Contraception xxx (2018) xxx–xxx

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Contraception

journal homepage: www.elsevier.com/locate/con

Commentary

Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined

hormonal contraception?
Thorne JGa, James PDb, Reid RLc,⁎
a
Contraception Advice Research and Education (CARE), Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada, K7L2V7
b
Department of Medicine, Division of Hematology, Queens University, Kingston, Ontario, Canada, K7L2V7
c
Department Obstetrics and Gynecology, Chair, Division of Reproductive Endocrinology, Queens University, Kingston, Ontario, Canada, K7L2V7

1. Introduction question making a systematic review impossible. However, extensive

Heavy menstrual bleeding (HMB), which affects as many as 30% of
women, has a well- established negative impact on quality of life and
work productivity [1,2]. In women with chronic HMB in the absence
of known anatomic abnormalities (fibroids, adenomyosis), options
such as non-steroidal anti-inflammatory drugs (NSAIDs) [3], combined
hormonal contraceptives [4], the levonorgestrel intrauterine system [5],
danazol [6] and tranexamic acid [7] show varying degrees of efficacy for
reduction of menstrual flow and are often able to restore normal day-to-
day function.
In urgent situations of acute HMB health care providers may resort
to higher than usual doses of combined hormonal contraceptives
(CHCs), intravenous conjugated equine estrogen [8] or high dose pro-
gestins alone [9] or in combination with CHCs [10] to control heavy
menstrual bleeding. The role of tranexamic acid, administered as a
short term adjunctive treatment in the face of a poor response to
CHCs, remains unsettled due to US labeling for this product. Whether
the use of TXA in a woman on CHCs should be avoided due to an in-
crease in the risk of VTE remains controversial.
2. Methods
In order to make recommendations on the use of TXA in heavy men-
strual bleeding, two of the authors (JT, RL) independently conducted lit-
erature reviews to identify published research. Reports were found by
searching the terms “tranexamic acid” “oral contraceptive”, “heavy
menstrual bleeding”, “thrombosis” in the databases Medline, PubMed,
and EMBASE. Existing guidelines on the management of heavy men-
strual bleeding and reference lists from relevant articles were reviewed.
Studies were limited to the English language and included publications
from 1976 until 2017. There were no studies that directly addressed this
safety data from the use of TXA in other situations, including some
with elevated risk of VTE, allowed us to draw inferences about this com-
bination therapy.
3. TXA for HMB
TXA is a synthetic analog of the amino acid lysine and acts by revers-
ibly binding to lysine receptor sites preventing plasminogen conversion
to plasmin and ultimately the degradation of fibrin. This effect is seen in
peripheral blood, menstrual fluid, and endometrium — all sites where
increased fibrinolysis is seen in women with HMB [11]. A strong corre-
lation has been demonstrated between the dose of TXA and the objec-
tively measured blood loss with decreases of 45-60% reported at
higher doses [12].
TXA has found a place in the management of acute bleeding in a
variety of clinical situations ranging from major gynecologic surgery in-
cluding myomectomy and Caesarian section [13,14] to trauma [15] and
post-partum hemorrhage [16]. TXA has been used in various countries
around the world for HMB for over 40 years and has been available
over-the-counter in Sweden for 20 years [12] and in the UK for almost
a decade [17,18] with no reports suggesting an increased rate of VTE.
4. Product labeling for TXA
There are few contraindications to TXA use. US [19] and Canadian
[20] labeling list these as a current or past history of thrombosis, an in-
creased risk of thrombosis, retinal vein or artery occlusion (US labeling
only), acquired defective color vision (Canadian labeling only) and com-
bined hormonal contraception use (US labeling only). Presumably the
reason why CHCs are listed as a contraindication in the US labeling is
due to fears that the combination of CHC and TXA will increase the
risk of VTE.

5. Clinical Experience with TXA

☆ Funding: The authors have had no involvement with the company marketing TXA
(including speaker’s bureaus or advisory boards) and this commentary was developed
without funding from agencies in the public, commercial, or not-for-profit sectors.
There are several case reports of individuals on TXA experiencing ad-
⁎ Corresponding author. Tel.: +1 614 453 9715; fax: +1 613 533 6779. verse thrombotic complications [21–25]. We could find only a single re-
URL: robert.reid@queensu.ca (R.L. Reid). port where the combination of a CHC and TXA was suggested as a cause

https://doi.org/10.1016/j.contraception.2018.02.008
0010-7824/© 2018 Published by Elsevier Inc.

