RIVET - Retrospective Cohort Study on the Risk of Venous Thromboembolism (RIVET-RCS)

Retrospective Cohort Study on the RIsk of VEnous Thromboembolism Associated With the Use of Combined Oral Contraceptives Containing Chlormadinone Acetate/Ethinylestradiol and Levonorgestrel/Ethinylestradiol

The risk of venous thromboembolism (VTE) associated with the use of chlormadinone acetate (CMA) compared to the gold-standard progestin levonorgestrel (LNG) as component of combined oral contraceptives (COC) is currently unknown. The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended a pooled analysis of four prospective cohort studies carried out by the Berlin Center for Epidemiology and Health Research (ZEG Berlin) in order to clarify whether CMA-containing COCs carry a different VTE risk compared to LNG-containing COCs.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism

Detailed Description

This study is designed as a retrospective cohort study. ZEG Berlin conducted several large prospective cohort studies on the risk of VTE associated with the use of hormonal contraceptives. Four of these studies included a substantial number of women using CMA/EE or LNG/EE-containing COCs. For this study, the data on CMA/EE and LNG/EE from the following four prospective cohort studies are combined: 1) EURAS-OC/LASS 2) INAS-OC 3) INAS-SCORE and 4) INAS-FOCUS.

Participants will be identified retrospectively from a pooled dataset which comprises four large, controlled, prospective, non-interventional active surveillance studies that focused on the risk of VTE associated with the use of combined oral contraceptives. All data were prospectively collected by ZEG Berlin and follow the EURAS/INAS study design. Inclusion and exclusion criteria, the method of patient recruitment and follow-up as well as research methods were similar across studies.

The EURAS-OC/LASS study was conducted in Europe only; the other three studies are transatlantic studies that include subjects from both Europe and the United States of America.

This analysis is specifically designed to assess the risk of VTE associated with the use of COCs containing CMA/EE compared to LNG/EE.

• Study Type: Observational
• Enrollment (Actual): 124000

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10115
    • Center for Epidemiology and Health Research Berlin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 49 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Participants will be identified retrospectively from a pooled dataset which comprises four large, controlled, prospective, non-interventional active surveillance studies that focused on the risk of VTE associated with the use of combined oral contraceptives. All data were prospectively collected by ZEG Berlin and follow the EURAS/INAS study design. Inclusion and exclusion criteria, the method of patient recruitment and follow-up as well as research methods were similar across studies.

Description

Inclusion: female, aged 15 to 49 years, participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS), COC new user (starters, switchers, and re-starters), applied COCs: CMA/EE or LNG/EE.

Exclusion of women with a personal history of VTE.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Users of Chlormadinone Acetate (CMA) combined with Ethinylestradiol (EE); CMA/EE users are defined as; aged 15 to 49 years; Participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS); COC new user (starters, switchers, and re-starters)
Users of Levonorgestrel (LNG) combined with Ethinylestradiol (EE); LNG/EE users are defined as; aged 15 to 49 years; Participation in one of the 4 observational studies conducted between 2000 and 2019 (LASS/EURAS-OC, INAS-OC, INAS-SCORE, INAS-FOCUS); COC new user (starters, switchers, and re-starters)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The risk of venous thromboembolic events (VTE) in the cohort of users of combined oral contraceptives (COCs) containing 2 mg CMA/30 µg EE compared to 0.15 mg LNG/30 µg EE.	VTE risk of users of CMA 2mg / EE 30µg compared to the VTE risk of users of LNG 0.15 mg / EE 30µg.	VTEs will be identified during the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years.

Secondary Outcome Measures

Outcome Measure	Time Frame
To assess the risk of venous thromboembolic events stratified by: COC user type, age and BMI	During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years.
To assess the risk of VTE in the sub-cohort of users of COCs containing CMA compared to LNG both combined with ≤30 µg EE.	During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years.
To characterize the baseline risk of users of the two formulations (lifetime history of co-morbidity, prognostic factors for VTE, co-medication, socio-demographic and life¬style data).	During the follow-up intervals, typically scheduled every 6 - 12 months, with a maximum follow-up of 10 years.

Collaborators and Investigators

• Sponsor: Center for Epidemiology and Health Research, Germany

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2022
• Primary Completion (Actual): January 15, 2024
• Study Completion (Actual): January 31, 2024

Study Registration Dates

• First Submitted: June 20, 2016
• First Submitted That Met QC Criteria: July 7, 2016
• First Posted (Estimated): July 12, 2016

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism
• Other Study ID Numbers: ZEG2014_05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO