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Correspondence |

What Justifies a Placebo-Controlled Trial of Varenicline for Smoking Cessation in Patients With COPD? FREE TO VIEW

Daniel Kotz, PhD; Onno C. P. van Schayck, PhD
Author and Funding Information

From the Department of General Practice, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre.

Correspondence to: Daniel Kotz, PhD, Department of General Practice, CAPHRI School for Public Health and Care, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, Maastricht, The Netherlands; e-mail: d.kotz@maastrichtuniversity.nl


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Funding/Support: Drs Kotz and van Schayck have received an unrestricted grant from Pfizer for a study on varenicline. Dr van Schayck has received honoraria from Pfizer for participation in speaking activities.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(4):968-969. doi:10.1378/chest.10-2919
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In a recent issue of CHEST (March 2011), Tashkin et al1 present results of a double-blind, placebo-controlled, two-arm trial of varenicline for smoking cessation in patients with COPD. The question arises: Why was a trial conducted in which varenicline was compared only with a placebo (and not with another active smoking cessation drug) in this patient group?

According to article 32 of the World Medical Association’s Ethical Principles for Medical Research Involving Human Subjects, “the effectiveness of a new intervention must be tested against those of the best current proven intervention.”2 The use of a placebo is only acceptable in studies in which no current proven intervention exists. However, nicotine replacement therapy and bupropion were available interventions recommended by international evidence-based guidelines as first-line pharmacologic treatments for smoking cessation in patients with respiratory disease.3 For example, an earlier trial in patients with COPD, notably, conducted by Tashkin et al4 as well, had shown that smokers who received bupropion for smoking cessation achieved higher continuous abstinence rates than smokers treated with placebo. Furthermore, two large-scale trials5,6 had clearly shown the greater benefit of varenicline compared with placebo and bupropion in the general smoking population—1 year before the current trial by Tashkin et al was initiated. The trial by Tashkin et al is the first to investigate the efficacy of varenicline in patients with COPD, but the authors do not provide compelling and scientifically sound methodologic reasons that justify the use of a placebo control instead of existing evidence-based smoking cessation medication. They only state that smokers with COPD have higher levels of nicotine dependence and are “more resistant to smoking cessation interventions” than smokers without COPD, but this is true for other subtypes of smokers as well, for example smokers with a lower socioeconomic background.

Two-arm placebo-controlled trials should no longer be conducted because they do not provide sufficient information on the effectiveness and safety of a new smoking cessation drug in relation to existing drugs. Given the evidence base of available pharmacologic aids for smoking cessation, future trials with varenicline (or other drugs) that provide good reasons for using a placebo as a comparator should at least incorporate a third study arm in which the best alternative pharmacologic treatment of smoking cessation is administered. However, a search of international registers (http://apps.who.int/trialsearch) shows that several trials are still recruiting smokers into two-arm placebo-controlled trials with varenicline (for example trials in patients with depression, schizophrenia, bipolar disorder, and HIV) and trials in smokers receiving alternative dosing schedules and varenicline for relapse prevention. Researchers, medical ethics committees, and regulatory authorities should keep in mind that the health of smokers in a placebo group is at stake. Smokers from the placebo group have a decreased chance of successful quitting, and each unsuccessful attempt increases the risk of smoking-related disease and reduced life expectancy, especially in a vulnerable group like patients with COPD.

Other contributions: We thank Jenny Fidler for her comments on a draft of this letter.

Tashkin DP, Rennard S, Hays JT, Ma W, Lawrence D, Lee TC. Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial. Chest. 2011;1393:591-599. [CrossRef] [PubMed]
 
World Medical AssociationWorld Medical Association WMA Declaration of Helsinki- ethical principles for medical research involving human subjects. WMA Web site.http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed October 26, 2010.
 
Tønnesen P, Carrozzi L, Fagerström KO, et al. Smoking cessation in patients with respiratory diseases: a high priority, integral component of therapy. Eur Respir J. 2007;292:390-417. [CrossRef] [PubMed]
 
Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo-controlled, randomised trial. Lancet. 2001;3579268:1571-1575. [CrossRef] [PubMed]
 
Jorenby DE, Hays JT, Rigotti NA, et al; Varenicline Phase 3 Study Group Varenicline Phase 3 Study Group Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;2961:56-63. [CrossRef] [PubMed]
 
Gonzales D, Rennard SI, Nides M, et al; Varenicline Phase 3 Study Group Varenicline Phase 3 Study Group Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;2961:47-55. [CrossRef] [PubMed]
 

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References

Tashkin DP, Rennard S, Hays JT, Ma W, Lawrence D, Lee TC. Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial. Chest. 2011;1393:591-599. [CrossRef] [PubMed]
 
World Medical AssociationWorld Medical Association WMA Declaration of Helsinki- ethical principles for medical research involving human subjects. WMA Web site.http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed October 26, 2010.
 
Tønnesen P, Carrozzi L, Fagerström KO, et al. Smoking cessation in patients with respiratory diseases: a high priority, integral component of therapy. Eur Respir J. 2007;292:390-417. [CrossRef] [PubMed]
 
Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo-controlled, randomised trial. Lancet. 2001;3579268:1571-1575. [CrossRef] [PubMed]
 
Jorenby DE, Hays JT, Rigotti NA, et al; Varenicline Phase 3 Study Group Varenicline Phase 3 Study Group Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;2961:56-63. [CrossRef] [PubMed]
 
Gonzales D, Rennard SI, Nides M, et al; Varenicline Phase 3 Study Group Varenicline Phase 3 Study Group Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;2961:47-55. [CrossRef] [PubMed]
 
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