Recent combined hormonal contraceptives (chcs) and the risk of thromboembolism and other cardiovascular events in new users

Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users Stephen Sidneya,⁎, T. Craig Cheetham b, Frederick A. Connell c, Rita Ouellet-Hellstrom d, David J. Graham d, Daniel Davis d, Michael Sorela, Charles P. Quesenberry, Jr.a, William O. Coopere aDivision of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA bPharmacy Analytical Services, Kaiser Permanente Southern California, Downey, CA, USA cUniversity of Washington, School of Public Health, Seattle, WA, USA dFDA Office of Surveillance and Epidemiology, Silver Spring, MD, USA eDepartment of Pediatrics, Vanderbilt University, Nashville, TN, USA Received 5 June 2012; revised 20 August 2012; accepted 13 September 2012 Background: Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) andarterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHCpreparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginalring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile.
Study Design: All VTEs and all hospitalized ATEs were identified in women, ages 10-55 years, from two integrated health care programsand two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogencomparator CHCs. The relative risk of thrombotic and thromboembolic outcomes associated with the newer CHCs in relation to thecomparators was assessed with Cox proportional hazards regression models adjusting for age, site and year of entry into the study.
Results: The hazards ratio for DRSP in relation to low-dose estrogen comparators among new users was 1.77 (95% confidence interval1.33-2.35) for VTE and 2.01 (1.06-3.81) for ATE. The increased risk of DRSP was limited to the 10-34-year age group for VTE and the35-55-year group for ATE. Use of the NGMN patch and ETON vaginal ring was not associated with increased risk of either thromboembolicor thrombotic outcomes.
Conclusions: In new users, DRSP was associated with higher risk of thrombotic events (VTE and ATE) relative to low-dose estrogencomparator CHCs, while the use of the NGMN patch and ETON vaginal ring was not.
2013 Elsevier Inc. All rights reserved.
Keywords: Contraceptives; Venous thromboembolism; Cardiovascular disease; Epidemiology thromboembolic events (ATEs), including acute myocardialinfarction (AMI) and ischemic stroke (IS) During the It is well known that the use of combined hormonal past 10 years, three new CHC preparations have been contraceptives (CHCs) is associated with an increased risk of approved for use by the US Food and Drug Administration venous thromboembolic events (VTEs), including deep vein (FDA), including drospirenone/ethinyl estradiol pills thrombosis (DVT) and pulmonary embolism (PE), and may (DRSPs), norelgestromin/ethinyl estradiol transdermal be associated with an increased risk of the arterial patch (NGMN) and the etonogestrel/ethinyl estradiol vaginalring (ETON).
Since marketing of these three new preparations began, there have been several studies evaluating the risk of ⁎ Corresponding author. Kaiser Permanente Northern California, thrombotic and thromboembolic events for two of them Division of Research, Oakland, CA 94612, USA. Tel.: +1 510 891 3753.
(DRSP and NGMN) compared to low-dose estrogen CHCs 0010-7824/$ - see front matter 2013 Elsevier Inc. All rights reserved.
S. Sidney et al. / Contraception 87 (2013) 93-100 that have been on the market for longer periods of time. The membership. We excluded 12,704 women with claims results have been mixed, with five out of eight studies evidence of severe life-threatening disease (sickle cell showing an increased risk of VTE with DRSP and disease, cystic fibrosis, cerebral palsy, cancer, HIV, organ two of five showing an increased risk with NGMN.
transplant, liver failure, severe congestive heart failure, renal It is unclear whether the differences in findings arose from failure, respiratory failure) or evidence of a study endpoint: differences in study methodologies or differences in the outpatient DVT or hospitalized VTE or ATE (AMI or IS) in populations studied. A recently published study showed a the 6 months before study entry. We additionally excluded modest increase of VTE risk with the ETON vaginal ring 9227 women whose only CHC exposures occurred during Only four studies have examined the risk of ATEs with periods of pregnancy and 2330 women whose only CHC any of these preparations, and none have shown significant prescription(s) was for two or more CHCs on the same date.
The final cohort included 835,826 women.
Thus, there is a great deal of concern and confusion From this cohort, we identified new users, defined as first among women and their health care providers regarding the exposure to any study CHC or comparator CHC during the safety of these newer preparations relative to older CHCs.
2001-2007 study period and no previous use of any CHC - We therefore performed this study to address methodolog- study, comparator or non-study CHC - during the study ical issues using a new user design to assess the risk of period. Additionally, women whose first exposure to a study each of the three newer CHCs relative to low-dose estrogen or comparator CHC occurred during the first 6 months of CHCs in a cohort of more than 573,000 new users of CHCs 2001 were required to have no previous use of any CHC from four geographically and demographically diverse during the 6 months preceding cohort entry. We identified 573,680 new users; these women had a total of 367,138person-years of exposure.
Exposure periods were calculated using the fill date of the CHC prescription. If a second prescription for the same CHC Study sites included Kaiser Permanente Northern Cali- was filled during the time period of the first prescription, fornia (KPNC), Kaiser Permanente Southern California then the start date of the second prescription was adjusted to (KPSC), Vanderbilt University (Tennessee State Medicaid) correspond to the day after the first prescription ended. This and University of Washington (Washington State Medicaid).
procedure was repeated until the time period covered by Computerized data files were used to obtain enrollment data, successive prescriptions with the first CHC ended or until a demographic information, ambulatory prescriptions from prescription for a second CHC was filled, thereby ending the pharmacy records or claims, hospitalization and outpatient exposure period to the first CHC. To reduce misclassifica- visit data with diagnoses from health plan records or claims, tion, we identified a period of indeterminate use, defined as and mortality obtained from state mortality files.
the 42-day period of time immediately after a prescription The study was approved by the institutional review board period ended, to account for any persisting physiological effects of CHCs on cardiovascular risk (i.e., increasedcoagulability). Since only 15% of person-time and 16% of the endpoints occurred during periods of "indeterminate The study CHCs included the following: drospirenone use," we did not analyze this group separately and included (3.0 mg)/ethinyl estradiol (30 mcg) tablets (DRSP), the the person-time and endpoints in our analysis of new users.
norelgestromin (6.0 mg)/ethinyl estradiol (750 mcg) trans- dermal patch (NGMN) and the etonogestrel (11.7 mg)/ethinyl estradiol (2700 mcg) vaginal ring (ETON). The Follow-up was evaluated independently for each of the comparator CHCs included the following low-dose estrogen study outcomes. End of follow-up for each woman in the CHCs: levonorgestrel (0.10 mg)/ethinyl estradiol (20 mcg) new user cohort was defined as the first of the following tablets (LNG10-20), levonorgestrel (0.15 mg)/ethinyl estra- dates: end of exposure to the study entry CHC or comparator, diol (30 mcg) tablets (LNG15-30), norethindrone (1 mg)/ last date of continuous membership, development of study ethinyl estradiol (20 mcg) tablets (NETA) and norgestimate endpoint, end of study follow-up (12/31/2007) or date of (0.18-0.25 mg)/ethinyl estradiol (35 mcg) tablets (NGM).
We identified 860,087 women, ages 10-55 years, who Because of the known hypercoagulability associated with had at least one prescription for a study CHC or comparator pregnancy, periods of pregnancy were estimated by CHC between January 1, 2001, and December 31, 2007, identifying claims for terminations and deliveries. For each which was also preceded by at least 6 months of continuous abortion, we estimated the period of pregnancy to include S. Sidney et al. / Contraception 87 (2013) 93-100 120 days prior to the date of the abortion, and we also causes (brain trauma, tumor, infection). Records of outpa- excluded CHC exposures and events occurring within 42 tient DVTs were obtained from one of the sites (KPNC) and days after the abortion. For each delivery, we estimated the were adjudicated by the lead principal investigator. Of the 48 period of pregnancy to include 270 days prior to the date of adjudicated outpatient DVTs in new users, 40 met the criteria the delivery, and we also excluded CHC exposure and for definite or probable VTE (83.3% positive predictive events occurring within 42 days after the delivery. The value). Validation of outpatient DVT was not possible at the pregnancy exclusion resulted in the exclusion of four Medicaid sites because the outpatient medical records were potential study endpoints and a small amount of potential unavailable and validation was not performed at KPSC.
Given the 83% validation rate for outpatient DVT at theKPNC site, we chose to include all 60 outpatient DVT cases from the three other sites in the final analysis.
The primary study endpoints were as follows: hospitalized ATE (including AMI and IS), hospitalized and outpatient Predefined covariates that were potential confounders or VTEs, and total mortality. All potential hospitalized cases effect modifiers were ascertained from the electronic were identified by the sites using the primary discharge codes: databases and were included if they were present in 1% or AMI (410.x), IS (430, 431, 432.0, 432.9, 433.x, 434.x, 436) more of the cohort. For the new user analysis, medical and VTE (PE code 415.1 and DVT codes 451.1, 451.1x, conditions were considered to be present from the first date 451.2, 451.8, 451.81, 451.82, 451.84, 451.89, 453.0, 453.1, they were identified, whether during the exposure period or 453.2, 453.3, 453.4, 453.8, 453.9). Outpatient DVT was during the 6 months prior to the exposure. Medications identified by a diagnosis of DVT in conjunction with a first during periods of CHC use were considered as time- prescription for an anticoagulant during the 30-day period dependent covariates based on prescription lengths and fill subsequent to the date of diagnosis. Mortality was assessed by dates. Hospitalizations for surgery or injury were evaluated linkage of membership data to state mortality files.
as time-dependent covariates. To account for hypercoagul- Medical records were requested on all potential hospital- ability following surgery and injury, we included a period of ized endpoints. The key elements of the hospitalization 6 weeks following the event as a time-dependent covariate.
medical record (e.g., admission and discharge summaries,laboratory tests, imaging study results) were deidentified and sent to the study lead site (KPNC) for adjudication.
Physician adjudicators (a cardiologist, neurologist and two Age-adjusted incidence rates were also calculated using other physicians) blinded to the case exposure status applied direct adjustment with the age distribution of the entire study case definitions based on clinical diagnosis of the study population at cohort entry as the standard. All data analyses endpoints utilizing clinical data about the patient, plus electrocardiogram and biomarker (blood creatine kinase- Cox proportional hazards regression was used to estimate MB, troponin) findings for AMI and imaging study findings the relative risk of study endpoints associated with current for stroke (e.g., brain computed tomography or magnetic use of each study CHC relative to comparator CHCs. CHC resonance imaging) and VTE (e.g., Doppler exam, ventila- exposure was considered as a four-level covariate, capturing tion-perfusion scan, pulmonary angiography). Potential current use of each of the three study CHCs with the four stroke and VTE cases for which imaging studies were not comparators combined as one category. We also performed performed or findings were unavailable were excluded from the analyses using LNG15-30 alone as the comparator and the analysis. Cases for which the adjudication decision was report the major findings for these analyses since LNG15-30 ambiguous were discussed and resolved with the lead is the only one of the four comparators that has the same ethinyl estradiol content (30 mcg) as the study CHC, DRSP.
We obtained 874 of 947 (92.3%) medical records for Time since cohort entry was the time scale in the models.
potential hospitalization endpoints, of which 377 were Cox regression models were stratified on age, allowing for medical records of new users (34 AMIs, 90 strokes, 253 separate baseline hazards for each age category (5-year VTEs). We excluded the 73 potential cases for which intervals); additional control for potential residual confound- medical records were not available from the analytic data set.
ing within age strata was achieved via inclusion of age as a In new users, 221 of the 253 (87.4%) potential cases continuous covariate in the regression model. Age (contin- reviewed were validated as true VTEs, and 28 of the 34 uous), site and calendar year of entry into study were AMIs (82.4%) reviewed were validated as true AMIs. Of the included in all models. Established risk factors (hyperten- 90 potential stroke cases reviewed, 55 (61.1%) were sion, hyperlipidemia and diabetes mellitus) were included as validated as true stroke syndromes, of which 37 were fixed covariates in the ATE models. Each of the other ischemic strokes (68.7%) (18 were of nonatherothrombotic potential covariates was tested individually in these base etiology). Of the 35 cases that did not meet the criteria of models, with a decision to include it in further model testing stroke, 5 were stroke-like syndromes attributable to other if the estimate of relative risk was associated with any of the S. Sidney et al. / Contraception 87 (2013) 93-100 Table 1New users: study and comparator CHC users by age and site (column percents) Study CHCS: DRSP, NGMN and ETON.
Comparators: LNG10-20, LNG15-30, NETA and NGM.
study CHCs was changed by 10% or more. None of the users of the comparator group. There were site differences covariates met this criterion for any of the models, so none in the use of new CHCs, most notably that the NGMN were included in the final modeling.
was the most commonly used study contraceptive at theMedicaid sites.
The prevalence of covariates by CHC is shown in The prevalence of most of the covariates associated with thestudy CHCs was lower than or similar to the prevalence in The final study cohort of the new CHC users included users of comparator CHCs except for acne (4% for DRSP 573,680 women. More than three quarters (78%) were 15-34 years of age (). The mean age of new users The overall crude incidence of the study endpoints was was 26.4 years at initiation of use, ranging from 23.4 1.77 per 10,000 person-years for ATE and 8.74 per 10,000 years for users of the NGMN patch to 27.2 years for person-years for VTE. The age-specific and age- and site- Table 2Distribution of covariates: study CHC in new users for combined sites Covariates selected because they each had a prevalence of at least 1% in at least one of the CHC categories.
ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs; NS, not significant.
p value of χ2 test for percentage of covariate for each exposure CHC with percentage of covariate for comparator group:*p valueb.01.
**p valueb.001.
Percent refers to new users of study CHC.
Comparators: LNG10-20, LNG15-30, NETA and NGM.
S. Sidney et al. / Contraception 87 (2013) 93-100 Table 3Age-specific incidence rates, and age- and site-adjusted rates for hospitalized ATEs, all VTEs and total mortality by study contraceptive type among new users(rates per 10,000 person-years, 95% CIs in parentheses) The person-years for each comparator are 15,440 for LNG10-20, 97,260 for LNH-15-30, 67,026 for NETA and 68,305 for NGM.
Comparators: LNG10-20, LNG15-30, NETA and NGM.
a Age-specific rates provided for age categories, with age- and site-adjusted rate provided in the total category.
b COMP includes all four comparators.
adjusted incidence rates of hospitalized ATE, all VTE and VTE (HR 1.57, 1.13-2.18) and was not statistically increased total mortality are shown in As expected, the for ATE (HR 1.64, 0.79-3.40), while the age-specific incidence rates for ATE and VTE increased with age, with findings of increased risk of VTE in DRSP new users 10- 57% of ATE and VTEs occurring in the 35-55-year agegroup even though only 23% of the follow-up time was in Relative hazarda of hospitalized ATEs, all VTEs and total mortality The relative hazards of study endpoints associated with associated with study exposure relative to combined comparators for all new new use of the study CHCs in relation to the combined comparators are shown in. New use of DRSP was associated with increased risk of VTE [relative hazard (HR) 1.77, 95% confidence interval (CI) 1.33-2.35] and ATE (HR 2.01, 1.06-3.81) when compared to all comparators. The increased risk of VTE in new users was restricted to women, ages 10-34 years (HR 2.12, 1.43-3.15), while the increased risk of ATE was restricted to women, ages 35-55 years (HR 2.60, 1.25-5.41). In secondary analyses, the DRSP risk estimates were elevated for outpatient DVT (HR 1.51, 1.00- 2.28), hospitalized DVT (HR 1.74, 1.00-3.02), all DVT (HR 1.58, 1.09-2.28), hospitalized PE (HR 2.22, 1.41-3.36) and all hospitalized VTE (HR 2.08, 1.46-2.98). NGMN andETON were not associated with an increased risk for any of ATE and mortality models are further adjusted for hypertension,hyperlipidemia, and diabetes.
Numbers in bold font are significant.
When comparing DRSP with LNG15-30 alone (137,311 a Estimates from Cox proportional hazards models. All models adjusted new LNG15-30 users), the relative risk was similar for all for age (within age group), site and year of entry into study.
S. Sidney et al. / Contraception 87 (2013) 93-100 Table 5Age- and site-adjusted incidence rates for hospitalized ATEs, all VTEs and all-cause mortality by study contraceptive type and duration of use among new users(rates per 10,000 person-years, 95% CI in parentheses) Study CHCS: DRSP, NGMN and ETON.
Comparators: LNG10-20, LNG15-30, NETA and NGM.
a COMP includes all four comparators.
34 years of age (HR 2.16, 1.32, 3.54) and of ATE in those 35- CHCs. The increased risk of ATE was present only in the 55 years of age (HR 2.42, 1.01, 5.82) were consistent with the older segment of the cohort (ages 35-55 years), while the overall findings with combined comparators.
increased risk of VTE was restricted to the younger women We also tested individually in the models each of the (ages 10-34 years). We did not find statistically significant covariates that had a prevalence of 1% or more in any of the associations for NGMN or ETON with any of the endpoints.
exposure groups (). None changed the relative hazard Of the four prior studies examining the association of the estimate by 10% or more so all were excluded from the final NGMN transdermal patch with VTE, one showed no increased models. A test for age interaction was not significant for risk relative to NGM-containing CHC pills two showed an approximate doubling of risk relative to either shows the incidence rates of study endpoints by NGM-containing or LNG-containing CHCs and duration of use. For VTE, the incidence was highest during one showed no increased risk relative to LNG-containing the first 3 months of use for DRSP and NGNM, as expected.
