Skip to main content

Randomised controlled trial testing effectiveness of feedback about lung age or exhaled CO combined with very brief advice for smoking cessation compared to very brief advice alone in North Macedonia: findings from the Breathe Well group



In 2019, smoking prevalence in North Macedonia was one of the world’s highest at around 46% in adults. However, access to smoking cessation treatment is limited and no co-ordinated smoking cessation programmes are provided in primary care.


We conducted a three parallel-armed randomised controlled trial (n = 1368) to investigate effectiveness and cost-effectiveness of lung age (LA) or exhaled carbon monoxide (CO) feedback combined with very brief advice (VBA) to prompt smoking cessation compared with VBA alone, delivered by GPs in primary care in North Macedonia. All participants who decided to attempt to quit smoking were advised about accessing smoking cessation medications and were also offered behavioural support as part of the “ACT” component of VBA. Participants were aged ≥ 35 years, smoked ≥ 10 cigarettes per day, were recruited from 31 GP practices regardless of motivation to quit and were randomised (1:1:1) using a sequence generated before the start of recruitment. The primary outcome was biochemically validated 7-day point prevalence abstinence at 4 weeks (wks). Participants and GPs were not blinded to allocation after randomisation, however outcome assessors were blind to treatment allocation.


There was no evidence of a difference in biochemically confirmed quitting between intervention and control at 4wks (VBA + LA RR 0.90 (97.5%CI: 0.35, 2.27); VBA + CO RR 1.04 (97.5%CI: 0.44, 2.44)), however the absolute number of quitters was small (VBA + LA 1.6%, VBA + CO 1.8%, VBA 1.8%). A similar lack of effect was observed at 12 and 26wks, apart from in the VBA + LA arm where the point estimate was significant but the confidence intervals were very wide. In both treatment arms, a larger proportion reported a reduction in cigarettes smoked per day at 4wks (VBA + LA 1.30 (1.10, 1.54); VBA + CO 1.23 (1.03, 1.49)) compared with VBA. The point estimates indicated a similar direction of effect at 12wks and 26wks, but differences were not statistically significant. Quantitative process measures indicated high fidelity to the intervention delivery protocols, but low uptake of behavioural and pharmacological support. VBA was the dominant intervention in the health economic analyses.


Overall, there was no evidence that adding LA or CO to VBA increased quit rates. However, a small effect cannot be ruled out as the proportion quitting was low and therefore estimates were imprecise. There was some evidence that participants in the intervention arms were more likely to reduce the amount smoked, at least in the short term. More research is needed to find effective ways to support quitting in settings like North Macedonia where a strong smoking culture persists.

Trial registration

The trial was registered at (ISRCTN54228638) on the 07/09/2018.

Peer Review reports


In 2019, population smoking prevalence in North Macedonia was one of the highest in the world at 46% (aged 15–64) [1, 2], with 247 deaths per 100,000 attributed to smoking [1]. In some high income countries, smokers are advised to stop smoking and are supported to quit within primary care with the most effective interventions combining pharmacotherapy and behavioral support [3], interventions also known to be highly cost-effective [4, 5]. However, in North Macedonia there are few organized smoking cessation programmes available, and none in primary care. Access to pharmacotherapy is also limited due to high out of pocket costs and there is no national quit line available. Alternative methods that could increase quitting need to be tested in this population with high smoking prevalence [6].

Brief physician advice is known to be effective in prompting a quit attempt, and also leads to a small but clinically significant increase in the chance of successful quitting even without the use of pharmacotherapy [7, 8]. Health concerns can also be a motivator to consider quitting [9, 10], and presenting smokers with information about their exposure and the harmful effects of smoking may encourage quitting [11]. Lung age (LA) [12], a biomarker of premature lung ageing, and exhaled carbon monoxide (CO) levels can be non-invasively measured and immediately communicated within primary care [13, 14], and have the potential to increase the number of people attempting to quit and being successful in low and middle income (LMIC) settings.

In 2017, the International Primary Care Respiratory Group (IPRCG) led a Global Bridges funded “teach the teachers” programme in North Macedonia which trained GPs to offer very brief advice (VBA) to tobacco dependent patients. This included training to deliver behavioural support to smokers who are willing to attempt to quit smoking [15]. We evaluated the effectiveness and cost-effectiveness of combining LA or CO feedback with VBA and behavioural support for smoking cessation compared to with VBA and behavioural support alone delivered by GPs in primary care in North Macedonia who had taken part in the train the trainers programme.


Trial design

A multicentre three parallel-armed randomised controlled trial (RCT) with process evaluation and cost-effectiveness analysis was conducted in primary care in North Macedonia from November 2018 to May 2020. The full protocol is reported elsewhere [16].

