Abstract
Background:
Although heavy menstrual bleeding (HMB) is a known complication of anticoagulant therapy, rates of HMB in users of the direct oral anticoagulants (OACs) apixaban and rivaroxaban are largely unknown.
Methods:
We performed a retrospective cohort study of menstruating women prescribed rivaroxaban, apixaban and warfarin over a six-year period (2012–2018). The primary outcome was HMB requiring medical or surgical intervention. We used descriptive statistics and logistic regression to evaluate associations between OAC type, age, history of HMB, and the primary outcome.
Results:
We identified 195 women of reproductive-age with a new therapeutic OAC prescription (62 on rivaroxaban, 54 on apixaban, 79 on warfarin). A minority (26/195, 13.3%) had a documented history of HMB, including 9 rivaroxaban users, 7 apixaban users and 10 warfarin users but most women (117/195, 60%) had no menstrual history documented. One third of subjects (64/195) required treatment for HMB within 6 months of starting OAC therapy. After controlling for a history of HMB, rivaroxaban users were 1.4 times more likely to require treatment as compared to users of other OACs.
Discussion:
We found an association between rates of HMB necessitating medical or surgical intervention and rivaroxaban use. We also found that the majority of women did not have a documented menstrual history, suggesting that many providers do not inquire about menstrual bleeding when starting OAC therapy. Menstruating women, particularly those with a history of HMB, may be at increased risk for HMB necessitating medical treatment depending on the type of OAC used.
Keywords: Heavy menstrual bleeding, Anticoagulation, Rivaroxaban, Apixaban, Warfarin
Introduction
Monthly menstruation is a natural, routine occurrence that can become pathological in the setting of anticoagulant use. Studies of oral anticoagulants (OACs) vary widely in their definition of pathological uterine bleeding and do not necessarily capture bleeding associated with menstruation.[1, 2] Consequently, there is a paucity of studies designed to not only identify women experiencing heavy menstrual bleeding (HMB) but quantify the significance of their bleeding during OAC use. Our lack of understanding is particularly problematic as women of reproductive-age are disproportionately affected by venous thromboembolism [3, 4]; thus making up a significant number of OAC users.
Newer OACs, like rivaroxaban and apixaban, have many advantages over previously approved agents - quickly making them the standard of care.[5, 6] Emerging data demonstrates that rates of abnormal uterine bleeding with these agents may be as high as 73% (rivaroxaban) and this in turn, may result in dose modification and/or temporary interruption of anticoagulation (9.6%).[7] Temporary interruption of therapy increases the risk of repeat thromboembolic events.
We designed this retrospective study to specifically focus on the impact of OACs on menstrual-associated bleeding. Here, we report on a retrospective cohort of reproductive-age women prescribed rivaroxaban, apixaban or warfarin within a single institution over a six-year time period. We hypothesized that women treated with rivaroxaban would experience more HMB requiring intervention as compared to women treated with apixaban or warfarin.
Methods
We conducted a retrospective review of case records from one US-based tertiary care center (Portland, OR) and its affiliated clinics from January 1, 2012 through December 31, 2018 using our electronic medical record database. We received authorization for a waiver of consent from the Oregon Health & Science University Institutional Review Board to perform this study.
Subject Selection
We identified medical records by searching for female patients between the ages of 18–50 with a prescription for rivaroxaban, apixaban or warfarin during the study period. A case record was excluded if surgical menopause was documented prior to OAC initiation, or if OAC use was within 6 months of a pregnancy or within 3 months of lactation. Additionally, any individuals not receiving follow up care within our healthcare system were excluded in an effort to ensure that treatments for HMB during OAC use were captured.
During data collection, we noticed that our search strategy captured a large proportion of medical records where OAC use was for prophylaxis and not treatment of VTE. These individuals were prescribed a lower dose of OAC (typically half of a therapeutic dose) for a shorter course of therapy (30 days or less). We made the decision to exclude these charts as they did not represent the population of interest, individuals receiving therapeutic anticoagulation for multiple menstrual cycles.
