Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database

PLoS One. 2017 Jul 21;12(7):e0182045. doi: 10.1371/journal.pone.0182045. eCollection 2017.

Abstract

Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3-71.4), 29.1 (23.5-35.9), 42.9 (32.3-57.0), 44.7 (32.7-61.1), and 38.6 (26.3-56.7), respectively. The medians (25%-75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3-314.0), 128.0 (27.0-279.0), 204.0 (44.0-660.0), 142.0 (41.3-344.0), and 16.5 (8.8-32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.

MeSH terms

  • Adolescent
  • Adult
  • Adverse Drug Reaction Reporting Systems
  • Androstenes / administration & dosage
  • Androstenes / adverse effects
  • Child
  • Contraceptives, Oral, Combined / administration & dosage
  • Contraceptives, Oral, Combined / adverse effects
  • Databases, Factual
  • Desogestrel / administration & dosage
  • Desogestrel / adverse effects
  • Drug-Related Side Effects and Adverse Reactions / genetics*
  • Estrogens / administration & dosage*
  • Estrogens / adverse effects*
  • Ethinyl Estradiol / administration & dosage
  • Ethinyl Estradiol / adverse effects
  • Female
  • Humans
  • Japan
  • Levonorgestrel / administration & dosage
  • Levonorgestrel / adverse effects
  • Male
  • Middle Aged
  • Norethindrone / administration & dosage
  • Norethindrone / adverse effects
  • Norgestrel / administration & dosage
  • Norgestrel / adverse effects
  • Odds Ratio
  • Progestins / administration & dosage*
  • Progestins / adverse effects*
  • Thromboembolism / chemically induced*
  • Young Adult

Substances

  • Androstenes
  • Contraceptives, Oral, Combined
  • Estrogens
  • Progestins
  • Norgestrel
  • Ethinyl Estradiol
  • Levonorgestrel
  • Desogestrel
  • drospirenone
  • Norethindrone

Grants and funding

This research was partially supported by JSPS KAKENHI Grant Number, 24390126 and 17K08452. JA was an employee of Medical Database Co., LTD during the time of the study and received a salary. The specific roles of these authors are articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.