Ethical permission was received from the ethical review board of Saints Cyril and Methodius University, North Macedonia (UKUM034/95) and institutional ethics committee at University of Birmingham (UoB), UK (ERN_18-12408). The trial was registered at (ISRCTN54228638) on the 07/09/2018. All methods were carried out in accordance with relevant guidelines and regulations.

Study participants and recruitment

Thirty-eight primary care practices that had participated in the International Primary Care Respiratory Group (IPCRG)/Global Bridges “Teach the teacher” programme were trained as research sites, and 31 GP practices from both urban and rural locations in North Macedonia recruited at least 1 participant. Smokers attending primary care for any reason were given a patient information leaflet and invited to enrol if they smoked ≥ 10 cigarettes per day (cpd) and were aged ≥ 35 years old. As the aim of the interventions were to prompt a successful quit attempt, it was not a requirement for smokers to be motivated to quit before enrolling in the trial. Eligible participants who took part in the trial provided written consent [16].


Participants were randomised to one of three conditions. These conditions were delivered at the baseline visit which took place at an appointment, or at a re-arranged visit:

  • Comparator - Very brief advice only (VBA) – Participants received very brief advice as described by the National Centre for Smoking Cessation Training (NCSCT) which had been adapted to the North Macedonia context. The adaption was developed as part of the “teach the teacher” programme in collaboration with the NCSCT [15], and in line with the IPCRG position statement on treatment of tobacco dependence [17]. The adapted version involved delivery of the three As: (1) Asking the participant if they smoked (ascertained during screening); (2) Advising about harms of smoking, benefits of quitting and the best way to stop; and Acting, where GPs asked all participants if they would like to take up the offer of support to quit smoking. The “Act” was dependent on their response. Participants responding no, or not yet, were advised that the offer of support remained available to be taken up at another time. Those responding yes were encouraged to set a quit date within a week and were offered behavioural support from the GP at 1, 2, 4 weeks and once between 8–12 weeks post-quit. The behavioural support visit protocol was based on the UK standard treatment program for smoking cessation [18]. As pharmacotherapy was not available on prescription at the time of the study, participants were advised where to purchase nicotine replacement therapies over the counter. GPs were trained to deliver the VBA and behavioural support as part of the Teach the Teacher programme and underwent a second refresher training from the research team before taking part as a research site in the trial. Regardless of quit intention, all participants were given a smoking information leaflet (supplementary file 1).

  • Intervention - Very brief advice with feedback about lung age (VBA + LA) – Lung age was calculated conservatively based on the lowest of three blows into a hand-held spirometer (Vitalograph COPD-6) performed without the use of bronchodilators [12]. The reading and its implications were explained as a motivator to stop smoking as part of “advice” within VBA (supplementary file 2).

  • Intervention - Very brief advice with feedback about exhaled CO levels (VBA + CO) – CO was measured with a piCO™ Smokerlyzer® (Bedfont Scientific Ltd) once. The reading in parts per million (ppm) and its implications were explained as a motivator to stop smoking as part of “advice” within VBA. Participants who attempted to quit also had their exhaled CO measurement repeated and fed back to them during their behavioural support sessions (supplementary file 3).

Outcome measures

Participants were followed up at 4, 12 and 26wks after baseline where they completed a questionnaire to collect outcome, process and cost data. Self-reported quitting was validated using a semi-quantitative salivary nicotine test (NicAlertCraig Medical Distribution Inc., CA, USA) [19], and in an exploratory analysis was validated using exhaled CO in a subset (Supplemental file 4). Electronic data were recorded in a REDCap database hosted by UoB [20, 21].

The primary outcome was the proportion of smokers who quit at 4wks (7-day point prevalence abstinence), biochemically validated with salivary cotinine (1) < 10ng/ml, or (2) < 100ng/ml for those who reported exposure to second hand cigarette smoke in the home on a daily basis, or (3) ≥ 10ng/ml in those who reported using Nicotine Replacement Therapy (NRT)/e-cigarettes at any time point during the study, irrespective of exposure to second hand cigarette smoke). Secondary outcomes were biochemically validated (as above) 7-day point prevalence abstinence at 12wks and 26wks, proportion who reported quitting smoking (self-report 7 day point prevalence abstinence), proportion who attempted to quit smoking, proportion who reduced the number of cigarettes smoked per day and motivation to quit smoking as measured by the motivation to stop smoking scale (MTSS) [22] at 4, 12 and 26wks.

Sample size

We initially expected to find a difference of 10% in quitting at 4wks between intervention and control arms (12% VBA vs 22% VBA + LA vs 22% VBA + CO) [23]. However, this was revised in consultation with the Trial Steering Committee due to low numbers of participants attempting to quit. We finally aimed to recruit at least 1182 participants, 394 participants per arm, to detect a difference of 5% in quitting between the intervention and control arms at 4 weeks (3% VBA vs 8% VBA + LA vs 8% VBA + CO) with 80% power and a significance level of 2.5% (due to comparison of each intervention arm to the control group).