Data Collection
Study staff reviewed any identified chart to confirm eligibility. Once eligibility was confirmed, they extracted the following information: type of OAC prescribed, indication for use, age at OAC initiation, and general demographics. Charts were also reviewed for a history of normal menses or HMB (yes/no) prior to initiation of OAC that could be noted on a problem list or in any chart note from a primary care provider or specialist. For those medical records that had no menstrual history documented, these were categorized as “HMB not mentioned.” Charts were also reviewed for use of hormonal therapies and type (progestin only or combined estrogen and progestin therapy) as well as indication as documented by the prescriber (contraception only, menstrual management only or both) immediately prior to OAC initiation but also post-OAC use. We categorized any treatment for HMB during OAC use as yes/no but further defined it as either surgical or medical therapy, including hormonal therapies, blood transfusion and intravenous or oral iron supplementation.
Statistical Analysis
Our primary outcome was evidence of treatment for HMB within 6 months of OAC (yes/no). We utilized descriptive statistics for summarizing all variables at OAC initiation and at six months post-OAC initiation. We performed logistic regression to evaluate for associations between age, prior history of HMB, OAC type, and the primary outcome. We created models utilizing age as both a continuous and binomial variable to assess possible differences in bleeding between young and potentially perimenopuasal (age 45–50) women. In order to assess the impact of prior HMB on the risk of HMB during OAC therapy, we created two logistic regression models. In the first model, we combined those women with no documented menstrual history and those with a documented history of normal menses into a single group, compared to women with a documented history of HMB. In the second model, we excluded women without mention of menstrual history from the model altogether, comparing only those women with a documented history of HMB to those women with documented normal menses. We controlled for both age and prior history of HMB when modeling the impact of OAC type on the primary outcome.
Results
Population
A total of 1,176 subjects were identified using the initial search strategy, 751 of which were between the ages of 18–50 and had a prescription for one of the included OACs during the study period (Figure 1). An additional 556 subjects met one or more exclusion criteria. Our study population were mostly white, mid-30s, and using OACs for VTE treatment (Table 1). Sixty-two (31.8%) were prescribed rivaroxaban, 54 (27.6%) were prescribed apixaban, and 79 (40.5%) were prescribed warfarin.
Figure 1.
Study Flow
OAC: oral anticoagulant
HMB: heavy menstrual bleeding
Table 1.
Characteristics of enrolled patients on therapeutic anticoagulation
| Rivaroxaban (n=62) | Apixaban (n=54) | Warfarin (n=79) | All Subjects (n=195) | |
|---|---|---|---|---|
| Age, years, mean (range) | 36.9 (18–50) | 36.9(18–50) | 36.4 (2050) | 36.4 (18–50) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 5(8.1) | 5(9.3) | 7 (8.9) | 17 (8.7) |
| Not Hispanic or Latino | 57 (91.9) | 48 (88.9) | 72 (91.1) | 176 (90.2) |
| Unknown | 0 | 1 (1.9) | 1 (1.3) | 2 (0.5) |
| Race, n (%) | ||||
| African American | 3 (4.8) | 2(3.7) | 4(5.1) | 9 (4.6) |
