Varenicline for smoking cessation

The manufacturer's primary analysis compared the standard 12‑week course of varenicline with bupropion and nicotine replacement therapy (NRT). The manufacturer identified 4 randomised controlled trials (RCTs). Two were 3‑arm trials that compared varenicline, bupropion and placebo (n=1,483 and 1,413). Another trial compared maintenance treatment (24-week course of varenicline) with placebo (n=2,416). The manufacturer also presented data from an open-label trial (n=957) that compared varenicline with NRT.

The 2 trials that compared varenicline and bupropion showed that the continuous quit rate for weeks 9 to 12 was statistically significantly greater for varenicline: odds ratio (OR) 1.93 (95% CI 1.40 to 2.68) and OR 1.90 (95% CI 1.40 to 2.68), respectively. Both trials also showed that the continuous quit rate for varenicline was statistically significantly greater than for placebo: OR 3.85 (95% CI 2.70 to 5.50) and OR 3.85 (95% CI 2.69 to 5.50), respectively. For the longer time horizon of weeks 9 to 52, the ORs for varenicline compared with bupropion, respectively for the 2 trials, were 1.46 (95% CI 0.99 to 2.17) and 1.77 (95% CI 1.19 to 2.63). The maintenance trial that compared 24-week varenicline with placebo showed that the continuous quit rate was statistically significantly greater with varenicline than with placebo: weeks 13 to 24 OR 2.47 (95% CI 1.95 to 3.15); weeks 13 to 52 OR 1.35 (95% CI 1.07 to 1.70). The results of the open-label trial were marked confidential by the manufacturer.

The manufacturer also submitted a meta-analysis of 70 NRT trials, 12 bupropion trials and 4 varenicline trials against control or placebo. The meta-analysis indirectly compared the efficacy of the treatments based on relative treatment effects. This indirect comparison showed that at 12 months, varenicline was superior to NRT (OR 1.66 [CI 1.17 to 2.36]) and bupropion (OR 1.58 [95% CI 1.22 to 2.05]). Varenicline was also superior at 3 months to both NRT (OR 1.78 [95% CI 1.23 to 2.57]) and bupropion (OR 1.61 [95% CI 1.17 to 2.22]).

The manufacturer presented a cost-effectiveness analysis based on a Markov model. It assumes an individual makes a single quit attempt at the beginning of the model. The individual is followed from this initial quit attempt to various health states and potential comorbidities including lung cancer, asthma exacerbations, chronic obstructive pulmonary disease, stroke and cardiovascular disease. The probabilities of relapsing and developing comorbidities are assumed to decrease over time from smoking cessation. The efficacy rates for the treatments are calculated from the odds ratios derived from the results of the pooled direct clinical trials and the indirect comparison. The probabilities associated with relapse are derived from relative risks reported in US-based long-term longitudinal and cohort studies into smoking and abstinence. The costs and utilities are derived from several published sources. Some health-related utility estimates are based on US data, including baseline health-related utilities.

The base-case analysis showed that over a lifetime horizon varenicline dominated bupropion and NRT – that is, it was cheaper and more effective. Variation of the time horizon used in the analysis showed that, at 20 years and over, varenicline maintained its dominating position. Sensitivity analyses included altering baseline health-related utilities and costs of NRT, and the use of efficacy rates from the direct open-label trial that compared varenicline with NRT. Over a lifetime horizon varenicline dominated NRT and bupropion in all sensitivity analysis.

The ERG noted that the inclusion and exclusion criteria of the meta-analysis in the manufacturer's submission differed from existing analyses by the Cochrane collaboration and considered that they could overestimate the efficacy of varenicline. The ERG also conducted its own meta-analysis and indirect comparison which suggested that the odds ratio for varenicline in comparison with NRT was lower than in the manufacturer's model: OR 1.54 (95% CI 1.10 to 2.16).

The ERG noted that the assumptions included in the model could make external validity questionable. For example, it considered that the assumption of a single quit attempt was a limitation that did not allow consideration of the impact of subsequent quit attempts on costs, morbidity or mortality. In addition, the extrapolation of data on 1-year quit rates to a lifetime is associated with considerable uncertainty surrounding the long-term relapse or abstinence experience of the model cohort. The ERG noted that the use of indirect comparison in the base case was inappropriate given the availability of direct trial evidence. The ERG further identified some computational errors in the calculation of transition probabilities and population calculations. The ERG commented that the method used to convert odds ratios to efficacy rates was not validated and a model constructed around odds ratios would have been more appropriate. The ERG compared the number of life years gained in the model with the results of 2 published analyses and found no substantial differences.

Full details of all the evidence are in the manufacturer's submission and the ERG report.

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of varenicline, having considered evidence on smoking cessation and the value placed on the benefits of varenicline by people who smoke tobacco products and want to quit, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee considered the clinical effectiveness evidence presented by the manufacturer. It concluded that the evidence from the direct trials and the systematic reviews carried out by the manufacturer and ERG demonstrated that varenicline was superior to NRT and bupropion in achieving continuous abstinence. The Committee heard from the clinical specialists and patient experts that the success rates with varenicline made it a useful addition to the variety of interventions available in smoking cessation, particularly because many smokers need to make multiple quit attempts. The availability of an additional treatment choice was mentioned by clinical specialists and patient experts as beneficial to those having difficulty maintaining abstinence and avoiding relapse because it enabled them to have more control.

The Committee considered the evidence on the cost effectiveness of varenicline submitted by the manufacturer. The Committee noted the comments of the ERG that the submission was not transparent and possessed limited external validity. The model included an extrapolation of 1-year clinical data to a lifetime horizon and included an assumption of a single quit attempt. The Committee also noted the computational errors identified by the ERG, and noted that the ERG had expressed concerns about a number of other assumptions in the model, in particular the use of US data for baseline risk and the use of all-cause morbidity instead of other-cause morbidity. Nevertheless, the Committee considered that these concerns were not sufficient to undermine the inference that the use of varenicline in smoking cessation was likely to be a cost-effective use of NHS resources.

The Committee heard from clinical specialists about the importance of counselling and support in smoking cessation to reinforce the commitment required to quit smoking. It noted that varenicline had been provided alongside counselling and support in the clinical trials. However, the Committee also heard from the clinical specialists that counselling and support are not always used by people aiming to stop smoking and that pharmacotherapies can be effective in the absence of such programmes. The Committee concluded that varenicline should normally be provided in conjunction with counselling and support, but that if such support is refused or is not available, this should not preclude treatment with varenicline.