Drospirenone-containing oral contraceptives and venous thromboembolism: an analysis of the FAERS database
Received 6 January 2018
Accepted for publication 3 February 2018
Published 11 April 2018 Volume 2018:9 Pages 29—32
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Igal Wolman
David Madigan, Jennifer Shin
Department of Statistics, Columbia University, New York, NY, USA
Introduction: Substantial evidence suggests that drospirenone-containing oral contraceptives may cause a higher risk of venous thrombotic events than earlier-generation oral contraceptives.
Methods: To gain insight into recent real-world implications, we conducted an analysis using the US Food and Drug Administration’s Adverse Event Reporting System.
Results: Venous thrombotic events continue to be reported at a much higher rate with drospirenone-containing oral contraceptives than the general background. The disproportionality has been rising since 2010. The same behavior is not seen with levonorgestrel-containing oral contraceptives.
Conclusion: Our results are consistent with decreased physician and patient awareness of risks associated with drospirenone-containing oral contraceptives.
Keywords: drug safety, Yaz, venous thrombotic events, FDA adverse event reporting system, disproportionality
Oral contraceptives are among the most widely used drugs1 and questions about oral contraceptive safety have occupied regulators, physicians, and patients for decades. Venous thrombotic risks associated with oral contraceptives have attracted particular scrutiny. A substantial body of evidence linked the first generation of oral contraceptive pills (OCPs) to significant risk of venous thromboembolism (VTE). The estrogen-like compounds in these OCPs appeared to be the cause. Subsequently, drug developers decreased the VTE risk of OCPs by lowering the delivered estrogen content by adding progestins such as levonorgestrel.2 More recently, OCPs with the progestin drospirenone (Yaz/Yasmin) have enjoyed considerable commercial success, in part by emphasizing potential benefits such as reduced acne.3,4
Evidence began to emerge in the 2000s, however, that drospirenone-containing OCPs may cause higher risk of VTE than earlier generation OCPs. Recent systematic reviews show elevated risk,5,6 but others emphasize the modest absolute risk: “Regardless of whether the thrombotic risk of drospirenone OCs compared to levonorgestrel OCs is increased by 1.5-fold or threefold, the absolute risk is still low.”7
The US Food and Drug Administration’s Adverse Event Reporting System (FAERS) database contains voluntarily submitted adverse event reports. The data can be downloaded from the FDA’s website (http://bit.ly/2naXeJU). To shed light on real-world experience with drospirenone OCPs and using standard analytical techniques, we considered reporting of VTE associated with drospirenone OCPs as compared with the rest of the drugs in FAERS and also considered reporting of VTE associated with levonorgestrel OCPs as compared with the rest of the drugs in the database.
For each year since the introduction of drospirenone-containing OCPs, we compared the cumulative reporting of VTE events in the FAERS database associated with these OCPs with the general background using a standard measure of disproportionality. We conducted a similar analysis for levonorgestrel-containing OCPs. Because this study involved analysis of publicly available deidentified data, no Institutional Board Approval was required.
Identification of VTE events
Our analysis uses the Standardized MedDRA Query (SMQ) “Embolic and Thrombotic Events, Venous.” Table 1 provides the included MedDRA preferred terms. SMQs are groupings of MedDRA preferred terms that relate to a defined medical condition or area of interest. The included terms may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory, and other physiologic test data, etc, related to the medical condition or area of interest. SMQs were developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. Below, we refer to the “Embolic and Thrombotic Events, Venous” SMQ endpoint as “Venous Thrombotic (SMQ).”
Table 1 MedDRA terms included in the SMQ Embolic and Thrombotic Events, Venous
Abbreviation: SMQ, Standardized MedDRA Query.
Inclusion criteria for oral contraceptives
The medical literature concerning epidemiological studies of oral contraceptives frequently groups oral contraceptives according to progestin (eg, Dinger et al8 or Jick et al9). In our analysis, we considered two progrestins: drospirenone and levonorgestrel. We included products that were listed on the investigational new drug application for each of these progestins and that have oral contraception as an indication. Table 2 lists the specific products that we included.
Table 2 Specific drugs included
We used the lower bound of a 90% interval for the “information component (IC)” statistic.10 This statistic is commonly referred to as IC05. Because it is the lower end of the interval, IC05 is always closer to one than the IC and is thus more conservative than IC. The IC05 calculations stratify by age, sex, and year of report.
In practice, disproportionality metrics are often used with “signal thresholds” that dictate whether or not a given drug–outcome pair generates a signal. For example, Szarfman et al11 proposed using a threshold of 2 for the “EB05” measure, quantitatively very similar to the IC05.11 We indicate this threshold in Figure 1.
Figure 1 IC05 values for drospirenone-containing OCPs and levonorgestrel-containing OCPs.
Abbreviations: OCP, oral contraceptive pills; SMQ, Standardized MedDRA Query.
A signal of disproportionate reporting for drospirenone-containing OCPs appeared in 2002, well before any epidemiological studies raised any concerns, and persists to this day. It is unclear why the IC05 declined in the 2005–2010 period (albeit remaining well above the standard signaling threshold of 2), but it has increased steadily since then and is currently above 11. The IC05 for drospirenone-containing OCPs is approximately five times higher than that for levonorgestrel-containing OCPs.
Figure 1 shows the IC05 values for each quarter from the first quarter of 2000 through the first quarter of 2016.
Spontaneous report databases remain a mainstay of modern pharmacoepidemiology. Lester et al13 provide a recent demonstration of the importance of spontaneous report analyses in characterizing drug safety issues. The article considered all drug label changes in 2010 and reported that “Spontaneous reports were the most common evidence source from which drug safety issues were identiﬁed that resulted in safety-related label changes in 2010 when analyzed both by unique safety issue and drug (52% and 55% of all evidence sources, respectively).” Moore et al14 conducted a similar exercise, in their case looking at 2009 label changes involving major regulatory safety actions. The authors state that spontaneous reports “formed the basis of 77 of 135 new regulatory actions (57%) and 19 of 25 new boxed warnings (76%).” Hennessy and Strom15 state: “Spontaneous reporting systems remain to this day a crucial means of uncovering important postapproval drug safety information.”
Spontaneous report data have some inherent, well-documented limitations relying as they do on voluntary reporting. Underreporting is a particular concern that has been well documented and, furthermore, the data provide limited temporal information to inform analyses.16 Some authors refer to the possibility of “stimulated” or publicity-triggered reporting to FAERS. A recent comprehensive review of FDA safety alerts suggests modest evidence for significant reporting changes associated with the issuance of alerts.17 Some earlier studies drew similar conclusions.18,19 Disproportionality analyses provide limited opportunity for adjustment for potential confounding and this possibility cannot be ruled out.
Our analysis suggests that drospirenone-containing OCPs may result in many more VTEs than levonorgestrel-containing OCPs and that the gap is widening in recent years.
Dr Madigan testified for plaintiffs in litigation related to Yaz in 2011. The authors report no other conflicts of interest in this work.
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