Smoking cessation in smokers with chronic obstructive pulmonary disease

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness of behavioural and/or pharmacological smoking cessation interventions in smokers with COPD.


Description of the condition

Chronic obstructive pulmonary disease (COPD), a common and largely preventable disease, is characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response to noxious particles or gases in the airways and the lung (GOLD 2013). Exacerbations and co-morbidities contribute to overall severity in individual patients. The diagnosis must be confirmed by spirometry-the most widely available reproducible test of lung function (GOLD 2013).

COPD prevalence, morbidity and mortality vary across countries and across different groups within countries (GOLD 2013). A worldwide prevalence study showed that the prevalence, for example, of moderate COPD (i.e. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II) in women 40 years of age or older ranged from 3.1% to 12.6%, and in men from 6.7% to 13.1% (Buist 2007). This variation in prevalence is due in part to differences in pack-years, which are shown by the odds ratios of COPD for 10-year intervals of pack-years: 1.28 (95% confidence interval (CI) 1.15 to 1.42) for women and 1.16 (95% CI 1.12 to 1.21) for men (Buist 2007). Except for exposure to risk factors, prevalence variation is due to differences in survey methods, diagnostic criteria and analytical approaches. Under-recognition and under-diagnosis of COPD also affect the accuracy of prevalence and mortality data. In a large-scale English study, the prevalence of COPD was highest among current smokers (19.3%), followed by ex-smokers (15.2%) and never smokers (8.2%) (Shahab 2006). Furthermore, the prevalence of undetected COPD was high among asymptomatic smokers. The prevalence of previously undiagnosed COPD in male smokers 40 years of age or older ranged from 12% in a Greek research population (Tzanakis 2004) to 30% in a Dutch research population (Geijer 2005). The Global Burden of Disease Study projected that COPD will become the third leading cause of death worldwide by 2020 (GOLD 2013). This increased mortality is driven mainly by the expanding epidemic of smoking, reduced mortality from other common causes of death and aging of the world population (GOLD 2013).

The risk for developing COPD results from an interaction between genetic factors and many different environmental exposures (Mannino 2007). Cigarette smoking is the most commonly encountered risk factor for COPD in high-income countries (Celli 2004; Kohansal 2009; GOLD 2013). Furthermore, a higher prevalence of respiratory symptoms and lung function abnormalities and a greater COPD mortality rate are seen among cigarette smokers with COPD than non-smokers with COPD (GOLD 2013). For example, an overview of the literature showed the effect of smoking on forced expiratory volume in one second (FEV1) in males with mild to moderate COPD (Willemse 2004). The FEV1 of these participants, who continued to smoke, declined within a range of 42 to 82 mL/y compared with 0 to 49 mL/y in COPD participants who quit smoking at the start of the study (Willemse 2004). This latter decline is comparable with the physiological lung function decline that naturally occurs with increasing age (Kerstjens 1997).

Smoking cessation is the only evidence-based intervention that reduces the risk of developing COPD and slows down the accelerated decline in lung function in patients with COPD (Anthonisen 2002). To date, none of the existing medications for COPD have been shown conclusively to modify the long-term decline in lung function (GOLD 2013). Furthermore, smoking cessation is the single most cost-effective way to reduce the risk of development of COPD and worsening of the disease (GOLD 2013).

Description of the intervention

For the current review, we will include randomised controlled trials if they assessed the effectiveness of any form of behavioural or pharmacological treatment, or combinations of both, as an aid to smoking cessation in patients with COPD. Behavioural treatment in this regard refers to any psychotherapeutic approach aimed at identifying and modifying the behaviours associated with smoking (Tobacco Use and Dependence Guideline Panel 2008). Pharmacological treatments include nicotine replacement therapy (NRT), nicotine replacement partial agonists (NRPAs), antidepressants for smoking cessation (ADs) and nicotine vaccines. Currently, the following NRT delivery systems are available: nicotine chewing gum, nicotine inhaler, nicotine lozenge, nicotine patch and nicotine nasal spray. Varenicline is the most commonly used NRPA, and bupropion and nortriptyline the most commonly used ADs. Currently, vaccines are not licensed for public use, but several vaccines are under development. A smoking cessation intervention is often a combination of a pharmacological and a behavioural treatment.

