Adapting Smoking Cessation Treatment According to Initial Response to Precessation Nicotine Patch

The study was a double-blind, parallel-arm adaptive treatment trial comprising two distinct phases (Figure 1).

Phase 1 assessed the effects of two potential precessation rescue treatments (varenicline or bupropion augmentation of nicotine patch) for smokers who did not respond adequately to open-label nicotine patch treatment before the target quit date. Smokers were classified as precessation “responders” or “nonresponders” to nicotine patch treatment, depending on whether their ad lib smoking (assessed by expired-air CO levels) decreased by more than 50% in the first week of precessation patch treatment. Nonresponders at that point (1 week before their target quit date) were randomly assigned to one of three double-blind treatment conditions: 1) a switch to varenicline (stopping nicotine patch treatment); 2) augmentation of nicotine patch with bupropion; and 3) continuation on nicotine patch alone. Varenicline was administered as a monotherapy because current labeling recommends against combining nicotine patch and varenicline because of an increased frequency of nausea and other side effects. Nicotine patch responders remained on open-label nicotine patches until Phase 2.

Phase 2 assessed the effects of postquit adaptive treatment changes for precessation nicotine patch responders who lapsed in the first week after the quit date. Lapsers were identified either by self-report of smoking (even a puff) within the first week after the quit date or by an expired-air CO level >10 ppm at 1 week after the quit date. These lapsers were scheduled for a second target quit date 1 week later and were randomly assigned to the same three double-blind treatment conditions as in phase 1. Nonlapsers remained on open-label nicotine patches for the duration of treatment.

Adult smokers expressing a desire to quit smoking were recruited through newspaper, radio, and television advertisements. To be eligible, participants had to be 18–65 years of age, report smoking an average of ≥10 cigarettes per day for 3 cumulative years, have an expired-air CO level ≥10 ppm, and have no exclusionary feature on history, physical examination, or laboratory evaluation (see the data supplement that accompanies the online edition of this article). After receiving a complete description of the study, participants provided written informed consent. Participants were compensated up to $320 for study participation.

After screening and enrollment in the study, participants were seen weekly at our research center for 2 weeks before the quit date and attended four to six sessions after the quit date. Brief (<15 minutes) support was provided at each session, and clinical trial materials were dispensed. Smoking diaries and measures of expired-air CO levels, withdrawal symptoms, and other adverse effects were also collected. Six months after the target quit date, participants were contacted and those who reported point (7-day) abstinence were invited to return to the center for an assessment of expired-air CO level.

The study was conducted in a double-blind and double-dummy fashion; all participants who were assigned to a treatment condition received active nicotine skin patches (NicoDerm CQ, GlaxoSmithKline, Philadelphia) or placebo (Rejuvenation Laboratories, Salt Lake City), capsules containing varenicline (Pfizer, New York) or placebo, and bupropion sustained-release tablets (GlaxoSmithKline) or placebo (Glatt Pharmaceutical Services, Ramsey, N.J.). The recommended dosing titration schedule was used for both varenicline (0.5 mg once daily on days 1–3, 0.5 mg twice daily on days 4–7, and 1 mg twice daily through week 12) and bupropion (150 mg daily for 3 days, followed by 150 mg twice daily through week 12).

Initial nicotine patch dosing was based on initial expired-air CO reading; participants with CO levels >30 ppm at baseline received 42 mg/day (two 21 mg/day patches) daily, and the remaining participants received a single 21 mg/day patch daily. In the 21 mg/day condition, an active patch was applied each morning; in the 42 mg/day condition, an active 21 mg patch was applied each morning and a second patch at noon. This personalized dosing regimen was based on previous research suggesting that heavy smokers may not receive adequate nicotine replacement with a 21 mg patch (15, 16). Dose reductions were allowed in the event of side effects.

For each of the two phases of the study, treatment groups were initially compared on demographic and smoking history variables, in order to identify potential confounding factors (none were identified).