| American Indian or American Native | 2 (3.2) | 0 | 1 (1.3) | 3 (1.5) |
| Asian | 0 | 0 | 2 (2.5) | 2 (1) |
| Caucasian | 54 (87.0) | 44 (81.5) | 68 (86.1) | 167 (85.6) |
| Native Hawaiian or Pacific Islander | 0 | 1 (1.9) | 1 (1.3) | 2 (1) |
| Unknown | 3 (4.8) | 7 (13.0) | 3 (3.8) | 13 (6.7) |
| Indication of OAC, n (%) | ||||
| Venous thrombosis | 53 (85.5) | 42 (77.8) | 59 (74.7) | 154 (79) |
| Arterial thrombosis | 3 (4.8) | 3(5.6) | 9 (11.4) | 15 (7.7) |
| Atrial fibrillation | 3 (4.8) | 5(9.3) | 4(5.1) | 12 (6.1) |
| Mechanical valve | 0 | 0 | 2 (2.5) | 2 (1) |
| Other | 3 (4.8) | 5(9.3) | 5 (10.1) | 12 (6.1) |
| HMB prior to OAC, n (%) | ||||
| Yes | 9 (14) | 7 (13.0) | 10 (12.7) | 26 (13.3) |
| No | 19 (30.6) | 12 (22.2) | 21 (26.6) | 52 (26.7) |
| Not mentioned | 34 (54.8) | 35 (64.8) | 48 (60.8) | 117 (60) |
| Hormonal medication at OAC initiation, n (%) | ||||
| Yes | 34 (54.8) | 19 (35.2) | 38 (48.1) | 91 (46.7) |
| No | 19 (30.6) | 16 (29.6) | 18 (22.8) | 53 (27.2) |
| Not mentioned | 9 (14.5) | 19 (35.2) | 23 (29.1) | 51 (26.1) |
| Hormone type, n (% of hormonal medication) | ||||
| Progestin | 14 (41.2) | 7 (36.8) | 12 (31.6) | 33 (36.3) |
| Combination | 20 (58.8) | 11 (57.8) | 26 (68.4) | 57 (62.6) |
| Other | 0 | 1 (5.3) | 0 | 1 (1) |
| Hormone Indication, n (% of hormonal medication) | ||||
| Contraception | 8 (23.5) | 5 (26.3) | 7 (18.4) | 20 (22) |
| Menstrual management only | 8 (23.5) | 3 (15.8) | 5 (13.2) | 16 (17.5) |
| Both | 3 (8.8) | 1 (5.3) | 5 (13.2) | 9 (10) |
| Not mentioned | 15 (44.1) | 10 (52.6) | 21 (61.8) | 46 (50.5) |
Baseline HMB and Hormonal Use
The majority of subjects (138/229, 60.3%) had no menstrual history documented in the chart prior to OAC initiation. Of the remaining 91 subjects, approximately 30% had a documented history of HMB and the remainder had normal menses. Nearly half (103/229, 45%) of subjects were using hormonal medication (e.g. contraception) immediately prior to initiation of anticoagulation, the majority (59, 57.2%) of whom were on combined estrogen and progestin therapies.
HMB and Hormonal Use at Six Months
In the cohort of subjects receiving OAC for therapeutic indications, 64 subjects (32.8%) needed treatment for uterine bleeding within six months of OAC initiation (Figure 2a). The majority of subjects needing an intervention for uterine bleeding were taking rivaroxaban (28/64, 43.8%) as compared to apixaban (14/64, 21.9%) or warfarin (22/64, 34.4%) (Chi-square test: p= 0.028). Most subjects received medical therapies only (57/64, 89%) while the remainder underwent both medical and surgical interventions. Based upon these findings, the number needed to harm, defined as excess cases of HMB, by prescribing rivaroxaban instead of apixaban is five.
Figure 2.
Prevalence of heavy menstrual bleeding and hormonal therapy at six months
Figure 2a Heavy menstrual bleeding (HMB) at six months by oral anticoagulant
Figure 2b Hormone therapy at six months by oral anticoagulant
At six months post OAC initiation only 75 subjects (38.5%) were using hormonal therapies in the six months following OAC initiation (Figure 2b). The vast majority of these (69/75, 92.1%) were using progestin-only therapies. Fourteen subjects were newly initiated on hormonal therapies after starting OAC therapy. One was prescribed a combined hormonal contraceptive and the remainder were prescribed progestin-only therapies (IUS, implant or pill).
