Study Of Lybrel In Relation To Venous Thromboembolism

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01297348
• Collaborator: Boston Collaborative Drug Surveillance Program (Other)
• Enrollment: 598,682
• Duration (Months): 57

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thrombosis; Pulmonary Embolism; Sinus Thrombosis, Intracranial	Drug: 90ug levonorgestrel / 20 ug ethinyl estradiol; Drug: Oral Contraceptives containing 20 ug 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.

Study Design

• Study Type: Observational
• Actual Enrollment: 598682 participants
• Observational Model: Case-Control
• Time Perspective: Retrospective
• Official Title: Postmarketing Study Of Lybrel In Relation To Venous Thromboembolism
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Lybrel® Current users of 90 ug levonorgestrel / 20 ug ethinyl estradiol - cases and controls (i.e., women diagnosed with new venus thromboembolism [VTE] and women not diagnosed with VTE).	Drug: 90ug levonorgestrel / 20 ug ethinyl estradiol; This is a non-interventional observational database study, thus no interventions are offered to patients in the study.; Other Names: Lybrel
Other OCs containing 20μg of ethinyl estradiol Current users of oral contraceptives containing 20μg of ethinyl estradiol - cases and controls (i.e. women diagnosed with new VTE and women not diagnosed with VTE)	Drug: Oral 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.; Other Names: Lessina, Aviane, Junel 1/20, Junel FE 1/20, Levlite, Lutera, Alesse, Loestrin FE 1/20, Loestrin 1/20, Microgestin 1/20, Microgestin FE 1/20

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 49 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• New users of the study drugs (i.e., Lybrel and the comparison OCs)

Exclusion Criteria:

• No specific exclusion criteria for the base study cohort.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Pfizer
• Boston Collaborative Drug Surveillance Program

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01297348
• Other Study ID Numbers: 0858A2-4406; B3121004; NCT01316640
• First Posted: Feb 16, 2011
• Last Update Posted: Jul 17, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Pfizer: Lybrel; levonorgestrel; ethinyl estradiol; venus thromboembolism (VTE); oral contraceptives (OC); safety; database study; case-control study
• Additional relevant MeSH terms: Pulmonary Embolism; Sinus Thrombosis, Intracranial; Intracranial Thrombosis; Thrombosis; Embolism; Thromboembolism; Venous Thromboembolism; Venous Thrombosis; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Levonorgestrel; Ethinyl Estradiol; Norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; Norinyl; Contraceptive Agents; Contraceptives, Oral; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Arm/Group Title	Lybrel	Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
Arm/Group Description	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.	Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed.
Period Title: Overall Study
STARTED	12281	586401
COMPLETED	12281	586401
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Lybrel	Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)	Total
Arm/Group Description	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.	Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed.	Total of all reporting groups
Overall Participants	12281	586401	598682
Age, Customized (participants) [Number]
15 to 19 years	1549 12.6%	151591 25.9%	153140 25.6%
20 to 24 years	1785 14.5%	128757 22%	130542 21.8%
25 to 29 years	1925 15.7%	99632 17%	101557 17%
30 to 34 years	2079 16.9%	79184 13.5%	81263 13.6%
35 to 39 years	2074 16.9%	56674 9.7%	58748 9.8%
40 to 44 years	1668 13.6%	41299 7%	42967 7.2%
45 to 49 years	1201 9.8%	29264 5%	30465 5.1%
Sex: Female, Male (Count of Participants)
Female	12281 100%	586401 100%	598682 100%
Male	0 0%	0 0%	0 0%
Percentage of Participants With Duration in Health Plan Before First Study OC Prescription (percentage of participants) [Number]
6 to 12 months	27.6 0.2%	24.0 0%	51.6 0%
12 to 24 months	39.1 0.3%	31.9 0%	71.0 0%
24 to 60 months	27.5 0.2%	37.0 0%	64.5 0%
More than 60 months	5.8 0%	7.1 0%	12.9 0%
Percentage of Obese Participants (percentage of participants) [Number]
Number [percentage of participants]	3.7 0%	3.0 0%	6.7 0%
Percentage of Participants With Gynecological Disorders (percentage of participants) [Number]
Endometriosis	6.3 0.1%	1.1 0%	7.4 0%
Menstrual disorder	26.8 0.2%	24.8 0%	51.6 0%
Uterine leiomyoma	0.1 0%	0.0 0%	0.1 0%
Percentage of Participants With Back Pain (percentage of participants) [Number]
Number [percentage of participants]	11.0 0.1%	8.5 0%	19.5 0%
Percentage of Participants With Cardiovascular Disease (percentage of participants) [Number]
Number [percentage of participants]	3.3 0%	2.8 0%	6.1 0%
Percentage of Participants With Hypertension (percentage of participants) [Number]
Number [percentage of participants]	6.3 0.1%	3.7 0%	10.0 0%
Percentage of Participants With Hyperlipidemia (percentage of participants) [Number]
Number [percentage of participants]	8.9 0.1%	5.5 0%	14.4 0%
Percentage of Participants With Diabetes (percentage of participants) [Number]
Number [percentage of participants]	2.2 0%	1.7 0%	3.9 0%
Percentage of Participants With Asthma (percentage of participants) [Number]
Number [percentage of participants]	6.9 0.1%	6.8 0%	13.7 0%
Percentage of Participants With Thyroid Disease (percentage of participants) [Number]
Number [percentage of participants]	0.8 0%	0.8 0%	1.6 0%
Percentage of Participants With Length of Stay in Health Plan (percentage of participants) [Number]
Less than 1 year	3.7 0%	4.4 0%	8.1 0%
1 to 2 years	14.6 0.1%	16.8 0%	31.4 0%
3 to 4 years	41.8 0.3%	41.6 0%	83.3 0%
Greater than or equal to 5 years	40.0 0.3%	37.2 0%	77.2 0%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of Idiopathic Venous Thromboembolism (VTE)
Description	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)

