Comparing the Effectiveness of Nicotine Patch With Gum Versus Nicotine Patch Alone in Smoking Cessation in Hong Kong Primary Care Clinics
Phase: NA
Conditions: Smoking Cessation
Sponsor: Hospital Authority, Hong Kong

Results_completed on 23 Nov 2018 
Results 
 
Participant characteristics  
A total of 560 smokers were recruited and randomized to either combined NRT group (274 participants) or single 
NRT group (286 participants) for smoking cessation from five clusters (112 each). 21 (3.75%) smokers withdrew 
from the study, 14 (4.9%) from the single NRT group and 7 (2.6%) from the combined group (Figure 1. Consort 
workflow diagram). There was no significant difference between the two groups (p=0.138). At baseline, most of 
the participants were male (477, 85.2%) and married (424, 75.7%), the average age was 50.48 years. Regarding 
the background smoking history, on average, the participants smoked 18.56 cigarettes per day for 32.05 years, 
i.e., 29.81 pack years. In terms of nicotine dependence, the average Fagerstrom score was 5.71 (moderate), and 
average baseline CO level was 20.59, for both groups. 56.6% of smokers were heavy smokers in both the single 
and combined NRT groups. About one third (185, 33.0%) of the participants had cardiovascular (CVS) disease, 
20.2% had endocrine disease, and 5.9% had respiratory disease. Overall, no significant differences were 
detected between single NRT and combined NRT groups for all characteristics in Table 1. 
 
Primary outcome 
Among observed data, smoking abstinent rate was 21.6% for single NRT group and 30.2% for combined NRT 
group at 52 weeks (OR=1.57, p=0.058); similar adjusted odds ratio (1.50, p=0.073) was obtained under the 
imputation scenario of ‘missing was non-quitter’ (Table 2). Over the study period, participants in combined NRT 
group were significantly more likely to quit smoking than those in single NRT group (OR=1.41, p=0.002). The 
treatment effect was also similar (OR=1.43, p<0.001) after imputing missing records as non-quitter. After adjusting 
for potential confounders, minor decrease of treatment effect at 52 weeks (AOR=1.45, p=0.138) and overall 
treatment effect (AOR=1.34, p=0.013) was detected for complete data. For imputed data, the result remains 
unchanged for overall treatment effect (AOR=1.43, p=0.0001) and slightly decreased at 52 weeks (AOR=1.49, 
p=0.086). As shown in Figure 2(a), point smoking abstinent rate was higher for combined NRT group than single 
NRT group at each assessment visit, especially for assessment at 26 and 52 weeks. For both groups, treatment 
effect was optimum at 4 weeks and attenuated with time. There was no crossing between the two lines during the 
follow-up visits, indicating there was no interaction between treatment and time, which was confirmed by the test 
on the interaction term in the GEE model (coefficient not reported). After imputing missing data for the scenario of 
‘missing was non-quitter’, the point smoking abstinent rate was lower for both groups at each assessment visit, 
but the differences between two groups and time trend stayed similar with the complete data Figure 2(b). 
 
Secondary outcome  
For secondary results, largest treatment effect was found at 26 weeks, participants in combined NRT group were 
1.71 times likely to quit smoking than those in single NRT group (p=0.039) for complete data. After imputation, 
there was significant treatment effect at 4 weeks (OR=1.43, p=0.048). Estimates of treatment effect from logistic 
regression with and without adjustment for age, sex, baseline CO and cluster were reported in Table 2. In this 
study, 69.6% (1560/560x4) of outcome records were obtained; highest missing rate was at 26 weeks (36.1%) and 
lowest at 4 weeks (17.9%). There was no significant difference in the missingness between single NRT and 
combined NRT groups at each visit (Table 3). From the missingness pattern plot, no obvious differences could be 
seen between two treatment groups across all visits Fiqure 3. Sub-anaylsis showed that baseline age and 

Results_completed on 23 Nov 2018 
number of years smoked were significantly associated with missingness at 52 weeks, participants were younger 
(average age 48.7 vs. 51.4, p-value=0.014) and had less years smoked (30.3 vs. 32.9, p-value=0.021). Sex, 
baseline CO level, baseline Fagerstrom score, number of cigarettes smoked per day and compliance (percentage 
of total patches used) were not significantly associated with missingness at 52 weeks.  
 
Side effect profile 
Overall, 3.4% smokers developed side effects after using NRT. The commonest side effect was skin itchiness and 
rash (Table 4). In the single NRT group, 12 (4.2%) reported side effects from nicotine patch. In the combined NRT 
group, 7 (2.6%) reported side effects from NRT. There was no significant difference between the two groups 
(p=0.315). 
 
