Medical management of heavy menstrual bleeding: a comprehensive review of the literature Johannes Bitzer, MD, PhD,1 Oskari Heikinheimo, MD, PhD,2 Anita L. Nelson, MD,3 Joaquin Calaf-Alsina, MD, PhD,4 Ian S. Fraser, MD, DSc 5 1 Department of Obstetrics and Gynecology, University Hospital of Basel, Basel, Switzerland; 2Department of Obstetrics and Gynaecology, Kätilöopisto Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; 3 Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA USA; 4Department of Obstetrics and Gynaecology, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma, Barcelona, Spain; 5University of Sydney, Sydney, New South Wales, Australia Corresponding author: Ian Fraser, Department of Obstetrics and Gynaecology, Central Clinical School, D02–QEII Research Institute for Mothers and Infants, The University of Sydney, Sydney, NSW 2006, Australia. Phone: +61 2 9351 2478; Fax: +61 2 9351 4560; E-mail: ian.fraser@sydney.edu.au 1 Supplemental tables Table 1: Characteristics and outcomes of trials that assessed the levonorgestrel-releasing intrauterine system (initial release rate of 20 µg LNG/24 hours after placement; LNG-IUS) for the treatment of heavy menstrual bleeding (HMB). Data shown for the LNG-IUS group only. Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Randomized controlled trial in women with AUB-E (or those described having HMB without further definition) Crosignani et al LNG-IUS (n=35) Randomized Women aged 38 years or older PBAC 12 months’ treatment 1997(1) open-label referred for hysterectomy for Endometrial resection 79% mean PBAC score HMB. Inclusion criteria Italy (n=35) reduction at 6 and 12 included uterine volume months (6 month data equivalent to an 8-week estimated from graph) pregnancy or less, a negative cervical smear in the last 12 Recurrent HMB months, no evidence of (defined as PBAC 100 atypical hyperplasia, no or higher) was adnexal tumors, and normal observed in 4/34 (12%) uterine cavity as determined at 12 months by hysteroscopy. Exclusions included desire for future childbearing, congenital or acquired uterine anomalies, pelvic inflammatory disease, or intramural or subserous myomas of more than 3 cm in diameter, as shown by transvaginal ultrasound Irvine et al LNG-IUS (n=22) Randomized Healthy women 18–45 years with a regular menstrual cycle, Alkaline 3 cycles’ treatment Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Adverse events were reported by 19/34 (n=10, bloating; n=8, weight gain; n=6, breast pain; n=4, headache; n=2 for pelvic pain, decreased libido, hair loss, acne, and anxiety-depression; n= 1 for hypertension and leg pain) Only 1 (3%) subject did not complete study (lost to follow up) 1 (3%) women scheduled for surgical treatment 2 (2/34; 5.9%) partial expulsions occurred. No perforations reported No difference in adverse events (headaches, acne, 20 (91%) completed 3 2 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) 1998(2) Norethisterone (5 mg TID from day 5 to 26; n=22) open-label hematin 88% and 99% median reduction in MBL at cycle 1 and 3 cycles of treatment: abdominal or back pain, nausea, oedema, weight gain, decreased libido, sweating, hair loss or greasy hair and increase in body hair) at baseline and over 3 months. Intermenstrual bleeding, breast tenderness and mood swings appeared to decrease relative to baseline. months UK a normal pelvic examination with a uterine sound < 10 cm, negative cervical cytology and MBL >80 mL (objectively confirmed during 1 pretreatment cycle) 17 (77%) elected to continue with the treatment <<Surgery avoided or required not reported>> 1/22 (5%) had LNG-IUS expulsion No perforations reported Hurskainen et al., 2001(3) Finland LNG-IUS (n=119) Hysterectomy (n=117) Randomized open label Women aged 35–49 year referred for HMB and who had completed their family and eligible for hysterectomy. Exclusion criteria included submucous fibroids; endometrial polyps; ovarian tumours or cysts (>5 cm); cervical disease; urinary and bowel symptoms or pain due to large fibroids; history of cancer; menopause; severe depression; metrorrhagia as a main complaint; severe acne; Alkaline hematin 12 months follow-up MBL was measured in only 25 subjects at 12 months. Mean MBL decreased from 130 mL to 13mL at 12 months (MBL only measure in 25 women at 1 year). One subject had HMB (MBL >80 mL). The remaining subjects had amenorrhoea or Adverse events not reported 1 (1%) expulsion of LNG-IUS occurred No perforations reported. 81 (68%) had the LNG-IUS in situ at 12 months, 24 (20%) had undergone hysterectomy 3 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method uterine malformation Soysal et al 2002(4) Turkey Barrington et al 2003(5) UK Rauramo et al 2004‡ (6) Finland/Norway LNG-IUS (n=36) Endometrial ablation (n=36) LNG-IUS (n=25) Endometrial ablation (n=25) LNG-IUS (n=30) Endometrial resection (n=29) Randomized open-label Randomized open-label Randomized open-label Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Adverse events reported by 21/36 subjects (n= 6,spotting; n= 5, mastalgia; n=10, weight gain; n=2, mood swings; n=8, bloating; n=7, acnegreasy skin; n=4, nausea; n=1, headache ) All patients were followed for 12 months negligible bleeding (not defined) Women aged over 40 years with no further desire for childbearing complaining of HMB. Exclusion criteria included: congenital and acquired uterine anomalies, pelvic inflammatory disease, uterine volume greater than 8week pregnancy, intramural and subserous myomas greater than 2 cm in diameter in high resolution transvaginal ultrasonography and any abnormalities in hysteroscopy PBAC Women with HMB refractory to medical therapy. Exclusion criteria included uterine cavity length >12 cm or subserous fibroids, and any malignant or pre-malignant pathology PBAC Women aged 30 to 49 years, with no further desire for children, and idiopathic HMB needing treatment, and with a normal uterine cavity. PBAC 12 months’ treatment 95% mean PBAC score reduction at 12 months 77% treatment success (PBAC≤100) at 12 months 1 (3%) subject lost LNGIUS No perforations reported 6 months’ treatment AEs not reported. 71% mean PBAC score reduction No LNG-IUS expulsions reported 71% median PBAC score reduction No perforations reported Study initially planned for 1 year, but extended to 3-years treatment In the LNG-IUS group, 3 subjects were diagnosed with endometritis, 2 with pelvic inflammatory disease, and 1 edema. Reduction in median PBAC scores: 95%, 97% and 97% at 1, 2 1 (3%) partial expulsion 21 (84%) completed 6 months 3 (12%) underwent surgical treatment 24 (80%) completed 12 months Of the 22 subject who consented to participate in 4 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) and 3 years, respectively occurred. extension phase 19 (86% completed 3 years) No perforations reported No women underwent subsequent surgical treatment Reid and Virtanen-Kari 2005(7) UK Malak and Shawki 2006(8) Egypt LNG-IUS (n=25) Mefenamic acid (500 mg TID from days 1-4; n=26) LNG-IUS (n=30) Endometrial resection (n=30) Randomized open-label Randomized open-label Women aged 18–47 years with regular ovulatory, menstrual cycles of 21–35 days and objective HMB (MBL ≥80 mL objectively confirmed in one pretreatment cycle). Exclusions included anovulatory cycle, submucous fibroids or fibroids with a total volume of >5 cm3, a uterine sound of >10 cm or abnormal cervical cytology. Alkaline hematin, PBAC and total menstrual fluid Women aged 40–50 years with spontaneous cycles scheduled to undergo hysterectomy for HMB. Exclusion criteria included: cavity ≥10 cm, one fibroid PBAC 6 cycles’ treatment Reduction in median MBL: 90%, and 96% in cycles 3 and 6, respectively Reduction in median PBAC scores: 80% and 89% in cycles 3 and 6, respectively Reduction in median total menstrual fluid loss: 71% and 85% in cycles 3 and 6, respectively 12 months’ treatment 87% mean PBAC score reduction at 12 months 87% median PBAC Common AEs with LNG-IUS included: headache (n=10; 40%); abdominal pain (n=8; 32%); ovarian cysts (n=6; 24%); breast pain (n=6; 24%); nausea (n=4; 16%); and upper respiratory infection (n=5; 20%). No perforations reported 21 (84%) completed study <<Surgery avoided or required not reported>> 4/25 (16%) partial or complete expulsions (all discontinued) Adverse events reported by 7/30 subjects (n=2, metrorrhagia; n=3, pelvic pain; n=4, vaginal discharge; n=5, abdominal pain; n=3, 87% completed 12 months treatment 4 (13%) underwent 5 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method >3cm of more than three fibroids, pelvic inflammatory disease Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) score reduction at 12 months breast tenderness; n=2, headache; n=2, acne; n=1, mood change) surgical treatment 77% treatment success (PBAC <75) No LNG-IUS expulsions reported No perforations reported Busfield et al 2006 (9) New Zealand Shaw et al 2007(10) UK LNG-IUS (n=40) Endometrial ablation (n=39) LNG-IUS (n=33) Endometrial ablation (n=33) Randomized open-label Randomized open-label Women aged 25–50 years with regular cycles, selfdescribed HMB and completed their families. Exclusion criteria included ultrasound abnormalities (submucousal fibroids, intramural fibroids greater than 3 cm in diameter, large subserosal fibroids, endometrial polyps), intermenstrual bleeding, chronic pelvic pain. PBAC Women aged 25–49 years who had completed their families and with HMB (PBAC >120 in two control cycles) that failed first-line oral therapy. Exclusion criteria included: submucus fibroid (>2.5 cm) identified on scan or hysteroscopy, Uterine cavity less than 7 cm or greater than PBAC 24 months’ treatment 74%, 85%, 92%, and 96% mean PBAC score reduction at 3, 6, 12 and 24 months, respectively AEs not reported in detail ( 1 subject had actinomycoses). 31 (78%) completed 12 months treatment 4 (10%) subjects had LNG-IUS expulsion. 26 (65%) completed 24 months treatment No perforations reported 6 (15%) subjected were treatment failures (defined as a major change in treatment) 7 (18%) underwent surgical treatment 12 months’ treatment AEs not reported. 62%, 72%, 93%, and 94% median PBAC score reduction at 3, 6, 9 and 12 months, respectively 2 (6%) subjects had LNG-IUS expulsion. No perforations reported 23 (70%) completed 12 months treatment 20 (61%) continued with the LNG-IUS to 24 months 8 (24%) had listed for or undergone 6 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) 11 cm. Kucuk and Ertan 2008(11) Assumed to be Turkey and/or Germany (not clear) Endrikat et al 2009(12) Canada. LNG-IUS (n=44) Oral MPA (5 mg daily; n=44) Randomized open-label Depot MPA (n=44); Perimenopausal women (aged >40 years) who were smokers. Those with organic pathology and nonsmokers were excluded. surgery PBAC 2 cycles’ treatment 73% mean PBAC score reduction by cycle 2 HMB confirmed using PBAC and hemogram (duration for confirmation not stated). LNG-IUS (n=20) NETA/EE (1mg/20µg; n=19) Randomized open-label Healthy women >30 years with idiopathic HMB (PBAC score ≥100 confirmed during 2 consecutive pre-treatment cycles) and a normal or only slightly enlarged uterus Continuation rates (for LNGIUS) Common adverse effects included intermenstrual bleeding (n=6; 14%) and breast tenderness (n=6; 14%) No LNG-IUS expulsions reported No perforations reported PBAC 12 months’ treatment Reduction in median MBL (estimated from graph): 77%, 95%, 94% and 94% during 3, 6, 9 and 12 months, respectively One (5%) patient reported an inguinal hernia No LNG-IUS expulsions reported No perforations reported Proportion completing study not reported 38 (86%) willing to continue <<Surgery avoided or required not reported>> 19 (95%) completed 12 months <<Surgery avoided or required not reported>> 83% mean reduction in PBAC score at 12 months de Sousa et al 2010(13) Brazil LNG-IUS (n=30) Endometrial ablation (n=28) Randomized open-label Women with HMB determined using PBAC. Inclusion criteria included PBAC 12 months’ treatment AEs not reported. 84%, 93% and 92% mean PBAC score No LNG-IUS expulsions reported Continuation rate not reported 1 (3%) opted for 7 Author (year)/Country Kaunitz et al 2010(14) United States, Canada, and Brazil Comparators LNG-IUS (n=82) MPA (10 mg daily from 16 to 25; n= 83) Study design Inclusion/Exclusion criteria Randomized open-label HMB refractory to medical treatment age 35 years or older, and no intracavitary abnormalities, pelvic inflammatory disease, suspected endometrial pathology, abnormal endometrial histology, abnormal cervical, large myomas or any ovarian disease for which hysterectomy would be more appropriate. In addition, all women had to have completed their families. Parous women aged ≥18 years with idiopathic HMB (MBL ≥80 mL objectively confirmed during 2–3 pre-treatment cycle), desiring intrauterine contraception and willing to use barrier contraception if required. Exclusions included fibroids (if they distorted the uterine cavity or cervical canal); history of organic causes of abnormal uterine bleeding. MBL assessment method Alkaline hematin Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) reduction at 1, 6 and 12 months, respectively (estimated from graph) No perforations reported hysterectomy 6 cycles’ treatment Headache (n=13; 16.3%), ovarian cysts (n=10; 12.5%), bacterial vaginitis (n=9; 11.3%), urinary tract infection (n=6; 7.5%), acne (n=5; 6.3%), hypertension (n=5; 6.3%), sinusitis (n=5; 6.3%), upper respiratory tract infection (n=5; 6.3%), breast tenderness (n=4; 5%), fatigue (n=4; 5%), pelvic pain (n=4; 5%), increased weight (n=4; 5%), lower abdominal 73 (89%) completed 6 cycles 83% and 95% median MBL reduction at cycle 3 and 6 62% and 71% mean MBL reduction at cycle 3 and 6 LNG-IUS successfully treated 67 (85%) of women (defined as proportion with MBL <80 mL at end of study and ≥50% reduction in MBL from baseline). <<Surgery avoided or required not reported>> 8 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) pain (n=3; 3.8%) 4/80 discontinued due to AEs 4/80 had partial or complete expulsion. No perforations occurred Ghazizadeh et al 2011(15) Iran LNG-IUS (n=52) Endometrial resection (n=52) Randomized open-label Women aged 35–45 years with HMB ((PBAC score > 100) and with no medical treatment in last 6 months. Exclusion included uncertain about future wish for pregnancy, abnormal endometrial histology, or any other pathology such as uterine prolapse or large myomas. Patients who were uncertain about their future wish for pregnancy were also excluded. PBAC 12 months’ treatment 90%, and 89% mean PBAC score reduction at 6 and 12 months, respectively 9 (17%) had no response to treatment Adverse events with LNG-IUS were cramps and pains in four (8.2%), spotting in 19 (38.8%), breast tenderness in ten (20.4%), headaches in nine (18.4%), acne in two (4.1%), mood changes in four (8.2%), weight gain in one (2%) and ovarian cyst in one (2%) patient 30 (58%) completed 12 months treatment. No women underwent subsequent surgical treatment in LNG-IUS group 9 (17%) subjects had LNG-IUS expulsion No uterine perforations occurred Shabaan et al 2011(16) Egypt LNG-IUS (n=56) LNG 150 µg/EE 30 µg; n= 56) Randomized open-label Women aged 20–50 years with self-defined HMB and requesting contraception. Exclusions included previous Alkaline hematin and PBAC 12 months’ treatment AEs not reported. 