Outcome Measure Data

Analysis Population Description

Analysis population included all enrolled participants who met the eligibility criteria.

Arm/Group Title	Lybrel	Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)	Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20)
Arm/Group Description	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.	Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed.	A subset of EE-20 group including participants who were current or past users of Levo-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and differing concentrations of levonorgestrel (progestin), were observed.
Measure Participants	12281	586401	142860
Current users	176.2	87.5	50.5
Past users	54.1	18.0	17.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Comments	Incidence rate ratio (Lybrel/EE-20) along with corresponding 95 percent (%) confidence interval (CI) was reported for current users.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	2.01
	Confidence Interval	(2-Sided) 95%; 1.23 to 3.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Comments	Incidence rate ratio (Lybrel/EE-20) along with corresponding 95% CI was reported for past users.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	2.99
	Confidence Interval	(2-Sided) 95%; 0.39 to 22.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20)
	Comments	Incidence rate ratio (Lybrel/Levo-20) along with corresponding 95% CI was reported for current users.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	3.49
	Confidence Interval	(2-Sided) 95%; 2.02 to 6.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20)
	Comments	Incidence rate ratio (Lybrel/Levo-20) along with corresponding 95% CI was reported for past users.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	3.07
	Confidence Interval	(2-Sided) 95%; 0.34 to 27.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Idiopathic Venous Thromboembolism (VTE) Cases and Matched Controls
Description	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)

Outcome Measure Data

Analysis Population Description

Analysis population included all enrolled participants who met the eligibility criteria.

Arm/Group Title	Lybrel	Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)	Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20)
Arm/Group Description	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.	Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed.	A subset of EE-20 group including participants who were current or past users of Levo-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and differing concentrations of levonorgestrel (progestin), were observed.
Measure Participants	12281	586401	142860
Current user: Case	17 0.1%	276 0%	53 0%
Current user: Matched Control	47 0.4%	1144 0.2%	254 0%
Past user: Case	1 0%	14 0%	4 0%
Past user: Matched Control	1 0%	39 0%	10 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 0.85 to 2.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lybrel, Other OCs: Levonorgestrel, Ethinyl Estradiol 20 Mcg (Levo-20)
	Comments	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).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.53
	Confidence Interval	(2-Sided) 95%; 0.98 to 6.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	The minimum criteria for reporting an adverse event (AE) (that is, identifiable participant, identifiable reporter, a suspect product, and event) were not available and adverse events were not reportable as individual AE reports in this observational non-interventional study.
Arm/Group Title	Lybrel		Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
Arm/Group Description	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.		Participants who were current or past users of EE-20, cyclic oral contraceptives (OCs) containing ethinyl estradiol 20 mcg and a progestin, were observed.
All Cause Mortality
	Lybrel		Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lybrel		Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Lybrel		Other OCs: Ethinyl Estradiol 20 Mcg (EE-20)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

Data for DVT, PE and CVST were not reported separately as the 3 were components of the primary endpoint VTE and not separate endpoints.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.