Thirty subjects who were on hormonal therapy prior to OAC initiation discontinued this therapy and did not initiate an alternative. This included 36.8% (7/19) of patients on apixaban, 17.6% of (6/34) patients on rivaroxaban and 47% (18/38) of patients on warfarin (p = 0.028). In the majority of cases (41/75, 54.7%) one of the stated indications for hormonal therapy was management of menstrual bleeding.
Predictors of HMB at Six Months
Rivaroxaban use was associated with an increased risk of HMB. Forty-five percent of subjects on rivaroxaban experienced HMB requiring treatment as compared to 26% of subjects on apixaban, representing a 1.2 fold (95% CI 1.02–1.44) difference in HMB at 6 months. Similar to users of apixaban, 27.8% of users of warfarin experienced HMB (OR 1.02, 95% CI 0.87–1.20). The association between rivaroxaban and HMB as compared to apixaban persisted after controlling for age and reported history of HMB compared to a history of normal menses (OR 1.42, 95% CI 1.12–1.82).
Independently of OAC type, subjects with a documented history of HMB were 1.81 fold (95% CI 1.52–2.15) more likely to have HMB at six months as compared to subjects with normal menses or no documented menstrual history. This effect was similar (OR 1.76, 95% CI 1.45–2.15) when subjects with a documented history of HMB were compared to only those with a documented history of normal menses, excluding those without mention of menstrual history in the chart.
Age was not a predictor of HMB when evaluated either as a continuous variable (OR 1.00, 95% CI 1.00–1.01), or when subjects were divided into two groups of over or under 45 years of age (OR 0.99, 95%CI 0.84–1.15) to capture potential effects of perimenopause on bleeding.
Discussion
A significant proportion of OAC users needed treatment for HMB but this varied based on the type of OAC. We found that 45% of women prescribed therapeutic doses of rivaroxaban required treatment for HMB within six months of initiating therapy as compared to 23% of women on apixaban or 35% of women on warfarin. We also found that a prior history of HMB strongly predicted HMB requiring an intervention within six months of initiating OACs but only a minority of patients had a menstrual history documented prior to initiating OAC therapy.
This lack of a standard definition to quantify HMB creates challenges when studying the impact of OAC’s on menstrual bleeding. Gynecology standards for diagnosing HMB no longer define it by a specific amount of blood loss (>80mL/menstrual cycle) but if the bleeding interferes with a woman’s quality of life.[8] The International Society of Thrombosis and Haemostasis defines major and non-major bleeding from any site but has no specific criteria for HMB. [9] Many studies group pre- and post-menopausal women and all types of uterine bleeding together, whether menstrual-related or not, and also suffer from small sample sizes or the inclusion of only one OAC agent.[1, 2] As a result, reported rates of uterine bleeding vary widely between studies and likely underestimate the impact of HMB. Using a definition of menstrual bleeding that required intervention of some kind allowed us to identify HMB that was clinically significant although may have missed cases that went unreported despite interfering with quality of life.
Our study is limited by the lack of menstrual history documentation at the time of OAC initiation. Rates of HMB in the general population are approximately 15%[10] which is similar to our documented baseline rate of 12%. We cannot determine a true baseline prevalence of HMB in our population which in turn limits our ability to document the incidence of HMB with OAC use which is why we chose a more definitive outcome, HMB requiring treatment. It is unlikely that we missed a significant HMB event as most patients were treated within our health system or we would have received a report of their treatment. We did have 46.7% of patients using hormone therapies at baseline. Concurrent use of hormonal therapies likely lowers the rates of significant HMB events with OAC use. Our study did not take into account hematological variables beyond anticoagulation, including platelet count or function, which are known to increase bleeding risk and in particular HMB although these are assumed to be normal in the majority of individuals prescribed OACs for VTE.[11, 12]
Our findings are consistent with those of prior studies demonstrating a relative increase in HMB among users of rivaroxaban as compared to users of apixaban or warfarin.[7, 13] Our study contains a larger cohort than prior studies, focuses on HMB, and includes several OAC types. Our primary outcome of HMB requiring treatment is meaningful both in terms of health impact and resource utilization. Weaknesses include the retrospective nature as well as the high likelihood, discussed above, of underestimating the actual incidence of HMB as many cases likely went undiagnosed and untreated.