Discussion 
This study helps us to understand more on the effect of nicotine replacement therapy on smoking cessation, both 
monotherapy and combined NRT, in Chinese people. To my knowledge, this is the first interventional study in our 
locality. Smokers in both groups had high nicotine dependence as shown by their average high Fagerstrome 
score. On average, the smokers smoked 18 cigarettes a day and for more than 31 years. Combined NRT showed 
a higher abstinence rate at all follow up intervals: 4, 12, 26 and 52 weeks in both complete data strategy and 
imputed data strategy. Combined NRT was statistically more superior to single NRT at 26 weeks with complete 
data strategy (26.4% vs 17.4%). However, with the imputed data strategy, combined NRT was only statistically 
superior to single NRT at 4 weeks (35.8% vs 28%). The imputed data strategy was adopted because of the high 
rate in loss of follow up, which was conservative and, thus, decreased the abstinence rates for both groups. 
 
Nevertheless, after applying imputation strategy and GEE model, the statistical power was increased to 93.7% 
and the study showed significant treatment effect across all visits. The study showed that combined NRT was 
significantly more superior to single NRT at 4 weeks (OR=1.43, p=0.048) and overall (OR=1.43, p<0.001). The 
superior effect of combined NRT could be detected as early as 4 weeks after quit date and the effect attenuated 
with time as confirmed by the GEE model. This result was similar to that noted in the network meta-analysis9, 
which showed combined NRT vs NRT patch OR was 1.43 (95% CI, 1.08 to 1.91) at 6 months or longer after 
quitting.   
 
In general, the use of NRT required a gradual tapering regimen over 8 to 12 weeks. In our study, it was shown 
that a total of 8 weeks of NRT was efficient enough to show better abstinence rates in sustaining overall. Besides, 
the low rate of side effects (2.6%) in the combined group also reassured that it is equally safe as single NRT to 
use for smoking cessation. In some studies, the common side effects such as skin itchiness and rash could occur 
in up to 10 to 20%37 of users. 
 
The study is not without limitations. In our study, only 70% of the total records were analysed due to a high rate of 
loss in follow up, which had exceeded our planned 10%. It had affected the overall statistical power of the study, 
by decreasing the statistical power to 54.1% and 47.4% at 26 and 52 weeks, respectively. In order to minimize the 

Results_completed on 23 Nov 2018 
effect, GEE was used for repeated measures and control for time*treatment interaction with all available records. 
This had helped to increase the statistical power increased to over 90%. The high rate in loss in follow up also 
had affected the abstinence rates. Further sub-analysis was carried out to review the pattern in missing data and 
the association with either treatment group. There was no significant difference in the missingness in both 
treatment groups. In fact, the sub-analysis showed that younger smokers and those with less years of smoking 
were significantly associated with higher missing data in both treatment groups. Based on these observations, the 
missingness was likely to be the result of a random pattern. Thus, a conservative single imputation strategy 
‘missing as non-quitter’ was employed instead of multiple imputation strategy. With the use of conservative single 
imputation strategy “missing as non-quitter”, the abstinent rates for 26 weeks for combined NRT (26.4% vs 36.5%) 
and single NRT (21.6% vs 23.4%) were lower than anticipated.  
 
The reasons for this high loss in follow up could be variable. Our study showed that it was associated with 
younger smokers, which could be due to their busy life and work schedule, or change in residence. Further 
studies can be focused in younger smokers to enhance their smoking cessation. 
 
Conclusion 
Smokers given 8 weeks of combined NRT with nicotine patch and gum had higher abstinence rates at 4, 12, 26 
and 52 weeks compared with single NRT and were more likely to quit over the study period. Results also showed 
that the regimen of combined NRT was as safe as single NRT. Thus, the use of combined NRT should be further 
promoted in smoking cessation clinics in our community. 
 
 

Results_completed on 23 Nov 2018 
Results 
Figure 1. Consort workflow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
286 allocated to single NRT 
Nicotine patch  
Nicotine patch with gum 
Follow up at 4, 12, 26 & 52 weeks 
Follow up at 4, 12, 26 & 52 weeks  
560 were randomized and discussed on quit date 
274 allocated to combined NRT 
229 were followed up: 4 weeks post quit 
192 were followed up: 12 weeks post quit 
231 were followed up: 4 weeks post quit 
178 were followed up: 12 weeks post quit 
174 were followed up: 26 weeks post quit 
182 were followed up: 52 weeks post quit 
184 were followed up: 26 weeks post quit 
190 were followed up: 52 weeks post quit 
777 records (267 subjects) were analysed 
783 records (272 subjects) were analysed 
361 records not analysed 
- 
14 subjects withdrew (4 refused, 
5 side effects, 1 geographical 
reason, 4 preferred to change 
regimen); 2 subjects passed 
away due to cancer 
319 records not analysed: 
- 
7 subjects withdrew (3 refused, 
1 geograhical reason, 3 
preferred to change regimen); 2 
subjects passed away due to 
cancer/pneumonia 

