Elsevier

Contraception

Volume 93, Issue 5, May 2016, Pages 378-385
Contraception

Original research article
Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives

https://doi.org/10.1016/j.contraception.2016.01.012Get rights and content

Abstract

Objectives

The “Long-term Active Surveillance Study for Oral Contraceptives” investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting.

Study design

Prospective, controlled, non-interventional cohort study conducted in seven European countries with three main exposure groups: new users of DRSP, levonorgestrel-containing OCs (LNG), and OCs containing other progestogens (Other OCs). 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 cardiovascular events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models.

Results

A total of 1,113 study centers enrolled 59,510 women. Overall 28%, 26% and 45% of these women used DRSP, LNG and Other OCs, respectively. Study participants were followed for up to ten years (mean value, 5.4 years), which generated 318,784 woman-years (WY) of observation. Low loss to follow-up and drop-out rates of 2.9% and 16.8% were achieved. DRSP, LNG, and Other OCs showed similar incidence rates of venous thromboembolism. Corresponding hazard ratios (HRs) were close to unity. For arterial thromboembolic events (ATE) and initiation of antihypertensive treatment statistically significant lower risks were found for DRSP compared to LNG and Other OCs.

Conclusion

DRSP use was associated with similar general health risks and a low risk of ATE compared to OCs containing other progestogens.

Implication statement

The 21-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risk of VTE compared to other combined oral contraceptives as well as potentially with a lower risk of ATE.

Introduction

This article describes the final results of the Long-term Active Surveillance Study for Oral Contraceptives (LASS), the follow-up study to the European Active Surveillance (EURAS) Study [1].

The EURAS study was initiated in November 2000 and completed in December 2005. A total of 59,510 users of oral contraceptives (OCs) was enrolled between November 2000 and June 2004 by 1,113 study centers in 7 European countries. Three OC user groups – users of preparations containing 3 mg of drospirenone (DRSP) and 30 μg of ethinylestradiol (EE), levonorgestrel-containing OCs, and OCs containing other progestogens – were followed throughout the study. The results suggested that the overall risk of adverse outcomes as well as the risk of venous and arterial thromboembolism do not differ materially from the risks associated with the use of levonorgestrel-containing OCs or other OCs.

However, the statistical power of the EURAS study to investigate the risk of rare outcomes – such as arterial thromboembolism – was limited. Therefore, another five-year follow-up study of the EURAS cohort, namely the LASS study, was conducted with the expectation that this extended follow-up would yield a substantial increase in statistical power. The presented paper reports the results on cardiovascular outcomes. Other outcomes will be reported elsewhere.

Section snippets

Materials and methods

A cohort of 58,674 women starting OC use was actively monitored for up to 10 years for the occurrence of rare or unexpected adverse outcomes possibly related to exposure to OCs. The methodology of the LASS study is identical to that of the EURAS study on oral contraceptives described elsewhere [1], so most methodological details are presented succinctly. Some, however, are described in more detail than in the original paper in order to address subsequent discussions of methodology.

Planning,

Results

A total of 59,510 women was enrolled by 1,113 active study centers. Overall, 836 of these 59,510 women (1.4%) had to be excluded because they: (1) declined to sign the informed consent form, (2) were enrolled two or more times by one or more study centers, (3) continued to use their old OC (long-term users), or (4) did not use any OC. The remaining 58,674 quality-controlled computerized data sets from the women (one per woman) with baseline information were analyzed. In the combined EURAS and

Discussion

No major differences were found between the OC groups for incidence rates of VTE. Crude and adjusted HRs also indicated similar risk levels for these outcomes. By contrast, a statistically significant reduced risk of ATE and initiation of antihypertensive treatment was found for the DRSP group compared to the LNG and Other OCs groups.

The methodological limitations of prospective, non-interventional, active surveillance cohort studies such as LASS have been discussed elsewhere [1], [5], [6].

Acknowledgements

The study was funded by an unrestricted grant from Bayer AG. The authors would like to express their appreciation to the members of the independent Safety Monitoring and Advisory Council for their constructive criticism and unfailingly fair scientific discussion. The authors would also like to highlight the contributions of numerous colleagues who were responsible for the field work in the individual countries. They clarified data inconsistencies and missing data, validated patient-reported

References (31)

  • K.J. Rothman et al.

    A strengthening programme for weak associations

    Int J Epidemiol

    (1988)
  • M.J. Khoury et al.

    Interpretation of recurring weak associations obtained from epidemiologic studies of suspected human teratogens

    Teratology

    (1992)
  • S. Shapiro

    Bias in the evaluation of low-magnitude associations: an empirical perspective

    Am J Epidemiol

    (2000)
  • S. Shapiro

    Causation, bias and confounding: a hitchhiker's guide to the epidemiological galaxy. Part 2. Principles of causality in epidemiological research: confounding, effect modification and strength of association

    J Fam Plann Reprod Health Care

    (2008)
  • S. Shapiro

    Causation, bias and confounding: a hitchhiker's guide to the epidemiological galaxy. Part 3: principles of causality in epidemiological research: statistical stability, dose- and duration response effects, internal and external consistency, analogy and biological plausibility

    J Fam Plann Reprod Health Care

    (2008)
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    Funding: Unconditional grant from Bayer AG, Germany.

    Conflict of Interest: The study was funded by a manufacturer of hormonal contraceptives. The study was supervised by an independent Safety Monitoring and Advisory Council with full authority over the study (including study protocol, protocol amendments, data analysis, and stopping the study). The funder had no access to the source data and did not participate in designing the study or analyzing the data.

    Registration Number at the clinical trials registry of the US National Library of Medicine: NCT00676065 (Please note: This is not a clinical trial.)

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