“Recent Combined Hormonal Contraceptives (CHCs) and the Risk of Thromboembolism and Other Cardiovascular Events in New Users” (2012), by Stephen Sidney, T. Craig Cheetham, Frederick A. Connell, Rita Ouellet-Hellstrom, David J. Graham, Daniel Davis et al.

In 2012, Stephen Sidney, T. Craig Cheetham, Frederick A. Connell, and colleagues published “Recent Combined Hormonal Contraceptives (CHCs) and the Risk of Thromboembolism and Other Cardiovascular Events in New Users,” hereafter “Combined Hormonal Contraceptives” in Contraception. The authors gathered records of major cardiovascular events in patients who were using combined hormonal contraceptive treatments, or CHCs. A CHC is a birth control medication that contains both estrogen and progestin hormones. The CHCs of focus, which the authors referred to as the study CHCs, included a pill, patch, and vaginal ring that the US Food and Drug Administration, or FDA, recently approved at the time of publication. The researchers compared the rates of cardiovascular events between users of the study CHCs to users of established CHCs to find any increased cardiovascular risk. “Combined Hormonal Contraceptives” showed that the study CHCs did come with some increased cardiovascular risk, and reconfirmed the known cardiovascular risks of CHCs in general, providing safety information for people who may want to start birth control.

The authors of “Combined Hormonal Contraceptives” contributed to the article from various institutions. At the time of publication, Stephen Sidney, Michael Sorel, and Charles P. Quesenberry, Jr. worked in the Division of Research at the healthcare company Kaiser Permanente Northern California in Oakland, California. T. Craig Cheetham worked in Pharmacy Analytical Services for Kaiser Permanente Southern California in Downey, California. Frederick A. Connell worked for the School of Public Health at the University of Washington in Seattle, Washington, and William O. Cooper worked in the Department of Pediatrics at Vanderbilt University in Nashville, Tennessee. Rita Ouellet-Hellstrom, David J. Graham, and Daniel Davis worked in the Office of Surveillance and Epidemiology at the Food and Drug Administration in Silver Spring, Maryland. As of 2023, Sidney continues to work as a scientist under Kaiser Permanente Northern California, and Connell continues to conduct research and teaches at the University of Washington.

“Combined Hormonal Contraceptives” is a research article that describes a retrospective cohort study examining the records of cardiovascular events among new users of recently formulated combined hormonal contraceptives. A retrospective cohort study analyzes past medical records to look for trends or outcomes with respect to a specific characteristic, such as treatment methods. The study CHCs the researchers analyze were drospirenone and ethinyl estradiol pills, hereafter DRSP pills, the norelgestromin and ethinyl estradiol transdermal patch, hereafter NGMN patch, and the etonogestrel and ethinyl estradiol vaginal ring, hereafter ETON ring. Prior to its publication, there were several existing studies about the cardiovascular risks of the DRSP pill, NGMN patch, although not on the ETON ring. The authors of those prior studies got mixed results and examined only venous thromboembolic events. Furthermore, there were only four papers prior to “Combined Hormonal Contraceptives” that examined the risk of arterial thromboembolic events, which occur when a blood clot blocks an artery, with the study CHCs. The researchers of those papers did not see any major correlations between such events and the study CHCs. Sidney and colleagues aimed to better investigate the study CHCs to provide a clearer understanding of the possible cardiovascular risks.

Two of the main cardiovascular risks that the authors observed in “Combined Hormonal Contraceptives” are venous thromboembolism and arterial thromboembolism. Venous thromboembolism is when a blood clot blocks a vein. The researchers refer to the venous thromboembolism as venous thromboembolic event, or VTE, in their study. The types of venous thromboembolism consist of deep vein thrombosis, which is when a clot forms in a deeper vein, for example in the lower leg, and pulmonary embolism, which is when the blood clot breaks off and reaches the lungs causing a blockage. The other cardiovascular event the researchers observe is arterial thromboembolism. The researchers refer to the arterial thromboembolism as arterial thromboembolic event, or ATE, in their study. The types of arterial thromboembolism consist of acute myocardial infarction, which is when the blood clot blocking an artery results in a heart attack, and ischemic stroke, which is when the blockage results in a stroke.