Results_completed on 23 Nov 2018 
Table 1. Baseline characteristics by treatment groups 
Characteristic 
Single NRT 
(N=286) 
Combined NRT 
(N=274) 
p-value 
Age (in years), mean (SD)  
50.56 (12.08) 
50.41 (12.30) 
0.884 
Male, No. (%) 
236 (82.5) 
241 (88.0) 
0.091 
Marital Status, No. (%) 
 
 
0.386 
Single 
48 (16.8) 
37 (13.5) 
 
Married 
208 (72.7) 
216 (78.8) 
 
Divorced/Separated 
23 (8.0) 
17 (6.2) 
 
Widowed 
7 (2.4) 
4 (1.5) 
 
Education, No. (%)  
 
 
0.565 
No formal schooling 
3 (1.0) 
7 (2.6) 
 
Primary 
60 (21.0) 
61 (22.3) 
 
Secondary 
203 (71.0) 
187 (68.2) 
 
Tertiary 
20 (7.0) 
19 (6.9) 
 
Work status, No. (%) 
 
 
0.310 
Unemployed 
61 (21.3) 
47 (17.2) 
 
Full time 
181 (63.3) 
188 (68.6) 
 
Part time 
16 (5.6) 
8 (2.9) 
 
Retired 
20 (7.0) 
24 (8.8) 
 
Housewife 
8 (2.8) 
7 (2.6) 
 
Payment status, No. (%)  
 
 
0.506 
Entitled patients 
234 (81.8) 
220 (80.3) 
 
Waivers 
18 (6.3) 
24 (8.8) 
 
Hospital Authority staff/Civil servants 
29 (10.1) 
28 (10.2) 
 
Others 
5 (1.7) 
2 (0.7) 
 
Cluster, No. (%) 
 
 
0.946 
HKEC 
56 (19.6) 
56 (20.4) 
 
KCC 
55 (19.2) 
57 (20.8) 
 
KEC 
61 (21.3) 
51 (18.6) 
 
NTEC 
57 (19.9) 
55 (20.1) 
 
NTWC 
57 (19.9) 
55 (20.1) 
 
Co-existing diseases 
 
 
 
Respiratory disease, No. (%) 
18 (6.3) 
15 (5.5) 
0.816 
CVS disease, No. (%) 
105 (36.7) 
80 (29.2) 
0.072 
Endocrine disease, No. (%) 
59 (20.6) 
54 (19.7) 
0.868 
Smoking history 
 
 
 
No. of cigarettes/day used, mean (SD) 
18.44 (6.90) 
18.68 (6.88) 
0.683 
Heavy Smoker (≥20 cigarettes/day), No. (%) 
162 (56.6) 
155 (56.6) 
0.988 
Years smoked, mean (SD)   
31.93 (11.94) 
32.17 (12.43) 
0.817 

Results_completed on 23 Nov 2018 
Pack-years, mean (SD) 
29.45 (15.37) 
30.18 (16.65) 
0.591 
Fagerstrom score, mean (SD)   
5.57 (2.01) 
5.85 (1.79) 
0.090 
Fagerstrom score, No. (%)  
 
 
0.347 
Low dependence (0-2) 
22 (7.7) 
12 (4.4) 
 
Low to Moderate (3-4) 
58 (20.3) 
51 (18.6) 
 
Moderate (5-7) 
160 (55.9) 
161 (58.8) 
 
High dependence (8+) 
46 (16.1) 
50 (18.2) 
 
Baseline CO level (ppm), mean (SD)   
20.36 (12.03) 
20.83 (12.49) 
0.652 
Note: 
NRT: nicotine replacement therapy. 
SD: standard deviation. 
For all continuous variables, mean and SD were reported and p-values were calculated from two sample 
t-test; for all categorical variables, number and proportion were reported and p-values were calculated 
from Chi-square test. 
 