How the intervention might work

Smoking is an addictive behaviour; therefore, the chances of successful smoking cessation are minimal without the use of behavioural and/or pharmacological treatments. In the general smoking population, several behavioural and pharmacological treatments have demonstrated efficacy in helping to achieve abstinence. For example, the antidepressants nortriptyline and bupropion aid long-term smoking cessation, and evidence suggests that the mode of action is independent of their antidepressant effects (Hughes 2012). Their efficacy is similar to that of NRT (Hughes 2012). A review of NRPAs showed that varenicline increased the chances of successful long-term smoking cessation compared with bupropion (Cahill 2012). Comparison of NRT and varenicline suggested a minor benefit of varenicline tending towards equivalency (Cahill 2012). Furthermore, a recent review showed the NRPA cytisine to be an effective treatment for smoking cessation (Hajek 2013). Interventions that combine behavioural and pharmacological treatments are even more successful in achieving abstinence (Stead 2012). Providing behavioural treatment in person or via telephone for people using pharmacotherapy to stop smoking showed a small but important effect (Stead 2012). However, these studies did not make a distinction between different kinds of smokers. As smokers are not a homogeneous group, it is important to make the intervention fit best for each specific group, such as people with COPD (Borrelli 2010), for example, by giving valuable and clear information on how smoking is related to COPD and to respiratory symptoms. Furthermore, it might be useful to specifically address the increased co-morbidities and nicotine dependence levels reported in COPD patients.

Why it is important to do this review

Smoking cessation is the most important intervention to reduce the risk of developing COPD and to improve the prognosis of patients with the disease. COPD patients have a more urgent need to stop smoking than the average smoker; moreover, many often find it more difficult to do so (Tonnesen 2007). Therefore, it is important to provide an overview of the evidence base for different smoking cessation interventions directed at these patients.

Compared with smokers from the general population, smokers with COPD might have greater difficulty in quitting smoking, in part because of their higher pack-years of smoking history, stronger dependence on nicotine and particular inhalation pattern (Jimenez-Ruiz 2001; Shahab 2006). A Dutch study showed that smokers with mild to severe COPD were less likely to achieve abstinence than smokers without COPD but at risk of developing the disease; the prolonged abstinence rate after six months with nortriptyline therapy was 21% in smokers with COPD compared with 32% in smokers without COPD (Wagena 2005). That study, however, did not control for baseline differences. Therefore, interventions aimed at smokers with COPD might have to be more tailored to the needs of COPD patients to increase their desire to stop and to address their increased levels of nicotine dependence (Shahab 2006). However, evidence for the effectiveness of tailored versus general smoking cessation interventions in this patient group is scarce.

The scope of this review will be the same as this previous Cochrane review: to review the evidence 'whether and which treatments are effective in COPD smokers' (van der Meer 2001). However, results might have changed because new trials on this subject have been published since 2003.


To evaluate the effectiveness of behavioural and/or pharmacological smoking cessation interventions in smokers with COPD.


Criteria for considering studies for this review

Types of studies

We will examine randomised controlled trials (RCTs).

Types of participants

We will include smokers with a diagnosis of COPD, according to criteria from the guidelines of the American Thoracic Society (ATS) (Qaseem 2011), the British Thoracic Society (BTS) (NICE 2010) or GOLD (GOLD 2013), or as confirmed by the treating physician.

Types of interventions

RCTs will be included when the effectiveness of any behavioural or pharmacological treatment, or combination, was assessed as an aid to smoking cessation in participants with COPD. We will include only studies that focus exclusively on participants with COPD. We will include the following comparisons.

  • Behavioural treatment versus no intervention or usual care.

  • One form of behavioural treatment versus a different form of behavioural treatment.

  • Pharmacological treatment versus placebo.

  • Pharmacological treatment versus a different pharmacological intervention.

  • Direct comparison of different combinations of behavioural and pharmacological treatments.

