title: Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis.
abstract: BACKGROUND
  Chronic smoking, theoretically, can interfere with warfarin metabolism through enzyme-inducing effects of polycyclic aromatic hydrocarbons. However, clinical evidence of interactions between warfarin and smoking are inconclusive. This study aimed to systematically review all relevant clinical evidence of this interaction.
  
  
  METHODS
  We performed a systematic search using computerized databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Allied and Complementary Medicine, PsycINFO, International Pharmaceutical Abstracts, and ClinicalTrials.gov from 1966 to December 2008. Keywords included "warfarin" with "smoking," "tobacco," "cigarette," and "polycyclic aromatic hydrocarbons." Original articles reporting interaction between warfarin and smoking were included. All articles were reviewed independently by two investigators for study design, population, outcomes, and quality of evidence.
  
  
  RESULTS
  Of the 1,240 studies retrieved, one experimental pharmacokinetic study and 12 cross-sectional studies were included. The pooled analyses of multivariate studies suggested that smoking was associated with a 12.13% (95% CI, 6.999-17.265; P < .001) increase in warfarin dosage requirement and an additional 2.26 mg (95% CI, 2.529-7.042; P = .355) per week compared with nonsmoking. Additional sensitivity analysis of four multivariate studies with adjustment for pharmacogenomic factors suggested that smoking was associated with a 13.21% (95% CI, 8.59%-17.83%; P < .001) increase in warfarin dosage requirement compared with nonsmokers. Results of an experimental pharmacokinetic study lend theoretical support to the findings.
  
  
  CONCLUSIONS
  Evidence suggests that smoking may potentially cause significant interaction with warfarin by increasing warfarin clearance, which leads to reduced warfarin effects. Close monitoring of warfarin therapy should be instituted when there is a change in smoking status of patients requiring warfarin therapy.
authors.affiliation: Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
authors.forename: Surakit
authors.initials: S
authors.lastname: Nathisuwan
authors.affiliation: Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
authors.forename: Piyameth
authors.initials: P
authors.lastname: Dilokthornsakul
authors.affiliation: Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; School of Population Health, University of Queensland, Brisbane, QLD, Australia; School of Pharmacy, University of Wisconsin, Madison, WI. Electronic address: chaiyakunapr@wisc.edu.
authors.forename: Nathorn
authors.initials: N
authors.lastname: Chaiyakunapruk
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
authors.forename: Tatiya
authors.initials: T
authors.lastname: Morarai
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
authors.forename: Thararat
authors.initials: T
authors.lastname: Yodting
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
authors.forename: Nichakorn
authors.initials: N
authors.lastname: Piriyachananusorn
mesh_terms: D000925:Anticoagulants / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D015999:Multivariate Analysis; D012907:Smoking / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D014859:Warfarin