Randomisation and blinding

The randomisation sequence was created prior to the commencement of participant recruitment and embedded within the REDCap database. The next allocation was concealed to the recruiter (the GP), and only revealed after a new participant record was created and the baseline questionnaire completed. Participants and GPs were not blinded to allocation after randomisation, however outcome assessors were blind to treatment allocation. Participants were randomised 1:1:1, stratified by GP practice.

Statistical methods

Data were analysed using Stata (version 16, Texas, USA) [24]. Baseline measures were reported as frequency and percentages for binary measures or mean and standard deviation or median and interquartile range (25% percentile and 75th percentile) for continuous measures where appropriate. Primary and secondary outcomes were analysed using Poisson regression models with robust standard errors adjusting for primary care practice as a random effect. Model estimates were reported as relative risks (RR) with confidence intervals (97.5% for the primary analysis and 95% for all other analyses). In accordance with the Russell Standard [25], an intention to treat analysis was conducted for smoking cessation outcomes, treating those lost to follow-up as smokers, and untraceable participants were removed from the analysis.

Planned sub-group and sensitivity analyses [16] were not undertaken due to the small numbers of participants who quit. Exploratory analyses conducted at 4, 12 and 26wks compared alternative definitions of the primary outcome in a subset of participants. Alternative definitions used different criteria for cotinine testing and used exhaled CO in place of cotinine for biochemical validation (supplemental file 4). This was conducted in order to explore the impact on the primary outcome of accounting for the use of nicotine replacement products or exposure to secondhand smoke.

Process evaluation

A process evaluation to describe fidelity in intervention delivery and also uptake was conducted using data captured within case report forms (CRF). This included describing the proportion with LA and CO measurements recorded, proportion setting a quit date, length of time between baseline and quit date, number of behavioural support sessions attended, and use of pharmacotherapy at any time point during the study. We also captured audio recordings of a sample of participant baseline visits in order to assess fidelity in intervention delivery.

Cost effectiveness analysis

An incremental cost-effectiveness analysis was used to calculate cost per additional quitter at 4wks for both interventions, and a cost-utility analysis conducted to calculate cost per quality-adjusted life year (QALY) gained over 26wks, using data from the EQ-5D-5L questionnaire [26].


Baseline characteristics

We assessed 1514 patients for eligibility and randomised 1367 into the study (VBA + LA (n = 457), VBA + CO (n = 450) or VBA (n = 460)). The flow of participants through the study is summarised in Fig. 1. Characteristics of included participants were well balanced between arms (Table 1). Overall, mean age was 51 years and 47.6% were male. Eligible patients who did not want to participate were slightly older (mean age 55 (SD 11) and more likely to be male (59.6%).

Fig. 1
figure 1

CONSORT diagram for the flow of participants. According to the Russel standard [25], participants who did not attend but were contactable remained in the study and were counted as smokers. Participants that were not contactable (i.e. moved with no forwarding contact details, unobtainable phone number, had died) were excluded from the denominator and not available for analysis. *Practice excluded due to protocol deviation

Table 1 Baseline characteristics of participants by treatment group

Primary outcome

In total, 23 of 1351 (1.7%) participants were biochemically validated as abstinent from smoking at 4wks (VBA + LA n = 7/449, 1.6%, VBA + CO n = 8/442, 1.8%, VBA n = 8/450, 1.8%). Compared to VBA, the point estimate showed a lower validated quit rate in the VBA + LA arm (RR 0.90 (97.5% CI: 0.35, 2.27)) and a slightly higher quit rate for VBA + CO (RR 1.04 (97.5%CI: 0.44, 2.44)) (Table 2). However, for both interventions, CIs were wide and therefore estimates are imprecise.

Table 2 Proportion of participants who quit smoking (biochemically confirmed and self-reported) and proportion who reduced the number of cigarettes smoked per day

Secondary outcomes

Biochemically validated and self-reported quitting

The total number of validated quitters at 12wks and 26wks was low (12wks: 24/1332 = 1.8%; 26wks: 11/1301 = 0.8%). Compared to VBA, point estimates for validated quit rates were lower in the VBA + LA arm at 12wks (RR 0.78 (95% CI:0.32, 1.89) but higher at 26wks (RR 6.98 (95% CI:1.09, 44.54). In the VBA + CO arm, rates were higher at both 12wks (RR 1.29 (95% CI:0.65, 2.57)) and 26wks (RR 3.11 (95% CI:0.28, 35.10)). However, the confidence interval for all estimates were also wide and included no effect apart from LA at 26 weeks where the point estimate was significant, but confidence intervals were very wide (Table 2).

