title: Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy.
abstract: BACKGROUND
  Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects.
  
  
  OBJECTIVE
  To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only.
  
  
  METHODS
  This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics.
  
  
  RESULTS
  The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92).
  
  
  CONCLUSIONS
  For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA.
  
  
  BACKGROUND
  This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript.
authors.affiliation: 1 Global Health Economics and Outcomes Research, Abbvie, North Chicago, Illinois.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Soliman
authors.affiliation: 2 Truven Health Analytics, Ann Arbor, Michigan.
authors.forename: Machaon
authors.initials: M
authors.lastname: Bonafede
authors.affiliation: 2 Truven Health Analytics, Ann Arbor, Michigan.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Farr
authors.affiliation: 1 Global Health Economics and Outcomes Research, Abbvie, North Chicago, Illinois.
authors.forename: Jane
authors.initials: J
authors.lastname: Castelli-Haley
authors.affiliation: 3 Georgetown University School of Medicine, Washington, DC.
authors.forename: Craig
authors.initials: C
authors.lastname: Winkel
mesh_terms: D000328:Adult; D015519:Bone Density / Q000187:drug effects; D004359:Drug Therapy, Combination / Q000379:methods; D004715:Endometriosis / Q000188:drug therapy*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D038801:International Classification of Diseases; D016729:Leuprolide / Q000627:therapeutic use*; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077563:Norethindrone Acetate; D012189:Retrospective Studies; D016903:Drug Monitoring
chemical_list: D004967:Estrogens; D007987:Gonadotropin-Releasing Hormone; D000077563:Norethindrone Acetate; D016729:Leuprolide; D009640:Norethindrone