To evaluate the main hypothesis of phase 1—that precessation adaptive treatment changes would rescue precessation nicotine patch nonresponders—abstinence outcomes were compared between each potential rescue treatment and the corresponding randomized nicotine patch group.

To evaluate the main hypothesis of phase 2—that postcessation adaptive treatment changes would rescue participants who lapsed in the first week after their quit date—abstinence outcomes were compared between each potential rescue treatment and the corresponding randomized nicotine patch group.

Logistic regression analyses were used to evaluate the primary outcome of continuous abstinence at end of treatment (abstinence during weeks 8–11 after the target quit date). Secondary outcomes included continuous 11 weeks of abstinence from the quit date, point (7-day) abstinence at 6 months, and continuous abstinence from the quit date at 6-months. Abstinence was identified by self-report of no smoking confirmed by end-expired CO levels ≤10 ppm. Participants who withdrew from the study or were lost to follow-up were classified as nonabstinent.

In addition to the above analyses, we sought confirmatory evidence in support of the two main assumptions underlying the adaptive treatment approach. In phase 1, to verify the assumption that precessation nicotine patch nonresponders would do poorly if left on nicotine patch alone, we compared the abstinence rate of precessation nicotine patch responders to that of nicotine patch nonresponders who were randomly assigned to remain on nicotine patch alone. Given that nicotine patch responders who lapsed after the quit date may have been assigned to treatments other than nicotine patch in phase 2, we eliminated the confounding effects of these postquit treatment changes by taking the outcome to be continuous abstinence from the initial quit date through end of treatment (11 weeks after the quit date). By using the continuous-abstinence endpoint, lapsers were considered nonabstinent before any potential confounding effects of postquit treatment changes could occur.

The second main assumption, in phase 2, was that participants who lapsed in the first week after the quit date who were assigned to nicotine patch alone would have a lower abstinence rate than participants on nicotine patch alone who had no lapses. To evaluate this assumption, abstinence outcome (4-week continuous abstinence at the end of treatment) was compared between lapsers and nonlapsers receiving nicotine patch alone in phase 2.

Forty-seven participants were excluded from data analyses (27 in phase 1 and 20 in phase 2) because of having initiated contraindicated medications (opiates, antidepressants, or other CNS-active medications) during the study or failing to meet other entry criteria. Another individual died before reaching the primary outcome point and was also censored from analysis. One participant was excluded from the analysis of percent change in CO level because of a value >35 standard deviations from the mean of the remaining sample.

Among smokers who did not reduce their smoking sufficiently in the first week of nicotine patch, as assessed by CO level (nicotine patch nonresponders), abstinence rates were significantly higher after the adaptive treatment change to bupropion augmentation of nicotine patch, compared with nicotine patch alone (Table 2). Not only was the primary treatment outcome of continuous abstinence during weeks 8–11 after the quit date enhanced (p=0.04; odds ratio=2.06, 95% CI=1.05–4.07), but so too were the secondary outcomes of 11-week continuous abstinence from the quit date (p=0.01; odds ratio=3.36, 95% CI=1.34–8.39), 6-month point abstinence (p=0.02; odds ratio=2.93, 95% CI=1.16–7.41), and 6-month continuous abstinence from the quit date (p=0.01; odds ratio=5.19, 95% CI=1.43–18.81).

The precessation adaptive change in treatment to varenicline did not yield a significant effect on the primary outcome of continuous abstinence during weeks 8–11 or on the measures of continuous abstinence from the quit date, but there was a significant effect on point abstinence at 6 months (p=0.03; odds ratio=2.80, 95% CI=1.11–7.06). To examine whether the emergence of an effect of varenicline at 6 months may have been due to smokers’ recovery from early lapses, a follow-up analysis compared 6-month point abstinence across conditions among smokers who lapsed at least once during the last 4 weeks of treatment (weeks 8–11). Among these participants, the percentage of smokers who ultimately achieved point abstinence at 6 months was 8.9% (7/79) in the varenicline condition, but only 1.1% (1/89) in the nicotine patch condition and 0% (0/71) in the bupropion plus nicotine patch condition (p=0.01 for varenicline compared with the other conditions; odds ratio=15.46, 95% CI=1.87–128.00). This 7%–8% difference between varenicline and the other treatment conditions accounts for most of the 10% higher 6-month point abstinence obtained with varenicline (Table 2).

