title: Comparative Safety of Testosterone Dosage Forms.
abstract: OBJECTIVE
  Increases in testosterone use and mixed reports of adverse events have raised concerns about the cardiovascular safety of testosterone. Testosterone is available in several delivery mechanisms with varying pharmacokinetics; injections cause spikes in testosterone levels, and transdermal patches and gels cause more subtle but sustained increases. The comparative cardiovascular safety of gels, injections, and patches has not been studied.
  
  
  OBJECTIVE
  To determine the comparative cardiovascular safety of testosterone injections, patches, and gels.
  
  
  METHODS
  A retrospective cohort study was conducted using administrative claims from a commercially insured (January 1, 2000, to December 31, 2012) and Medicare (January 1, 2007, to December 31, 2010) population in the United States and general practitioner records from the United Kingdom (January 1, 2000, to June 30, 2012). Participants included men (aged ≥18 years) who initiated use of testosterone patches, gels, or injections following 180 days with no testosterone use. Our analysis was conducted from December 11, 2013, to November 12, 2014.
  
  
  METHODS
  New initiation of a testosterone dosage form, with use monitored for up to 1 year.
  
  
  METHODS
  Inpatient or outpatient medical records, diagnoses, or claims for cardiovascular and cerebrovascular events including myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization.
  
  
  RESULTS
  We identified 544,115 testosterone initiators between the 3 data sets: 37.4% injection, 6.9% patch, and 55.8% gel. The majority of men in the Medicare cohort were injection initiators (51.2%), most in the US commercially insured population were gel initiators (56.5%), and the UK database included equal proportions of injections and gel users (approximately 41%). With analysis conducted using hazard ratios and 95% CIs, compared with men using gels, injection initiators had higher hazards of cardiovascular events (ie, MI, unstable angina, and stroke) (1.26; 1.18-1.35), hospitalization (1.16; 1.13-1.19), and death (1.34; 1.15-1.56) but not VTE (0.92; 0.76-1.11). Compared with gels, patches did not confer increased hazards of cardiovascular events (1.10; 0.94-1.29), hospitalization (1.04; 1.00-1.08), death (1.02; 0.77-1.33), or VTE (1.08; 0.79-1.47).
  
  
  CONCLUSIONS
  Testosterone injections were associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels. Patches and gels had similar risk profiles. However, this study did not assess whether patients met criteria for use of testosterone and did not assess the safety of testosterone among users compared with nonusers of the drug.
authors.affiliation: Department of Epidemiology, The University of North Carolina at Chapel Hill.
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Layton
authors.affiliation: Department of Pharmaceutical Sciences, Basel University, Basel, Switzerland.
authors.forename: Christoph R
authors.initials: CR
authors.lastname: Meier
authors.affiliation: Department of Medicine, The University of North Carolina at Chapel Hill.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Sharpless
authors.affiliation: Department of Epidemiology, The University of North Carolina at Chapel Hill.
authors.forename: Til
authors.initials: T
authors.lastname: Stürmer
authors.affiliation: Department of Epidemiology, Boston University School of Public Health, Lexington, Massachusetts.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Jick
authors.affiliation: Department of Epidemiology, The University of North Carolina at Chapel Hill.
authors.forename: M Alan
authors.initials: MA
authors.lastname: Brookhart
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000728:Androgens / Q000008:administration & dosage* / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D005782:Gels; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013739:Testosterone / Q000008:administration & dosage* / Q000009:adverse effects*; D057968:Transdermal Patch
chemical_list: D000728:Androgens; D005782:Gels; D013739:Testosterone