Birth Control Pill vs Birth Control Patch Study
Condition: Venous Thrombosis
MeSH terms: Thrombosis; Venous Thrombosis
Study type: Interventional

Summary: 
      This study was a randomized, investigator-blinded, cross-over, clinic trial using twenty-four
      healthy women aged 18-35. All women received two months of the birth control patch or birth
      control pill, two months without any drug, then two months of the alternative drug. The birth
      control patch contained 0.75 milligrams ethinyl estradiol and 6 milligrams norelgestromin.
      The birth control pill contained 35 micrograms ethinyl estradiol and 250 micrograms
      norgestimate. Blood samples were taken before and after each treatment and were analyzed for
      the following lab values: D-dimer, von Willebrand factor, factor VIII, total and free protein
      S, antithrombin, fibrinogen, C-reactive protein and normalized activated protein C
      sensitivity ratio (nAPCsr). Two thrombin generation-based assays were used: the
      α2macroglobulin-thrombin endpoint method (α2M-IIa) and calibrated automated thrombinography
      (CAT).
    

Detailed description: 
      Twenty-four non-pregnant women 18-35 years of age, who had not been on hormonal contraception
      for at least 2 months prior to the study or who were least 3 months postpartum and
      non-lactating, were enrolled in this study between October 2003 and February 2005. The study
      protocol was approved by the University of Vermont Institutional Review Board, and all
      participants gave written informed consent. Exclusion criteria for participation were
      personal or family history of venous thromboembolism or coagulation disorders, pregnancy,
      uncontrolled hypertension, cardiovascular disease, complicated migraine headaches, breast
      cancer, diabetes, abnormal uterine bleeding, liver disease, or desire for pregnancy in less
      than 6 months.

      This study was a randomized investigator-blind, cross-over clinical trial. The daily oral
      contraceptive contained 35 micrograms ethinyl estradiol and 250 micrograms norgestimate
      (Ortho Cylen®). The weekly transdermal hormonal contraceptive contained 0.75 milligrams
      ethinyl estradiol and 6.0 milligrams norelgestromin (Ortho Evra®). Norelgestromin is the
      active progestin metabolite of orally administered norgestimate. For the oral form the
      average steady state plasma concentration (Css) of ethinyl estradiol was 49.3
      picograms/milliliter and of norelgestromin 0.73 nanograms/milliliter and for the transdermal
      form these concentrations were 80.0 picograms/milliliter and 0.888 nanograms/milliliter,
      respectively at the end of the second month of use.17 The average weekly exposure, calculated
      as area under the curve (AUC0-168pg.h/mL) for ethinyl estradiol was 55% higher with
      transdermal than with the oral contraceptive. The maximum ethinyl estradiol and
      norelgestromin levels (Cmax) were 133 pg/ml and 2.16 ng/ml for the oral form and 97.4 pg/ml
      and 1.12 ng/ml for the transdermal form.17 The application location of the patch does not
      alter the Css or Cmax.18 Medications were supplied to the patients by a research nurse and
      the completed packets were returned to document compliance. The contraceptives and the
      funding for the study were supplied by research grants from the University of Vermont
      Department of Obstetrics and Gynecology.

      Prior to enrollment, participants underwent a physical examination including gynecologic
      examination. Women on hormonal contraceptives at recruitment were given barrier
      contraceptives for two months prior to starting the study. Participants were assigned a
      random identification number which indicated the sequence in which transdermal or oral
      contraceptives would be given. The daily oral contraceptive or weekly transdermal
      contraceptive was given with the typical dosing of three weeks active treatment followed by
      one week without hormone use. Following the first two months of hormonal contraceptive, each
      participated returned to barrier contraceptive for a two month washout period, then received
      two months of the alternative hormonal contraceptive. The investigators were blind to the
      order of contraceptive assigned for each participant.

      There were four phlebotomies performed for each subject. Blood was drawn on menstrual cycle
      day 18 to 21 prior to the study, within 4 days of either the last pill or removal of the last
      patch, and on cycle day 18 to 21 in the second month of the washout period. Blood was
      collected using standardized methods with minimal stasis into vacutainer tubes, immediately
      placed on ice and centrifuged at 4oC. Plasma and serum was stored at -70oC until completion
      of the study.

      Laboratory assays were performed in batch with each participant's serial samples analyzed in
      the same run. D-dimer, von Willebrand factor and antithrombin were measured using
      immuno-turbidometric assays on the STA-R analyzer (Liatest D-Di, Liatest vWF, Liatest ATIII,
      Diagnostica Stago, Parsippany, NJ) with coefficients of variation (CVs) of 3.0%, 3.85%, and
      4.0-8.0% respectively. Factor VIII was determined by measuring the clotting time of the
      sample in factor VIII deficient plasma (STA-Deficient VIII; Diagnostica Stago, Parsippany,
      NJ) with a CV of 3.5%. Free and total protein S were measured by immunoassay (Asserachrom
      Free and Total Protein S, Diagnostica Stago, Parsippany, NJ) with CVs of 14.0% and 4.0%
      respectively. Fibrinogen and C-reactive protein were measured by immunonephelometry using the
      BNII instrument (N Antiserum to Human Fibrinogen, N High Sensitivity CRP, Dade-Behring,
      Deerfield, IL) with CVs of 2.3-4% and 2.6% respectively.

      The normalized activated protein C sensitivity ratio (nAPCsr) was measured using two thrombin
      generation assays. In the first assay, coagulation was triggered in defibrinated plasma with
      tissue factor in the presence and absence of activated protein C and the amount of thrombin
      captured in complex with a2-macroglobulin over 30 minutes was taken as a measure for thrombin
      generation and used to calculate the nAPCsr (nAPCsr α2M-IIa).14 In the second assay, the
      nAPCsr (nAPCsr CAT) was determined by measuring thrombin generation in the presence and
      absence of activated protein C in full plasma in real-time with a fluorogenic thrombin
      substrate using calibrated automated thrombinography (CAT).19 The CV's of the nAPCsr α2M-IIa
      and nAPCsr CAT were 3.5% and 7%, respectively.

      Repeated measures analyses of variance corresponding to a cross-over design incorporating
      both baseline and washout periods were used to determine the significance associated with
      differences between the hormonal contraceptive treatments for each of the biomarkers tested.
      Pre-planned contrasts were used to test for differences between the pre-treatment periods
      corresponding to oral and transdermal active treatments. Contrasts were also used to test for
      changes from pre-treatment to active treatment within each treatment and to determine whether
      these changes were parallel across the two active treatments. Biomarkers that had non-normal
      distributions based on residual plots were log transformed prior to analysis. Based on the
      analyses of variance results, there was no evidence of any significant order effects for any
      of the biomarkers. Analyses were performed using SAS Version 8.2 (SAS Institute, Cary, NC).
      Statistical significance was determined based on a=.05
    

Intervention name(s): Ethinyl estradiol and norgestimate; Ethinyl estradiol and norelgestromin
Intervention type(s): Drug; Drug
Intervention description(s): Oral contraceptive; Transdermal hormonal contraceptive changed weekly
Other intervention name(s): Ortho Cyclen; Ortho Evra
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Ethinyl Estradiol; Norgestimate; Norelgestromin; Ortho Evra; Estradiol; Polyestradiol phosphate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Contraceptive; Venous thrombosis; Coagulation parameter