For self-reported quitting, point estimates for quit rates were higher in the VBA + LA and VBA + CO arm in comparison to VBA at 4wks (RR 1.15 95% CI:0.51, 2.59; RR 1.95 95% CI:0.92, 4.10;), 12wks (RR 1.02 95% CI: 0.45, 2.30; RR 1.69 95% CI: 0.73, 3.91) and at 26wks (RR 1.58 (95% CI: 0.74, 3.38; RR 1.41 (95% CI: 0.65, 3.08)). However, these estimates also did not reach statistical significance (Table 2).

Reduction in cigarettes smoked per day

There was a relative increase in participants reporting reduction in the number of cigarettes smoked per day in VBA + LA and VBA + CO arms compared to VBA at all follow up points. At 4wks this was statistically significant in both the VBA + LA arm (RR 1.30 (95% CI: 1.10, 1.54)) and the VBA + CO arm (RR 1.23 (95% CI: 1.03, 1.49)). At 12wks (RR 1.15 (95% CI: 1.00, 1.32), (RR 1.11 (95% CI: 0.93, 1.32)) and 26wks (RR 1.03 (95%CI: 0.94, 1.14)), (RR 1.09 (95%CI: 0.95, 1.26)) CIs included no effect (Table 2).

Motivation and attempts to quit smoking

Motivation and attempts to quit smoking broadly followed the same pattern as validated quit rates. In the VBA + LA arm, fewer were motivated and had attempted to quit compared to the VBA arm at earlier timepoints but more at 26wks. In the VBA + CO arm, a higher proportion were motivated to quit and had attempted quitting at all three timepoints compared with the VBA arm, but only attempts to quit at 12wks were significantly higher (RR 1.62 (95% CI: 1.10, 2.39)) (Table 3).

Table 3 Motivation and attempts to quit smoking during the follow-up time points

Process measures

Of 1351 participants with baseline measurements, 65 (4.8%) set a quit date. The median length of time between randomisation and quit date was 6 days (interquartile range = 2–8). Twenty-two (33.8%) of those setting a quit date used NRT or e-cigarettes. The mean number of behavioural support visits was 2.43 (SD = 1.73) out of a total possible of 5 visits. The majority of participants were recorded within the CRF as receiving VBA across all trial arms (98.7–99.8%), and the CO (99%) and LA components (98%) in the intervention arms.

Thirty-three baseline visits were recorded capturing intervention delivery. Recordings also indicated that the LA and CO components were delivered with high fidelity, whereas fidelity to the VBA protocol was higher in the VBA-only arm (supplementary file 5).

Health economic evaluation

Overall, the costs of the VBA intervention were lower at 114.67 MKD per patient compared with 119.80 and 136.29 for the VBA + LA and VBA + CO arms respectively. Furthermore, the VBA arm had slightly more quitters at the 4wk primary endpoint and slightly higher total QALYs over 26wks (0.4525 (SD 0.0514)), resulting in VBA being the dominant intervention (cheaper and more effective than other approaches). Few patients reported expenditure on products to stop smoking, but this expenditure was high for the 31 reporting it—3000–4000 MKD (Table 4).

Table 4 Descriptive health outcomes and costs. Values are mean (SD) unless otherwise stated


This study tested the effectiveness of simple interventions to prompt smoking cessation delivered to smokers in primary care in North Macedonia. As these were interventions advising smokers to quit, they were delivered to all smokers, regardless of motivation to quit smoking, with the aim of prompting a successful quit attempt. Point estimates indicated that biochemically validated quit rates, self-reported quit rates, motivation to quit, attempts to quit and the proportion reducing the number of cigarettes smoked per day were higher in the CO + VBA arm compared to VBA at all follow up points, whereas point estimates were more inconsistent for the LA + VBA arm. However, it was not possible to draw conclusions about effectiveness of the interventions as the absolute number of participants quitting was lower than expected and estimates were imprecise incorporating the possibility of no effect, with the exception of the proportion who had reduced the number of cigarettes smoked at 4wks and attempts to quit at 12wks in the VBA-CO arm. After taking into account the costs incurred and QALYs gained, the health economic analysis indicated that VBA alone was the dominant intervention (less costly, more effective) however interpretation of this is also limited due to negligible differences in QALYs.

Strengths and limitations

This is the first trial testing effectiveness of interventions to prompt smoking cessation in primary care in North Macedonia [27], a middle income country with high smoking prevalence and limited tobacco control measures in place [1, 6]. Given the limited availability of affordable pharmacotherapy, we sought to test other interventions which could feasibly be delivered in primary care. These were identified with local stakeholders through a prioritisation exercise conducted before designing the trial [28] and we were able to build on an existing in-country programme training general practitioners to deliver VBA for smoking cessation with behavioural support for smokers who choose to quit (IPCRG/Global Bridges teach the teacher programme) [15]. There are no data describing demographic characteristics of smokers in North Macedonia, however characteristics of participants were similar to those of the general population, and eligible patients declining participation were not substantially different to trial participants. Primary care practices from both rural and urban areas participated in the trial and attrition bias was minimised with high follow up rates in each arm. Therefore, an important strength of the study is that generalisability of the findings to the smoking population in North Macedonia is likely to be high.

