Pulmonary Embolism, Sinus Thrombosis, Intracranial, Venous Thrombosis
Conditions
Keywords
Lybrel, levonorgestrel, ethinyl estradiol, venus thromboembolism (VTE), oral contraceptives (OC), safety, database study, case-control study
Brief summary
Lybrel® is an oral contraceptive that delivers low doses of levonorgestrel and ethinyl estradiol (90 μg/20 μg). Lybrel is taken on a continuous basis without a placebo or pill-free interval to inhibit menstrual cycle bleeding by delivering a steady level of the 2 hormones for as long as the drug is used. Lybrel was marketed in the US in July of 2007. The objective of this database case-control study is to estimate the risk of idiopathic VTE (deep vein thrombosis and pulmonary embolism) in current users of Lybrel (ethinyl estradiol 20ug/levonorgestrel 90ug) compared to current users of other oral contraceptives containing 20μg of ethinyl estradiol.
Detailed description
The base population consists of all currently available data on current users (15-49 years old) of Lybrel and other oral contraceptives (OC) containing 20 µg ethinyl estradiol in the PharMetrics/IMS and MarketScan databases. From among the base population, the databases are then searched for any diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE), or cerebral venous sinus thrombosis (CVST) \[referred to collectively as venous thromboembolism or VTE\] that occurred after receipt of Lybrel or other oral contraceptives containing 20 µg ethinyl estradiol. The intent is to include newly diagnosed cases of VTE.
Interventions
DRUG90ug levonorgestrel / 20 ug ethinyl estradiol
This is a non-interventional observational database study, thus no interventions are offered to patients in the study.
DRUGOral Contraceptives containing 20 ug of ethinyl estradiol
This is a non-interventional observational database study, thus no interventions are offered to patients in the study.
Sponsors
Boston Collaborative Drug Surveillance Program
Pfizer
Study design
Observational model
CASE_CONTROL
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 49 Years
Healthy volunteers
No
Inclusion criteria
* New users of the study drugs (i.e., Lybrel and the comparison OCs)
Exclusion criteria
* No specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Index date (date of VTE diagnosis for case and corresponding date for matched control) | Idiopathic VTE=deep vein thrombosis (DVT), pulmonary embolism (PE), or cerebral venous sinus thrombosis (CVST) occurring in absence of known risk factors. Incidence rate reported for current, past users. Current user=had claim for study OC prescription (Lybrel or other OCs containing ethinyl estradiol 20 mcg) whose filled use occurred within 30 days prior to or at index date. Past user=had claim for a study OC prescription whose filled use occurred between 90 to 31 days prior to index date. Index date=date of VTE diagnosis for case and corresponding date for matched control. |
| Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Index date (date of VTE diagnosis for case and corresponding date for matched control) | Idiopathic VTE cases=new DVT, PE or CVST occurring in absence of known risk factors. Matched Control was defined as participants with no diagnosis of VTE matched for age, calendar time, exposure status and database. Current user=had claim for study OC prescription (Lybrel or other OCs containing ethinyl estradiol 20 mcg) whose filled use occurred within 30 days prior to or at index date. Past user=had claim for a study OC prescription whose filled use occurred between 90 to 31 days prior to index date. Index date=date of VTE diagnosis for case and corresponding date for matched control. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lybrel Participants who were current or past users of Lybrel, a continuous use oral contraceptive containing levonorgestrel 90 microgram (mcg) and ethinyl estradiol 20 mcg, were observed. | 12,281 |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed. | 586,401 |
| Total | 598,682 |
Baseline characteristics
| Characteristic | Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Lybrel | Total |
|---|---|---|---|
| Age, Customized 15 to 19 years | 151591 participants | 1549 participants | 153140 participants |
| Age, Customized 20 to 24 years | 128757 participants | 1785 participants | 130542 participants |
| Age, Customized 25 to 29 years | 99632 participants | 1925 participants | 101557 participants |
| Age, Customized 30 to 34 years | 79184 participants | 2079 participants | 81263 participants |
| Age, Customized 35 to 39 years | 56674 participants | 2074 participants | 58748 participants |
| Age, Customized 40 to 44 years | 41299 participants | 1668 participants | 42967 participants |
| Age, Customized 45 to 49 years | 29264 participants | 1201 participants | 30465 participants |
| Percentage of Obese Participants | 3.0 percentage of participants | 3.7 percentage of participants | 6.7 percentage of participants |
| Percentage of Participants With Asthma | 6.8 percentage of participants | 6.9 percentage of participants | 13.7 percentage of participants |
| Percentage of Participants With Back Pain | 8.5 percentage of participants | 11.0 percentage of participants | 19.5 percentage of participants |
| Percentage of Participants With Cardiovascular Disease | 2.8 percentage of participants | 3.3 percentage of participants | 6.1 percentage of participants |
| Percentage of Participants With Diabetes | 1.7 percentage of participants | 2.2 percentage of participants | 3.9 percentage of participants |
| Percentage of Participants With Duration in Health Plan Before First Study OC Prescription 12 to 24 months | 31.9 percentage of participants | 39.1 percentage of participants | 71.0 percentage of participants |
| Percentage of Participants With Duration in Health Plan Before First Study OC Prescription 24 to 60 months | 37.0 percentage of participants | 27.5 percentage of participants | 64.5 percentage of participants |
| Percentage of Participants With Duration in Health Plan Before First Study OC Prescription 6 to 12 months | 24.0 percentage of participants | 27.6 percentage of participants | 51.6 percentage of participants |
| Percentage of Participants With Duration in Health Plan Before First Study OC Prescription More than 60 months | 7.1 percentage of participants | 5.8 percentage of participants | 12.9 percentage of participants |
| Percentage of Participants With Gynecological Disorders Endometriosis | 1.1 percentage of participants | 6.3 percentage of participants | 7.4 percentage of participants |