Types of outcome measures

As the primary outcome, we are interested in the percentage of participants who meet the criteria for 'continuous or prolonged smoking cessation' over a period of six months or longer. Continuous abstinence refers to abstinence periods that begin on the quit date. Prolonged abstinence refers to continuous abstinence after a initial grace period (Hughes 2003). The preferred outcome will be biochemically validated continuous or prolonged abstinence at the longest reported time point. However, because biochemically validated abstinence might be lacking, both self-reported abstinence and biochemically validated abstinence will be examined. Unfortunately, lack of clarity is evident in the literature about the reliability of self-reported abstinence (Hilberink 2011; Wilson 2011). When it is not clear whether the given quit rate is a point prevalence or a continuous or prolonged abstinence rate, we will define the quit rate as point prevalence. Point prevalence abstinence rate refers to the proportion of participants who were non-smokers at a specific point in time during follow-up. It is a considerably less valid estimate of smoking abstinence than continuous/prolonged abstinence because participants could be classified as non-smokers even if they have smoked a week before the reference date (West 2005; Strassmann 2009). Therefore, continuous or prolonged abstinence will be used as the primary outcome measure, and point prevalence will be considered as the secondary outcome measure.

Primary outcomes
  • Percentage of participants with continuous or prolonged abstinence over a period of six months or longer

Secondary outcomes
  • Percentage of participants with point prevalence abstinence over a period of six months or longer

Search methods for identification of studies

Electronic searches

We will identify trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which is derived from systematic searches of bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO (please see Appendix 1 for further details). We will search all records in the CAGR using the search in Appendix 2. In addition to the electronic search, we will search clinical trial registries for planned, ongoing and unpublished trials (e.g. and All databases will be searched from their inception to the present, and no restriction on language of publication will be applied.

Searching other resources

We will check the reference lists of all included studies and of other systematic reviews in relevant topic areas. We will search for errata or retractions from eligible trials on and will report the date this was done within the review.

Data collection and analysis

Selection of studies

Two review authors (EVE and RMVDM) will independently select studies to be included by applying selection criteria. We will resolve any disagreement through discussion; if required, we will consult a third review author (DK). We will identify and exclude duplicates and will collate multiple reports on the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (Liberati 2009) flow diagram and a 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (EVE and RMVDM) will independently extract study characteristics from included studies. We will use a standard data collection form for study characteristics and outcome data. We will note in the 'Characteristics of included studies' table whether outcome data were reported in an unusable way. One review author (EVE) will copy the data from the data collection form into the Review Manager file. We will double-check that the data have been entered correctly by comparing the study reports with how the data are presented in the systematic review. A second review author will spot-check study characteristics for accuracy against the trial report. We will resolve disagreements by consensus or by involving a third review author (DK). The following study characteristics will be extracted.

  • Methods: study setting, study design, method of recruitment of participants, number of participants randomly assigned and followed-up.

  • Participants: age, sex, cigarettes smoked per day, mean score on Fagerström Test for Nicotine Dependence (FTND), severity of COPD baseline lung function (FEV1 and forced vital capacity (FVC)).

  • Interventions: description of the experimental and control group(s); type and intensity of the behavioural treatment, therapist providing the treatment, dose of the pharmacological treatment.

  • Outcomes: primary and secondary outcomes, respectively, percentage of participants with prolonged and/or continuous abstinence, percentage of participants with point prevalence abstinence, biochemical validation of abstinence.

  • Statistical analyses: complete case analyses or imputation of outcome data.

  • Notes: funding for trial, notable conflicts of interest of trial authors.

Assessment of risk of bias in included studies

Two review authors (EVE and RMVDM) will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion or by involving a third review author (DK). We will assess the risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of the outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We will grade each potential source of bias as high, low or unclear and will provide a quote from the study report, together with a justification for our judgement, in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. When information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and will report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

Results for dichotomous outcomes will be expressed as risk ratios (RRs). RRs will be calculated as follows: (number of participants who quit smoking in the intervention group/number of participants randomly assigned to the intervention group)/(number of participants who quit smoking in the control group/number of participants randomly assigned to the control group). An RR greater than 1 favours the intervention group.

We will undertake meta-analyses only when this is meaningful, for example, if treatments, participants and the underlying clinical question are similar enough for pooling to make sense.

Trialists commonly indicate that they have skewed data by reporting medians and interquartile ranges. When we encounter this, we will note that the data are skewed and will consider the implications of this.

When multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. drug A vs placebo and drug B vs placebo) must be entered into the same meta-analysis, we will halve the control group to avoid double counting.

Unit of analysis issues

The unit of analysis will be the participant.

Dealing with missing data

We will contact investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. when a study is identified as abstract only).

Furthermore, regarding smoking cessation, we will consider participants with missing outcome data as smokers.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the trials in each analysis. The I² statistic describes the percentage of variability in the summary estimate due to systematic heterogeneity rather than random chance stemming from sample error alone (Higgins 2011). Values greater than 50% suggest moderate heterogeneity, and values greater than 75% suggest substantial heterogeneity. If we identify substantial heterogeneity, we will explore this through prespecified subgroup analysis.

Assessment of reporting biases

When we suspect reporting bias, we will attempt to contact study authors to ask them to provide missing outcome data. When this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.

If we are able to pool more than ten trials, we will create and examine a funnel plot to explore possible publication biases.

Data synthesis

'Summary of findings' table

We will create a 'Summary of findings' table by using the following outcomes: the primary outcome percentage of participants with prolonged and/or continuous abstinence and the secondary outcome percentage of participants with point prevalence abstinence. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta-analyses for the prespecified outcomes. We will use methods and recommendations as described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and as used in GRADEpro software. We will justify all decisions to down-grade or up-grade the quality of studies by using footnotes and making comments to aid the reader's understanding of the review when necessary.

Subgroup analysis and investigation of heterogeneity

To examine whether the intervention effect varies in different subgroups, we plan to carry out the following subgroup analyses, when applicable.

  • Severity of COPD: mild/moderate versus severe/very severe.

  • Level of behavioural treatment: low versus high.

  • Type of pharmacotherapy: NRT, NRPA, AD, nicotine vaccines.

  • Definition of abstinence: percentage of participants with continuous or prolonged abstinence over a period of 12 months or longer versus less than 12 months versus percentage of participants with point prevalence.

The following outcomes will be used in the subgroup analysis:

  • Smoking status (% of group) at a minimum of six months from the quit date.

Sensitivity analysis

We will undertake sensitivity analyses to assess the effect of removing studies with a high risk of bias.


We would very much like to thank the editorial team of the Cochrane Airways Group (CAG), Dr Emma Welsh and Emma Jackson, for their advice, reading and comments. Furthermore, we would like to thank the CAG Trials Search Co-ordinator, Liz Stovold, for her advice.


Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRAL (The Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly


Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards


MEDLINE search strategy used to identify trials for the CAGR

COPD  search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.





10. or/1-9

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

Appendix 2. Search strategy for the Cochrane Airways Group Register

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All

#2 MeSH DESCRIPTOR Bronchitis, Chronic

#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)



#6 #1 OR #2 OR #3 OR #4 OR #5


#8 MeSH DESCRIPTOR Smoking Cessation


#10 MeSH DESCRIPTOR Tobacco Use Disorder

#11 MeSH DESCRIPTOR Tobacco Use Cessation

#12 MeSH DESCRIPTOR Nicotine

#13 ((nicotin* or tobacco or smok* or cigarette*) NEAR5 (replac* or cessat* or ceas* or control* or quit* or stop* or abstin* or abstain* or self-help* or "self help*" or behaviour* or behavior* or educat* or counsel* or support* or advice or treatment* or intervention*)):ti,ab,kw

#14 "nicotine replacement therapy" or NRT

#15 (nicotin*) NEAR3 (gum or patch or inhal* or nasal* or spray or lozenge* or polacrilex or agonist* or vaccin*)

#16 Varenicline

#17 Champix

#18 Chantix

#19 Bupropion

#20 Zyban

#21 Nortriptyline

#22 Nortrilen

#23 (nicotin* or tobacco or smok* or cigarette*) NEAR5 (antidepressant*)

#24 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23

#25 #6 and #24

NOTE: The Airways Register is maintained in specialist software developed for The Cochrane Collaboration; the CRS (Cochrane Register of Studies). Line #4 in the strategy denotes the field in the CRS reference record in which the record has been coded for condition, in this case, COPD.

Contributions of authors

EVE wrote the protocol and will be the guarantor of the review. RMVDM and DK gave detailed comments on the draft protocol. Furthermore, AAR and CPVS gave comments on the draft protocol.

Declarations of interest

CPVS received unrestricted grants for nicotine addiction studies in both primary care and public health. DK received an unrestricted grant from Pfizer for a trial on the effectiveness of practice nurse counselling and varenicline for smoking cessation in primary care.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • SBOH, Netherlands.

    The employer for family doctor trainees in the Netherlands provided the salary for the first review author.