title: Drospirenone and non-fatal venous thromboembolism: is there a risk difference by dosage of ethinyl-estradiol?
abstract: BACKGROUND
  Previous studies concluded that there was an increased risk of non-fatal venous thromboembolism (VTE) with drospirenone. It is unknown whether the risk is differential by ethinyl-estradiol dosage.
  
  
  OBJECTIVE
  To assess the risk of VTE with drospirenone and to determine whether drospirenone and ethinyl-estradiol 20 μg (DRSP/EE20) has a lower VTE risk than drospirenone and ethinyl-estradiol 30 μg (DRSP/EE30).
  
  
  METHODS
  Our cohort included women aged 18-46 years taking drospirenone or levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in the IMS claims database between 2001 and 2009. VTE was defined using ICD-9-CM coding and anticoagulation. The hazard ratio (HR) from Cox proportional hazards models was used to assess the VTE relative risk (RR) with drospirenone compared with levonorgestrel, adjusted by a propensity score used to control for baseline co-morbidity and stratified by EE dosage and user-type (new/current).
  
  
  RESULTS
  The study included 238 683 drospirenone and 193,495 levonorgestrel users. Among new and current users, a 1.90-fold (95% CI, 1.51-2.39) increased VTE relative risk was observed for drospirenone (18.0 VTE/10,000 women-years) vs. levonorgestrel (8.9 VTE/10,000 women-years). In analysis of new users, DRSP/EE20 had a 2.35-fold (95% CI, 1.44-3.82) VTE RR versus LNG/EE20. New users of DRSP/EE30 observed an increased RR versus LNG/EE30 among women starting to use COCs between 2001 and 2006 (2.51, 95% CI, 1.12-5.64) but not between 2007 and 2009 (0.76, 95% CI, 0.42-1.39), attributable to an increased incidence rate with LNG/EE30 from 2007 to 2009. In direct comparison, DRSP/EE20 had an elevated risk of VTE compared with DRSP/EE30 (RR, 1.55; 95% CI, 0.99-2.41).
  
  
  CONCLUSIONS
  We observed a modestly elevated risk of VTE with drospirenone, compared with levonorgestrel. The larger VTE incidence rate observed in DRSP/EE20 than in DRSP/EE30 and the increasing VTE incidence rate with levonorgestrel between 2007 and 2009 were unexpected.
authors.affiliation: Pharmaceutical Outcomes and Policy, College of Pharmacy and Epidemiology, University of Florida, Gainesville, FL 32611, USA. bird.steven@gmail.com
authors.forename: S T
authors.initials: ST
authors.lastname: Bird
authors.forename: J A C
authors.initials: JA
authors.lastname: Delaney
authors.forename: M
authors.initials: M
authors.lastname: Etminan
authors.forename: J M
authors.initials: JM
authors.lastname: Brophy
authors.forename: A G
authors.initials: AG
authors.lastname: Hartzema
mesh_terms: D000293:Adolescent; D000328:Adult; D000736:Androstenes / Q000009:adverse effects*; D015331:Cohort Studies; D003276:Contraceptives, Oral / Q000008:administration & dosage; D016208:Databases, Factual; D004997:Ethinyl Estradiol / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000009:adverse effects*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk; D013997:Time Factors; D014481:United States; D054556:Venous Thromboembolism / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000736:Androstenes; D003276:Contraceptives, Oral; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; C035144:drospirenone
keywords: Levonorgestrel; comparative study; contraception; drospirenone; venous thromboembolism