatinib era for all ethnic groups. In the post-imatinib era, three-year relative survival rates among young AA women were significantly lower (Z-value = -2.54, p = 0.011) than young Caucasian women, 80.5 ± 4.5% (n = 105) vs. 90.3 ± 1.4% (n = 589). CONCLUSIONS: The relative survival rates of CML patients have improved in the post-imatinib era. However, the improvement in survival rates has been modest in this population-based data compared to those reported from randomized trials. Improvement in survival among older patients is lower than in younger patients. Young (<50 years) AA women with CML had lower relative survival rates compared to young Caucasian women in the post-imatinib era.

Should all smokers use combination smoking cessation pharmacotherapy? Using novel analytic methods to detect differential treatment effects over 8 weeks of pharmacotherapy.

INTRODUCTION: Combination pharmacotherapy for smoking cessation has been shown to be more effective than monotherapy in meta-analyses. We address the question of whether combination pharmacotherapy should be used routinely with smokers or if some types of smokers show little or no benefit from combination pharmacotherapy versus monotherapy. METHODS: Two smoking cessation trials were conducted using the same assessments and medications (bupropion, nicotine lozenge, nicotine patch, bupropion + lozenge, and patch + lozenge). Participants were smokers presenting either to primary care clinics in southeastern Wisconsin for medical treatment (Effectiveness trial, N = 1,346) or volunteering for smoking cessation treatment at smoking cessation clinics in Madison and Milwaukee, WI (Efficacy trial, N = 1,504). For each trial, decision tree analyses identified variables predicting outcome from combination pharmacotherapy versus monotherapy at the end of treatment (smoking 8 weeks after the target quit day). RESULTS: All smokers tended to benefit from combination pharmacotherapy except those low in nicotine dependence (longer latency to smoke in the morning as per item 1 of the Fagerström Test of Nicotine Dependence) who also lived with a spouse or partner who smoked. CONCLUSIONS: Combination pharmacotherapy was generally more effective than monotherapy among smokers, but one group of smokers, those who were low in nicotine dependence and who lived with a smoking spouse, did not show greater benefit from using combination pharmacotherapy. Use of monotherapy with these smokers might be justified considering the expense and side effects of combination pharmacotherapy.