| Percentage of Participants With Gynecological Disorders Menstrual disorder | 24.8 percentage of participants | 26.8 percentage of participants | 51.6 percentage of participants |
| Percentage of Participants With Gynecological Disorders Uterine leiomyoma | 0.0 percentage of participants | 0.1 percentage of participants | 0.1 percentage of participants |
| Percentage of Participants With Hyperlipidemia | 5.5 percentage of participants | 8.9 percentage of participants | 14.4 percentage of participants |
| Percentage of Participants With Hypertension | 3.7 percentage of participants | 6.3 percentage of participants | 10.0 percentage of participants |
| Percentage of Participants With Length of Stay in Health Plan 1 to 2 years | 16.8 percentage of participants | 14.6 percentage of participants | 31.4 percentage of participants |
| Percentage of Participants With Length of Stay in Health Plan 3 to 4 years | 41.6 percentage of participants | 41.8 percentage of participants | 83.3 percentage of participants |
| Percentage of Participants With Length of Stay in Health Plan Greater than or equal to 5 years | 37.2 percentage of participants | 40.0 percentage of participants | 77.2 percentage of participants |
| Percentage of Participants With Length of Stay in Health Plan Less than 1 year | 4.4 percentage of participants | 3.7 percentage of participants | 8.1 percentage of participants |
| Percentage of Participants With Thyroid Disease | 0.8 percentage of participants | 0.8 percentage of participants | 1.6 percentage of participants |
| Sex: Female, Male Female | 586401 Participants | 12281 Participants | 598682 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Incidence Rate of Idiopathic Venous Thromboembolism (VTE)
Idiopathic VTE=deep vein thrombosis (DVT), pulmonary embolism (PE), or cerebral venous sinus thrombosis (CVST) occurring in absence of known risk factors. Incidence rate reported for current, past users. Current user=had claim for study OC prescription (Lybrel or other OCs containing ethinyl estradiol 20 mcg) whose filled use occurred within 30 days prior to or at index date. Past user=had claim for a study OC prescription whose filled use occurred between 90 to 31 days prior to index date. Index date=date of VTE diagnosis for case and corresponding date for matched control.
Time frame: Index date (date of VTE diagnosis for case and corresponding date for matched control)
Population: Analysis population included all enrolled participants who met the eligibility criteria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lybrel | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Current users | 176.2 incidence rate per 100000 person-years |
| Lybrel | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Past users | 54.1 incidence rate per 100000 person-years |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Current users | 87.5 incidence rate per 100000 person-years |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Past users | 18.0 incidence rate per 100000 person-years |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Current users | 50.5 incidence rate per 100000 person-years |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Incidence Rate of Idiopathic Venous Thromboembolism (VTE) | Past users | 17.6 incidence rate per 100000 person-years |
Comparison: Incidence rate ratio (Lybrel/EE-20) along with corresponding 95 percent (%) confidence interval (CI) was reported for current users.95% CI: [1.23, 3.29]
Comparison: Incidence rate ratio (Lybrel/EE-20) along with corresponding 95% CI was reported for past users.95% CI: [0.39, 22.8]
Comparison: Incidence rate ratio (Lybrel/Levo-20) along with corresponding 95% CI was reported for current users.95% CI: [2.02, 6.02]
Comparison: Incidence rate ratio (Lybrel/Levo-20) along with corresponding 95% CI was reported for past users.95% CI: [0.34, 27.47]
Primary
Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls
Idiopathic VTE cases=new DVT, PE or CVST occurring in absence of known risk factors. Matched Control was defined as participants with no diagnosis of VTE matched for age, calendar time, exposure status and database. Current user=had claim for study OC prescription (Lybrel or other OCs containing ethinyl estradiol 20 mcg) whose filled use occurred within 30 days prior to or at index date. Past user=had claim for a study OC prescription whose filled use occurred between 90 to 31 days prior to index date. Index date=date of VTE diagnosis for case and corresponding date for matched control.
Time frame: Index date (date of VTE diagnosis for case and corresponding date for matched control)
Population: Analysis population included all enrolled participants who met the eligibility criteria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lybrel | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Case | 17 participants |
| Lybrel | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Matched Control | 47 participants |
| Lybrel | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Case | 1 participants |
| Lybrel | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Matched Control | 1 participants |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Matched Control | 39 participants |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Case | 276 participants |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Case | 14 participants |
| Other OCs: Ethinyl Estradiol 20 Mcg (EE-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Matched Control | 1144 participants |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Matched Control | 10 participants |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Matched Control | 254 participants |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Past user: Case | 4 participants |
| Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20) | Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls | Current user: Case | 53 participants |
Comparison: Current user, case and matched control: Odds ratio (Lybrel/EE-20) and 95% CI were estimated using conditional logistic regression, conditional on matching factors (age, calendar time, exposure status and database).95% CI: [0.85, 2.67]
Comparison: Current user, case and matched control: Odds ratio (Lybrel/Levo-20) and 95% CI were estimated using conditional logistic regression, conditional on matching factors (age, calendar time, exposure status and database).95% CI: [0.98, 6.54]