CHC TXA VTE No Risk Increase

Contraception xxx (2018) xxx –xxx

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Commentary

Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception? Thorne JGa, James PDb, Reid RL c,⁎ a b c

Contraception Advice Research and Education (CARE), Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada, K7L2V7  Department of Medicine, Division of Hematology, Queens University, Kingston, Ontario, Canada, K7L2V7  Department Obstetrics and Gynecology, Chair, Division of Reproductive Endocrinology, Queens University, Kingston, Ontario, Canada, K7L2V7 

1. Introduction

Heavy menstrual 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] productivity [1,2].. In women with chronic HMB in the absence of known anatomic abnormalities ( �broids broids,, adenom adenomyosis) yosis),, options such as non-steroidal anti-in�ammatory drugs (NSAIDs) [3] (NSAIDs) [3],, combined hormonal contraceptives [4] [4],, the levono levonorgestr rgestrel el intrau intrauterine terinesyste system m [5] [5],, danazol [6] and tranex tranexamic amic acid [7] sho show w var varyin ying g deg degree reess of ef �cac cacy y for reduction reduc tion of mens menstrual trual �ow and areoftenable to res restor tore e nor normalday-to malday-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] estrogen [8] or  or high dose progestins alone [9] alone  [9] or  or in combination combination with CHCs [10] CHCs  [10] to  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 increase in the risk of VTE remains controversial. 2. Methods

In or orde derr to ma make ke re reco comm mmen endat datio ions ns on th the e us use e of TX TXA A in he heav avy y me mennstrual str ual ble bleedi eding, ng, two of the aut author horss (JT (JT,, RL)indepe RL)independe ndentl ntly y con conduc ducted ted lit 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 menstrual str ual ble bleedi eding ng and ref refere erence nce lis lists ts fro from m rel releva evant nt art articl icles es wer were e rev review iewed. ed. Studies were limited to the English language and included publications from fro m 197 1976 6 unt until il 201 2017. 7. The There re wer were e no stu studie diess tha thatt dir direct ectly ly add addres ressedthis sedthis

question making a systematic review impossible. However, extensive safety data from the use of TXA in other situations, including some with wit h ele elevat vated ed ris risk k of VTE VTE,, all allowe owed d us to dra draw w inf infere erence ncess abo about ut thi thiss com com-bination therapy. 3. TXA for HMB

TXA TX A is a sy synt nthe heti ticc an anal alog og of th the e am amin ino o ac acid id ly lysi sine ne an and d ac acts ts by re reve vers rs-ibly bin ibly bindin ding g to lys lysine ine rec recept eptor or sit sites es pre preven ventin ting g pla plasmi sminog nogen en con conve versi rsion on to pla plasmi smin n and ult ultima imatel tely y the deg degrad radati ation on of �br brin in.. Th This is ef effe fect ct is se seen en in peripheral peripher al blood, menstrual � uid, and endometri endometrium um  —  all sites where increased � brinolysis is seen in women with HMB  [11]  [11].. A strong correlation has been demonstrated between the dose of TXA and the objectively measured blood loss with decreases of 45-60% reported at higher doses [12] doses [12].. TXA has found a place in the management of acute bleeding in a variet var iety y of cli clinic nical al sit situat uationsrangi ionsranging ng fro from m maj major or gyn gyneco ecolog logic ic sur surger gery y including cludi ng myome myomectomy ctomy and Caesarian Caesarian section [13,14] to trauma [15] trauma [15] and  and 6].. TXA has been used in various countries post-partum hemorrhage [1 hemorrhage [16] around the world for HMB for over 40 years and has been available over-the-counter in Sweden for 20 years  [12]  [12] and  and in the UK for almost a decade [17,18] decade [17,18] with  with no reports suggesting an increased rate of VTE. 4. Product labeling for TXA 

There are few contraindications to TXA use. US  [19]  [19] and  and Canadian [20] labeling list these as a current or past history of thrombosis, an in[20] labeling creased risk of thrombosis, retinal vein or artery occlusion (US labeling only),acqui onl y),acquired red def defect ectivecolor ivecolor vis vision(Canad ion(Canadianlabel ianlabelingonly) ingonly) andcombined hormonal contraception contraception use (US labeling only). Presuma Presumably bly 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-pro�t sectors. ⁎ Corresponding author. Tel.: +1 614 453 9715; fax: +1 613 533 6779. URL: [email protected]  [email protected] (R.L.  (R.L. Reid). ☆ 

There aresever There areseveral al cas case e rep report ortss of ind indivi ividua duals ls on TXAexper TXAexperien ienci cing ng adversethromb verse thrombotic otic compl complicati ications ons [21–25] 25].. Wecou Wecould ld �nd on only ly a si sing ngle le re re-port po rt wh wher ere e thecomb thecombina inati tion on of a CH CHC C an and d TX TXA A wa wass su sugg gges este ted d as a ca caus use e

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 (2018), https://doi.org/10.1016/j.contraception.2018.02.008