Postquit adaptive changes in treatment had no significant effects on any of the abstinence outcomes (Table 2).

The assumption underlying the design of phase 1 was that participants showing less of a decrease in ad lib smoking after 1 week of nicotine patch would have lower abstinence rates than those showing larger spontaneous reductions in smoking. This assumption was confirmed based on several analyses. First, among participants receiving nicotine patch, continuous smoking abstinence 11 weeks after the quit date was strongly predicted by the reduction of ad lib smoking 1 week before the quit date. Abstinence was significantly related to all measures of smoking reduction analyzed at this time point, including absolute CO level (p<0.0001; odds ratio=1.09, 95% CI=1.05–1.12), percent decrease in CO level (p<0.0001; odds ratio=1.04, 95% CI=1.03–1.06), and dichotomous classification of whether or not there was greater than 50% decrease in CO level (p<0.0001; odds ratio=6.76, 95% CI=2.98–15.32). When all three variables were entered into a multiple logistic regression analysis, percent reduction in CO level was the only predictor that remained significant (p=0.001). This result suggested that quantitative information about the extent of smoking reduction, above and beyond the dichotomization of >50% or not, has additional predictive value. Quartiles of percent CO level reduction, however, captured the relevant information, reflected by the findings that the correlation between the quartile score and abstinence was as high as for percent reduction (r=0.38 and r=0.36, respectively) and that when quartile was entered into a multiple logistic regression model with percent CO reduction, the percent reduction variable was rendered nonsignificant (p=0.16). Moreover, the quartile percent reduction in CO was a highly significant univariate predictor in its own right (p<0.0001; odds ratio=2.51, 95% CI=1.88–3.36). Figure 2 shows the monotonic increase in abstinence rate as a function of quartile percent reduction in CO level.

A similar analysis on prequit reduction in cigarettes per day yielded a similar conclusion. Abstinence was significantly correlated with all three indices reflecting cigarette reduction at week 1, including the absolute level of cigarettes per day, the percent reduction, and the dichotomous classification of whether or not there was a reduction >50%. As with CO level, when all three variables were entered into a multiple logistic regression analysis, only percent reduction remained significant. Moreover, as with CO level, a quartile score was defined and found to be largely redundant with the continuous index of percent reduction, as well as being a significant univariate predictor of smoking abstinence (p<0.0001; odds ratio=2.51, 95% CI=1.88–3.36). Figure 2 shows the relationship between quartile percent cigarette reduction and smoking abstinence.

The second assumption underlying the adaptive treatment design (phase 2), that participants who lapsed in the first week after their initial quit date would do worse at the end of treatment than those who did not lapse, was evaluated by comparing outcomes between the precessation nicotine patch responders who had a lapse and those who did not lapse and remained on nicotine patch alone. The lapsers showed a much lower rate of continuous 4-week abstinence at the end of treatment: 26.7% compared with 59.2% (p=0.002; odds ratio=0.25, 95% CI=0.10–0.61).

Treatments were generally well tolerated; however, 25% of participants received dose reductions at some point during the study, with no difference between treatment conditions (range 20%–30%). A number of adverse events occurred that had no definitive causal relationship to treatment: one death believed to be due to stroke, two nonfatal heart attacks, one case of cancer, one participant with tachycardia with transient loss of consciousness, five participants reporting chest pain (including one left bundle branch block, one unifocal premature ventricular contractions, and one report of chest pain with vomiting and hallucinations), one participant with nausea/vomiting, three participants with hives or rash, one participant diagnosed with depression, and one participant reporting weakness, lightheadedness, and difficulty breathing.