A challenge with this study was the ability to accurately predict expected quit rates in the control and intervention arms. One study testing LA + VBA in smokers regardless of motivation to quit and reporting quit rates at 4wks was found when we were designing the trial, and this had been conducted in Ireland [23]. Our initial sample size calculation, which was based on this Irish study, was revised as advised by the Trial Steering Committee due to a lower observed proportion attempting to quit in our study. An increased recruitment target was approved, with an expectation of 3% quit at 4wks in the VBA arm and increase of 5% in the intervention arms. However, these expected rates were also not met and although we exceeded our recruitment target, the trial may not have been adequately powered to detect a difference in the primary outcome. A statistically significant difference was seen in the VBA CO arm in reduction in cigarettes smoked per day and in attempts to quit, but it should be noted that even when reducing the number of cigarettes smoked per day, smokers may not experience a reduction in harm due to compensatory smoking [29].

Comparison with literature

The available evidence on effectiveness of delivering LA or exhaled CO feedback on smoking cessation is summarised in a Cochrane review published in 2019 [11]. This reported moderate certainty evidence from five studies that feedback on CO measurement did not increase quitting at 6 months (RR 1.00 (95% CI 0.83 to 1.21); I2 = 0%; n = 2368). When designing the trial, we considered that this finding may not be replicated in North Macedonia as these studies were all conducted in high income countries (HICs) and did not repeat CO measurements during behavioural support as was the case in our study. In addition, three out of five of the studies were at high risk of bias. However, we did not find evidence to the contrary suggesting that use of CO measurements as an augmented aspect of advice in VBA and repeated as part of behavioural support in those who attempt to quit is not effective within the North Macedonia context.

The Cochrane review also included two studies testing LA. The first study was small (n = 50) and did not show a positive effect [30]. The second was a trial conducted in 561 smokers in primary care that used spirometry and immediate feedback of lung age using a graphical display [14]. Participants receiving the intervention were told their LA if this was older than their chronological age and participants in the control arm received the raw spirometry reading. Contrary to our findings, the study found evidence of an increase in quitting (Intervention 13.6% v control 6.4% (RR 2.12 (1.24, 3.62) at 12 months). However, this study was conducted in a HIC, and may not be transferable to the North Macedonian context.

VBA is recommended as standard care in primary care in LMIC settings by the World Health Organisation [31]. Although some GPs may deliver VBA, at the time of this study there was no national clinical tobacco guidance in North Macedonia. Evidence from a Cochrane review shows that brief advice for smoking cessation delivered by physicians in primary care is effective (OR 1.66 (95% CI 1.42–1.94)) [8], and has a small but significant long term effect on quitting in absolute terms that are deemed to be clinically important (~ 2% increase above no intervention, with absolute quit rates of ~ 4% after at least 26 weeks) [7, 8]. Many of the trials testing brief advice included in the Cochrane review were conducted decades ago in the US or UK when smoking prevalence was closer to the current prevalence in North Macedonia and implementation of tobacco control measures was similarly less well advanced. It would therefore be reasonable to expect that brief advice delivered in the North Macedonia context may have similar effectiveness. Despite this, our study found that only 1/435 (0.2%) smokers who received VBA were quit at 26wks, and the quit rate was also lower than expected at 4wks. There are few studies testing VBA delivered by healthcare providers in LMIC settings for comparison [27, 32]. However, two small studies conducted in Malaysia [33] and China [34] reported a 15% quit rate in smokers unselected by motivation or pre-existing health condition at 6 and 12 months, respectively. This suggests that absolute quit rates in North Macedonia may be particularly low, and more work is required to understand how to increase the impact of VBA from physicians in this context.

There are a number of factors that may have contributed to the low absolute quit rates seen within our study. In terms of fidelity to intervention delivery, quantitative measures taken across all trial participants indicated that this was high for the LA, CO and VBA protocols, however recordings of a sample of baseline consultations indicated that fidelity to the VBA protocol was reduced for the lung age and CO arms compared to the VBA arm alone. It is possible that delivery of the LA and CO components distracted GPs from delivering the full VBA protocol, and this may have masked differences in effectiveness between these approaches. In line with the protocol, participants setting a quit date did so within a week of the baseline visit. However, uptake of behavioural support was low with participants receiving an average of two out of a possible five sessions offered as part of the standard programme for behavioural support, and only 34% indicated that they had used some form of pharmacotherapy.

In addition to these reasons, generally speaking, smoking remains a strong part of the culture within North Macedonia. National smoking prevalence is high [35,36,37], including among healthcare workers [38]. It is the fifth largest producer of raw tobacco leaf in Europe, representing 13.9% of European tobacco product [36], and a fifth of our GP practices were based in tobacco producing areas. North Macedonia are a signatory country to the WHO Framework Convention on Tobacco Control, but tobacco prices remain affordable, there is not a complete ban of smoking in public places, there is no standardised packaging of cigarettes or mass media campaign, and availability of support services and pharmacotherapies is low [38].

