PART I

1. Forming a Clinical Question

1.1 Clinical Vignette
Andrew, a 40-year-old male medical officer has been smoking ever since he graduated high
school. He now wants to quit smoking for good and is discovering the various methods to aid
him in his resolve. However, he recently read about e-cigarettes and how it will help in
smoking cessation. In a dilemma, Andrew wants to compare both vaping and nicotine patches
to see which will help him in smoking cessation. In the end, Andrew finds you, a 3rd year
medical student, to help him decide which is best.
1.2 Information Gap
Vaping is defined as smoking out of an e-cigarette. An e-cigarette is an electronical device
that mimics smoking a cigarette by heating up liquid nicotine to be breathe in by the
consumer. Safety in regard to e-cigarettes is still poorly understood.

Nicotine patches are a type of transdermal patch which releases nicotine via the skin. Many
argue that nicotine patches are very low in effectiveness but on the other hand, not much
studies have been done regarding vaping.

1.3 PICO
Patient: Adult middle-aged male smokers who wish to quit
Intervention: E-cigarettes
Comparison: Nicotine patches
Outcome: Smoking cessation
1.4 Clinical Question
In adult middle-aged smokers who wish to quit, are e-cigarettes more effective than
nicotine patches in smoking cessation?
2. Search Method
2.1 Selection of Database
Once a clinical scenario was created to determine the aim of the research, an information
gap was obtained, and the PICO elements were isolated out. Hence, a clinical question was
formed from the PICO framework. The clinical question was searched using Ovid MEDLINE,
PubMed, UpToDate and NEJM. In the end, Ovid MEDLINE was selected as its user interface
was easier to navigate and the results of the search were the most relevant to the clinical
vignette.
Figure 1: using Ovid MEDLINE as the choice to search for a suitable paper
First keyword used was vaping, which was searched along with ‘Map term to subject
heading’. The term ‘vaping’ was also searched as a keyword.

Figure 2: first keyword used was “vaping”

Figure 3: search ‘vaping’ as keyword
Next keyword used was e-cigarettes, also with ‘Map term to subject heading’

Figure 4: ‘e-cigarettes was searched next

Figure 5: ‘Vaping’ and ‘e-cigarettes’ were combined with the Boolean operator OR to avoid
leaving out any results.

Figure 6: Next search term was ‘nicotine replacement therapy’.

Figure 7: The results obtained from ‘vaping’ OR ‘e-cigarettes’ was combined with ‘nicotine
replacement therapy’ using AND.

Figure 8: Additional limits to limit results to randomized controlled trials and within the last 5
years were placed to ensure irrelevant studies were filtered out.

Based on the search conducted, 3 papers were found to have met the criteria. These are the
results:
Figure 9: Results obtained after filtering results
2.2 Results Obtained from Search
1. A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy.
2. A Pragmatic Trial of E-Cigarettes, Incentives, and Drugs for Smoking Cessation.
3. Smokers making a quit attempt using e-cigarettes with or without nicotine or
prescription nicotine replacement therapy: Impact on cardiovascular function (ISME-
NRT) - a study protocol.
2.3 Justifications for Study Exclusion
Study 2 was not chosen because it investigates the efficacy of adding a monetary reward
upon smoking cessation in helping smokers quit.
Study 3 was excluded because they look into the body physiology of smokers who are trying
to quit. The primary outcome was macrovascular function, which is not compatible with the
clinical vignette.
2.4 Justification for Chosen Article
2.4.1 Relevance to clinical scenario
Patient: The subjects in the study match with Andrew as the mean age is around 40 years
old. It compares between smokers which fit the patient in the scenario. The patient criteria
is that they must not be on either type of product, consistent with the scenario given. They
must have no strong preference to either therapy, making it compatible with the clinical
vignette.
Intervention: E-cigarettes
Comparison: nicotine replacement therapy
Outcome: abstinence from smoking
2.4.2 Reliability
Apart from being the most relevant study which correlates directly to the clinical vignette,
the study chosen was also a randomized controlled trial (RCT). RCT are ranked high in the
pyramid of evidence for unfiltered evidence. The sample size was also very large (n=886)
allowing for smaller confidence intervals and higher reliability.
Figure 9: pyramid of evidence
2.4.3 Study Duration
The study was also carried out for a year. This ensures that the results obtained are not just
short term but also can be reliable in the long run. As smoking cessation is a life long goal, it
is of utmost importance to measure long term effects as study did. One year is a long term
for such a study and also outcomes at 6 months were also obtained to get short term effects
as well.
2.4.4 Publication Date
The study was published in 2018, making it much more relevant to the current generation. It
also may open new doors of opportunity for future clinical practice usage.
2.4.5 Publishing Journal
The paper chosen was published in the New England Journal of Medicine. This means that
the paper has been peer reviewed and went through much filtering before it was published.
The primary outcome studied in the paper is being abstinent from cigarettes for 1 year after
the drug was administered. This correlates with the vignette which states smoking cessation
as the outcome measured.
Citation
Hajek P, Waller AP, Przulj D, Pesola F, Smith KM, Bisal N, et al. A Randomized Trial of E-
Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med [Internet]. 2018 Jan [cited
2019 Mar 16]; Vol. 380(7) 629–637. Available from: https://dx-doi-
org.ezproxy.lib.monash.edu.au/10.1056/NEJMoa1808779