87% mean MBL reduction at12 months 1 (2%) expulsion of LNG-IUS occurred 48 (86%) completed 12 months 9 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method ectopic pregnancy, ultrasound abnormalities including fibroids (any size), previous endometrial ablation. Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) 90% and 87% reduction in mean PBAC scores at 6 and 12 months No perforations reported 5/56 underwent surgical treatment due to treatment failure 12 months’ treatment AEs not reported. 96%, 94%, >99% and 94% mean PBAC score reduction at 3, 6, 12 and 24 months, respectively No LNG-IUS expulsions reported Continuation rates not reported. 6 of 56(11%) failed treatment (defined as initiation of a different treatment). Sesti et al 2012(17) Italy LNG-IUS (n=36) Laparoscopic Supracervical Hysterectomy (n=36) Randomized open-label Women aged 35–50 years who had completed their families and with confirmed HMB (PBAC score ≥ 100 average of two consecutive cycles).unresponsive to medical treatment were eligible for the study. PBAC No perforations reported <<Surgery avoided or required not reported>> Exclusion criteria included: any uterine pathology on scan or hysteroscopy Non-randomized studies in women with AUB-E (or those described as having HMB without further definition) Andersson and LNG-IUS (n=20) NonParous women aged ≤45 years Alkaline 12 months’ treatment Rybo, 1990 (18) randomized, with HMB not planning hematin 86% 91%, and 97% prospective pregnancy were considered. Sweden median MBL reduction Inclusion criteria included at 3, 6 and 12 months, were: regular periods, no respectively intermenstrual bleedings or spottings; normal sized or only slightly enlarged uterus and no AEs not reported (one subject discontinued because of acne, weightgain (2,5 kg), mood changes and intermenstrual spotting). 17 (85%) continuation rate at 12 months 2 (10%) of the subject had hysterectomies 1 (5%) subject had LNG- 10 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) sign of pelvic pathology; confirmed HMB (80 mL or more during two consecutive cycles). Milsom et al.,1991 (19) Sweden Tang et al 1995 (21) LNG-IUS (n=20) Flurbiprofen and tranexamic acid data previously presented as Andersch et al 1988(20) LNG-IUS (n=10) Hong Kong Nonrandomized study with LNG-IUS Nonrandomized, prospective Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) IUS expulsion Women with confirmed HMB (>80 mL) pretreatment with a normal-sized or only slightly enlarged uterus and no signs of pelvic pathologies on gynecologic examination were recruited. Exclusion criteria included pelvic pathologic conditions, e.g., palpable fibroids diagnosed by gynecologic examination. Alkaline hematin Parous women aged ≥35 years with HMB were considered. Endometrial pathology was ruled out and uterine size less than an 8 week pregnancy. Alkaline hematin 12 months with the LNG-IUS Adverse events not reported for all women 83%, 88% and 96% reduction in mean MBL at 3, 6 and 12 months with the LNGIUS 1(5%) subject had LNGIUS expulsion, Up to 22 months’ follow up AEs not reported. 51% 75%, and 88% mean MBL reduction at 1, 3 and 6 months, respectively. No perforations reported 2 (20%) subjects had LNG-IUS expulsion 16 (80%) completed 12 months 1(5%) subject had hysterectomy Continuation rates over 12 months not reported 2 (20%) subjects had hysterectomy 54% 87%, and 95% median MBL reduction at 1, 3 and 6 months, respectively. Barrington et al 1997 (22) LNG-IUS (n=50) Nonrandomized, Women aged 28 to 53 years with HMB who had failed previous medical therapy and PBAC Up to 9 months followup of treatment AEs not reported. 6 (12%)subjects had 8 (16%) of women withdrawn at 3 11 Author (year)/Country Comparators UK Xiao et al., 2003(23) Study design Inclusion/Exclusion criteria prospective LNG-IUS (n=34) China Nonrandomized, prospective MBL assessment method awaiting surgical treatment were recruited. Those recruited underwent endometrial sampling to exclude those with malignancy or premalignant change. Women aged 27–43 years who experienced regular and heavy menstrual bleeding with a normal sized or slightly enlarged uterus were recruited. Exclusion criteria included: deformity of the uterine cavity or cervical canal, undiagnosed abnormal bleeding, or any other systemic diseases. Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) 74% mean PBAC score reduction at 3 months LNG-IUS expulsion months No perforations reported 2 (4%) opted for surgical treatment Common adverse events reported included abdominal pain (n=5) and weight gain (n=6) 12 month continuation rate not reported 75% reduction in median PBAC score Alkaline hematin 36 months follow-up 79%, 84%, 98% and 85% reduction in mean MBL at 6, 12, 24 and 36 months, respectively 4(12%) subject had LNG-IUS expulsion, 24 (71%) completed 36 months. <<Surgery avoided or required not Insignificant or small fibroids, detected by ultrasound, were acceptable. Gupta et al., 2006 (24) India LNG-IUS (n=25) Endometrial resection (n=25) Nonrandomized, comparative Women with no desire for another pregnancy and HMB unresponsive to oral or injectable hormonal and nonhormonal treatment. Exclusion criteria included pelvic disease; active genital tract infection; use of an intrauterine contraceptive PBAC 12 months follow-up 87%, 94%, 88% and 97% reduction in mean PBAC score at 3, 6, 9 and 12 months, respectively Common AEs with LNG-IUS included: irregular spotting (n = 11); abdominal pain (n = 9); and backache (n = 6). 2 (8%) subjects had LNG-IUS expulsion No perforations reported 17 (68%) attended 12 month followup No women underwent hysterectomy n the LNG-IUS group 12 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) PBAC Up to 4 years follow-up of treatment Prolonged intermenstrual bleeding/spotting reported by 45 (71.4%) subjects during the first 3 months. Other common adverse events reported included: increased vaginal discharge (n=20 [33.3%]), weight gain (n=18 [30.5%]), backache (n=23 [38.3%]), leg pain (n=12 [2.0%]), amenorrhea (n=17 [26.9%]), headache (n=8 [13.3%]), body swelling (n=7 [11.7%]), breast tenderness (n=6 [1.0%]), sleeping problems (n=5 [8.3%]), mood changes (n=5 [8.3%]), hot flushes (n=4 [6.7%]), cholasma (n=3 [5.0%]), weakness (n=3 [5.0%]). 12 month continuation rate not reported device in the last 2 months; and atypical hyperplasia of the endometrium. Kriplani et al 2007 (25) India LNG-IUS (n=63) Nonrandomized, prospective Women with HMB aged 29– 52 years were recruited. Exclusion criteria included endometrial carcinoma, endometrial hyperplasia with atypia, uterine size greater than that of a 12-weekpregnant uterus, uterocervical length greater than 10 cm, or an endocrinopathy or systemic illness causing menorrhagia 71%, 78%, 90%, 98%, 99%, 99% and 99% mean PBAC score reduction at ,1 3, 6, 12, 24, 36 and 48 months, respectively 70%, 80%, 90%, 95%, 95%, 95% and 97% median PBAC score reduction at ,1 3, 6, 12, 24, 36 and 48 months, respectively 45 (71.4%) continued over 4 years 10 (16%) underwent hysterectomy 8 (13%) subjects had LNG-IUS expulsion 13 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) No perforations reported Gorgen et al, 2009(26) LNG-IUS (n=66) Turkey Chattopdhyay et al 2011 (27) LNG-IUS (n=42) India Nonrandomized, prospective Nonrandomized, prospective Women aged 26–55 years with HMB that failed conservative medical therapy. The women had normal uterine cavity with histological benign endometrium. Those with PBAC score ≥75 points were eligible for the study. Women with intracavitary abnormalities were excluded. PBAC Women aged 35 to 55 years with idiopathic HMB with or without irregular cycle. PBAC 74% reduction in mean PBAC score at 6 months LNG-IUS (patients with Nonrandomized, Women aged 25 to 45 years with HMB and desire to Common adverse events reported include: spotting (17%); pelvic pain (13%); bloating (5%) and weight gain (5%) 60 (91%) completed 6 months 2 (3%) women underwent hysterectomy No LNG-IUS expulsions reported No perforations reported Up to 36 months follow-up of treatment 83%, 92%, 96%, 96% and 98% median PBAC score reduction at 3, 6, 12, 24 and 36 months, respectively Exclusion criteria included any organic pelvic pathology (uterine fibroids >2 cm in size), endometrial carcinoma, atypical endometrial hyperplasia, uterine cervical length more than10 cm presence of any hematological disorder like platelet disorders, bleeding diathesis, coagulopathy, endocrinopathy or diabetes mellitus. Kriplani et al 6 months follow-up Adverse event reported with irregular bleeding (29%) and pelvic pain (5%) 1 (2%) subjects had LNG-IUS expulsion No perforations occurred PBAC Up to 4 years follow-up Most common adverse effects in group I was 100%, 90% , 88%, 88% and 64% completed 3, 6, 12, 24 and 36 months follow up, respectively <<Surgery avoided or required not reported>> 12 month continuation rate 14 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria 2012(28) no pathologies; n=50) prospective India LNG-IUS (leiomyoma patients; n=54) preserve fertility. Two groups of women sort, group 1 had at least one myoma and group 2 were aged matched women with HMB of no obvious cause. Exclusion criteria included active pelvic inflammatory disease or type 0 or 1 submucous myoma, adenomyosis, congenital or acquired uterine malformation. MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Group 1 (leiomyoma group) 87%, 92%, 97%, 97%, 100%, and 100% median PBAC reduction at 1, 3, 12, 24. 36 and 48 months prolonged bleeding/spotting 31/46 [67.3%]) in first 3 months. Other adverse events included: not reported 80%, 87%, 94%, 97%, 98% and 99% mean PBAC reduction at 1, 3, 12, 24. 36 and 48 months Group 2 (HMB with no obvious cause) 74%, 92%, 98%, 100%, 100%, and 100% median PBAC reduction at 1, 3, 12, 24. 36 and 48 months 74%, 79%, 93%, 99%, 99% and 99% mean PBAC reduction at 1, 3, 12, 24. 36 and 48 months weight gain (10 [18.5%], backache (14 [25.9%]), leg pain (4 [7.4%]), amenorrhea at 1 year (9/41 [21.9%]), vaginal discharge (6 [11.1%]), headache (5 [9.3%]), body swelling (7 [13.0%]), breast tenderness (3 [5.6%]), sleeping problems (5 [9.3%]), hot flushes (3 [5.6%]), an ovarian cysts (2 [3.7%]) 40 (75%) continued therapy to 4 years in group 1 and 42 (84%) in group 2 Group 1 (leiomyoma): 4 (7%) underwent hysterectomy Group 2 (no obvious pathology): 5 (10%) underwent hysterectomy Most common adverse effects in group I was prolonged bleeding/spotting 23/39 (58.9%) in first 3 months. Other adverse events: weight gain (12 [24%]), amenorrhea at 1 year (17 [34.0%]), backache (10 [20.0%]), vaginal discharge (7 15 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Significant reduction in uterine volume, but not leiomyoma volume [14.0%]), breast tenderness (5 [10.0%]), and body swelling (3 [6.0%]) Continuation rates (for LNGIUS) 6 (11%) expulsion of LNG-IUS occurred in group 1 3 (6%) expulsion of LNG-IUS occurred in group 1 Studies in women with HMB secondary to uterine structural pathology or coagulopathy Kingman et al LNG-IUS (n=16) NonWillebrand’s disease 2004 (29) randomized, Women aged 15 to 50 years prospective UK with HMB and von Willebrand’s disease were recruited. Inclusion criteria included no symptoms of pelvic and previous failed medical treatment. Exclusion criteria included planning pregnancy within the next year or significant pelvic pathology on transvaginal ultrasound such as uterine fibroids. PBAC Up to 9 months followup of treatment 78% reduction in median PBAC score at 9 months AEs not reported. No LNG-IUS expulsions reported No perforations reported Continuation rates not reported <<Surgery avoided or required not 16 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Choudry et al 2009 (30) LNG-IUS (n=24) Nonrandomized, prospective PBAC Up to 12 months follow-up of treatment AEs not reported. 22 (92%) continued over 12 months treatment. Pakistan Kilic et al 2009(31) Turkey Grigorieva et al.,2003 (32) Russia LNG-IUS (n=20) No treatment controls (n=20) LNG-IUS (n=69) (26 women had HMB, PBAC score >100 at baseline) Randomized open-label. Nonrandomized, prospective Bleeding disorders HMB without pelvic pathology but underlying bleeding disorder or use of oral anticoagulants. Anticoagulant therapy 61%, 75% and 84% reduction in median PBAC score at 3, 6 and 12 months, respectively PBAC Women who had undergone cardiac valve replacement procedures and on anticoagulant therapy with a PBAC score > 185 were eligible for the study. Leiomyomas Women aged 20-45 years with uterine leiomyomas who chose the LNG IUS as their method of contraception (strictly not a HMB study but included for completeness). Inclusion criteria included: least one leiomyoma ≥2.5 cm in diameter; multiple leiomyomas, at least one of which ≥1.5 cm on ultrasound. PBAC 1 (4%) subjects had LNG-IUS spontaneously expelled No perforations reported <<Surgery avoided or required not reported>> 6 months’ treatment AEs not reported. 