“Combined Hormonal Contraceptives” consists of four main sections titled “Introduction,” “Materials and Methods,” “Results,” and “Discussion.” In the “Introduction,” the authors discuss the current known risk of cardiovascular events with previous CHCs, and introduce the DRSP pill, NGMN patch, and ETON ring as newer CHCs requiring further study on the health risks. In “Materials and Methods,” in nine subsections, the authors discuss the set-up of the study, how they gathered information primarily by studying the subjects’ health records, and the statistical tests they performed to draw conclusions. The authors also convey in that section that they also examined subjects who were using other CHCs, or comparator CHCs, that have been on the market longer and have been researched more than the study CHCs. In the “Results” section, the authors discuss trends in age and preexisting medical conditions among the cohort, and the overall incidence of cardiovascular events in the study, and found DSRP pills to have a higher risk of cardiovascular events. In the “Discussion,” the authors state their main conclusion was that new users of DRSP pills show an increased risk of ATEs and VTEs compared to the comparator CHCs. They close the article with a caution about the prescription of DRSP pills due to the documented increased risk.

In the “Introduction,” the authors state that there is a known increased risk among users of combined hormonal contraceptives for VTEs, as well as a possible increased risk for ATEs. The researchers then introduce the three CHC medications that they studied, the DRSP pill, NGMN patch, and ETON ring, which the FDA approved ten years prior to their paper. All three CHCs contain some combination of a type of progestin, or synthetic progesterone, and ethinyl estradiol, or synthetic estrogen. The DRSP pill is a tablet taken once daily. A NGMN patch user places the patch on the skin and replaces it every seven days for a period of twenty-one days, and then on day twenty-two should remove the patch for seven days before doing it all again. Similarly, the ETON ring, also known as NuvaRing, stays in the vagina for twenty-one days before the user replaces it after a week.

The authors continue to discuss in the “Introduction” that other researchers have conducted studies comparing the incidence of cardiovascular events with use of the three medications in comparison to older CHCs on the market, which contain a lower dose of estrogen. They state that the results of prior studies have been mixed in the differences in risk of VTEs associated with the new medications, and that studies that have assessed risk of ATEs have also not drawn significant associations. The authors explain that the lack of conclusive safety information about newer CHCs can cause confusion for patients and physicians when considering a birth control method. Finally, the authors proclaim that in “Combined Hormonal Contraceptives,” they address issues of previous studies by using a large cohort of over 573,000 patients from four diverse health plans.

Throughout the nine subsections of the “Materials and Methods” section, the authors list the sites they collected data from and discuss that they collected patients’ data regarding their use of CHCs and the cardiovascular events they experienced, which they call the study endpoints. First off, the authors list the study sites from where they took patient data, which were Kaiser Permanente Southern California, Kaiser Permanente Northern California, Vanderbilt University, in Nashville, Tennessee, and University of Washington in Seattle, Washington. Kaiser Permanente sites reported data from the company’s insurance department, which is integrated into their healthcare company. Vanderbilt University and University of Washington provided data from Tennessee State Medicaid and Washington State Medicaid programs, respectively. The researchers obtained data about patients and their CHC prescriptions through health documentations such as pharmacy, hospitalization, and health plan records. The authors describe that they calculated the time of CHC exposure for a patient using the fill dates of prescriptions and accounted for other factors such as persisting effects of the CHC after use. They did not count the time period of when patients were pregnant, and also excluded the time period shortly after pregnancy ended. The authors further explain the study endpoints, which include if the patient was hospitalized with ATE or VTE, outpatient VTEs, and the total mortality, or death rate. The researchers verified the patients’ diagnoses with specialized physicians like cardiologists to obtain an accurate number of cardiovascular events. Finally, the authors describe their methods of statistical analysis on the data to estimate the risk of cardiovascular events associated with the use of study CHCs.

Continuing in the nine subsections of the “Materials and Methods” the authors describe their criteria for including patients in the study, such as what CHC a patient was on, and how they narrowed down their subjects for the study. Along with the study CHCs, the comparator CHCs the researchers included were two different combined dosages of levonorgestrel and ethinyl estradiol tablets, hereafter LNG10-20 and LNG15-30, norethindrone and ethinyl estradiol pills, hereafter NETA pills, and norgestimate and ethinyl estradiol pills, hereafter NGM pills. The authors write that they included patients in the study who were between ten and fifty-five years of age with at least one prescription for a study CHC or comparator CHC during the dates of 1 January 2001 to 31 December 2007. The researchers initially recognized 860,087 potential study patients, and then refined the cohort by excluding patients due to specific factors, such as if they had a life-threatening illness unrelated to their use of the CHCs. Next, the researchers further refined the cohort by only picking out patients who had their first exposure to either the study or comparator CHC between 2001 to 2007 and had no previous use of a CHC. The number of new users the authors confirmed were 573,680 patients, who made up the authors’ total study cohort. The researchers report that the total combined time that all the patients in the study were exposed to CHCs amounted to 367,138 years. The authors also considered various covariates in the study, which were other treatments, medications, or conditions that could potentially interfere with results.

In the “Results” section, the authors found that in comparison to the comparator CHCs, the DRSP pill showed an increased risk of VTEs and ATEs, while the NGMN patch and ETON ring did not show an increased risk. The authors start off by reporting general findings that seventy-eight percent of patients in the study cohort were from fifteen to thirty-four years in age, and that the NGMN patch was the most used CHC at Medicaid study sites. The authors state that the chance of cardiovascular events from the cohort information was that, for every 10,000 years of the participants’ combined exposure to the CHC, there were 1.77 ATEs, and 8.74 VTEs. The authors also state that the incidence of both ATE and VTE increased with age of patients, with fifty-seven percent of events occurring in patients aged thirty-five to fifty-five. The authors also include six tables in the “Results” section that list data about the patients, including the number of patients using each CHC of interest, how long they used it for, the number of cardiovascular events experienced, mortality, and general information about patient demographics.

In the “Discussion” section, the authors state their main conclusion was that there is an increased risk of ATEs and VTEs in new users of DRSP pill in comparison to older CHC. They note that within the cohort, the risk of ATE was higher in the older age group, from ages thirty-five to fifty-five, and the risk of a VTE was higher in the younger age group, from ages ten to thirty-four years. They restate that they did not find statistically significant information to conclude that NGMN patch or ETON ring use correlated with an increased risk of cardiovascular events. The authors again discuss that prior studies have had inconsistent results that can be possibly attributed to issues with study design, inclusion criteria, or failure to focus on new users. They highlight the strength of their study in having a large, geographically, and demographically diverse sample and analyzing three different and recently approved CHC medications in new users. The authors mention that some shortcomings of the study were that they based the exposure period to the CHC purely on pharmaceutical data instead of the patient’s actual intake, and they lacked access of significant covariates like obesity, family medical history, smoking, and lifetime use of CHCs. They summarize their findings by stating that new use of DRSP pills showed a seventy-seven percent increase in risk of hospitalization for a VTE compared to comparator CHCs and encourage caution of physicians and patients in considering the prescription and use of the DRSP pill.

According to Google Scholar, “Combined Hormonal Contraceptives” has 168 citations as of 2023. Other articles regarding contraceptive use, hormone therapy, and associated cardiovascular conditions and risks have cited the article. For example, an article published on the management of venous thromboembolism in 2019, by a group of researchers and physicians primarily studying transgender medicine, cited Sidney and colleagues when putting into perspective the risks of combined oral contraceptives, or COC. Using Sidney and colleagues’ data, the researchers explain that even though there is a risk of VTE in people using COC, the risk is much higher to pregnant people and recently pregnant people.

“Combined Hormonal Contraceptives” has also helped establish the health risks of common CHCs, and has been incorporated into some warning labels. For example, though the NuvaRing label initially included no warning of cardiovascular risk, in 2013, the NuvaRing label information changed to include a summary and citation of “Combined Hormonal Contraceptives” as well as information from a similar study published in 2013 to inform users about known cardiovascular risks of CHC use. The NuvaRing label change occurred following a controversy involving NuvaRing’s original manufacturing company, called Organon at the time. According to HuffPost, Organon executives allegedly opposed having a significant warning on the original NuvaRing label. A user who experienced blood clots felt that the company mislabeled the product and did not properly test it before its public distribution. The later inclusion of “Combined Hormonal Contraceptives” on the new NuvaRing label helps to better inform users or potential users of the NuvaRing of the risks for cardiovascular events, especially with respect to different age groups.

“Combined Hormonal Contraceptives” allowed for researchers and physicians to further understand the health conditions associated with CHCs, and helped make consumers aware of potential risks of using certain CHCs, such as vaginal rings. The article provides health information to help physicians and patients understand and evaluate different birth control methods to best suit a particular patient with a specific health history and contraceptive needs.