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Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial

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Summary

Background

Substantial variability exists in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimise treatment choice for individual smokers might improve treatment outcomes. We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3′-hydroxycotinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation.

Methods

We undertook NMR-stratified multicentre, randomised, placebo-controlled clinical trial from Nov 16, 2010, to Sept 12, 2014, at four sites. Smokers seeking treatment were randomly assigned by baseline NMR status and study site, in blocks of 12 patients (1:1:1 ratio), to 11 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioural counselling. Participants and investigators were masked to group allocation and NMR status. An intention-to-treat analysis was done. Participants were followed up for 12 months after the target quit date. The primary endpoint was biochemically verified 7 day point prevalence abstinence at the end of treatment to estimate the pharmacological effect of treatment by NMR. The trial is registered at ClinicalTrials.gov, number NCT01314001.

Findings

1246 participants (662 slow metabolisers of nicotine, 584 normal metabolisers of nicotine) were enrolled and randomly assigned to the three interventions (408 placebo, 418 nicotine patch, 420 varenicline). At end of treatment, varenicline was more efficacious than nicotine patch in normal metabolisers (OR 2·17, 95% CI 1·38–3·42; p=0·001), but not in slow metabolisers (OR 1·13, 0·74–1·71; p=0·56). In the longitudinal model including all timepoints, the NMR-by-treatment interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11–3·46; p=0·02). An NMR-by-treatment interaction showed that slow (vs normal) metabolisers reported greater overall side-effect severity with varenicline versus placebo (β=–1·06, 95% CI −2·08 to −0·03; p=0·044).

Interpretation

Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects.

Funding

National Institutes of Health, Canadian Institutes of Health Research, Abramson Cancer Center, Centre for Addiction and Mental Health Foundation, and Pennsylvania Department of Health.

Introduction

Despite substantial reductions in tobacco use since the 1960s, rates of tobacco use have remained stable in the USA for the past decade1 and have increased in low-income countries.2 Worldwide, about 6 million annual deaths are attributable to tobacco use,2 and US$200 billion is spent on tobacco-related health-care costs.3 Smoking cessation treatments approved by the US Food and Drug Administration include nicotine replacement therapies, bupropion, and varenicline. Although transdermal nicotine patch is the safest and most widely used form of pharmacotherapy in the USA and Europe,4 end-of-treatment quit rates in clinical trials rarely exceed 30%.5 The efficacy of nicotine patch is comparable with bupropion,6 but could be lower than varenicline.7, 8 However, varenicline's efficacy might be offset by the greater likelihood of side-effects.9 The substantial individual variability in therapeutic response and side-effects provides a strong rationale to validate novel biomarkers to optimise pharmacotherapy choice.10

We identified a genetically informed biomarker of nicotine clearance, specifically the ratio of two metabolites derived from nicotine during smoking, 3′-hydroxycotinine and cotinine, referred to as the nicotine-metabolite ratio (NMR). The NMR reflects the activity of the liver enzyme CYP2A6, the major nicotine-metabolising and cotinine-metabolising enzyme. A substantial advantage of the NMR over CYP2A6 genotyping is that it incorporates both genetic and environmental (eg, oestrogen) effects on CYP2A6 activity and nicotine clearance.11 Retrospective analyses of previous randomised trials have shown that slow metabolisers (lower NMR values and rates of nicotine clearance) respond well to nicotine patch, with no incremental benefit from the non-nicotine replacement therapy medication bupropion; normal metabolisers do more poorly than slow metabolisers on nicotine patch, but benefit from bupropion.12, 13, 14, 15 To date, no study has examined whether the NMR predicts the efficacy of varenicline, a widely used non-nicotine replacement therapy medication that is more efficacious than bupropion.16, 17

To translate these findings to practice, we did the first NMR-stratified placebo-controlled randomised trial of nicotine patch versus varenicline among 1246 smokers. Although CYP2A6 does not contribute to varenicline metabolism, previous bupropion trial data14 suggested that a non-nicotine replacement therapy medication would aid quitting among normal metabolisers. Among normal metabolisers, we expected varenicline to be more efficacious than nicotine patch, whereas among slow metabolisers, we expected nicotine patch and varenicline to be equally efficacious.

Section snippets

Study design and participants

We randomly assigned participants by NMR group to one of three treatment groups: placebo (placebo pill plus placebo patch); nicotine patch (placebo pill plus active patch); or varenicline (active pill plus placebo patch) (figure 1). Our primary aim was to compare the efficacy of nicotine patch versus varenicline by NMR group (normal metabolisers vs slow metabolisers). A placebo condition was included to examine side-effects of treatment by NMR group.

We undertook the clinical trial at four

Results

Retention rates at end of treatment exceeded 70% and retention did not vary across treatment groups or NMR group (figure 1). The treatment groups did not differ on demographic and smoking history variables (table 1). Slow metabolisers were younger (p=0·02), less likely to be white (p<0·0001), more likely to be male (p=0·001), and smoked fewer cigarettes per day (p<0·001), versus normal metabolisers, as reported previously.27 Sex differences in the NMR groups are expected because of oestrogen

Discussion

In this biomarker-stratified randomised clinical trial, varenicline was better than nicotine patch for normal metabolisers, but had equivalent efficacy for slow metabolisers. Slow metabolisers, but not normal metabolisers, reported more overall side-effects on varenicline (vs placebo). Although slow metabolisers were oversampled to be about 50% of the intention-to-treat sample, 40% of smokers attending the study intake were classified as slow metabolisers by the 0·31 cutpoint (appendix). Thus,

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