13% and 35% mean MBL reduction at 3 and 6 months, respectively No LNG-IUS expulsions reported 12 months follow-up Most common AEs were spotting and breast tenderness 61 (88%) completed 12 months 2(3%) discontinued due to AEs <<Surgery avoided or required not reported>> 67%, 77% and 84% reduction in mean PBAC score at 3, 6 and 12 months, respectively Significant reduction in the uterine and leiomyoma volume No perforations reported 4 (6%) expulsion of LNG-IUS occurred All women completed the study <<Surgery avoided or required not No perforations reported Exclusion criteria included; 17 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) PBAC 12 months follow-up AEs not reported. 40%, 50%, 65% and 69% reduction in median PBAC score at 3, 6, 9 and 12 months, respectively 4 (13%) expulsion of LNG-IUS occurred 19 (59%) completed 12 months distortion of the uterine cavity. Mercorio et al. 2003 (33) LNG-IUS (n=32) Italy Nonrandomized, prospective Leiomyomas Women referred for hysterectomy because of myoma-related HMB. Those who wished to retain their uterus were invited to participate. No perforations reported 7(22%) scheduled for hysterectomy Persistent HMB (PBAC score >100) remained in 14 women at 12 months Inclusion criteria included: HMB of at least 3 months; a wish to retain their uterus; a uterine volume equivalent to 8–10 week pregnancy; PBAC score >100. Effect on leiomyomas not reported Exclusion criteria included: uterine abnormalities; submucous fibroids; uterine cavity >12 week pregnancy. Soysal et al 2005 (34) Turkey LNG-IUS (n=32) Endometrial ablation (n=32; historical cohort) Nonrandomized, historical cohort comparison Leiomyomas Women aged >40 years with a desire to retain their fertility and HMB were considered eligible for the study. Inclusion criteria included: PBAC score >15; iron deficiency; myomatous uterus as determined by transvaginal ultrasound; presence of at least PBAC 12 months’ follow up AEs not reported. 85% 88%, and 90% mean MBL reduction at 3, 6 and 12 months, respectively. No LNG-IUS expulsions occurred Effect on leiomyomas not reported No perforations reported 28 (88%) completed 12 months 4 (13%) underwent hysterectomy 18 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) PBAC 6 months follow-up AEs not reported. 85% mean PBAC reduction at 6 months No LNG-IUS expulsions reported Continuation rates not reported No reduction of uterine or leiomyoma volumes No perforations reported 12 months follow-up Common adverse events included: Ovarian cysts (n=11; 16%), weight gain (n=6; 9%), pelvic pain (n=4; 6%), bloating (n=3; 5%) and headache (n=3; 5%) one type II myoma; individual myomas < 5 cm in diameter. Exclusion included active pelvic disease, premalignant and malignant uterine and breast diseases. Murat Naki et al., 2010 (35) LNG-IUS (n=46) Turkey Nonrandomized, prospective Leiomyomas Women with HMB and leiomyoma uteri were considered. Exclusion criteria included: uterine size >12 pregnancy weeks at pelvic examination; history of PID; history or risk for STD; submucous leiomyomas; endometrial polyps. Shawki et al 2009(36) Egypt LNG-IUS (n=68) Nonrandomized, prospective Leiomyomas Women aged 35 to 50 years with HMB over the last 6 months and ultrasound-proven submucous uterine leiomyoma were eligible. Exclusion criteria included: current or recent pelvic inflammatory disease, abnormal pap smear; endometriosis; breast cancer; PBAC 83% and 88% reduction in median PBAC score at 6 and 12 months, respectively No significant effect on fibroid or uterine volume <<Surgery avoided or required not reported>> 50 (74%) completed 12 months 7 (10%) had a hysterectomy No LNG-IUS expulsions reported 19 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Alkaline hematin and PBAC 12 months’ treatment AEs not reported. 91% mean MBL reduction at12 months 3 (10%) expulsion of LNG-IUS occurred 23 (79%) completed 12 months 92% and 88% reduction in mean PBAC scores at 6 and 12 months No perforations reported history of venous thromboembolism or liver disease. Sayed et al 2011 (37) LNG-IUS (n=29) COC (Microvlar; n=29) Randomized , open-label. Egypt Socolov et al 2011(38) Romania LNG-IUS (n=102) Nonrandomized, prospective Leiomyomas Women aged between 20 and 50 years requesting contraception and with HMB and fibroids with recruited. Exclusion criteria included pelvic inflammatory disease, defective coagulation, abnormalities on ultrasound, including submucous fibroids of any size if they distort the uterine cavity or intramural or subserous fibroids >5 cm in diameter, history of malignancy or evidence of hyperplasia in the endometrial biopsy, incidental adnexal or abnormality on ultrasound . Leiomyomas Women with myoma and HMB and/or frequent irregular bleeding were eligible for the study. Myomas included 3(10%) underwent surgical treatment due to treatment failure 6 of 29 (23.1%) failed treatment (defined as initiation of a different treatment, or the confirmed expulsion or removal of LNG-IUS). Significant reduction in uterine weight but not diameter of leiomyomas PBAC 12 months follow-up 83, 91% and 92% reduction in mean PBAC score at 3, 6 and 12 months, respectively Adverse effects included: mastodynia (n= 20; 20%), headache (n=12; 12%), pelvic pain (n=12; 12%), weight gain over 5% from initial Continuation rates not reported 3 (3%) had a hysterectomy 20 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method subserous, intramural and submucous type II, with at least one myoma having a diameter greater than 20 mm. Exclusion criteria included: submucous myomas type 0. Jindabanjerd & Taneepanichskul 2006(39) LNG-IUS (n=22) Nonrandomized, prospective Thailand Xie et al 2012(40) LNG-IUS (n=30) China (24 with HMB; PBAC score >100 at baseline) Nonrandomized, prospective Leiomyomas PBAC Women aged 20 to 45 years and uterus less than 12 week pregnancy and at least one myoma ultrasound examination. Exclusion criteria included sub-mucous myoma with distortion of cavity and history of pelvic inflammatory disease. Leiomyomas Women aged 30 to 50 years and uterus less than 12 week pregnancy and at least one myoma ultrasound examination. Exclusion criteria included sub-mucous myoma with distortion of cavity, malignancy of the reproductive system and history of pelvic inflammatory Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) No significant change in leiomyoma volume. Significant reduction in uterine volume observed weight(n=10; 10%), bloating in (n=4; 4%), dyspareunia (n=2; 2%) 6 months’ treatment Adverse events reported included in women who completed study (n=16): bleeding disorders (n=11; 69%); amenorrhea (n=6; 38%); irregular bleeding (n=5; 31%); breast tenderness (n=5; 31%). 80% and 97% reduction in median PBAC score at 3 and 6 months, respectively Significant reduction in myoma and uterine volume at 6 months Continuation rates (for LNGIUS) 6 (6%) expulsion of LNG-IUS occurred 16 (73%) completed study 3 (14%) underwent hysterectomy 1 (5%) expulsion of LNG-IUS occurred PBAC 12 months’ treatment 40%, 70% and 75% reduction in mean PBAC score at 3, 6 and 12 months, respectively No significant reduction in myoma or uterine volume up 12 months Adverse events reported at three months included bleeding disturbance (n=12; 40%); breast tenderness (n=10; 33%) and pelvic pain (n=7; 23%) 29 (97%) completed 12 months <<Surgery avoided or required not reported>> 1 (3%) expulsion of LNG-IUS occurred 21 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) PBAC Up to 4 years follow-up Most common adverse effects in group I was prolonged bleeding/spotting 31/46 [67.3%]) in first 3 months. Other adverse events included: 12 month continuation rate not reported disease. Kriplani et al 2012(28) LNG-IUS (leiomyoma patients; n=54) India LNG-IUS (patients with no pathologies; n=50) Nonrandomized, prospective Leiomyomas Women aged 25 to 45 years with HMB and desire to preserve fertility. Two groups of women sort, group 1 had at least one myoma and group 2 were aged matched women with HMB of no obvious cause. Group 1 (leiomyoma group) 87%, 92%, 97%, 97%, 100%, and 100% median PBAC reduction at 1, 3, 12, 24. 36 and 48 months Exclusion criteria included active pelvic inflammatory disease or type 0 or 1 submucous myoma, adenomyosis, congenital or acquired uterine malformation. 80%, 87%, 94%, 97%, 98% and 99% mean PBAC reduction at 1, 3, 12, 24. 36 and 48 months Group 2 (HMB with no obvious cause) 74%, 92%, 98%, 100%, 100%, and 100% median PBAC reduction at 1, 3, 12, 24. 36 and 48 months 74%, 79%, 93%, 99%, 99% and 99% mean PBAC reduction at 1, 3, weight gain (10 [18.5%], backache (14 [25.9%]), leg pain (4 [7.4%]), amenorrhea at 1 year (9/41 [21.9%]), vaginal discharge (6 [11.1%]), headache (5 [9.3%]), body swelling (7 [13.0%]), breast tenderness (3 [5.6%]), sleeping problems (5 [9.3%]), hot flushes (3 [5.6%]), an ovarian cysts (2 [3.7%]) 40 (75%) continued therapy to 4 years in group 1 and 42 (84%) in group 2 Group 1 (leiomyoma): 4 (7%) underwent hysterectomy Group 2 (no obvious pathology): 5 (10%) underwent hysterectomy Most common adverse effects in group I was prolonged bleeding/spotting 23/39 (58.9%) in first 3 months. Other adverse events: weight gain (12 22 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) 12, 24. 36 and 48 months Significant reduction in uterine volume, but not leiomyoma volume Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) [24%]), amenorrhea at 1 year (17 [34.0%]), backache (10 [20.0%]), vaginal discharge (7 [14.0%]), breast tenderness (5 [10.0%]), and body swelling (3 [6.0%]) 6 (11%) expulsion of LNG-IUS occurred in group 1 3 (6%) expulsion of LNG-IUS occurred in group 1 Fedele et al 1997 (41) Italy LNG-IUS (n=25) Nonrandomized, prospective Adenomyosis PBAC 12 months follow-up Women aged 38 to 45 years with recurrent HMB associated with adenomyosis were eligible 77, 80% and 80% reduction in mean PBAC score at 3, 6 and 12 months, respectively Exclusion criteria included: endometrial disorders, uterine myomas, or adnexal disease, cardiovascular disease or documented lipid metabolism disorders. Significant decrease in endometrial thickness Adverse event reported included: headache (n=6; 24%); breast tenderness (n=3; 16%); seborrhea greasy hair, or acne (n=6; 24%); and weight gain >1kg (n= 7; 28%) 23 (92%) completed 12 months 1 (4%) had a hysterectomy 1 (4%) expulsion of LNG-IUS occurred No perforations reported 23 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for LNGIUS) Adverse effects (for LNG-IUS) Continuation rates (for LNGIUS) Cho et al 2008(42) LNG-IUS (n=47) Nonrandomized, prospective PBAC 36 months follow-up AEs not reported. 95%, 95%, 95% and 89% reduction in mean PBAC score at 6, 12, 24 and 36 months, respectively 2 (4%) expulsion of LNG-IUS occurred 45 (96%) completed 12 months South Korea Adenomyosis Women aged 31 to 45 years with HMB and dysmenorrhea for at least 6 months, and diagnosed with adenomyosis by transvaginal ultrasound. PBAC of 75 corresponds to ≥60 mL HMB. Significant decrease in uterine volume 32 (68%) completed 36 months <<Surgery avoided or required not reported>> ‡Same study as Istre and Trolle (43) and Kittelesen and Istre 1998 (44) AE, adverse events; EE, ethinylestradiol; HMB, heavy menstrual bleeding; LNG-IUS, levonorgestrel-releasing intrauterine system; LNG, levonorgestrel; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate (norethisterone acetate); PBAC, pictorial blood assessment chart; 24 Table 2: Characteristics and outcomes of trials that assessed combined hormonal contraceptives for the treatment of heavy menstrual bleeding (HMB). Data shown for the combined hormonal contraceptive group only. Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Adverse effects Continuation rates (for combined oral contraceptives) Adverse events not reported Not reported by drug (cross-over design) Randomized controlled trial in women with AUB-E (or those described as having HMB without further definition) Fraser and McCarron 1991(45) Australia LNG 150µg/EE 30 µg (n=12) Randomized cross-over Danazol (200 mg daily from day 5, continuously; n =12). Naproxen (500 mg at onset of menses followed by 250 mg TID until 24 hours after the usual duration of menses, max 5 days; n=14) History of HMB and regular periods. Pelvic and systemic causes of HMB were excluded. Most had undergone diagnostic dilatation and curettage and/or hysteroscopy within the previous year. Alkaline hematin Healthy women >30 years with idiopathic HMB (PBAC score ≥100 confirmed during 2 consecutive pre-treatment cycles) and a normal or only slightly enlarged uterus PBAC 2 cycles’ treatment Mean MBL reduction during treatment, 43% <<Surgery avoided or required not reported>> Mefenamic acid (500mg TID from onset of menses until 24 hours after the usual duration of menses, max 5 days; n=38) Endrikat et al 2009 (12) NETA 1mg/EE 20µg; (n=19) Canada LNG-IUS (n=20) Randomized open-label 12 months’ treatment Reduction in median MBL (estimated from graph): 78%, 77%, 80% and 75% during 3, 6, 9 Most frequent reasons for study discontinuation were intermenstrual bleeding, menstrual disorder, and headache 14 (74%) completed 12 months <<Surgery avoided or required not 25 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Adverse effects and 12 months, respectively Continuation rates (for combined oral contraceptives) reported>> 68% mean reduction in PBAC score at 12 months Fraser et al 2011(46) Phasic E2V/DNG# (n=149) Australia and Europe (Czech Republic, Finland, Germany, Hungary, the Netherlands, Poland, Sweden, the UK and Ukraine) Placebo (n=82) Randomized double-blind Women had to be aged ≥18 years with heavy, prolonged and/or frequent menstrual bleeding. Those with organic pathology (including chronic endometritis, adenomyosis, endometriosis, endometrial polyps, leiomyomas or uterine, malignancy) were excluded. Alkaline hematin Phasic E2V/DNG# (n=120) United States and Placebo (n=70) Randomized double-blind Women had to be aged ≥18 years with heavy, prolonged and/or frequent menstrual bleeding. Those with organic 79% median MBL reduction in cycle 7 (vs 7% median reduction with placebo) Reduction in median MBL for OC (estimated from graph): 11%, 72%, 74%, 79%, 83%, 85% and 89% during cycle 1 to 7, respectively Reduction in median MBL for placebo (estimated from graph):1%, 6%, 5%, 12%, 3%, –5%, and 13% during cycle 1 to 7, respectively Patients underwent 90-days run-in phase to objectively confirm HMB (MBL ≥80 mL). Jensen et al 2011(47) 7 cycles’ treatment Alkaline hematin 7 cycles’ treatment 71% median MBL reduction in cycle 7 (vs Adverse events occurring in >5% of patient included: breast pain (n=8; 6%); headache (n=21; 15%); metrorrhagia’(n=8; 6%); nasopharyngitis (n=12; 8%). Serious adverse events were reported by two women (chronic cholecystitis, breast cancer). 