Please cite this article as: Thorne JG, et al, Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception?,
Contraception (2018), https://doi.org/10.1016/j.contraception.2018.02.008
2 J.G. Thorne et al. / Contraception xxx (2018) xxx–xxx
of a thrombosis in a coronary vessel [26]. It is quite possible that this
event would have occurred due to the CHC alone.
Concerns about an increased risk of VTE when CHCs and TXA are
used in combination are not supported by long term clinical experience.
Estimates suggest that 1% of the 1.7 million Swedish women of repro-
ductive age use TXA for control of HMB [27]. During 19 years of prescrib-
ing of TXA for HMB in Sweden (amounting to 238,000 women years of
use) no increased risk of VTE was observed [28]. A retrospective case-
control study involving 662 women with thrombosis and 1506 controls
was reported from Sweden in 2001. Although CHCs increased the risk of
thrombosis (OR 2.41, CI 1.98–2.92) TXA usage did not increase throm-
boembolic events when compared to controls (OR 0.55 CI 0.31–0.97)
[27]. In a US-based clinical trial that utilized an intention-to-treat anal-
ysis, 196 women were treated with TXA (1.3 g orally TID for up to 5
days each cycle.) After monitoring the women through nine menstrual
cycles no thromboembolic related events were diagnosed [29]. In the
20 years that TXA has been available over-the-counter in Sweden
there can be no doubt that many women who were taking CHCs used
this treatment with no evidence of increased rates of VTE [12].
In an international, randomized, double-blind, placebo-controlled
trial involving 20,600 women with postpartum hemorrhage, no in-
creased risk of venous thromboembolism (VTE) was observed in
women randomized to TXA (n=10,050) compared to placebo (n=
10,009) [16]. This is despite the increased propensity for VTE due to
pregnancy-related hormonal effects on the coagulation system changes,
obstetrical trauma, and reduced mobility [30,31].
In major surgery tranexamic acid is used at a loading dose of 2–7 g
with anesthesia, and then given as an infusion at 20–250 mg/h for the
duration of surgery to a maximum dose of 3–10 g. In placebo-
controlled trials TXA reduced blood loss intra-op and post-op by 20-
56% with no documented VTE [32]. No clinical experience with intrave-
nous TXA in women using CHCs has been reported so caution should be
exercised in translating findings with oral TXA combined with CHCs.
In a study of N3000 women age 30-54 years given 1 g IV TXA during
laser conization of the cervix and 1 g TID for 14 days thereafter, no VTEs
were diagnosed or reported in the 8 weeks following therapy [33]. Sub-
sequently a systematic review and meta-analysis of the effects of short
term TXA in major benign gynecologic surgery reported reduced
blood loss for Caesarian sections and myomectomy with no increase
in VTE compared to placebo [14].
The background rate of VTE among women of reproductive age is re-
ported to reach 4-5/10,000 women years [34]. CHCs are thought to dou-
ble that risk to approximately 8–9/10,000 [35]. In comparison the risk of
VTE in the postpartum period is reported to range from 300–400/10,000
[30,31]. In the past decade there has been debate about whether certain
progestins confer greater risks than others, the most recent assessments
indicate that any differences are small and likely not to have clinical sig-
nificance [35–37].
VTE in women using CHCs is a rare but serious event. TXA does not
increase the risk of development of a VTE [18]; however, its anti-
fibrinolytic activity would reduce the chance for spontaneous resolution
when a subclinical event occurs and could worsen a clinical event prior
to initiation of anticoagulant therapy.
6. Clinical Considerations When Considering Combination CHC and
TXA
The extensive clinical experience demonstrating the safety of short
term TXA exposure and its very beneficial effects for acute HMB suggest
that the benefits of therapy even when combined with CHCs for most
women will outweigh potential risks. Women with increased risks for
VTE beyond the risk conferred by CHCs (immobility, obesity, coagulop-
athy, etc.) should probably avoid this combination therapy.
CHCs are often effective for ongoing treatment of HMB and may con-
fer additional contraceptive and non-contraceptive benefits. There are,
however, few options as effective as TXA for the management of acute
Please cite this article as: Thorne JG, et al, Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception?,
Contraception (2018), https://doi.org/10.1016/j.contraception.2018.02.008
hemorrhage. As per routine recommendations, women starting CHCs
should be counseled about the slight risk of VTE and what to do if
signs or symptoms appear. The first few withdrawal bleeds may be
very heavy, especially if the antecedent cause was chronic anovulation,
and in our opinion concomitant prescription for TXA 1 g TID or QID (to
be taken on days of heavy flow) is appropriate.
7. Future research
Any future research directly examining the safety of CHCs and con-
comitant TXA would present significant challenges due to ethical con-
cerns about randomizing individuals to receive or not receive highly
effective therapy for HMB and due to the large numbers of subjects re-
quired. At present, clinical experience with TXA in other situations
that increase the risk for VTE is reassuring and we believe combination
therapy with CHCs and TXA in appropriately selected patients will re-
main an important tool in the gynecologist’s armamentarium.
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