At this time, many questions remain unanswered, including true rates of meaningful outcomes such as iron deficiency anemia and impaired quality of life in this population. A better understanding of the physiology behind differences in bleeding rates with rivaroxaban vs apixaban is warranted. One likely explanation for this difference is the higher peak anticoagulant level achieved with once daily rivaroxaban as compared to apixaban, which may be compounded in obesity by the increased lipophilicity of rivaroxaban. Studies of reduced anticoagulant doses during the heaviest days of menses have been proposed but not completed and could potentially offer yet another strategy to improve management.
In conclusion, nearly half of reproductive-aged women will have HMB requiring treatment within six months of starting rivaroxaban therapy. Users of apixaban and warfarin will have lower, but still unacceptably high rates of HMB. Prescribers of OACs frequently neglect to document menstrual histories at the time of OAC initiation or to adequately document inquiries regarding menstrual bleeding during OAC therapy, almost certainly resulting in missed diagnoses and treatment opportunities. This highlights a few simple interventions which may lead to improved outcomes in this population. First and foremost it is essential that prescribers start asking patients about menstrual history, past and present, when prescribing and managing OAC therapy. Additionally, patients who discontinued estrogen-containing hormonal contraception at the time of VTE diagnosis need assessment for alternative contraceptive options. Contraception is essential for patients with a recent history of VTE and progestin contraceptives are both safe and effective for treating HMB. Women who discontinue hormonal therapies and do not transition to an alternate agent are highly likely to experience a recurrence of HMB, potentially worsened by anticoagulant therapy.[14] Menstruating women who initiate anticoagulation therapy outside of the setting of hormonal therapy may also benefit from initiation of progestin based contraceptives for both contraception and prevention of HMB. Routine history taking and counseling is a virtually zero risk intervention and will provide an important opportunity to manage and ideally prevent consequences of heavy bleeding in this high-risk patient population.
Table 2.
Medical and Surgical Therapies for Treatment of HMB
| Rivaroxaban (n=62) | Apixaban (n=54) | Warfarin (n=79) | All Subjects (n=195) | |
|---|---|---|---|---|
| Medical Therapy, n (%) | ||||
| Hormonal therapy | 18 (29.0) | 4 (7.4) | 15 (18.9) | 37 (19.0) |
| Antifibrinolytic therapy | 0 | 0 | 0 | 0 |
| Modification of anticoagulation | 5 (8.1) | 1 (1.9) | 2 (2.5) | 8 (4.1) |
| Blood transfusion | 2 (3.2) | 2 (3.7) | 1 (1.3) | 5 (2.6) |
| Other medical therapy | 11(17.7) | 9 (16.7) | 6(7.6) | 26 (13.3) |
| Multiple medical therapies | 0 | 0 | 0 | 0 |
| Surgical Therapy, (%) | ||||
| Dilation and curettage | 1 (1.6) | 0 | 0 | 1 (0.5) |
| Ablation | 2 (3.2) | 1 (1.9) | 2 (2.5) | 5 (2.6) |
| Uterine artery embolization | 0 | 0 | 0 | 0 |
| Hysterectomy | 1 (1.6) | 1 (1.9) | 0 | 2 (1.0) |
| Hysteroscopy | 1 (1.6) | 0 | 0 | 1 (0.5) |
| Other surgical therapy | 0 | 0 | 0 | 0 |
| Multiple surgical therapies | 0 | 0 | 0 | 0 |
Highlights.
Menstrual history is infrequently assessed prior to and during anticoagulant therapy
Prior heavy menstrual bleeding is predictive of heavy bleeding on anticoagulation
Rivaroxaban is associated 1.4 times more heavy menstrual bleeding than other agents
Acknowledgements
We would like to thank Dr. Michael Recht for support provided for statistical services.