109 (73%) completed 7 cycles (62 [76%] completed 7 cycles with placebo) <<Surgery avoided or required not reported>> Adverse events occurring in >5% of patient in placebo group: headache (n=12; 14.8%); nausea/vomiting (6; 7.4%) Adverse events occurring in >5% of patient included: acne (n=6; 5%); metrorrhagia (n=6; 84 (70%) completed 7 cycles 26 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria Canada MBL assessment method pathology (including chronic endometritis, adenomyosis, endometriosis, endometrial polyps, leiomyomas or uterine, malignancy) were excluded. LNG150 µg/ EE30 µg (n= 56) Egypt LNG-IUS (n=56) Randomized open-label Women aged 20–50 years with self-defined HMB. Exclusions included previous ectopic pregnancy, ultrasound abnormalities including fibroids (any size), previous endometrial ablation. Adverse effects Continuation rates (for combined oral contraceptives) 19% median reduction with placebo) 5%); nasopharyngitis(n=9; 8%); nausea (n=6; 5%); vaginitis bacterial (n=6; 5%) (51 [73%] completed 7 cycles with placebo) Reduction in median MBL for OC (estimated from graph): 20%, 76%, 80%, 78%, 76%, 78% and 87% during cycle 1 to 7, respectively Reduction in median MBL for placebo (estimated from graph):23%, 16%, 27%, 28%, 24%, 35%, and 31% during cycle 1 to 7, respectively Patients underwent 90-days run-in phase to objectively confirm HMB (MBL ≥80 mL). Shabaan et al 2011(16) Duration of treatment/MBL outcome Alkaline haematin and PBAC 12 months treatment 35% mean MBL reduction at12 months Adverse events occurring in >5% of patient in placebo group: anemia (n=4; 6%); headache (n=9; 14%); nasopharyngitis(n=6; 9%); nausea (n=5; 8%); vaginitis bacterial (n=4; 6%) Adverse events not reported. 42% or 3% reduction in mean PBAC score at 6 and 12 months Vaginal ring (NuvaRing; Randomized Parous women aged 20–35 PBAC 3 cycles’ treatment 47 (84%) completed 12 months <<Surgery avoided or required not reported>> 18 of 56(32%) failed treatment (defined as initiation of a different treatment). Abu Hashim et al <<Surgery avoided or required not reported>> Breakthrough All participants 27 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria 2012(48) n=48) open-label Egypt Norethisterone (5 mg TID form days 5 to 26; n=47) MBL assessment method years requiring contraception and had HMB (mean PBAC score > 185 over two control cycles). Other inclusion criteria included regular menstrual cycles, no pelvic pathology, uterine sound measurement <10 cm. Exclusion criteria included obesity (BMI >30 kg/m2), smoking, hormone therapy or medication that may interfere with MBL, injectable hormone contraception in last 12 months. Duration of treatment/MBL outcome Mean reduction in PBAC score: 25%, 53% and 69% in cycles 1, 2 and 3 (cycle 1 and 2 data estimated from graph) Non-randomized studies in women with AUB-E (or those described as having HMB without further definition) Larsson et al DSG 150 µg/EE 30 µg NonOtherwise healthy women and Alkaline 6 months’ treatment 1992(49) (n= 5) randomized , no history or evidence of hematin 32% or 45% reduction prospective pelvic pathology. Sweden (only women with MBL in mean MBL at 3 and >80 mL summarized 6 months here) Studies in women with HMB secondary to uterine structural pathology or coagulopathy Sayed et al 2011 LNG 150 µg/ EE 30 µg Randomised, Leiomyomas (37) (n=29) open-label. Women aged between 20 and Alkaline hematin 12 months’ treatment 13% mean MBL Adverse effects Continuation rates (for combined oral contraceptives) bleeding/spotting (4.2%), breast tenderness (4.2%), headache (6.3%), leukorrhea (10.4%), vaginal discomfort (4.2%), vaginitis (8.3%), ring-related events (6.3%) completed three cycles Adverse events not reported. All women with HMB completed treatment <<Surgery avoided or required not reported>> <<Surgery avoided or required not reported>> Adverse events not reported. 21 (72%) completed 12 28 Author (year)/Country Comparators Egypt, LNG-IUS (n=29) #E Study design Inclusion/Exclusion criteria 50 years requesting contraception and with HMB and fibroids with recruited. Exclusion criteria included pelvic inflammatory disease, defective coagulation, abnormalities on ultrasound, including submucous fibroids of any size if they distort the uterine cavity or intramural or subserous fibroids >5 cm in diameter, history of malignancy or evidence of hyperplasia in the endometrial biopsy, incidental adnexal or abnormality on ultrasound. MBL assessment method Duration of treatment/MBL outcome Adverse effects Continuation rates (for combined oral contraceptives) and PBAC reduction at12 months months 75% and 54% reduction in mean PBAC scores at 6 and 12 months <<Surgery avoided or required not reported>> 11 of 29 (38%) failed treatment (defined as initiation of a different treatment). 2V 3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25 and 26 and placebo on days 27 and 28. AE, adverse events; DSG, desogestrel; E2V, estradiol valerate; EE, ethinylestradiol; HMB, heavy menstrual bleeding; LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate (norethisterone acetate); PBAC, pictorial blood assessment chart 29 Table 3: Characteristics and outcomes of trials that assessed tranexamic acid for the treatment of heavy menstrual bleeding (HMB). Data shown for tranexamic acid group only. Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition) Nilsson & Rybo Tranexamic acid (0.25g Assumed to Patients aged 15–49 years Alkaline 1 cycle of treatment 1967(50) six times daily on days 1 be a referred for suspected hematin Mean MBL reduction Sweden to 4; n=6) randomized HMB. Bleeding determined to (calculated from data double-blind be ovulatory in 22/36 women provided): Tranexamic acid (0.5g cross-over (not determined in the others). Tranexamic acid six times daily on days 1 study (0.25g group): 34% to 4; n=26) Tranexamic acid Tranexamic acid (1g six (0.5g group): 41% times daily on days 1 to Tranexamic acid 4; n=20) (1g group): 55% Placebo: 15% Placebo (n=31) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) Tranexamic acid (0.5g group): abdominal pain (n=4); nausea (n=3) No patient reported to discontinue study Tranexamic acid (1g group): abdominal pain (n=3); diarrhoea (n=6) Placebo: nausea (n=3); headache (n=2) (excluding those with fibroids) Andersch et al 1988(20) Sweden Tranexamic acid (1.5 g TID for days 1 to 3 and 1 g BID on days 4 and 5; n=15) Flurbiprofen (100 mg BID for 5 days; n=15) Randomized cross-over Women seeking help for idiopathic HMB (MBL > 80 mL objectively confirmed during two pre-treatment periods). All women has regular menstrual cycles and no evidence of pelvic pathology. Alkaline hematin 2 cycles’ treatment 47% and 47% mean reduction during cycles 1 and 2. 47% mean reduction in MBL during treatment Adverse event reported in 7 (46%) women during tranexamic acid treatment included nausea, dizziness, numbness, “restless legs”, headache and in 3 women vomiting and No patients discontinued therapy <<Surgery avoided or required not 30 Author (year)/Country Edlund et al 1995(51)a Sweden Comparators Kabi 2161 (tranexamic acid prodrug, 600 mg BID from days 1 to 5; n=26) Study design Inclusion/Exclusion criteria Randomized , double blind Kabi 2161 (600 mg four times daily; n=28) Placebo (n=14) Preston et al 1995(52) UK Tranexamic acid (1 g QID on days 1 to 4; n=25) Randomized double-blind Norethisterone (5 mg BID on days 19 to 26; n=21) Bonnar and Sheppard Tranexamic acid (1 g QID from days 1 to 5; Randomized (blinding not stated but MBL assessment method Women aged ≥18 years with regular menstrual cycles, menorrhagia (defined as MBL > 80 mL confirmed objectively during two run-in cycles) and a normal-sized uterus. Exclusion criteria included pelvic pathology, CIN in cervical smear, thromboembolic disease, hemorrhagic or fibrinolytic disorder. Alkaline hematin Women aged ≥18 years complaining of heavy regular cycles (average MBL >80 mL objectively confirmed during two placebo cycles). Exclusions included any previous hormonal use in the last three months, abnormalities during pelvic examination and positive cervical cytology. Alkaline hematin Patients 35-46 years with regular HMB (MBL >80 mL objectively confirm during 3 Alkaline hematin Duration of treatment/MBL outcome (for tranexamic acid) 3 cycles’ treatment Mean MBL reduction during treatment: Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) difficulty in swallowing. reported>> 8 women reported adverse events such as nausea and diarrhoea (not stated by group) 23 women did not complete study (not stated by group) Kabi 2161 (BID), 39% <<Surgery avoided or required not reported>> Kabi 2161 (four times daily), 31% Placebo, no reduction (4% increase) 2 cycles’ treatment Mean MBL reduction: 55% and 34% MBL reduction with tranexamic acid during cycles 1 and 2 Dysmenorrhoea (80%), headache (32%), gastrointestinal (including diarrhea, nausea, vomiting, and dyspepsia; 12%) 2 patients did not complete both cycles Not specifically described for tranexamic 22 (85%) completed 3 <<Surgery avoided or required not reported>> Mean overall reduction during treatment, 45%. 3 cycles’ treatment Tranexamic acid: 31 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria 1996(53) n=26) Ireland Ethamsylate (500 mg QID from days 1 to 5; n=27) assumed to randomised open-label) Mefenamic acid (500 mg TID from days 1 to 5; n= 23) Kriplani et al 2006(54) India Tranexamic acid (500 mg QID form day 1 to 5; n=49) MPA (10 mg BID from day 5 to 25; n=45) Lukes et al 2010(55) USA Tranexamic acid (1.3 g TID on days 1 to 5; n=123)* Placebo (n=73) MBL assessment method pre-treatment cycles). Those with organic causes of HMB excluded by gynaecological investigation, including hysteroscopy, endometrial biopsy, and a cervical smear. Duration of treatment/MBL outcome (for tranexamic acid) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) 55%, 56%, 54% MBL reduction during cycles 1, 2 and 3 acid cycles. 20 (77%) taking tranexamic acid wished to continue the treatment 54% MBL reduction (average treatment effect over 3 treatment cycles vs baseline) Randomized (blinding not stated but assumed to randomised open-label) PBAC score >100 (confirmed during pre-treatment cycle). General and gynaecological examinations to rule out any pelvic pathology and to measure endometrial thickness. PBAC Randomized double-blind Women age 18–49 years with HMB (objectively confirmed during two pretreatment cycles; average ≥ 80 mL with lowest MBL assessed ≥ 60 mL) and normal findings on pelvic Alkaline hematin 3 cycles’ treatment. Mean PBAC score reduction with tranexamic acid: 58%, 61%, 60% during cycles 1, 2 and 3 6 cycles’ treatment Mean MBL reduction (data estimated from graphs): 43%, 40%, 37% and 39% MBL <<Surgery avoided or required not reported>> Eight (16.3%) cases reported adverse events with tranexamic acid including: allergic reaction (n=1; 2%); headaches (n=3; 6%); gastrointestinal upsets (n=3; 6%); giddiness (n=1; 2%) 47 (96%) completed 3 months Treatment-emergent adverse events occurring in ≥5% of patient included: menstrual discomfort/cramps (n=72; 62%); headache (n=65; 56%); back pain 94 (76%) completed 6 cycles (vs 74% on placebo) 2 (4%) out of the 49 recruited into the tranexamic acid group underwent hysterectomy <<Surgery 32 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria examination, no clinically important cervical cytology abnormalities, and no clinically important uterine pathologic findings by transvaginal ultrasonography. Leiomyomas not considered an abnormal finding unless sufficient in number and size to warrant surgery. MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) reduction with tranexamic acid during cycles 1, 2, 3 and 6 5%, 7%, 10% and 12% MBL reduction with placebo during cycles 1, 2, 3 and 6 Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) (n=28; 24%); nausea (n=17; 15%); anemia; arthralgia (n=11; 9%); (n=12; 10%), upper viral tract infection (n=9; 8%), allergies (n=10; 9%); abdominal discomfort (n=8; 7%), cough (n=7; 6%), insomnia (n=6; 5%); fatigue (n=8; 7%); muscle cramps (n=8; 7%); migraine (n=7; 6%); sinus headache (n=9; 8%) avoided or required not reported>> Treatment-emergent adverse events occurring in ≥5% of patient on placebo included: menstrual discomfort/cramps (n=36; 50%); headache (n=36; 50%); back pain (n14; 19%); nausea (n=11; 15%); anemia (n=4; 6%); arthralgia (n=5; 7%); viral upper tract infection (n=7; 10%); allergies (n=5; 7%); abdominal discomfort (n=6; 8%); 33 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) cough (n=5; 7%); insomnia (n=6; 8%); dyspepsia (n=8; 11%) and migraine (n=4; 6%) Najam et al 2010(56) India Tranexamic acid (500 mg TID from days 1 to 5; n=55) Randomized single-blind Tranexamic acid (500 mg TID) plus mefenamic acid (250 mg TID) from days 1 to 5; n=55) Women aged 12-45 years with heavy