The low numbers of quitters in our study may mean that our trial was underpowered, and small effects of brief interventions in primary care cannot be ruled out. However, the findings highlight the difficulty of influencing smokers through primary care services within North Macedonia alone. Tackling high national smoking prevalence will also be reliant on more complete adoption of the WHO FCTC population based tobacco control measures, and on making known effective pharmacotherapies more accessible and affordable. More research is needed to find effective ways to prompt and support quitting in primary care in North Macedonia.


There was insufficient evidence to draw strong conclusions regarding the effectiveness of adding LA and CO to VBA for smoking cessation when delivered in primary care in North Macedonia. Overall, absolute quit rates were much lower than reported in HIC and other LMIC settings and confidence intervals were wide including the possibility of no effect. However, there was evidence of willingness to attempt quitting in some smokers. Further work is needed to identify barriers to successful quitting and to find effective and cost-effective methods to support patients to quit smoking in primary care in North Macedonia.

Availability of data and materials

Data are available subject to reasonable request to the corresponding author Rachel Jordan (, and further ethical approvals.



Lung age


Carbon Monoxide


Very brief advice


Low and middle income


International Primary Care Respiratory Group


Randomised Controlled Trial


University of Birmingham


National Centre for Smoking Cessation Training


Case report form


Quality-adjusted life year


Relative risk


Macedonia Denar


Motivation to Stop Scale


  1. GBD 2019 Tobacco Collaborators. Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet. 2021;Published online May 27, 2021.

  2. World Health Organisation. WHO report on the global tobacco epidemic 2019: Offer help to quit tobacco use. Powered by the California Digital Library; 2019.

  3. Stead L, Koilpillai P, Fanshawe T, et al. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev. 2016;3:CD008286.

    PubMed  Google Scholar 

  4. Parrott S, Godfrey C, Raw M, et al. Guidance for commissioners on the cost effectiveness of smoking cessation interventions. Thorax. 1998;53(2):Suppl 5: S2-S3.

    PubMed Central  Google Scholar 

  5. Shahab L. Cost-effectiveness of pharmacotherapy for smoking cessation. National Centre for Smoking Cessation Training - Briefing 7; 2012.

  6. World Health Organisation. Who report on the global tobacco epidemic, 2019. 2019.

  7. West R, Stapleton J. Clinical and public health significance of treatments to aid smoking cessation. Eur Respir Rev. 2008;17(110):199–204.

    Article  Google Scholar 

  8. Stead LF, Buitrago D, Preciado N, Sanchez G, Hartmann-Boyce J, Lancaster T. Physician advice for smoking cessation. Cochrane Database Syst Rev. 2013(5):CD000165.

  9. McBride C, Emmons K, Lipkus I. Understanding the potential of teachable moments: the case of smoking cessation. Health Educ Res. 2003;18(2):156–70.

    Article  CAS  PubMed  Google Scholar 

  10. McCaul KD, Hockemeyer JR, Johnson RJ, et al. Motivation to quit using cigarettes: a review. Addict Behav. 2006;31:42–56.

    Article  PubMed  Google Scholar 

  11. Clair C, Mueller Y, Livingstone-Banks J, et al. Biomedical risk assessment as an aid for smoking cessation. Cochrane Database Syst Rev. 2019;3:CD004705.

    PubMed  Google Scholar 

  12. Morris J, Temple W. Spirometric, “lung age” estimation for motivating smoking cessation. Prev Med. 1985;14(5):655–62.

    Article  CAS  PubMed  Google Scholar 

  13. Ripoll J, Girauta H, Ramos M, et al. Clinical trial on the efficacy of exhaled carbon monoxide measurement in smoking cessation in primary health care. BMC Public Health. 2012;12:322.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Parkes G, Greenhalgh T, Griffin M, et al. Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial. BMJ. 2008;336(7644):598–600.

    Article  PubMed Central  PubMed  Google Scholar 

  15. International Primary Care Respiratory Group. IPCRG teach the teacher funded by Global Bridges. 2016.

  16. Gjorgjievski D, Ristovska R, Stavrikj K, et al. Effectiveness of combining feedback about lung age or exhaled carbon monoxide levels with very brief advice (VBA) and support for smoking cessation in primary care compared to giving VBA and support alone–protocol for a randomized controlled trial withi. Open Access Maced J Med Sci. 2020;8(E):28–36.

    Article  Google Scholar 

  17. Van Schayck OCP, Williams S, Barchilon V, et al. Treating tobacco dependence: guidance for primary care on life-saving interventions. Position statement of the IPCRG. NPJ Prim Care Respir Med. 2017;27(1):38.

