This is the first systematic review of the long‐term effect of NRT in the treatment of tobacco dependence. Therefore, it provides the most reliable evidence to date that NRT aids in achieving the treatment goal of permanent smoking cessation. The odds ratio in favour of NRT at long‐term follow up was similar to that found after only 12 months, suggesting that the relative effect of NRT remains stable over time. The addition of NRT to the brief advice or behavioural support offered in the included studies gave an odds ratio of 2 and represents a 70–90% increase in the cessation rate achieved without NRT. However, since the long‐term success rate without NRT is extremely modest, these figures disguise the true overall impact of NRT which is similarly modest and represents success for only about 7% of all those treated in these trials.
The results show that an estimated 30% of those regarded as quitters after 12 months will subsequently relapse. Although this rate was similar for NRT and control arms, leaving the odds ratio essentially unchanged, it had the effect of reducing the benefit attributable to NRT in terms of the percentage of additional ex‐smokers. This attrition of continuing abstainers “closed the difference” between NRT and control rates simply by lowering both in equal proportions. Importantly, we could detect no greater relapse among trials with longer rather than shorter follow up, suggesting that most of the relapse after 12 months takes place in the following year or two. Further, it suggests that the effect of NRT estimated here is likely to be permanent and that studies with longer follow ups are unlikely to reveal further relapse. Although initially surprising, our results are supported by those modelled from the large cross‐sectional NHANES‐I population survey (National Health and Nutrition Examination Survey) of self‐help cessation attempts.25
This study observed an asymptote in relapse at five years, with only a very small, non‐detectable, change in survival rates between three and five years. The estimated 35% relapse rate after 12 months was similar to the rate in the current study. It should be noted, however, that late relapse is not specific to NRT but occurs as well for untreated smokers.27
All the trials included in our review are also included in the major meta‐analyses of NRT efficacy during the initial 6–12 months after the start of treatment.3,4
The odds ratio for NRT in the more recent Cochrane review is 1.77 (95% CI 1.66 to 1.88). The estimate for the 12 month results in the 12 long‐term trials (OR 1.99, 95% CI 1.50 to 2.64) is slightly larger and lies outside this confidence interval. However, confidence intervals for the two estimates have considerable overlap and there is no evidence of a difference between the two (Z
0.2). Although this cannot be regarded as evidence that the long‐term trials are a representative subset of all trials, it does suggest that the long‐term results, in essentially clinical settings, might also hold for the larger group of more diverse Cochrane trials where no long‐term follow‐ups are available, including those in community and over‐the‐counter (OTC) settings.
What this paper adds
There are now sufficient trials with follow‐ups beyond one year to give a good estimate of the long‐term benefit of nicotine replacement therapy (NRT). This study shows that results after only 6–12 months of follow‐up, as used in existing reviews and treatment guidelines, will overestimate the lifetime benefit and cost‐efficacy of NRT by about 30%. Because the long‐term benefit of NRT is modest, tobacco dependence treatment might be better viewed as a chronic, relapsing disorder requiring repeated episodes of treatment.
We found that small trials tended to have larger NRT effects leading to an asymmetric funnel plot. Using the “trim and fill” method, which attempts to impute the results of the “missing”, less effective, small trials marginally reduced the overall estimate. However, in this context bias detection and adjustment methods based on the assumption that the effect size will be similar in small and large trials may not be appropriate.9
Trials with smaller sample sizes tend to be conducted in specialist centres, where more intensive behavioural support is given and the adjunctive effect of NRT is consequently expected to be larger. Compared to larger trials in generalist settings, such as primary care, these trials may also exert more control over trial procedures, producing higher compliance with treatment and perhaps most importantly, successfully following up a higher proportion of participants over many years.23
Such factors may have contributed to a possibly false impression that some small trials with results similar to those in larger trials have not reached publication, when in fact they do not exist.
This review focused on the long‐term impact of the current “one‐shot” therapeutic approach to treatment with NRT and found significant but modest effects. Although such treatment is still likely to be highly cost‐effective in terms of life‐years gained,28
the substantial amount of relapse observed even after a year of abstinence, and the fact that more than 90% of those treated do not succeed, questions whether this therapeutic approach is the most appropriate. Our results support the notion that nicotine addiction, like others, should be viewed as a chronic recurring disease of the brain,29
and that its treatment should probably be closer to the long‐term treatment of other chronic diseases, such as hypertension, than that used for acute diseases like infections. For many smokers at least, a chronic, prolonged treatment is probably necessary and should include the encouragement to make repeated quit attempts accompanied with multiple treatment episodes over many years. To date, only one study has thoroughly investigated the effect of prolonged treatment on health outcomes. The results in terms of reducing smoking and morbidity have been encouraging.2