Evidence map›Paper›PMID 25588294›Full record

Trial reportThe Lancet. Respiratory medicine2015

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.

Caryn Lerman, Robert A Schnoll, Larry W Hawk, Paul Cinciripini, Tony P George, E Paul Wileyto, Gary E Swan, Neal L Benowitz, Daniel F Heitjan, Rachel F Tyndale and 1 more

2 registry-linked trialsOpen access · greenAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The Lancet. Respiratory medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 203 papers, 11 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
203citing papers in PubMed, 11 pooled it
20.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01314001 phase3completednot on this map

Pharmacogenetics of Nicotine Addiction Treatment (PNAT)

TypeinterventionalSponsorUniversity of PennsylvaniaRan2010 to 2014Enrolled1,246ConditionsNicotine AddictionArmsVarenicline, Placebo, Transdermal Nicotine
NCT03227679 nacompletednot on this mapstarted 2016, after this paper: background citation

Metabolism-informed Care for Smoking Cessation

TypeinterventionalSponsorVanderbilt University Medical CenterRan2016 to 2017Enrolled82ConditionsTobacco Use, Tobacco Use CessationArmsNicotine Metabolite Ratio, Varenicline, Bupropion, Nicotine patch
3 · Its place in the literature

Who cites it

203 citing papers in PubMed, 11 syntheses or guidelines pooled it, 296 citations in OpenAlex.

  1. Guideline
  2. Nicotine receptor partial agonists for smoking cessation.The Cochrane database of systematic reviews · 2023
    Pooled it
  3. The Promise of Polygenic Risk Prediction in Smoking Cessation: Evidence From Two Treatment Trials.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2022
    Pooled it
  4. Pooled it
  5. Pooled it
  6. Pooled it
  7. Pooled it
  8. Nicotine replacement therapy versus control for smoking cessation.The Cochrane database of systematic reviews · 2018
    Pooled it
  9. Pooled it
  10. Pooled it
  11. Sex Differences in Varenicline Efficacy for Smoking Cessation: A Meta-Analysis.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2016
    Pooled it
  12. Trial
  13. Daily Cigarette Abstinence and Smoking Rate With Varenicline: Relationships With Treatment, Craving, and Affect During the First Week of the Quit Attempt.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2025
    Trial
  14. Trial
  15. Trial
  16. Trial
  17. Trial
  18. Trial
  19. Trial
  20. Relationships Between the Nicotine Metabolite Ratio and Laboratory Assessments of Smoking Reinforcement and Craving Among Adults in a Smoking Cessation Trial.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2024
    Trial

143 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 6 institutions in 2 countries.

Caryn LermanDepartment of Psychiatry, Annenberg School for Communication, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: clerman@upenn.edu.
Robert A SchnollDepartment of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Larry W HawkDepartment of Psychology, University at Buffalo, SUNY, Buffalo, NY, USA.
Paul CinciripiniDepartment of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Tony P GeorgeCentre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
E Paul WileytoDepartment of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
Gary E SwanDepartment of Medicine, Stanford University, Palo Alto, CA, USA.
Neal L BenowitzDepartments of Medicine, and Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA, USA.
Daniel F HeitjanDepartment of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
Rachel F TyndaleCentre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
PGRN-PNAT Research Group
University of Pennsylvania · USUniversity of Toronto · CAStanford University · USThe University of Texas MD Anderson Cancer Center · USUniversity at Buffalo, State University of New York · USUniversity of California, San Francisco · US

Funding

UNIVERSITY OF PENNSYLVANIA CAN CTR SUPPORT GRANTP30CA016520 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Robert H. Vonderheide · 1985 to 2026
$222.3M
University of Toronto Coordinating Genetics Core & Clinical Trial SiteU01DA020830 · NIDA · UNIVERSITY OF PENNSYLVANIA · PI CONTI, DAVID V · 2005 to 2014
$22.4M
Cognitive and Behavioral Effects of Sleep Restriction in Adolescents with ADHDR03MH109787 · NIMH · CINCINNATI CHILDRENS HOSP MED CTR · PI BECKER, STEPHEN P · 2016 to 2017
$156k
Canadian Institutes of Health Research TMH109787NCI NIH HHS P30 CA016520NCI NIH HHS P30 CA16520NIDA NIH HHS U01 DA020830NIDA NIH HHS U01-DA20830NIMH NIH HHS R03 MH109787
6 · The paper itself

Abstract

backgroundSubstantial 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.

methodsWe 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.

findings1246 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).

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

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

Indexed as

Tobacco Use Cessation DevicesAdultBiomarkersCotinineFemaleHumansMaleMiddle AgedNicotineNicotinic AgonistsSmoking CessationTreatment OutcomeVareniclineBiomarkersCotininehydroxycotinineNicotineNicotinic AgonistsVarenicline

Identifiers

PMID25588294
PMCPMC4480925
OpenAlexW1984116490

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.