    Article  PubMed Central  PubMed  Google Scholar 

  18. National Centre for Smoking Cessation and Training. Standard treatment programme. 2019. Available from:

  19. Cooke F, Bullen C, Whittaker R, et al. Diagnostic accuracy of NicAlert cotinine test strips in saliva for verifying smoking status. Nicotine Tob Res. 2008;10(4):607–12.

    Article  CAS  PubMed  Google Scholar 

  20. Harris P, Taylor R, Minor B, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Harris P, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

    Article  PubMed  Google Scholar 

  22. Kotz D, Brown J, West R. Predictive validity of the Motivation To Stop Scale (MTSS): a single-item measure of motivation to stop smoking. Drug Alcohol Depend. 2013;128(1–2):15–9.

    Article  CAS  PubMed  Google Scholar 

  23. Ojedokun J, Keane S, O’Connor K. Lung Age Bio-feedback Using a Portable Lung Age Meter with Brief Advice During Routine Consultations Promote Smoking Cessation – Know2quit Multicenter Randomized Control Trial. J Gen Pract. 2013;1:123.

  24. StataCorp. Stata statistical software: release 16. College Station: StataCorp LLC; 2019.

    Google Scholar 

  25. West R, Hajek P, Stead L, et al. Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction. 2005;100(3):299–303.

    Article  PubMed  Google Scholar 

  26. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Kumar N, Janmohamed K, Jiang J, et al. Tobacco cessation in low- to middle-income countries: a scoping review of randomised controlled trials. Addict Behav. 2021;112:106612.

    Article  PubMed  Google Scholar 

  28. Dickens A, et al. Using a rapid prioritisation process to identify health research priorities in LMICs. In: ERS Paris International Congress Primary care management of COPD theme. 2018.

  29. Begh R, Lindson-Hawley N, Aveyard P. Does reduced smoking if you can’t stop make any difference? BMC Med. 2015;13:257.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Drummond M, Astemborski J, Lambert A, et al. A randomized study of contingency management and spirometric lung age for motivating smoking cessation among injection drug users. BMC Public Health. 2014;14:761.

    Article  PubMed Central  PubMed  Google Scholar 

  31. World Health Organisation. WHO package of essential noncommunicable (pen) disease interventions for primary health care. 2020.

  32. Akanbi M, Carroll A, Achenbach C, et al. The efficacy of smoking cessation interventions in low-and middle-income countries: a systematic review and meta-analysis. Addiction. 2019;114(4):620–35.

    Article  PubMed Central  PubMed  Google Scholar 

  33. De Silva W, Awang R, Samsudeen S, et al. A randomised single-blinded controlled trial on the effectiveness of brief advice on smoking cessation among tertiary students in Malaysia. J Health Med Inform. 2016;7:217.

    PubMed Central  PubMed  Google Scholar 

  34. Lin PR, Zhao ZW, Cheng KK, et al. The effect of physician’s 30 s smoking cessation intervention for male medical outpatients: a pilot randomized controlled trial. J Public Health (Oxf). 2013;35:375–83.

    Article  PubMed  Google Scholar 

  35. Analytica. Survey on tobacco consumption in SEE countries North Macedonia. 2019.

  36. Hristovska Mijovic B, Spasova Mijovic T, Trpkova-Nestorovska M, et al. Tobacco farming and the effects of tobacco subsidies in North Macedonia, Analytica, Skopje, North Macedonia. 2022.

  37. Spasova T, Hristovska B. Accelerating progress on effective tobacco tax policies in low- and middle income countries National study - Macedonia. Tobacotaxation. 2018.

  38. Nikovska DG, Spasovski M, Gjorgjev D, et al. Social determinants of smoking in the population of the Republic of Macedonia - results from a nested case-control study. GJMEDPH. 2014;3(4):1–8.

    Google Scholar 

Download references


We gratefully acknowledge the IPCRG for introducing us to the primary care networks involved in this study and for its continued facilitation of clinical engagement; the trial steering and international scientific advisory committees: Debbie Jarvis, Niels Chavannes, Semira Manaseki-Holland and David Mannino; all the participants and staff of participating general practices. Biljana Tanevska for management support for the trial.


This article is in memory of Dr Radmila Ristovska (1955–2020), respected friend and colleague. Thanks to her and her enthusiasm, this research was obtained and she actively worked in its design and implementation. Unfortunately, she lost her life to cancer in 2020 and was unable to see the final results of this research.


This research was funded by the National Institute for Health Research (NIHR) NIHR global group on global COPD in primary care, University of Birmingham, (project reference: 16/137/95) using UK aid from the UK Government to support global health research. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham.