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J.G. Thorne et al. / Contraception xxx (2018) xxx xxx– – xxx

of a thrombosis in a coronary vessel [26] 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 use d in com combin binati ation on are not sup suppor ported ted by lon long g ter term m cli clinic nical al exp experi erienc ence. e. Estimatess suggest that 1% of the 1.7 million Swedish Estimate Swedish women of reproductiv duc tive e ageuse TXAfor con contro troll of HMB HMB[27] [27].. Dur During19 ing19 yea years rs of pre prescr scribibing of TXA for HMB in Sweden (amounting to 238,000 women years of  use) no increased risk of VTE was observed [28] observed [28].. A retrospe retrospective ctive casecontro con troll stud study y inv involv olving ing 662 wom women en wit with h thr thromb ombosi osiss and 150 1506 6 cont control rolss was rep report orted ed fro from m Swe Swedenin denin 200 2001. 1. Alt Althou hough gh CHC CHCss inc increa reasedthe sedthe ris risk k of  thrombosis (OR 2.41, CI 1.98–2.92) TXA usage did not increase thromboembolic 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[27] ysis, 196 women were treated 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 diagnosed [29]  [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]  [12].. In an international, randomized, double-blind, placebo-controlled trial involving 20,600 women with postpartum hemorrhage, no increased crease d risk of venous thromboembolis thromboembolism m (VTE) was obser observed ved in women randomized to TXA ( n=10,050) compared to placebo (n= 10,009) [16] 10,009)  [16].. This is despite the increased propensity for VTE due to pregnancypregna ncy-relate related d horm hormonal onal effec effects ts on the coagul coagulation ation syste system m chang changes, es, obstetrical trauma, and reduced mobility [30,31] mobility  [30,31].. In major surgery tranexamic tranexamic acid is used at a loading dose of 2 –7 g with anesthesia, 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 placebocontrolled trials TXA reduced blood loss intra-op and post-op by 2056% 56 % wi with th no doc docum umen ente ted d VT VTE E [32] [32].. No cli clinic nical al exp experi erienc ence e wit with h int intrav raveenous no us TX TXA A in wo wome men n us usin ing g CH CHCs Cs ha hass be been en re repo port rted ed so ca caut utio ion n sh shoul ould d be exercised in translating �ndings with oral TXA combined with CHCs. In a stu study dy of N300 3000 0 wom women en age 3030-54 54 year yearss given given 1 g IV TXA TXA dur during ing laser las er co coni niza zati tion on of thecer thecervi vix x an and d 1 g TI TID D fo forr 14 da days ys th ther ereaf eafte ter, r, no VT VTEs Es were wer e dia diagno gnosed sed or rep report orted ed in the 8 wee weeks ks fol follow lowing ing the therap rapy y [33] [33].. Su Subbsequently 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] placebo  [14].. Thebackgroun Thebackg round d rat rate e of VTEamong wom women en of rep reprod roduct uctive ive age is reported por ted to rea reach ch 4-5 4-5/10 /10,000women ,000women yea years rs[34] [34].. CH CHCs Cs ar are e tho thoug ught ht to dou dou-ble tha thatt ris risk k to app approx roxima imatel tely y 8–9/10,000 [35] [35].. In co comp mpar aris ison on th the e ri risk sk of  VTEin thepostpa thepostpart rtum um per period iod is rep report orted ed to ran range ge fro from m 300–400/10,000 [30,31].. In thepastdeca [30,31] thepastdecade de the there re ha hass be been en de deba bate te ab abou outt wh whet ethe herr ce cert rtai ain n proges pro gestin tinss con confergreat fergreater er ris risks ks tha than n oth others ers,, themost rec recentasses entassessm sment entss indica ind icate te tha thatt any dif differ ferenc ences es are sma small ll and lik likely ely not to hav have e cli clinic nical al sig sig-ni�cance cance [35  [35–37] 37].. VTE in women using CHCs is a rare but serious event. TXA does not increase in crease the risk of development of a VTE  [18]  [18];; however, its anti�brino brinolytic lyticactiv activity ity would reduc reduce e the chanc chance e for spont spontaneousresolution aneousresolution when a subclinical event occurs and could worsen a clinical event event prior to initiation of anticoagulant therapy. 6. Clinical Considerations When Considering Combination Combination CHC and  TXA 

The extensive clinical experience demonstrating the safety of short term TX term TXA A ex expo posu sure re an and d itsverybene�cialeffec cialeffects ts for acu acute te HMB sug sugges gestt that the bene�ts 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, coagulopathy, etc.) should probably avoid this combination therapy. CHCss are oft CHC often en eff effect ective ive for ong ongoin oing g tre treatm atmentof entof HMBand mayconfer additional contraceptive and non-contraceptive bene�ts. There are, however, few options as effective as TXA for the management of acute

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  � rst 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 � ow) is appropriate. 7. Future research

Any future research directly examining the safety of CHCs and concomitant TXA would present signi�cant challenges due to ethical concerns about randomizing individuals to receive or not receive highly effective therapy for HMB and due to the large numbers of subjects required. 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 selected patients will remain an important tool in the gynecologist’s armamentarium. References [1] Lukes AS, Baker J, Eder S, Adomak Adomako o TL. D aily menstrual menstrual blood loss and quality of life in women with heavy menstrua menstruall bleeding. Womens Health 2012;8(5):503 2012;8(5):503–11. [2] Singh S, Best C, Dunn S, Leyland N, Wolfman Wolfman WL. Abnormal Abnormal uterine bleeding bleeding in premenopausal woman. SOGC Clinical Practice Guideline 292. J Obstet Gynecol Can 2013;35(5 e-Suppl):S1–S28. 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Please cite this article as: Thorne JG, et al, Heavy menstrual menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception contraception?, ?, Contraception (2018), https://doi.org/10.1016/j.contraception.2018.02.008 (2018), https://doi.org/10.1016/j.contraception.2018.02.008

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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 (2018), https://doi.org/10.1016/j.contraception.2018.02.008