Cardiovascular and general safety of a 24-day regimen of drospirenone-containing  combined oral contraceptives: final results from the International Active  Surveillance Study of Women Taking Oral Contraceptives

Dinger J, Bardenheuer K, Heinemann K

doi:10.1016/j.contraception.2014.01.023

Contraception, 89(4), 253-263, 2014

Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives

Kristina Bardenheuer , Jürgen Dinger , Klaas Heinemann

Author affiliations

Berlin Center for Epidemiology and Health Research ROR

DOI10.1016/j.contraception.2014.01.023 PMID24576793

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Abstract

Objectives

The "International Active Surveillance Study of Women Taking Oral Contraceptives" investigated the risks of shortand long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP24d) compared to established oral contraceptives (OCs) in a routine clinical setting.

Study Design

Prospective, controlled, noninterventional cohort study conducted in the United States and six European countries with three main cohorts: new users of DRSP24d, DRSP21d (21-day regimens of DRSP-containing OCs), and non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP24d vs. non-DRSP.

Results

A total of 2285 study centers enrolled 85,109 women. Study participants were followed for 2 to 6 years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP24d, DRSP21d, non-DRSP and levonorgestrel-containing OCs (LNG) showed similar incidence rates of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP24d, DRSP21d, non-DRSP and LNG were 7.2, 9.4, 9.6 and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP24d vs. non-DRSP and DRSP24d vs. LNG were 0.8 [95% confidence interval (CI), 0.5-1.3] and 0.8 (95% CI, 0.4-1.5).

Conclusion

DRSP24d, DRSP21d, non-DRSP and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use. IMPLICATION STATEMENT: The 24-day regimen of drospirenone-containing combined OCs is associated with similar risks of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined OCs, OCs without drospirenone and LNGs.

Topics

Contraception/Comparison > Oral Contraceptives > Cardiovascular Safety Contraception/Comparison > Side Effects > Venous Thromboembolism Research Methodology > Prospective Cohort Studies > Pharmacovigilance

drospirenone oral contraceptive venous thromboembolism risk, DRSP 24-day regimen cardiovascular safety surveillance, oral contraceptive VTE incidence prospective cohort study, drospirenone vs levonorgestrel thromboembolism risk, International Active Surveillance Study oral contraceptives INAS-OC, combined oral contraceptive serious adverse events long-term, progestin type venous thromboembolism hazard ratio, extended regimen oral contraceptive arterial thromboembolism, drospirenone ethinylestradiol safety noninterventional study, oral contraceptive cancer depression fatal outcomes

PMID 24576793 24576793 DOI 10.1016/j.contraception.2014.01.023 10.1016/j.contraception.2014.01.023

Cite this article

Dinger, J., Bardenheuer, K., & Heinemann, K. (2014). Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception, 89(4), 253-263. https://doi.org/10.1016/j.contraception.2014.01.023

Keywords

Androstenes, Contraceptives, Oral, Combined, Mineralocorticoid Receptor Antagonists, Drospirenone

Contraception/ComparisonCardiovascular SafetyVenous ThromboembolismProspective Surveillance

The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation

Dinger JC et al., 2007Contraception

The study was conducted to compare risks of adverse cardiovascular and other events associated with the use of drospirenone (DRSP)-containing oral contraceptives (OCs) and other OCs. The European Active Surveillance study (EURAS) was a multinational, prospective, noninterventional cohort study of new users of DRSP, levonorgestrel (LNG) and other progestin-containing OCs. Semiannual follow-up was based on mailed questionnaires, with additional follow-up procedures when needed. Overall, 58,674 women were followed for 142,475 women-years of observation. Loss to follow-up was 2.4%. Serious adverse and fatal events were rare, and rate ratios were close to unity (1.0). Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. Risks of adverse cardiovascular and other serious events in users of a DRSP-containing OC are similar to those associated with the use of other OCs.

Contraception/ComparisonCombined Oral ContraceptivesVenous ThromboembolismProgestins

Hormonal Profiles in Users of the Ovulation Method

Farris M et al., 2025

Contraception/ComparisonVenous ThromboembolismContraception SafetyHormonal Contraception

Systematic Review of Hormonal Contraception and Risk of Venous Thrombosis

Keenan L et al., 2018Linacre Q

Hormonal contraception (HC) is widely used throughout the world and has been associated with venous thrombosis (VT) such as deep vein thrombosis, pulmonary emboli, and cerebral VT. To provide a current comprehensive overview of the risk of objectively confirmed VT with HC in healthy women compared to nonusers. PubMed was searched from inception to April 2018 for eligible studies in the English language, with hand searching from past systematic reviews. We selected original research evaluating risk of objectively confirmed VT in healthy women taking oral or nonoral HC compared with nonusers. The primary outcome of interest was a fatal or nonfatal VT in users of HC compared to nonusers or past users. Studies with at least twenty events were eligible. Adjusted relative risks with 95 percent confidence intervals were reported. Three independent reviewers extracted data from selected studies. 1,962 publications were retrieved through the search strategy, with 15 publications included. Users of oral contraception with levonorgesterol had increased risk of VT by a range of 2.79-4.07, while other oral hormonal preparations increased risk by 4.0-48.6. Levonorgestrel intrauterine devices did not increase risk. Etonogestrel/ethinyl estradiol vaginal rings increased the risk of VT by 6.5. Norelgestromin/ethinyl estradiol patches increased risk of VT by 7.9. Etonogestrel subcutaneous implants by 1.4 and depot-medroxyprogesterone by 3.6. The risk of fatal VT was increased in women aged fifteen to twenty-four by 18.8-fold. Users of HC have a significant increased risk of VT compared to nonusers. Current risks would project at least 300-400 healthy young women dying yearly in the United States due to HC. Women should be informed of these risks and offered education in fertility-awareness-based methods with comparable efficacy for family planning. HC is widely used throughout the world and has been associated with blood clots in the legs and lungs. We searched the literature and found the risks of currently used forms of birth control increased between threeand ninefold for blood clots for healthy women. The risks found would project 300-400 women dying from using HC each year in the United States.

Contraception/ComparisonVenous ThromboembolismCombined vs Progestin-OnlyCardiovascular Risk

Hormonal contraception, thrombosis and age

Lidegaard Ø, 2014Expert Opin Drug Saf

This paper reviews the risk of thrombosis with use of different types of hormonal contraception in women of different ages. Combined hormonal contraceptives with desogestrel, gestodene, drospirenone or cyproterone acetate (high-risk products) confer a sixfold increased risk of venous thromboembolism as compared with nonusers, and about twice the risk as compared with users of products with norethisterone, levonorgestrel or norgestimate (low-risk products). Transdermal patches and vaginal ring belong to high-risk products. The risk of thrombotic stroke and myocardial infarction is increased 50 - 100% with use of combined products, with little difference in risk between different progestins. Progestin-only products do not confer any increased risk of venous or arterial thrombosis, except for progestin depot, which may double the risk of venous thrombosis. First choice in women below 35 years should be a combined low-risk pill, that is, with a second-generation progestin, with the lowest compliable dose of estrogen. Young women with risk factors of thrombosis such as age above 35 years, genetic predispositions, adiposity, polycystic ovary syndrome, diabetes, smoking, hypertension or migraine with aura should not use high-risk products, but should primarily consider progestin-only products, and be careful to use low-risk combined products.