CHCs in women 39 years or younger, but could not rule out The number of VTEs was low in all duration time intervalsfor ETON. For ATE and total mortality, the number ofevents in each of the duration time intervals was small (≤8) Relative hazard of hospitalized ATEs, all VTEs and total mortality shows the association of duration of use on the associated with study exposure contraceptive relative to the combinedcomparator CHCs group by duration of use in new users hazard ratio for the newer CHCs relative to comparatorsbased on Cox proportional hazards regression. As expected, DRSP use of less than 12 months was associated with increased risk of VTE (HR 1.96, 95% CI 1.25-3.70 for b3 1.35 (0.17-10.87) 12.40 (1.36-113.49) months and HR 1.88, 95% CI 1.20-2.93 for 3-12 months).
The other increased risks (NGMN N12 months and VTE, ETON N12 months and ATE) occurred in association with small cell sizes and were possibly chance findings.
The major finding from this population-based cohort of Estimates from Cox proportional hazards models. All models adjusted forage, site and year of entry into study.
573,680 women who initiated new use of study CHCs was ATE and mortality models are further adjusted for hypertension, an increased risk of ATE and VTE associated with DRSP use relative to the use of the four comparator low-dose estrogen Numbers in bold font are significant.
S. Sidney et al. / Contraception 87 (2013) 93-100 an increased risk in women ages 40-44 years Two Food and Drug Administration, Office of Surveillance and studies examined NGMN patch use with ATE, but both had Epidemiology, Center for Drug Evaluation and Research).
small numbers of the endpoints and found no Diana Petitti, M.D., M.P.H. (Arizona State University), association. There have been no published studies of ETON The following individuals at the study sites are acknowl- Another study reporting ATE and death associated with edged for their contributions to the study: the use of DRSP was the European Active Surveillance Study on oral contraceptives. There were 25 ATEs (none in Patricia Leighton (project management).
DRSP users) and 32 deaths associated with a mortality rate Mike Sorel and Kim Tolan (computer programming and of 1.4 per 10,000 In the present study, we found 14 women who initiated drospirenone-containing oral contra- Barbara Rowe (medical record analyst).
Charles Quesenberry (biostatistician).
It is unclear why the results have been inconsistent Karin Winter (research coordinator).
regarding the risk of VTE with DRSP. It is likely that some Luisa Hamilton, Arthur Klatsky and Allan Bernstein of the variation in study findings relate to methodological differences including whether or not the analyses were restricted to new users, inclusion or exclusion of women with cancer and other serious events which increased risk of thromboembolic events, capability for case adjudication and Felicia Bixler, Theresa Im, Claire Mesirov (research The major strengths of this study are inclusion of a large geographically and demographically diverse cohort of new CHC users and the capability to evaluate all three of the Shannon Stratton (research coordinator).
newer contraceptive preparations in the same analytic data Michelle DeRanieri, Patricia Gideon and Leanne Balmer set. Additionally, the ability to evaluate risk of non-VTE endpoints, namely, ATE and mortality, and the ability to adjudicate endpoints by medical record review were Karen Young, Mark Konodi, Farah Khan (Medical record Limitations of the study include (a) the assessment of CHC exposure periods based on the electronic pharmacy records of filled prescriptions rather than information on Content of manuscript was in part derived from the final actual intake and (b) the absence of some important report of the study to the Food and Drug Administration covariates. Although electronic pharmacy data may not titled Food and Drug Administration, Office of surveillance represent the actual use of the medications, these data have and epidemiology. Combined hormonal contraceptives been shown to provide reasonably unbiased information on (CHCs) and the risk of cardiovascular disease endpoints.
medication use. We also did have not have access to data on key confounders including obesity, personal and family history of thrombosis, lifetime use of hormonal contracep-tives and smoking. However, the studies which have included these variables in their analyses or a subset ofthem found that estimates of relative risk were not [1] Cardiovascular disease and steroid hormone contraception. Technical In summary, we found that the initiation of new use of [2] Chan WS, Ray J, Wai EK, Ginsburg S, Hannah ME, Corey PN, Ginsberg JS. Risk of stroke in women exposed to low-dose oral DRSP-containing CHCs was associated with a 77% increase contraceptives: a critical evaluation of the evidence. Arch Intern Med in the risk of hospitalization for VTE relative to the use of a comparator group of four low-dose estrogen CHCs. Though [3] Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association the absolute incidence of VTE is low, the growing number of between the current use of low-dose oral contraceptives and studies showing an increased risk of VTE with DRSP cardiovascular arterial disease: a meta-analysis. J Clin EndocrinolMetab 2005;90:3863-70 [Epub 2005 Apr 6].
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