Author information

Authors and Affiliations



RJ, PA, CC, KKC, BC, JC, KR, APD, AE, AF, NG, KJ, SJ, MM, TM, SM, ASt, KS, RS, AT, SS, FT and SW initiated the study. RJ, PA, KS, AF and KR led the development of the protocol and supervised the study. AF guided development of the intervention protocols and advised on trial outcomes. KS was principal investigator in North Macedonia, and RJ, AF and KR were UK leads. KR provided day to day support for setup and the pilot. KS, GS, DG, ASt, EK, FT and SS undertook recruitment, data collection and analysis, supported by KR, RA, CE, ASi, AF and APD. SJ designed and undertook the health economic analysis. RA provided day to day support during data collection and reporting and CE for data analysis. GS, DG, KS, RA, CE, SJ and AF wrote the initial draft of the paper. All authors contributed to the final manuscript. KS and RJ are the study guarantors.

Corresponding author

Correspondence to Rachel Jordan.

Ethics declarations

Ethics approval and consent to participate

Ethical permission was received from the ethical review board of Saints Cyril and Methodius University, North Macedonia (UKUM034/95) and institutional ethics committee at University of Birmingham (UoB), UK (ERN_18-12408). All participants recruited into the study were able to read and sign the consent form and informed consent was obtained from all participants. The trial was registered at (ISRCTN54228638) on the 07/09/2018. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

P Adab declares grant funding paid to her institution from NIHR, MRC and Colt Foundation, funding to Institution and to cover expenses as Chair of NIHR Public Health Research Funding Committee, Deputy Director of NIHR School for Public Health Research, funding to cover expense as Member of Wellcome Trust Early Career Advisory Group in Population and Public Health, Output Assessor for Panel A, subpanel 2 in 2021 Research Excellence Framework, and unfunded contributions as Chair for several NIHR funded TSCs, Member of the MRC funded Natural Experiments Evaluations Project Oversight Group, Member of Obesity Health Alliance Independent Obesity Strategy Working Group, Member of NIHR palliative and End of Life Care Research Partnerships call Panel, NIHR/UKRI Long COVID funding call Panel, NIHR COVID-19 Recovery and Learning Funding Committee; J Correia-De-Sousa declares grant funding to his institution from AstraZeneca and GSK, advisory board and consulting fees paid to himself from Boheringer Ingelheim, GSK, AstraZeneca, Bial, Medinfar, Payment for lectures from GSK, AstraZeneca and Sanofi Pasteur, support for attending meetings from Mundipharma and Mylan, leadership role for International Primary Care Respiratory Group (IPCRG); A Farley declares grant funding paid to her institution from NIHR GHR for the present manuscript, grant funding from NIHR HTA, NIHR EME, MRC and Ethicon (Johnson and Johnson) for other work, membership on DMEC for NIHR funded e-cigarette trial (no honorarium), leadership role for International Primary Care Respiratory Group (IPCRG); K Jolly declares grant funding paid to her institution from NIHR and MRC, participant in Data Safety Monitoring Board or advisory board for NIHR funded studies (no honorarium), Sub-committee chair of NIHR Programme Grants for Applied Health Research (payments to institution); R Jordan declares grant funding to her institution from NIHR, membership of Boehringer Ingelheim Primary Care Advisory Board, leadership role for International Primary Care Respiratory Group (IPCRG) – research sub-committee; S M Martins declares leadership or fiduciary role in Brazilian Society of Medicine and Family and Community; ABC School of Medicine, GEPRAPS ( respiratory group of study and research in primay care), IPCRG (Internacional Primary Care Respiratory Group); A Sitch declares grant funding to her institution from NIHR GHR for present manuscript, NIHR Birmingham BRC and AstraZeneca; A Turner declares grant funding to her institution from NIHR GHR for present manuscript, grant funding from AstraZeneca and Chiesi for other work, payment of honoraria from GSK and Boehringer, support for attending meetings and/or travel from AstraZeneca and Chiesi; S Williams declares grants from the University of Birmingham paid to her institution; K K Cheng, A Dickens, N Gale, S Jowett R declare grant funding to their institution from NIHR GHR for current manuscript; Adams, C Chi, B Cooper, C Easter, A Enocson, D Gjorgjievski, E Krstevsha, T Maghlakelidze, M Maglakelidze, K Rai; A Stamenova, G Stanoevski, S Simonovska, K Stavrikj, R Stelmach, F Trpcheski have no conflicts to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Supplementary file 1.

VBA Protocol including behavioural support for smokers who choose to quit. Supplementary file 2. Protocol for conducting lung age test and explaining significance to the participant. Supplementary file 3. Protocol for conducting CO test and explaining significance of the result to the participant. Supplementary file 4. Exploratory analyses (validation method for quitting smoking). Supplementary file 5. Process evaluation - CRF measures and fidelity recordings.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gjorgjievski, D., Stavrikj, K., Jordan, R. et al. Randomised controlled trial testing effectiveness of feedback about lung age or exhaled CO combined with very brief advice for smoking cessation compared to very brief advice alone in North Macedonia: findings from the Breathe Well group. BMC Public Health 23, 1887 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: