The authors concluded that nicotine replacement therapy, bupropion and varenicline are effective methods for aiding smoking cessation. The conclusion of this well-conducted and clearly reported review is likely to be reliable, but the reliance on published studies may mean that treatment effects have been overestimated.

To evaluate the efficacy of nicotine replacement therapy (NRT), bupropion and varenicline in improving smoking cessation rates.

MEDLINE, EMBASE, the Cochrane CENTRAL Register, AMED, CINAHL, TOXNET, DART (Development and Reproductive Toxicology), Hazardous Substances Data Bank, PsycINFO, Web of Science, Ovid, ScienceDirect and Ingenta were searched from inception to September 2006. No language restrictions were applied. Only published studies were eligible.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) of at least 1 year' duration were eligible for inclusion in the review.

Specific interventions included in the review

Studies that evaluated any method of delivery of NRT, bupropion or varenicline for smoking cessation were eligible for inclusion. Studies of maintenance therapy were excluded. Most of the included NRT studies evaluated NRT gum or NRT patches; other NRT studies evaluated nicotine inhalers, nasal sprays and lozenges, or a combination of these. Other studies evaluated bupropion sustained release (100 to 300 mg/day) and varenicline (0.3 to 300 mg/day). The control interventions included placebo, no treatment and other pharmacological agents. The duration of treatment, where reported, ranged from 2 weeks to 24 months.

Participants included in the review

It was clear that male and female smokers of any age were included in the review. Where reported, the participants in the included NRT studies had been smoking 1 or more to 25 or more cigarettes per day for between 1 week and 33 years.

Outcomes assessed in the review

Studies that used chemical methods to confirm smoking cessation at 1 year were eligible for inclusion. The secondary review outcomes were smoking cessation at 3 months (or the closest time point) after the start of treatment and adverse effects. Studies had to report either sustained abstinence at the given time periods or point-prevalence of abstinence; in the review, sustained abstinence was preferred where possible. Studies that presented self-reported outcomes were excluded.

How were decisions on the relevance of primary studies made?

Two reviewers independently selected the studies.

Two reviewers independently assessed validity and resolved any differences through discussion. The studies were assessed for allocation concealment, generation of randomisation sequence, blinding, intention-to treat (ITT) analysis and reporting of losses to follow-up.

Two reviewers independently extracted the data and resolved any differences through discussion. For each study, the number of abstinent patients was extracted and used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Where zero events were reported for any treatment arm, the value 1 was added.

How were the studies combined?

The studies were grouped by type of pharmacological intervention and within this by control. Pooled ORs with 95% CIs were calculated using a random-effects model (DerSimonian and Laird).

How were differences between studies investigated?

Statistical heterogeneity was examined using forest plots and assessed using the I-squared statistic. Meta-regression was used to examine the effects of the following variables: placebo control; reporting of sequence generation method; reporting of allocation concealment; use of gum or patch and method of chemical confirmation of smoking cessation for NRT studies; and plans to quit for bupropion studies. When heterogeneity was indicated, differences in treatment effects between studies reporting covariates and all studies were tested using z-tests. The interventions were compared directly where head-to-head studies were found, otherwise they were compared indirectly.

Seventy RCTs evaluated NRT versus control (n=28,343). Twelve RCTs evaluated bupropion (n=5,228). Four RCTs provided data on varenicline (n=2,528).

NRT (70 studies).

Study quality: sequence generation methods were reported in 22 studies, allocation concealment in 11 studies, blinding status in 64 studies, appropriate blinding in 45 studies, ITT analysis in 67 studies and appropriate description of follow-up in 44 studies. NRT significantly improved smoking cessation rates at 1 year compared with any control (OR 1.71, 95% CI: 1.55, 1.88, p<0.0001; I-squared 26.5%, heterogeneity p=0.02). The results were similar for NRT versus placebo only studies (OR 1.78, 95% CI: 1.60, 1.99, p<0.0001; 49 studies; I-squared 27.4%, heterogeneity p=0.04), NRT gum (OR 1.60, 95% CI: 1.37, 1.86, p<0.0001; 33 studies; I-squared 35.8%, heterogeneity p=0.02) and NRT patch (OR 1.63, 95% CI: 1.41, 1.89, p<0.0001; 23 studies; I-squared 12.3%, heterogeneity p=0.24).

Bupropion (12 studies).

Study quality: sequence generation methods were reported in 4 studies, allocation concealment in 4 studies, blinding status in 11 studies, ITT analysis in 12 studies and appropriate description of follow-up in 10 studies.

Bupropion significantly improved smoking cessation rates at 1 year compared with any control (OR 1.56, 95% CI: 1.10, 2.21, p=0.01; I-squared 71.5%, heterogeneity p<0.001).

Varenicline (4 studies).

Apart from one study that did not report the method of sequence generation, studies met all methodological criteria.

Varenicline significantly improved smoking cessation rates at 1 year compared with placebo (OR 2.96, 95% CI: 2.12, 4.12, p<0.0001; I-squared 20.5%, heterogeneity p=0.20).

Comparisons between pharmacological therapies.

Direct comparisons.

There was no statistically significant difference in smoking cessation rates at 1 year between bupropion and NRT (OR 1.14, 95% CI: 0.20, 6.42, p=0.88; 2 studies, n=548; I-squared 59%, heterogeneity p=0.11). Varenicline significantly improved smoking cessation rates at 1 year compared with bupropion (OR 1.58, 95% CI: 1.22, 2.05, p=0.001; 3 studies; I-squared 0%, heterogeneity p=0.81).

Indirect comparisons.

There was no significant difference in smoking cessation rates at 1 year between bupropion and NRT (OR 0.92, 95% CI: 0.64, 1.32, p=0.65). Varenicline was associated with significantly improved smoking cessation rates at 1 year than NRT when compared with placebo controls (OR 1.66, 95% CI: 1.17, 2.36, p=0.0004) or to all controls (OR 1.73, 95% CI: 1.22, 2.45, p=0.001).

Adverse effects were not systematically different across studies. Other results were also reported.

NRT, bupropion and varenicline are effective methods for aiding smoking cessation.

The review addressed a clear question that was defined in terms of the intervention, outcomes and study design. A considerable number of sources were searched and some attempts were made to minimise language bias. No attempt was made to locate unpublished studies, thus raising the possibility of publication bias, as the authors acknowledged. Validity was assessed using specified criteria and the results of this assessment were reported. Methods were used to minimise reviewer errors and bias in the study selection, validity assessment and data extraction processes.

The results were based on valid smoking cessation measures. The studies were combined using meta-analysis, statistical heterogeneity was assessed, and the effects of various predefined variables on treatment effects were examined. Significant heterogeneity was found for some meta-analyses but the direction of treatment effect appeared consistent among studies. The methods used to compare the relative efficacy of active treatments seemed appropriate, although it should be noted that there were few direct comparisons. The review was reasonably well conducted and reported and the authors' conclusions are likely to be reliable. However, the fact remains that the review was based exclusively on published studies, which may mean that treatment effects have been overestimated.

Practice: The authors did not state any implications for practice. Research: The authors stated that since NRT, bupropion and varenicline have different mechanisms of action, future studies could evaluate combinations of these agents. Studies could also further evaluate the effects of these agents on morbidity and mortality in patients with active smoking-related diseases. There is also a need for further studies that compare varenicline with NRT or bupropion.

Pfizer Global Solutions; Canadian Institutes of Health Research.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.