ARE THE RESULTS VALID?

1. Was the assignment of patients to treatments randomised?
Yes. Eligible patients were randomly assigned in 2 groups to either nicotine replacement
products of their choice (patch, spray, gum, inhaler and lozenges or combination of
products) or an e-cigarette starter pack.
2. Was the randomisation list concealed?
No, due to the design of the experiment, it is impossible to conceal the randomisation list.
Randomization took place on the quit date to limit dropouts. The randomization sequence
using a 1:1 ratio in permuted blocks of 20 was generated by a pseudorandom number
generator. This prevents the possibility of selection bias from arising among the
experimenters during allocation of subjects to groups.
3. Were the groups similar at the start of the trial?
Yes. The groups had an equal number of participants allocated in both. N=438 for e-
cigarette group and N=446 in nicotine replacement therapy group. The groups’ baseline
characteristics were similar in terms of gender, age, employment status, median number
of cigarettes per day and past use of either nicotine replacement therapy or e-cigarettes
and scores on the Fagerstrom Test for cigarette dependence. (refer table 1)
4. Were patients and clinicians kept "blind" to treatment?
No. It is not possible to do so owing to the nature of the experiment as both control and
intervention arms have drastically different devices (e-cigarette vs nicotine replacement
products). The study is thus not a blinded study. The patients hence are not blinded giving
rise to possibility of performance bias. The clinicians are also not blinded as it is not stated
in the study but the text highly suggest that there is no blinding as there happens to be
much communication between both groups throughout the study. This makes
performance bias and detection bias very possible in this study.
5. Was the follow-up of patients sufficiently long and complete?
The patients were followed up weekly on one-on-one sessions with their local clinicians.
The patients were followed up via telephone at 26 and 52 weeks. Those that reported
abstinence or reduction in smoking at least of 50% were invited back to check for their
carbon monoxide readings to confirm their reports. Expired carbon monoxide was also
monitored for at least 4 weeks after the quit date. Use and ratings of trial products,
ratings of withdrawal symptoms (weeks 1 through 6), adverse reactions (presence or
absence of nausea, sleep disturbance, and throat or mouth irritation), and respiratory
symptoms (presence or absence of shortness of breath, wheezing, cough, and phlegm)
were also recorded. In the e-cigarette group, out of 438, 3 stopped treatment and refused
follow up, 13 stopped but allowed follow up. In the nicotine therapy group, 5 stopped
refusing follow up and 36 stopped but allowing follow up. This allows attrition bias to take
place as not all the randomized patients went through with their assigned treatment.
6. Were all patients analysed in the groups to which they were randomised?
The analysis method was using Intention to Treat in the primary analysis. This means
participants that were lost to follow up or did not provide biochemical confirmation were
counted as non-abstinent. This prevents attrition bias which might not reflect the efficacy
in the real world.
7. Were study personnel (i.e. outcome assessors) kept "blind" to treatment?
The outcome was self-reported by the subjects with clinical validation. However, they
mention there is blinding of outcome assessors as the data analyses were carried out with
blinding to treatment assignments. One thing to note is that the patients who died were
excluded from the study according to the paper.
8. Were the groups treated equally, apart from the experimental treatment?
All the subjects were asked not to use their non assigned product for at least 4 weeks
after they started the study. Patients in both arms are followed up at regular intervals.
The other external factors were not accounted for in the study leaving the possibility of
performance bias open. All subjects were allowed to quit the experiment anytime. One
difference is that nicotine replacement products were given up to 3 months whereas the
e-cigarette arm have to buy their own nicotine supply from any shops. This could give rise
to performance bias due to external factors such as high costs and availability of e-
cigarettes products.