Sources of funding
This work was supported by grants from the National Institutes of Health (1 L30 HL154449-01 To BTSB, R01HL101972 to OJTM, HD089957 to ABE and UL1TR002369 to the Oregon Clinical and Translational Research Institute for the use of REDCap).
Footnotes
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Disclosures
The authors declare no competing financial interests.
References:
- [1].Bradley LD, Gueye NA, The medical management of abnormal uterine bleeding in reproductive-aged women, Am J Obstet Gynecol 214(1) (2016) 31–44. [DOI] [PubMed] [Google Scholar]
- [2].Godin R, Marcoux V, Tagalakis V, Abnormal uterine bleeding in women receiving direct oral anticoagulants for the treatment of venous thromboembolism, Vascul Pharmacol 93–95 (2017) 1–5. [DOI] [PubMed] [Google Scholar]
- [3].Beckman MG, Hooper WC, Critchley SE, Ortel TL, Venous thromboembolism: a public health concern, Am J Prev Med 38(4 Suppl) (2010) S495–501. [DOI] [PubMed] [Google Scholar]
- [4].E.C.W. Group, Venous thromboembolism in women: a specific reproductive health risk, Human Reproduction Update 19(5) (2013) 471–82. [DOI] [PubMed] [Google Scholar]
- [5].Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ, Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week, J Am Coll Cardiol 75(11) (2020) 1341–1350. [DOI] [PubMed] [Google Scholar]
- [6].Lutsey PL, Walker RF, MacLehose RF, Alonso A, Adam TJ, Zakai NA, Direct oral anticoagulants and warfarin for venous thromboembolism treatment: Trends from 2012 to 2017, Res Pract Thromb Haemost 3(4) (2019) 668–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].De Crem N, Peerlinck K, Vanassche T, Vanheule K, Debaveye B, Middeldorp S, Verhamme P, Peetermans M, Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists, Thrombosis Research 136(4) (2015) 749–753. [DOI] [PubMed] [Google Scholar]
- [8].Screening and Management of Bleeding Disorders in Adolescents With Heavy Menstrual Bleeding: ACOG COMMITTEE OPINION SUMMARY, Number 785, Obstet Gynecol 134(3) (2019) 658–659. [DOI] [PubMed] [Google Scholar]
- [9].Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee A on Control of, Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH, J Thromb Haemost 13(11) (2015) 2119–26. [DOI] [PubMed] [Google Scholar]
- [10].Fraser IS, Mansour D, Breymann C, Hoffman C, Mezzacasa A, Petraglia F, Prevalence of heavy menstrual bleeding and experiences of affected women in a European patient survey, Int J Gynaecol Obstet 128(3) (2015) 196–200. [DOI] [PubMed] [Google Scholar]
- [11].Rocheleau AD, Khader A, Ngo ATP, Boehnlein C, McDavitt C, Lattimore S, Recht M, McCarty OJT, Haley KM, Pilot study of novel lab methodology and testing of platelet function in adolescent women with heavy menstrual bleeding, Pediatr Res 83(3) (2018) 693–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Zia A, Jain S, Kouides P, Zhang S, Gao A, Salas N, Lau M, Wilson E, DeSimone N, Sarode R, Bleeding disorders in adolescents with heavy menstrual bleeding in a multicentre prospective US cohort, Haematologica (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Martinelli I, Lensing AW, Middeldorp S, Levi M, Beyer-Westendorf J, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Trajanovic M, Gebel M, Lam P, Wells PS, Prins MH, Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use, Blood 127(11) (2016) 1417–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Bistervels IM, Scheres LJJ, Hamulyak EN, Middeldorp S, Sex matters: Practice 5P’s when treating young women with venous thromboembolism, J Thromb Haemost 17(9) (2019) 1417–1429. [DOI] [PMC free article] [PubMed] [Google Scholar]