Table 2. Test for Treatment Effect on Primary Outcome - Smoking Quit Status. 
Outcome 
Single NRT 
Combined NRT 
OR 
p-value 
AOR 
p-value 
No. of 
Success 
Abstinent 
Rate (%) 
Available 
No. 
No. of 
Success 
Abstinent 
Rate (%) 
Available 
No. 
Complete Data 
4 weeks 
80 
34.6 
231 
98 
42.8 
229 
1.41 
0.073 
1.35 
0.136 
12 weeks 
48 
27.0 
178 
60 
31.2 
192 
1.23 
0.370 
1.13 
0.604 
26 weeks 
32 
17.4 
184 
46 
26.4 
174 
1.71 
0.039* 
1.53 
0.110 
52 weeks 
41 
21.6 
190 
55 
30.2 
182 
1.57 
0.058 
1.45 
0.138 
GEE 
201 
25.7 
783 
259 
33.3 
777 
1.41 
0.002** 
1.34 
0.013** 
Imputed Data 
4 weeks 
80 
28.0 
286 
98 
35.8 
274 
1.43 
0.048* 
1.38 
0.087 
12 weeks 
48 
16.8 
286 
60 
21.9 
274 
1.39 
0.130 
1.37 
0.153 
26 weeks 
32 
11.2 
286 
46 
16.8 
274 
1.60 
0.057 
1.56 
0.080 
52 weeks 
41 
14.3 
286 
55 
20.1 
274 
1.50 
0.073 
1.49 
0.086 
GEE 
201 
17.6 
1114 
259 
23.6 
1096 
1.43 
<0.001** 
1.43 
0.001** 
Notes:  
NRT: nicotine replacement therapy. 
Complete Data: available records without any imputation. 
Imputed Data: missing records were imputed as ‘failure’ (non-quitter) for the primary outcome. 
OR: odds ratio. At each visit, crude odds ratio (combined NRT vs. single NRT) and p-value was 
reported from logistic regression without adjustment; for repeated measures, adjusted odds ratio and 
p-value was reported from Generalized Estimating Equation (GEE) adjusted for time. 
AOR: adjusted odds ratio. At each visit, adjusted odds ratio (combined NRT vs. single NRT) and p-value 
was reported from logistic regression with adjustment for age, sex, baseline CO and cluster; for 

Results_completed on 23 Nov 2018 
repeated measures, adjusted odds ratio and p-value was reported from GEE adjusted for time, age, 
sex, baseline CO and cluster. 
 
Table 3. Obtained Primary Outcome across Visits, by Treatment Group. 
 
Single NRT 
Combined NRT 
p-valuea 
Expected N 
286 
274 
- 
4 weeks 
231 (80.8%) 
229 (83.6%) 
0.449 
12 weeks 
178 (62.2%) 
192 (70.1%) 
0.062 
26 weeks 
184 (64.3%) 
174 (63.5%) 
0.907 
52 weeks 
190 (66.4%) 
182 (66.4%) 
1.000 
All visits 
783 (69.3%) 
777 (70.9%) 
0.219b 
 
Notes: 
a. P-values from Chi-square test. 
b. P-value from Mantel-Haenszel Chi-squared test with continuity correction. 
 
Table 4. Reported side effects in both treatment groups 
 
Single NRT 
(N=286) 
Combined NRT 
(N=274) 
p-value 
No of patients reported side effects  
12 (4.2) 
7 (2.6) 
0.315 
Frequency of side effects 
 
 
 
Abdominal pain 
1  
0 
 
Dizziness 
1 
0 
 
Dreams 
1 
0 
 
Insomnia 
1 
0 
 
Palpitation 
3 
0 
 
Skin itchiness 
3  
3  
 
Skin rash 
6 
4 
 
Stomach 
1 
1  
         
 
 
 

Results_completed on 23 Nov 2018 
Figure 2(a). Abstinent Rate across Visits, by Treatment Group: Complete Data. 
 
Notes: 
NRT: nicotine replacement therapy. 
Abstinent rate, i.e., proportion of successful quitters was calculated at 4 weeks, 12 weeks, 26 weeks 
and 52 weeks for complete data (all available records). 
Figure 2(b). Abstinent Rate across Visits, by Treatment Group: Imputed Data 
 
Note: 
NRT: nicotine replacement therapy. 
Abstinent rate, i.e., proportion of successful quitters was calculated at 4 weeks, 12 weeks, 26 weeks 
and 52 weeks for worst scenario: missing records were imputed as ‘failure’ (non-quitter). 
 

Results_completed on 23 Nov 2018 
Fiqure 3. Missing pattern analysis for primary outcome. 
 
Missing pattern analysis for primary outcome. 
There’s no significant difference in missingness by treatment group at each visit (see table below). 
 
Single NRT 
Combined NRT 
p-value 
 
(Expected N =286) 
(Expected N =274) 
 
N missing (%) 
4 weeks 
55 (19.2) 
45 (16.4) 
0.449 
12 weeks 
108 (37.8) 
82 (29.9) 
0.062 
26 weeks 
102 (35.7) 
100 (36.5) 
0.907 
52 weeks 
96 (33.6) 
92 (33.6) 
1 
 
(light area means missing)