WHAT ARE THE RESULTS?

9. What is the relative risk/risk ratio?
The primary outcome is abstinence sustained for 52 weeks defined via a self-report of
smoking no more than five cigarettes from 2 weeks after the target quit date, validated
biochemically by an expired carbon monoxide level of less than 8 ppm at 52 weeks at a
clinic. Relative risk in the primary analysis is RR: 1.83 (1.30-2.58). In the adjusted RR for
missing data, the value is 1.75 (1.24-2.46). The p-value<0.001. (refer table 2)
10. How large is the treatment effect between intervention and outcome?
Calculating the relative risk reduction value obtained below, there was a significant
difference in abstinence rates for e-cigarettes (79%) vs nicotine replacement therapy
(44%).
11. How precise was the estimate of the risk? (i.e what is the confidence interval for the
RR?)
Confidence interval for RR in the primary analysis is 1.30-2.58 at 95% CI. Since CI does not
cross 1, the difference between both treatment arms is similar is significant. The CI when
adjusted for the absent data is 1.24-2.46 at 95% CI. It also does not cross 1 meaning that it
is significant.
Table: Clinically useful measures of the effects of treatment
Outcome Control Experimental Relative Relative Absolute Number
event event rate risk risk risk needed to
rate RR=X/Y reduction reduction treat
(X) (Y) RRR=1-RR ARR=X-Y NNT=1/ARR
79/438 44/446 1.83 0.83 0.081 12
Primary (95% CI
outcome =0.180 =0.099 1.30-
(abstinence 2.58)
at 52
weeks)
HOW CAN I APPLY THE RESULTS TO PATIENT CARE?
12. Were the study patients similar to the patient under consideration in my practice?
The study patients and the patient in the clinical vignette were similar as both have been
cigarette smokers, are both in the same age group and consumes a similar number of
cigarettes. Despite this, the patient described in the vignette may not respond similarly as
the ones in the study as there may be many other unknown confounders. One difference
is that the patients in the study were given free cessation aid to help them quit. This
policy may differ from the one used in the vignette due to different location and rules.
Another factor maybe the demographics as the study was carried out in the United
Kingdom while the clinical vignette was set in the Asian setting. External validity may be
an issue here due to different patients’ demographics.
13. Is the treatment feasible in your setting?
Yes. E-cigarettes or vaping devices can be easily obtained from ‘vaping’ stores if our
patient in the clinical vignette decides to use e-cigarettes to help him quit.
14. Were all clinically important outcomes considered?
Yes. The primary outcome, which is abstinence for 52 weeks, was recorded and compared
between both groups. Adverse effects were also tabulated such as shortness of breath,
wheezing, cough and phlegm production. The urge to smoke among participants was also
noted as this may cause relapsing into the habit.
15. Are the likely treatment benefits worth the potential harms and costs?
The adverse effects e.g. shortness of breath, wheezing, cough and phlegm production
were similar in both groups. The difference in numbers between both groups are not
significant when it comes to shortness of breath and wheezing as the CI does crosses 1.
The difference in numbers in cough and phlegm production is significant as the CI does
not cross 1, meaning that the incidence of cough and phlegm was significantly lesser in
the e-cigarette group. It is thus more effective to quit smoking with the aid of electronic
cigarettes compared to conventional nicotine replacement therapies. Hence, e-cigarettes
should be further studied to determine its usefulness in smoking cessation.