title: Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison.
abstract: OBJECTIVE
  To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events.
  
  
  METHODS
  Systematic review, meta-analysis, and indirect comparisons.
  
  
  METHODS
  Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar.
  
  
  METHODS
  Randomized trials of clopidogrel, prasugrel, or ticagrelor that examined clinical outcomes among subgroups of smokers and nonsmokers.
  
  
  METHODS
  Two authors independently extracted all data, including information on the patient populations included in the trials, treatment types and doses, definitions of clinical outcomes and duration of follow-up, definitions of smoking subgroups and number of patients in each group, and effect estimates and 95% confidence intervals for each smoking status subgroup.
  
  
  RESULTS
  Of nine eligible randomized trials, one investigated clopidogrel compared with aspirin, four investigated clopidogrel plus aspirin compared with aspirin alone, and one investigated double dose compared with standard dose clopidogrel; these trials include 74,489 patients, of whom 21,717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers.
  
  
  CONCLUSIONS
  In randomized clinical trials of antiplatelet drugs, the reported clinical benefit of clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke was seen primarily in smokers, with little benefit in nonsmokers.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gagne
authors.forename: Katsiaryana
authors.initials: K
authors.lastname: Bykov
authors.forename: Niteesh K
authors.initials: NK
authors.lastname: Choudhry
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Toomey
authors.forename: John G
authors.initials: JG
authors.lastname: Connolly
authors.forename: Jerry
authors.initials: J
authors.lastname: Avorn
mesh_terms: D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control / Q000523:psychology; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D010043:Outcome and Process Assessment, Health Care; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects* / Q000453:epidemiology
chemical_list: D010975:Platelet Aggregation Inhibitors
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