Original Article| Volume 79, P41-45, November 2016

Evidence of nicotine replacement's effectiveness dissolves when meta-regression accommodates multiple sources of bias



      To accommodate and correct identifiable bias and risks of bias among clinical trials of nicotine replacement therapy (NRT).

      Study Design and Setting

      Meta-regression analysis of a published Cochrane Collaboration systematic review of 122 placebo-controlled clinical trials.


      Both identified risks of bias and potential publication (or reporting or small sample) bias are associated with an increase in the reported effectiveness of NRT. Whenever multiple sources of biases are accommodated by meta-regression, no evidence of a practically notable or statistically significant overall increased rate of smoking cessation remains. Our findings are in stark contrast with the 50% to 70% increase in smoking cessation reported by the Cochrane Collaboration systematic review.


      After more than 100 randomized clinical trials have been conducted, the overall effectiveness of NRT is in doubt. Simple, well-established meta-regression methods can test, accommodate, and correct multiple sources biases, often mentioned but dismissed by conventional systematic reviews.


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        • Mokdad A.H.
        • Marks J.S.
        • Stroup D.F.
        • Gerberding J.L.
        Actual causes of death in the United States, 2000.
        JAMA. 2004; 291: 1238-1245
        • WHO
        WHO model list of essential medicines, 18th list.
        2013 (Available at) (Accessed March 15, 2015)
        • Stead L.F.
        • Perera R.
        • Bullen C.
        • Mant D.
        • Hartmann-Boyce J.
        • Cahill K.
        • et al.
        Nicotine replacement therapy for smoking cessation.
        Cochrane Database Syst Rev. 2012; (Review): CD000146
        • Higgins J.P.
        • Altman D.G.
        • Gøtzsche P.C.
        • Jüni P.
        • Moher D.
        • Oxman A.D.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Doucouliagos H.
        • Stanley T.D.
        Publication selection bias in minimum-wage research? A meta-regression analysis.
        Brit J Ind Relat. 2009; 47: 406-428
        • Egger M.
        • Smith G.D.
        • Scheider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 316: 629-634
        • Havranek T.
        Measuring intertemporal substitution: the importance of method choices and selective reporting.
        J Eur Econ Assoc. 2015; 13: 1180-1204
        • Stanley T.D.
        Meta-regression methods for detecting and estimating empirical effect in the presence of publication selection.
        Oxford B Econ Stat. 2008; 70: 103-127
        • Stanley T.D.
        • Doucouliagos H.
        Meta-regression analysis in economics and business.
        Routledge, Oxford2012
        • Stanley T.D.
        • Doucouliagos H.
        Meta-regression approximations to reduce publication selection bias.
        Res Synth Methods. 2014; 5: 60-78
        • Havranek T.
        Rose effect and the euro: is the magic gone?.
        R World Econ. 2010; 146: 241-261
        • Redmond S.
        • von Elm E.
        • Blümle A.
        • Gengler M.
        • Gsponer T.
        • Egger M.
        Cohort study of trials submitted to ethics committee identified discrepant reporting of outcomes in publications.
        J Clin Epidemiol. 2013; 66: 1367-1375
        • Moreno S.G.
        • Sutton A.J.
        • Ades A.E.
        • Stanley T.D.
        • Abrams K.R.
        • Peters J.L.
        • et al.
        Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study.
        BMC Med Res Methodol. 2009; 9: 2
        • Stanley T.D.
        • Jarrell S.B.
        • Doucouliagos H.
        Could it be better to discard 90% of the data? A statistical paradox.
        Am Stat. 2010; 64: 70-77
      1. Stanley TD, Doucouliagos H. Better than random: weighted least squares meta-regression analysis. Res Synth Methods, in press.

        • Stanley T.D.
        • Doucouliagos H.
        Neither fixed nor random: weighted least squares meta-analysis.
        Stat Med. 2015; 34: 2116-2127

      Linked Article

      • Is nicotine replacement really ineffective? A reply to Stanley and Massey
        Journal of Clinical EpidemiologyVol. 81
        • Preview
          Drs. Stanley and Massey [1] used a series of meta-regression analyses of the Cochrane Library review of nicotine replacement therapy (NRT) for smoking cessation [2,3] to estimate what the effectiveness of NRT would be if there were no publication, reporting, and small sample bias. They concluded NRT would not be effective. We believe this conclusion to be incorrect.
        • Full-Text
        • PDF
      • New insights into smoking cessation question the effectiveness of nicotine replacement therapy
        Journal of Clinical EpidemiologyVol. 79
        • Preview
          Stanley and Massey's [1] recent analysis of a Cochrane systematic review on smoking cessation is an important addition to the ongoing debate around the efficacy of nicotine replacement therapy (NRT) and other pharmaceutical interventions in helping smokers to quit. Proponents of NRT, including leading clinical and professional bodies in the United States [2], the United Kingdom [3], and Australia [4] base their position on randomized clinical trials (RCTs) which typically report that the use of pharmacotherapy increases cessation success rates, compared to placebo or no assistance, by as much as 50–70% [5].
        • Full-Text
        • PDF