regular cycles (PBAC >100 confirmed during pretreatments cycle). Exclusions included any pelvic pathology, organic disease, recent IUD or hormonal therapy, anovulatory or irregular cycles. PBAC 6 months’ treatment Mean PBAC score reduction (data estimated from graphs): Nausea and gastrointestinal disturbances in 9 cases and leg cramps in 7 cases Not reported Treatment-emergent adverse events occurring in >5% of TA–treated women and 2-fold that in placebo group: Tranexamic acid doses 0.65mg TID (91% completed study) Mean 26%, 37%, 50% PBAC score reduction with tranexamic acid during cycles 1, 3 and 6 <<Surgery avoided or required not reported>> Mean 38%, 51%, 59% PBAC score reduction with Tranexamic acid plus mefenamic acid during cycles 1, 3 and 6 Freeman et al 2011(57) USA Tranexamic acid doses 0.65g TID form days 1-5; n=117) Tranexamic acid doses 1.3 g TID from days 1-5; Randomized double-blind Women aged 18-49 years with a history of cyclic HMB (MBL ≥80 mL objectively confirmed during two pretreatment cycles). Exclusions included pelvic pathology Alkaline hematin 3 cycles’ treatment Mean MBL reduction (data estimated from graphs): Tranexamic acid doses 0.65mg TID Placebo; upper Tranexamic acid doses 1.3 mg TID 34 Author (year)/Country Comparators n=118) Placebo (n=69) Study design Inclusion/Exclusion criteria (women with fibroids were not excluded automatically unless they required surgical management), abnormal cervical cytology, coagulopathy. MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) (27%, 27% and 31% during cycles 1, 2 and 3; mean overall reduction during treatment 26%) Tranexamic acid doses 1.3 mg TID (39%, 38% and 38% during cycles 1, 2 and 3; mean overall reduction during treatment 39%) Placebo (4% increase, 6% and 4% during cycles 1, 2 and 3; mean overall reduction during treatment 2%) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) respiratory viral tract infection (4.5%), fatigue (4.5%), musculoskeltal pain (3.0%), arthralgia (1.5%), myalgia (0%) nasal congestion (0%), sinusitis (1.5%), allergies (0%), throat irritation (3.0%) anemia (1.5%) (87% completed study) Tranexamic acid doses 0.65 mg TID; upper respiratory viral tract infection (10.4%), fatigue (11.3%), musculoskeltal pain (8.7%), arthralgia (6.1%), myalgia (4.4%) nasal congestion (7.0%), sinusitis (6.1%), allergies (5.2%), throat irritation (6.1%) anemia (5.2%) Placebo (90% completed study) <<Surgery avoided or required not reported>> Tranexamic acid doses 1.3 mg TID; upper respiratory viral tract infection (7%), fatigue (3.5%), musculoskeltal pain (5.2%), arthralgia (4.4%), myalgia (5.2%), nasal congestion (2.6%), sinusitis (2.6%), allergies 35 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) (3.5%), anemia (0.8%) Non-randomized trials in women with AUB-E (or those described as having HMB without further definition) Gleeson et al 1994 Tranexamic acid (500 mg NonWomen with regular HMB Alkaline 3 cycles’ treatment (58) QID on days 1 to 5 of randomized, and no endocrine dysfunction hematin 55%, 64% and 52% menses; n=15) prospective or bleeding diathesis were Ireland median MBL recruited. Exclusion criteria (MBL reported for 15 reduction at 1, 2 and included pelvic abnormalities, women) 3 cycles of treatment, endometrial pathology. All respectively women undertook 3 cycles of (estimated from observation. graph) Adverse events not reported separately for those with HMB Discontinuations not reported None of the patients reported adverse events 100% continuation (no patient discontinued) Not reported separately for this group No patient reported to discontinue study 58% reduction in median MBL across all 3 treatment cycles vs baseline Srinil et al 2005(59) Thailand Tranexamic acid (1 g TID on days 1 to 5 of menses; n=40) Nonrandomized, prospective Women aged 18 to 45 years with HMB and no systemic disease related to HMB were eligible. Women with pelvic pathologies were excluded through pelvic examination and transvaginal ultrasonography. Studies in women with HMB secondary to uterine structural pathology or coagulopathy Nilsson & Rybo Tranexamic acid (0.5g Assumed to Leiomyoma 1967(50) six times daily on days 1 be a Sweden to 4; n=5) randomized Patients aged 15–49 years double-blind referred for suspected PBAC 2 cycles’ treatment 26% and 49% reduction in mean MBL in cycles 1 and 2, respectively Alkaline hematin 1 cycle of treatment Mean MBL reduction (calculated from data provided): 36 Author (year)/Country Kouides et al 2009(60) USA Comparators Study design Inclusion/Exclusion criteria Tranexamic acid (1g six times daily on days 1 to 4; n=5) cross-over study HMB. Bleeding determined to be ovulatory in 22/36 women (not determined in the others). Tranexamic acid (1 g four times each day for the first 5 day of menses) Randomized, cross-over Bleeding disorder Desmopressin (nasal spray at 300 µg per nostril on days 2 days and 3 of cycle) Desmopressin/ tranexamic acid sequence (n=49) Tranexamic acid Desmopressin/sequence (n=67) Women aged 18–50 years referred for HMB to a hemophilia treatment centre, bleeding disorder clinic, or gynaecology care centre. Inclusion criteria included negative pelvic examination (fibroids were allowed if the uterus was <12 weeks gestational size), a negative Papanikolaou smear, PBAC score ≥100, and detectable bleeding disorder. MBL assessment method PBAC Duration of treatment/MBL outcome (for tranexamic acid) Tranexamic acid (0.5g group): 18% Tranexamic acid (1g group): 36% 2 cycles per treatment period (data shown for tranexamic acid period only) Desmopressin/ tranexamic acid sequence: 47% and 52% mean reduction in cycles 1 and 2 of tranexamic acid (vs baseline) 38% and 42% median reduction in cycles 1 and 2 of tranexamic acid (vs baseline) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) Of the 90 patients who used either study medication for at least one cycle, 13 (14%) had adverse events; seven patients with desmopressin and six with tranexamic acid. Discontinuation rates were 43% for the nasal desmopressintranexamic acid sequence and 33% for tranexamic acid – desmopressin sequence <<Surgery avoided or required not reported>> Tranexamic acid/ desmopressin sequence: 31% and 43% mean reduction in cycles 1 and 2 of desmopressin (vs 37 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for tranexamic acid) Adverse effects (for tranexamic acid) Continuation rates (for tranexamic acid) baseline) 38% and 42% median reduction in cycles 1 and 2 of desmopressin (vs baseline) a Kabi (tranexamic acid prodrug) *New oral formulation of tranexamic acid (LYSTEDA) designed minimizing gastrointestinal adverse effects but with higher per-tablet dose and increases drug absorption BID, twice daily; HMB, heavy menstrual bleeding; LNG-IUS; levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; PBAC, pictorial blood assessment chart; TID, three times a day; QID, four times daily 38 Table 4: Characteristics and outcomes of trials that assessed danazol for the treatment of heavy menstrual bleeding (HMB). Data shown for the danazol group only Author (year)/Country Comparators and number randomized Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for danazol) Adverse effects (for danazol) Continuation rates (for danazol) Adverse effects reported include: Not reported Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition) Chimbira et al 1980(61) Danazol (200 mg daily; n=16) UK Danazol (100 mg daily; n=16) Randomized (blinding not stated) Women with regular cycles and HMB (MBL >60 mL objectively confirmed in two pre-treatment cycle). Exclusion criteria included detectable pelvic pathology such as fibroids, polyps or malignancy. Alkaline hematin 3 cycles’ treatment Mean MBL reduction Danazol (200 mg daily): 22%, 79% and 86% reduction during cycles 1, 2 and 3, respectively. Danazol (100 mg daily; (data estimated from graphs): 30%, 55% and 61% reduction during cycles 1, 2 and 3, respectively. Cameron et al 1987(62) Danazol (200 mg daily; n=6) UK Norethisterone (5 mg BID from day 15-25; Randomized (blinding not stated but assumed to Ovulatory cycles and mean monthly blood loss >50 mL (objectively confirmed during two pre-treatment cycles). Alkaline hematin 2 cycles’ treatment Reduction in median MBL during Danazol (200 mg daily): tiredness/sleepiness(n=5) , musculoskeletal pain (n=4), skin rash (n=3), headaches (n=6), irritability (n=3), vaginitis (n=3) <<Surgery avoided or required not reported>> Danazol (100 mg daily): tiredness/sleepiness(n=6) , musculoskeletal pain (n=2), skin rash (n=2), headaches (n=5), irritability (n=1), vaginitis (n=2) Not reported Not reported <<Surgery 39 Author (year)/Country Comparators and number randomized Study design Inclusion/Exclusion criteria n=8) randomized open-label) Progesterone IUS (65 mg progesterone daily; n = 8) MBL assessment method Duration of treatment/MBL outcome (for danazol) Adverse effects (for danazol) treatment, 75% Continuation rates (for danazol) avoided or required not reported>> Mefenamic acid (500 mg TID during menses; n = 8) Dockeray et al 1989(63) Danazol (100 mg BID; n=20) Ireland Mefenamic acid (500 mg TID for 3 to 5 days; n=20) Fraser and McCarron 1991(45) Danazol (200 mg daily from day 5, continuously; n =12). Australia Naproxen (500 mg at onset of menses followed by 250 mg TID until 24 hours after the usual Randomized open-label Randomised open-label cross-over Otherwise health parous women with a HMB (MBL >80mL objectively confirmed during two pre-treatment cycles) and clinically normal pelvic organs and the absence of any endometrial pathology at diagnostic curettage. Alkaline hematin History of HMB and regular periods. Pelvic and systemic causes of HMB were excluded. Most had undergone diagnostic dilatation and curettage and/or hysteroscopy within the previous year. Alkaline hematin 2 cycles’ treatment Mean MBL reduction: 46% and 76% MBL during cycles 1 and 2 of treatment (60% overall reduction during treatment) 2 cycles’ treatment 13% and 86% mean MBL reduction at cycles 1 and 2, respectively. Mean MBL reduction Adverse effects reported (by ≥2 patients) include: Breast atrophy (n=3), acne (n=3), irritability/aggression (n=3), headache (n=8), nausea/vomiting (n=6), musculoskeletal pain (n=5), breast pain (n=2), flushes (n=2), depression (n=2), dizziness (n=2), backache (n=2), tiredness (n=2), off-color (n=2) Adverse events not reported Ten patients refused to continue treatment after study <<Surgery avoided or required not reported>> Not report by drug (cross-over design) <<Surgery avoided or required not 40 Author (year)/Country Comparators and number randomized Study design Inclusion/Exclusion criteria MBL assessment method duration of menses, max 5 days; n=14) Duration of treatment/MBL outcome (for danazol) Adverse effects (for danazol) during treatment, 49% Continuation rates (for danazol) reported>> Mefenamic acid (500mg TID from onset of menses until 24 hours after the usual duration of menses, max 5 days; n=38) Low-dose COC (n=12) Higham and Shaw 1993(64) Danazol (recommended dose 200 mg daily; n=19) UK Danazol (reduced dose 200, 100, and 50 mg daily in cycles, 1, 2 and 3, respectively; n=19) Norethindrone (5 mg TID from days 19 to 26; n= 19) Randomized single-blind Women aged 20–50 years with objectively proven HMB (MBL >80 mL objectively confirmed during two pretreatment cycles). Those with underlying organic pathologies were excluded. Alkaline hematin 3 cycles’ treatment Change in median MBL (estimated using the two baseline values): Danazol (200 mg): 40% decrease in cycle 3 Danazol (reduced dose): 28% decrease in cycle 3 Adverse events reported in ≥2 patients include: Danazol (200 mg): headache/migraine (n=7), abdominal bloating (n=3), weight gain (n=5), muscle cramps (n=5), intermenstrual bleeding (n=4), acne (n=2), depression (n=2), dizziness (n=2), edema (n=2), dysmenorrhea (n=2), nausea/vomiting (n=2) Danazol (200 mg): 3 patients discontinued treatment phase Danazol (reduced dose): 5 patients discontinued treatment phase <<Surgery avoided or required not reported>> Danazol (reduced dose): headache/migraine (n=8), abdominal bloating (n=5), weight 41 Author (year)/Country Comparators and number randomized Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for danazol) Adverse effects (for danazol) Continuation rates (for danazol) gain (n=4), muscle cramps (n=4), intermenstrual bleeding (n=3), acne (n=2), depression (n=2), dizziness (n=2), dysmenorrhea (n=2) Dunphy et al 1998(65) Danazol (200 mg daily; n=12) Canada MPA (10 mg daily from days 16 to 25; n=11) Randomized double-blind Women aged ≥ 18 years with HMB (MBL> 80 mL during one pre-treatment cycle). Dysfunctional bleeding was diagnosed by exclusion using hysteroscopy with endometrial biopsy or curettage PBAC 3 cycles’ treatment Mean PBAC score reduction: 66%, 77%, 88% during cycle 1, 2 and 3 cycles, respectively Non-randomized trials in women with AUB-E (or those described as having HMB without further definition) Women aged between 25 to Chimbira et al Danazol (400 mg daily NonAlkaline 3 months’ treatment 50 years with HMB (>80 mL 1979(66) starting during randomized hematin Mean MBL confirmed pretreatment) and menstruation; n=18) prospective UK reduction: 42%, 91%, no detectable pelvic pathology 99% during cycle 1, 2 and desire to avoid and 3, respectively hysterectomy were recruited. Chimbira et al 1980(67) UK Danazol (400 mg daily starting immediately after menstruation; n=13) Nonrandomized prospective Women with regular (ovulatory) cycles and HMB (MBL >80 mL objectively confirmed) and no detectable pelvic pathology on Alkaline hematin 3 cycles’ treatment 52%, 91% and 96% mean MBL reduction at 1st, 2nd and 3rd Adverse events reported in eight of nine patients (not specified) 2 patients withdrew due to adverse events 9 (75%) completed study <<Surgery avoided or required not reported>> Adverse events included: tiredness/sleepiness (n=7; 39%); musculoskeletal pain (n=7; 39%); skin rash (n=6; 33%); headache (n=5; 28%); irritability (n=4; 22%); hot flushes (n=3; 17%) Not reported Adverse events not reported Not reported <<Surgery avoided or required not reported <<Surgery avoided or 42 Author (year)/Country Comparators and number randomized Study design Inclusion/Exclusion criteria MBL assessment method examination and uterine curettage. Chimbira et al 1980(61) Danazol (200 mg daily; n=8) UK Placebo (n=8) Nonrandomized, single-blind, prospective Women with regular cycles and HMB (MBL >60 mL objectively confirmed in two pre-treatment cycle). Exclusion criteria included detectable pelvic pathology such as fibroids, polyps or malignancy. Duration of treatment/MBL outcome (for danazol) Adverse effects (for danazol) episodes of bleeding Alkaline hematin 3 months’ treatment (2 cycles placebo run-in) Continuation rates (for danazol) required not reported>> Adverse events not reported Not reported <<Surgery avoided or required not reported>> Mean MBL reduction (vs baseline): 58%, 92%, 90% during cycle 1, 2 and 3, respectively Mean MBL reduction with placebo: 1% (mean over two placebo cycles) Chimbira et al 1980(61)† UK Danazol (600 mg daily from days 1-7 of each cycle; n=11) Nonrandomized, prospective Women with regular cycles and HMB (MBL >60 mL objectively confirmed in two pre-treatment cycle). Exclusion criteria included detectable pelvic pathology such as fibroids, polyps or malignancy. Alkaline hematin 3 months’ treatment (2 cycles placebo run-in) Mean MBL reduction: 2% and 40% in cycles 2 and 3, respectively Adverse events not reported Not reported <<Surgery avoided or required not reported>> † Report appears to include data from at least two studies BID, twice daily; HMB, heavy menstrual bleeding; IUS, intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; PBAC, pictorial blood assessment chart; TID, three times daily 43 Table 5: Characteristics and outcomes of trials that assessed oral progestogens for the treatment of heavy menstrual bleeding (HMB). Data shown for the oral progestogens group only Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for oral progestin) Adverse effects (for oral progestin) Continuation rates (for oral progestin) Not reported Not reported Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition) Short course Cameron et al 1987(62) UK Norethisterone (5 mg BID from day 15-25; n=8) Progesterone IUS (65 mg progesterone daily; n = 8) Not stated (assumed to randomized open-label) Ovulatory cycles and mean monthly blood loss>50 mL (objectively confirmed during two pre-treatment cycles). Alkaline hematin 2 cycles’ treatment Not stated (assumed to randomized open-label) Women with subjective HMB and no organic pathology. HMB objectively confirmed in two pre-treatment cycles (only those with >80 mL included). Alkaline hematin 2 cycles’ treatment Reduction in median MBL during treatment, 30% <<Surgery avoided or required not reported>> Mefenamic acid (500 mg TID during menses; n = 8) Danazol (200 mg daily; n=6) Cameron et al 1990(68) UK Norethisterone (5 mg BID from day 19-26, n=15) Mefenamic acid (500 mg TID during menses, n=17) Median 20% reduction in MBL during treatment Adverse events reported included: Headache (33%) Abdominal pain (20%), Nausea (7%) 1 patient discontinued treatment in third cycle <<Surgery avoided or required not reported>> 44 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for oral progestin) Adverse effects (for oral progestin) Continuation rates (for oral progestin) Higham and Shaw 1993(64) Norethindrone (5mg TID from days 19 to 26; n= 19) Randomized single-blind Women aged 20–50 years with objectively proven HMB (MBL >80 mL objectively confirmed during two pretreatment cycles). Those with underlying organic pathologies were excluded. Alkaline hematin 3 cycles’ treatment Adverse events reported in ≥2 patients include: 2 patients discontinued treatment phase Women aged ≥18 years complaining of heavy regular cycles (average MBL >80 mL objectively confirmed during two placebo cycles). Exclusions included any previous hormonal use in the last three months, abnormalities during pelvic examination and positive cervical cytology. Alkaline hematin Women aged ≥ 18 years with HMB (MBL> 80 mL during one pre-treatment cycle). Dysfunctional bleeding was diagnosed by exclusion using hysteroscopy with endometrial PBAC UK Danazol (recommended dose 200 mg daily; n=19) Danazol (reduced dose 200, 100, and 50 mg daily in cycles, 1, 2 and 3, respectively; n=19) Preston et al 1995 (52) UK Norethisterone (5 mg BID on days 19 to 26; n=21) Randomized double-blind Tranexamic acid (1 g four times daily on days 1 to 4; n=25) Dunphy et al 1998(65) MPA (10 mg daily from days 16 to 25; n=11) Canada Danazol (200 mg daily; n=12) Randomized double-blind Change in median MBL (estimated using the two baseline values): 4% decrease in cycle 3 2 cycles’ treatment Mean MBL increased: muscle cramps (n=4), dysmenorrhea (n=3), depression (n=3); headache/migraine (n=2); breast discomfort (n=2); premenstrual tension (n=2) Dysmenorrhoea (85%), headache (48%), gastrointestinal (33%) <<Surgery avoided or required not reported>> 2 patients did not complete both cycles <<Surgery avoided or required not reported>> 13% and 27% MBL with norethisterone during cycles 1 and 2 MBL increased by 20% during treatment 3 cycles’ treatment Mean PBAC score reduction: 25% and 41% during cycle 1 and 2 cycles, but 12% increase in score Adverse events reported in 2 of 7 patients (not specified) 1 patient withdrew due to adverse events 9 (82%) completed study <<Surgery avoided or required not 45 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method biopsy or curettage. Kaunitz et al 2010(14) MPA (10 mg daily from 16 to 25; n= 83) United States, Canada, and Brazil LNG-IUS (n=82) Randomized open-label Parous women aged ≥18 years with idiopathic HMB (me≥80 mL per cycle). Exclusions included fibroids (if they distorted the uterine cavity or cervical canal); history of organic causes of abnormal uterine bleeding. Duration of treatment/MBL outcome (for oral progestin) Adverse effects (for oral progestin) observed in cycle 3. Alkaline hematin 6 cycles’ treatment 2% and 13% median MBL reduction at cycle 3 and 6 11% and 22% mean MBL reduction at cycle 3 and 6 MPA successfully treated 18 (22%) of women (defined as proportion with MBL <80 mL at end of study and ≥50% reduction in MBL from baseline). Continuation rates (for oral progestin) reported>> Adverse effects reported in more than patient included: headache (11%); acne (6.1%; weight gain (6.1%), lower abdominal pain (6.1%); breast tenderness (3.7%), bacterial vaginitis (3.7%); urinary tract infection 3.7%; sinusitis (3.7%); fatigue (2.4%), ovarian cysts (2.4%), pelvic pain (2.4%) 72 (87%) completed 6 cycles <<Surgery avoided or required not reported>> 2/82 discontinued due to AEs Long course Irvine et al 1998(2) UK Norethisterone (5 mg TID from day 5 to 26; n=22) LNG-IUS (n=22) Randomized open-label Healthy women 18–45 years with a regular menstrual cycle, a normal pelvic examination with a uterine sound < 10 cm, negative cervical cytology and MBL >80 mL. Alkaline hematin 3 cycles’ treatment 63% and 78% median reduction in MBL at cycle 1 and 3 of treatment No difference in adverse events (headaches, acne, abdominal or back pain, nausea, oedema, weight gain, decreased libido, sweating, hair loss or greasy hair and increase in body hair) at baseline and over 3 months. Intermenstrual bleeding, 16 (73%) completed 3 months 4 (22%) elected to continue with the treatment. 46 Author (year)/Country Comparators Kriplani et al 2006(54) MPA (10 mg BID from day 5 to 25; n=45) India Tranexamic acid (500 mg four times daily form day 1 to 5; n=49) Kucuk and Ertan 2008(11) Oral MPA (5 mg daily; n=44) Assumed to be Turkey and Germany (not clear) Depot MPA (n=44); Shravage et al 2011(69) MPA (10 mg for 21 days starting from day 2 to 5; n =42) Study design Inclusion/Exclusion criteria Randomized open-label Randomized open-label LNG-IUS (n=44) MBL assessment method PBAC score >100 (confirmed during pre-treatment cycle). General and gynaecological examinations to rule out any pelvic pathology and to measure endometrial thickness. PBAC Perimenopausal women (aged >40 years) who were smokers. Those with organic pathology and nonsmokers were excluded. PBAC Duration of treatment/MBL outcome (for oral progestin) 3 cycles’ treatment Mean PBAC score reduction with MPA: 55%, 52%, 58% during cycles 1, 2 and 3 2 cycles’ treatment Oral MPA: 33% mean PBAC score reduction by cycle 2 Adverse effects (for oral progestin) Continuation rates (for oral progestin) breast tenderness and mood swings appeared to decrease relative to baseline. <<Surgery avoided or required not reported>> 15 (33.3%) cases reported adverse events with MPA including: intermenstrual bleeding (n=5; 11%); tiredness (n=3; 7%); headaches (n=2, 4%); breast tenderness (n=2; 4%); gastrointestinal upsets (n=2; 4%); mood changes (n=1; 2%) 33 (73%) completed 3 months Common adverse effects included intermenstrual bleeding (n=12; 27%) and breast tenderness(n=12; 27%) Proportion completing study not reported Depot MPA: 49% mean PBAC score reduction by cycle 2 Randomized double-blind Women aged 35 to 50 years with HMB. Exclusion criteria include pelvic pathology, PBAC 3 months’ treatment 8 (17.8%) out of the 45 patients recruited underwent hysterectomy 19 (43%) willing to continue <<Surgery avoided or required not reported>> Not reported Not reported Mean reduction in PBAC score with 47 Author (year)/Country Comparators India Ormeloxifene (60 mg taken two days a week at an interval of 3 day; n=42) Abu Hashim et al 2012(48) Norethisterone (5 mg TID form days 5 to 26; n=47) Egypt Vaginal ring (NuvaRing; n=48) Study design Inclusion/Exclusion criteria MBL assessment method systemic disorders, severe anemia, chronic cervicitis and cervical dysplasia. Randomized open-label Parous women aged 20–35 years requiring contraception and had HMB (mean PBAC score > 185 over two control cycles). Other inclusion criteria included regular menstrual cycles, no pelvic pathology, uterine sound measurement <10 cm. Exclusion criteria included obesity (BMI >30 kg/m2), smoking, hormone therapy or medication that may interfere with MBL, injectable hormone contraception in last 12 months. Duration of treatment/MBL outcome (for oral progestin) Adverse effects (for oral progestin) Continuation rates (for oral progestin) Breakthrough bleeding/spotting (12.8%), breast tenderness (6.4%), nausea (4.2%), headache (4.2%) All participants completed three cycles Adverse event reported included weight gain (n=2), abdominal bloating (n=3), minor acne (n=2), mild nausea (n=2), headache (n=2) All participants completed treatment cycles MPA: 41%, 55% and 60% during cycle 1, 2 and 3 PBAC 3 cycles’ treatment Mean reduction in PBAC score: 26%, 51% and 70% in cycles 1, 2 and 3 (cycle 1 and 2 data estimated from graph) Non-randomized trials in women with AUB-E (or those described as having HMB without further definition) Fraser 1990(70) Cyclic oral progesterone NonStudy included six women Alkaline 2 cycles of treatment (norethisterone or randomized, with anovulatory HMB (>80 hematin Australia Anovulatory HMB medroxyprogesterone prospective mL confirmed in pretreatment 39% and 51% acetate) cycles) and no obvious pelvic mean MBL pathology or systemic disease. Anovulatory HMB (NET reduction during Ten women with ovulatory 5mg TID or MPA 10mg cycles 1 and 2 HMB and no obvious pelvic TID from day 12 to 25 pathology or systemic disease. <<Surgery avoided or required not reported>> 48 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome (for oral progestin) Adverse effects (for oral progestin) Continuation rates (for oral progestin) Ovulatory HMB (overall for both MPA- and NETtreated patients): See above See above inclusive; n=6) Non-randomized trials in women with AUB-O Fraser 1990(70) Ovulatory HMB Australia MPA (10 TID for 21 days from day 5 to 25 inclusive; n=5) NET (5mg TID for 21 days from day 5 to 25 inclusive; n=5) 32% and 36% mean MBL reduction during cycles 1 and 2 Ovulatory HMB (MPA): 32% and 37% mean MBL reduction during cycles 1 and 2 Ovulatory HMB (NET): 32% and 36% mean MBL reduction during cycles 1 and 2 BID, twice daily; BMI, body mass index; HMB, heavy menstrual bleeding; IUS, intrauterine system; LNG-IUS, levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethisterone acetate; PBAC, pictorial blood assessment chart; TID, three times daily 49 Table 6: Characteristics and outcomes of trials that assessed non-steroidal anti-inflammatory drugs for the treatment of heavy menstrual bleeding (HMB). Data shown for the non-steroidal anti-inflammatory drugs group only. Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome Adverse effects Continuation rates (for nonsteroidal antiinflammatory drugs) No significant increase in number of days with adverse effects reported with mefenamic acid relative to placebo Not applicable. Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition) Fraser et al 1981(71) Australia Fraser et al 1983(72) (Fraser 1981)[longer-term follow-up of Fraser et al 1981] Mefenamic acid (500mg TID from onset of menses until end; n=30) (data presented for women with MLB >80 mL) Randomized double blind, placebocontrolled, cross-over 36 women continued with mefenamic acid after completion of randomized double blind, cross-over trail (includes women with subjective HMB) Follow-on Convincing history of HMB. Only those classified with HMB (i.e. HMB with mean MBL >80 mL during two placebo cycles) are summarized here. Alkaline hematin 2 cycles’ treatment Mean MBL reduction during treatment, 30% (vs placebo) Mean reduction vs placebo cycles: 31% during 2 cycles in the double blind, cross-over phase <<Surgery avoided or required not reported>> Few women complained of adverse effects. Only 2 women discontinued because of dyspepsia 25% during 6 to 9 months 35% during 12 to 15 months Muggeridge and Elder 1983(73) Mefenamic acid (500 mg TID; n=15) UK Placebo (n=15) Randomized doubleblind, crossover Women with regular, proven HMB (≥75mL during to control cycles) were recruited Women with pelvic pathology on diagnostic curettage were excluded. Alkaline hematin 2 months treatment mean MBL reduction over 2 cycle: 30% with mefenamic acid Adverse events occurred at <10% for nausea, headaches, and dizziness and similar to placebo cycles No discontinuations reported <<Surgery avoided or required not 50 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome Adverse effects 12% with placebo Makarainen, 1986(74) Finland Ibuprofen (600 mg/day from day one until end of bleeding or for a maximum of 10 days; n=13) Ibuprofen (200 mg/day from day one until end of bleeding or for a maximum of 10 days; n=13) Ylikorkala et al 1986 (75) Finland Naproxen (500 mg at onset of menses followed by repeated 3-5 hrs later, then 500 mg in morning and evening for 5 days; n=14) Randomized doubleblind, placebocontrolled cross-over Women with primary HMB (MBL >70mL). Alkaline hematin 1 cycle’ treatment for each drug (over 3 consecutive cycles) Continuation rates (for nonsteroidal antiinflammatory drugs) reported>> Not specifically described in women with primary HMB Reduction in median MBL (vs placebo): Not specifically described in women with primary HMB <<Surgery avoided or required not reported>> Ibuprofen 200 mg, 25% 600 mg, 16% Assumed to be a randomized double-blind cross-over Placebo (n=14) Patients with regular cycles and HMB (>80mL) confirmed during two run-in cycles. The women had normal pelvic finding s during in gynecological and ultrasound examinations. Alkaline hematin Two treatment cycles. Mean MBL reduction during treatment (vs baseline): No adverse effects occurred during naproxen use. Not reported Adverse events not reported Not reported <<Surgery avoided or required not reported>> Naproxen, 29% Placebo, 11% increase Cameron et al 1987(62) UK Mefenamic acid (500 mg TID during menses; n = 8) Not stated (assumed to randomized Ovulatory cycles and mean monthly blood loss>50 mL (objectively confirmed during Alkaline hematin 2 cycles’ treatment Reduction in median MBL during <<Surgery avoided or 51 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria Norethisterone (5 mg BID from day 15-25; n=8) open-label) two pre-treatment cycles). Randomized double blind, cross-over Women aged ≥18years with HMB and no pelvic inflammation, fibroids or other local disease. MBL ≥80 ml objectively confirmed during two initial control cycles. MBL assessment method Duration/MBL outcome Adverse effects treatment, 45% Continuation rates (for nonsteroidal antiinflammatory drugs) required not reported>> Progesterone IUS (65 mg progesterone daily; n = 8) Danazol (200 mg daily; n=6) Hall et al 1987(76) UK Mefenamic acid (SO0 mg was taken every 8 htotal dose 1500 mg; first, n=34) Naproxen (initial loading dose of 550 mg followed by 275 mg every h for 5 days; first, n=35) Tsang et al 1987 (77) Canada Mefenamic acid (500 mg at the onset of menses followed by 250 mg every 6 hrs for 3 to 5 Alkaline hematin 2 cycles’ treatment MBL reduction during treatment: Mefenamic acid: Median 47% Naproxen: Median 46% Randomized double-blind cross-over Women (aged 26-47) with regular menstrual cycles with a mean ML ≥80 mL per cycle or a history of prolonged or profuse menses that warranted Alkaline hematin Two cycles of treatment Reduction in median MBL vs placebo Gastro-intestinal and central nervous system symptoms were experienced 6, and 5 patients, respectively, with mefenamic acid. Not reported <<Surgery avoided or required not reported>> Gastro-intestinal and central nervous system symptoms were experience 13 and 6 patients, respectively, with naproxen. Adverse events not reported Of 14 women who started only 10 completed the study. 1 woman had a 52 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria days; n=10) medical and (or) surgical intervention. Placebo (n=10) Vargyas et al 1987(78) USA Meclofenamate sodium (100 mg TID from onset on menses for 6 days or until the cessation of menses; n=29) Placebo (n=29) Andersch et al 1988(20) Flurbiprofen (100 mg BID for 5 days; n=15) Sweden Tranexamic acid (1.5 g TID for days 1 to 3 and 1 g BID on days 4 and 5; n=15) MBL assessment method Randomized double-blind cross-over (twotreatment four-period cross-over) Randomized cross-over Women aged 16 to 42 years old with a history of HMB. (>60 mL during at least one observation cycle). Adverse effects (estimated from graph): mean 10% reduction vs placebo Alkaline hematin 2 cycles’ treatment Mean MBL reduction during treatment: Meclofenamate sodium, 51% Patients were excluded from the study if they had anovulatory cycles, histologic evidence of pathologic changes in the endometrium, an extrauterine disease or underlying organic disease. Women seeking help for idiopathic HMB. All women has regular menstrual cycles and no evidence of pelvic pathology. Duration/MBL outcome Placebo, 4% Alkaline hematin 2 cycles’ treatment 32% and 17% mean MBL reduction in cycles 1 and 2, respectively Continuation rates (for nonsteroidal antiinflammatory drugs) hysterectomy (histopathology revealed that she had adenomyosis and intramural leiomyomas), 5 patients experienced side effects with meclofenamate sodium: 4 had episodes of nausea and vomiting that may have been related to the drug or prostaglandin release at the onset of menses and 1 patient had epigastric distress after ingestion of the medication on an empty stomach One patient discontinued the study because of gastric distress after one cycle of meclofenamate sodium. Adverse event reported during flurbiprofen use included tiredness, stomach pains and nausea. No patients discontinued therapy <<Surgery avoided or required not reported>> 24% mean reduction in MBL during 53 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome Adverse effects Continuation rates (for nonsteroidal antiinflammatory drugs) Adverse effects reported were: nausea/vomiting (n=4), abdominal discomfort (n=2), headache (n=2); diarrhea (n=1), dizziness (n=1), fluid retention (n=1) Nine patients refused to continue treatment after study Adverse events reported included: 1 patient discontinued treatment in third cycle treatment Dockeray et al 1989(63) Ireland Mefenamic acid (500 mg TID for 3 to 5 days; n=20) Randomized open-label Danazol (100 mg BID; n=20) Cameron et al 1990(68) UK Mefenamic acid (500 mg TID during menses, n = 17) Norethisterone (5 mg BID from day 19-26, n = 15) Chamberlain et al 1991 (79) UK Mefenamic acid (500 mg TID from days 1 to 5; n=22) Ethamsylate (500 mg four times daily from days 1 to 5; n=22) Not stated (assumed to randomized open-label) Otherwise health parous women with a HMB (MBL >80mL objectively confirmed during two pre-treatment cycles) and clinically normal pelvic organs and the absence of any endometrial pathology at diagnostic curettage. Alkaline hematin Women with subjective HMB and no organic pathology. HMB objectively confirmed in two pre-treatment cycles (only those with >80 mL included). Alkaline hematin 2 cycles’ treatment Mean MBL reduction: 27% and 13% MBL during cycles 1 and 2 of treatment (20% overall reduction during treatment) 2cycles’ treatment Median 24% reduction in MBL during treatment Headache (24%) Abdominal pain (18%), Nausea (12%) Doubleblind, allocated treatment by minimizatio n (nonrandomized) Women aged 18-55 with confirmed HMB (MBL >80 mL, during 2 pre-treatment cycles) and regular cycles. Exclusion criteria included inflammatory bowel disease or endocrine disorders, anemia or notable uterine enlargement Alkaline hematin 3 cycles’ treatment Mean MBL reduction: 31%, 21% and 20% in cycles 1, 2 and 3, respectively (data estimated from graph) 10 of 18 (56%) who completed study reported adverse effects: abdominal discomfort (n=4), headache (n=4), tiredness (n=1) and swollen ankles (n=1) <<Surgery avoided or required not reported>> <<Surgery avoided or required not reported>> 18 (82%) women completed treatment <<Surgery avoided or required not reported>> 54 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome Adverse effects Continuation rates (for nonsteroidal antiinflammatory drugs) Alkaline hematin 2 cycles’ treatment Adverse events not reported Not report by drug (cross-over design) due to fibroids. Fraser and McCarron 1991(45) Australia Naproxen (500 mg at onset of menses followed Naproxen 250 mg TID until 24 hours after the usual duration of menses, max 5 days; n=14) Randomized open-label, cross-over Mefenamic acid (500mg TID from onset of menses until 24 hours after the usual duration of menses, max 5 days; n=38) History of HMB and regular periods. Pelvic and systemic causes of HMB were excluded. Most had undergone diagnostic dilatation and curettage and/or hysteroscopy within the previous year. Mean MBL reduction during treatment: <<Surgery avoided or required not reported>> Naproxen, 12% Mefenamic acid, 20%–39% Low-dose COC (n=12) Danazol (200 mg daily from day 5, continuously; n =12). van Eijkeren et al 1992 (80) The Netherlands Mefenamic acid (500 mg TID, treatment started 5 days before expected menstruation until bleeding stopped; n= 6) Placebo (n = 5) Randomized double-blind Patients scheduled for hysterectomy because of subjective HMB. Inclusion criteria included: age <45years; objectively confirmed MBL >80 ml; regular menstrual cycle; normal-sized uteri as assessed by bimanual palpation. Alkaline hematin One treatment cycle Reduction in mean MBL vs baseline: Mefenamic acid; 40% Placebo; 25% increase Three patient reported adverse events in mefenamic group: stomach pains and itching Two patients in placebo group reported headache and itching, respectively. Not specifically reported by group <<Surgery avoided or required not reported for separate groups>> 55 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome Adverse effects Continuation rates (for nonsteroidal antiinflammatory drugs) Bonnar and Sheppard 1996(53) Mefenamic acid (500 mg TID from days 1 to 5; n= 23) Alkaline hematin 3 cycles’ treatment Not specifically described for mefenamic acid 20 (87%) completed 3 cycles. Ireland Tranexamic acid (1 g four time daily from days 1 to 5; n=26) Randomized (blinding not stated but assumed to randomised open-label) Ethamsylate (500 mg four times daily from days 1 to 5; n=27) Reid and Virtanen-Kari 2005(7) Mefenamic acid (500 mg TID from days 1-4; n=26) UK LNG-IUS (n=25) Randomized open-label Patients 35-46 years with regular HMB (MBL >80 mL objectively confirm during 3 pre-treatment cycles).. Those with organic causes of HMB excluded by gynaecological investigation, including hysteroscopy, endometrial biopsy, and a cervical smear. Women aged 18–47 years with regular ovulatory, menstrual cycles of 21–35 days and objective HMB (MBL ≥80 mL objectively confirmed in one pretreatment cycle). Exclusions included anovulatory cycle, submucous fibroids or fibroids with a total volume of >5 cm3, a uterine sound of >10 cm or abnormal cervical cytology. Mefenamic acid: 26%, 24%, 10% MBL reduction during cycles 1, 2 and 3 17 (74%) patients taking mefenamic acid wished to continue treatment 20% MBL reduction (average treatment effect over 3 treatment cycles vs baseline) Alkaline hematin, PBAC and total menstrual fluid loss 6 cycles of treatment Reduction in median MBL: 22%, and 17% in cycles 3 and 6, respectively Reduction in median PBAC scores: 31% and 32% in cycles 3 and 6, respectively Reduction in median total menstrual fluid <<Surgery avoided or required not reported>> Common AEs with mefenamic acid included: headache (n=10; 38%); abdominal pain (n=2; 8%); ovarian cysts (n=3; 12%); breast pain (n=2; 8%); nausea (n=4, 15%); diarrhoea (n=4; 15%); and upper respiratory infection (n=5; 19%) 21 (81%) completed study <<Surgery avoided or required not reported>> 56 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Duration/MBL outcome loss: 28% and 26% in cycles 3 and 6, respectively Non-randomized studies in women with AUB-E (or those described as having HMB without further definition) Anderson et al Women with HMB (>80 mL Alkaline 3 cycles of treatment Mefenamic acid (500 mg Non1976(81) hematin TID during menstruation; randomized, during 3 successive control 37% mean MBL prospective cycles) who had undergone n=5) UK reduction during dilatation and curettage. treatment Haynes et al 1980(82) UK Mefenamic acid (500 mg four time daily for first 3 days of menses; n=23) Nonrandomized, prospective Women aged 16 to 50 years with HMB (>80 mL during at least 1 control cycle) who had undergone examination and curettage to exclude pelvic pathologies. Alkaline hematin 2 cycles of treatment Median 45% reduction in MBL across the 4 treatment cycles vs baseline Adverse effects Continuation rates (for nonsteroidal antiinflammatory drugs) 4/26 (15%) discontinued mefenamic acid Adverse events not reported Discontinuations not reported <<Surgery avoided or required not reported>> Adverse events not reported 1 (4%) woman discontinued <<Surgery avoided or required not reported>> Studies in women with HMB secondary to uterine structural pathology or coagulopathy Makarainen, 1986(74) Finland Ibuprofen (600 mg/day from day one until end of bleeding or for a maximum of 10 days; n=10) Ibuprofen (200 mg/day Randomized doubleblind, placebocontrolled cross-over Women with myomaassociated HMB (MBL >70mL). Alkaline hematin 1 cycle’ treatment for each drug (over 3 consecutive cycles) Reduction in median MBL (vs placebo): Not specifically described in women with myoma-associated HMB Not specifically described in women with primary HMB <<Surgery avoided or 57 Author (year)/Country Comparators Study design Inclusion/Exclusion criteria MBL assessment method Finland Placebo (n=11) Continuation rates (for nonsteroidal antiinflammatory drugs) required not reported>> 600 mg, 7% n=10) Naproxen (500 mg at onset of menses followed by repeated 3-5 hrs later, then 500 mg in morning and evening for 5 days; n=11) Adverse effects Ibuprofen 200 mg, 11% from day one until end of bleeding or for a maximum of 10 days; Ylikorkala et al 1986 (75) Duration/MBL outcome Assumed to be a randomized double-blind cross-over Women with HMB caused by fibromyomas (as determined by pelvic examination and/or ultrasound, or on hysterectomy on completion of study). Alkaline hematin Two treatment cycles. Mean MBL reduction during treatment (vs baseline): No adverse effects occurred during naproxen use. Not reported 8 (73%) women underwent hysterectomy after end of study Naproxen, 18% Placebo, 8% increase BID, twice daily; HMB, heavy menstrual bleeding; LNG-IUS, levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; TID, three times daily; 58 Table 7: Characteristics and outcomes of trials that assessed “additional potential therapies” for the treatment of heavy menstrual bleeding (HMB). Data shown for the “other medical therapies” group only. Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition) Nilson and Rybo Epsilon aminocaproicRandomized, Women aged 17 to 50 years Alkaline 1 months treatment 1965(83) acid (18 g daily for first placebowith suspected HMB and hematin In women with HMB three days followed by controlled, anemia. Curettage undertaken (MBL >60 mL) 12, 9, 6 and 3 g for the double-blind to prove bleeding was next four days, principle ovulatory. 63% mean reduction respectively; n=26) (cross-over) vs placebo (data presented for women with HMB; MBL > 60 mL) Harrison and Cambell 1976(84) UK Ethamsylate (250mg four times a day starting 5 days before expected menses and continuing for 10 days; n=9) Placebo (n=9) (here we focus on those women with “primary Adverse effects Continuation rates (for “other medical therapies”) Adverse events with esilon aminocaproicacid (in women with HMB, >60mL) were nausea (n=2); meteorism (n=1); diarrhea (n=1); orthostatism (n=1); dizziness (n=1) No discontinuations reported <<Surgery avoided or required not reported>> Adverse events with placebo were: abdominal pain (n=3), nausea (n=2 diarrhea (n=1), fainting (n=1), slight orthostatism (n=2) Randomized double-blind crossover Women aged between 18 to 49 years with primary menorrhagia (complaint of excessive menstrual loss, a regular menstrual cycle, and no evidence of organic disease). Iron atomic absorption (after alkaline extraction) 2 cycles’ treatment Ethamsylate period: mean 46% MBL reduction relative to pre-treatment Placebo period: mean 1% MBL increase relative to pre- Not reported specifically for patients with primary menorrhagia Not reported specifically for patients with primary menorrhagia <<Surgery avoided or 59 Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method menorrhagia”) Bonnar and Sheppard 1996(53) Ethamsylate (500 mg four times daily from days 1 to 5; n=27) Ireland. Mefenamic acid (500 mg TID from days 1 to 5; n= 23) India Ormeloxifene [SERM] (60 mg two days a week at an interval of 3 days; n=42) MPA (10mg daily for 21 days starting from day2– 5 of cycle; n=42) Adverse effects Continuation rates (for “other medical therapies”) required not reported>> Not specifically described for ethamsylate 16 (59%) completed 3 cycles. treatment Randomized (blinding not stated but assumed to randomised open-label) Tranexamic acid (1 g four time daily from days 1 to 5; n=26) Shravage et al. 2011 (69) Duration of treatment/MBL outcome Randomized double-blind, Patients 35-46 years with regular HMB (MBL >80 mL objectively confirm during 3 pre-treatment cycles). Those with organic causes of HMB excluded by gynaecological investigation, including hysteroscopy, endometrial biopsy, and a cervical smear. Women age 35–50 years with HMB (PBAC score >100 during two pre-treatment cycles). Those with pelvic pathology, systemic disorders, severe anemia, chronic cervicitis and cervical dysplasia were excluded. Alkaline hematin 3 cycles’ treatment Ethamsylate: 5%, -9% (increase), 1% MBL reduction during cycles 1, 2 and 3 18 (67%) taking tranexamic acid did not wish to continue the treatment (poor efficacy the reason for 9 patients) 3% increase in MBL (average treatment effect over 3 treatment cycles vs baseline) PBAC 3 cycles’ treatment Mean PBAC score reduced with ormeloxifene by 46%, 77% and 88% at 1. 2 and 3 months respectively. Non-randomized studies in women with AUB-E (or those described as having HMB without further definition) Turnbull and Rees Gestrinone (2.5 mg twice NonWomen aged 37 to 46 years Alkaline 3months’ treatment <<Surgery avoided or required not reported>> 9.5% amenorrhea with Ormeloxifen. Other adverse events not reported. Study completion not stated by group Adverse events included: Discontinuations <<Surgery avoided or required not reported>> 60 Author (year)/Country Comparators 1990(85) weekly from first day of menstruation; n=19) UK Chamberlain et al 1991 (79) UK Ethamsylate (500 mg four times daily from days 1 to 5; n=22) Mefenamic acid (500 mg TID from days 1 to 5; n=22) Kriplani et al 2009(86) India Ormeloxifene [SERM] (60 mg twice a week for 3 months and then once a week for 1 month; n=42) Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Adverse effects randomized, single-blind, placebo controlled and regular HMB (>80mL confirmed during two control cycles) and no pelvic abnormalities on pelvic examination and endometrial biopsy were recruited. hematin 23% increase in median MBL at first menstruation headaches, dizziness/giddiness and tiredness reported by one-third of women Double-blind, allocated treatment by minimization (nonrandomized) Women aged 18-55 with confirmed HMB (MBL >80 mL, during 2 pre-treatment cycles) and regular cycles. Exclusion criteria included inflammatory bowel disease or endocrine disorders, anemia or notable uterine enlargement due to fibroids. Alkaline hematin Nonrandomized, prospective Women with confirmed HMB (PBAC score >100). PBAC Exclusion criteria included: uterine size >8 weeks pregnancy, submucus fibroids, fibroids >3 cm detected by ultrasound, polyps, adnexal mass, history of breast malignancy, suspected 65%, 60, 36% and 71% median MBL decrease in 2nd, 3rd, 4th and 5th menstruation, respectively (data estimated from graphs) 3 cycles’ treatment 13%, 25% and 22% mean MBL reduction: in cycles 1, 2 and 3, respectively (data estimated from graph) Women followed up at 2 and 4 months of therapy, then at 3 and 6 months after treatment was stopped 79% and 97% median reduction at 2 and 4 months’ treatment, Continuation rates (for “other medical therapies”) not reported 9 (47%) underwent hysterectomy 5 of 16 (31%) who completed study reported adverse effects: abdominal discomfort (n=2), headache (n=2) and backache (n=1) 16 (73%) women completed treatment Adverse effects included ovarian cyst (n=3; 7.1%), cervical erosion and discharge (n=3; 7.1%), gastric upset (n=3; 7.1%), vague abdominal pain (n=2 ; 4.8%) and headache (n=2; 4.8%). 3 (7.1%) women discontinued treatment <<Surgery avoided or required not reported>> 9 (21.4%) underwent hysterectomy during the whole study 61 Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method adenomyosis, current genital infection and endometrial hyperplasia with atypia, abnormal coagulation profile, endocrinopathy or other systemic diseases causing menorrhagia. Duration of treatment/MBL outcome Adverse effects Continuation rates (for “other medical therapies”) 20 (47.6%) had surgery 1 year after completing study period 8 adverse events occurred during desmopressin treatment vs 10 with placebo treatment. No specific details provided. No reported 24 (83%) of women experienced at least one adverse event during study. Adverse events were primarily headache, facial flushing and weight gain. Headache was reported by 6(23%) 1 (3%) who started treatment did not complete study respectively. Studies in women with HMB secondary to uterine structural pathology or coagulopathy Edlund et al. 2002(87) Sweden. Desmopressin (nasal spray at 300 µg per inhalation BID on first 2 days of cycle; n=20) Randomized double-blind, cross-over Placebo (n=20) All patients received desmopressin plus tranexamic acid, 1.5 g TID on first 2 days of third cycle (data presented for randomised section of study) Kadir et al 2002(88) UK Desmopressin (nasal spray at 150 µg per nostril twice daily on days 1 and 2 of cycle; n=29) Placebo (n=29) Randomized, double-blind crossover Prolonged bleeding time Women age ≥18 years with regular cycles and HMB (MBL >80 mL objectively confirmed during 1 pretreatment cycle), prolonged bleeding time (>570 s) not due to known cause. Bleeding disorder Women aged 18–50 years with bleeding disorders, including von Willebrand disease, heterozygote factor XI deficiency, hemophilia and objectively confirmed HMB (PBAC score > 100) were Alkaline hematin 1 cycle’ treatment Desmopressin: mean 17% reduction in MBL relative to baseline <<Surgery avoided or required not reported>> Placebo: mean 7% reduction in MBL relative to baseline PBAC 2 months per treatment period Placebo/ desmopressin sequence: 60% median reduction with Two women withdrew for surgery before receiving any 62 Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method eligible. Duration of treatment/MBL outcome placebo 67% median reduction with desmopressin Exclusion criteria included: type 2B von Willebrand disease, a history of renal and hepatic impairment, endocrine disorders, thromboembolic disease and nasal pathology interfering with absorption of the spray, including rhinitis, nasal polyp or significantly deviated septum . Time effect observed with lower PBAC score in the second treatment phase irrespective of treatment. Adverse effects and 7 (24%) of women during desmopressin and placebo, respectively. Weight gain was reported in 3 (12%) of women during desmopressin, and none during the placebo treatment Continuation rates (for “other medical therapies”) medication No significant difference with placebo Rose et al 2008 (89) USA Bagaria et al 2009(90) Desmopressin (nasal spray at 150 µg per nostril on days 1 and 2 of cycle; n=11) Nonrandomized, prospective Mifepristone (10 mg daily; n=20) Randomized, double-blind placebo- Platelet dysfunction PBAC Women aged 18 to 45 years with HMB (PBAC score ≥ 100) and platelet dysfunction were eligible. Other inclusion criteria included negative pelvic examination and uterine size ≤12 week pregnancy. Exclusion criteria included history of thromboembolism, anticoagulation therapy or vascular disease. Leiomyoma Women with symptomatic 2 consecutive cycles of treatment Adverse events not reported 42% median PBAC reduction over 2 cycles PBAC 3 months treatment Mifepristone Discontinuations not reported <<Surgery avoided or required not reported>> No adverse events occurred in either group Only 1 woman lost to follow-up in mifepristone 63 Author (year)/Country Comparators India Placebo (n=20) Inclusion/Exclusion criteria controlled MBL assessment method Duration of treatment/MBL outcome Adverse effects Continuation rates (for “other medical therapies”) group Of the 90 patients who used either study medication for at least one cycle, 13 (14%) had adverse events; seven patients with desmopressin and six with tranexamic acid. Discontinuation rates were 43% for the nasal desmopressintranexamic acid sequence and 33% for tranexamic acid – desmopressin 71, 88% and 95% leiomyoma were eligible. Exclusion criteria included pelvic inflammatory disease or other adnexal pathology, surgical intervention for leiomyoma. mean PBAC reduction at 1, 2 and 3 months’ treatment, respectively. Placebo No reduction occurred 7% and 6% mean PBAC increase at 1 and 2 months, and <1% decrease at 3 months Significant reduction in uterine and leiomyoma volume vs. baseline Kouides et al 2009(60) USA Desmopressin (nasal spray at 300 µg per nostril on days 2 days and 3 of cycle) Tranexamic acid (1 g four times each day for the first 5 day of menses) Desmopressin/ tranexamic acid sequence Randomized, cross-over Bleeding disorder Women aged 18–50 years referred for HMB to a hemophilia treatment centre, bleeding disorder clinic, or gynaecology care centre. Inclusion criteria included negative pelvic examination (fibroids were allowed if the PBAC 2 cycles per treatment period (data shown for desmopressin period only) Desmopressin/ tranexamic acid sequence: 13% and 21% mean reduction in 64 Author (year)/Country Comparators Inclusion/Exclusion criteria (n=49) uterus was <12 weeks gestational size), a negative Papanikolaou smear, PBAC score ≥100, and detectable bleeding disorder. Tranexamic acid Desmopressin/sequence (n=67) MBL assessment method Duration of treatment/MBL outcome Adverse effects cycles 1 and 2 of desmopressin (vs baseline) Continuation rates (for “other medical therapies”) sequence <<Surgery avoided or required not reported>> 21% and 24% median reduction in cycles 1 and 2 of desmopressin (vs baseline) Tranexamic acid/ desmopressin sequence: Ragni et al 2011(91) USA Interlukin-11 (recombinant human interlukin-11 25 μg/kg/day by subcutaneous selfinjection for up to seven days during each of six Nonrandomized, prospective von Willebrand disease Women age 18–45 years with mild von Willebrand disease, and menorrhagia, unresponsive to or intolerant of hemostatic or hormonal PBAC 31% and 25% mean reduction in cycles 1 and 2 of desmopressin (vs baseline) 31% and 32% median reduction in cycles 1 and 2 of desmopressin (vs baseline) 6 months treatment 71% and 70% mean reduction at 2 and 6 months, respectively Drug well tolerated. Grade 1 or less toxicity, include conjunctival erythema (n=7), mild fluid retention (n=6), injection site bruising (n=6), flushing (n=3), Discontinuations not reported <<Surgery avoided or required not 65 Author (year)/Country Donnez et al. 2012 (Pearl I) (92) Czech Republic, Hungary, India, Romania, Russian Federation, Ukarine Comparators Inclusion/Exclusion criteria consecutive menstrual cycles; n=7) agents. Placebo daily (n=48) 5 mg of ulipristal acetate daily (n=95) 10 mg ulipristal acetate daily (n=94) Randomized double-blind Leiomyoma Women aged 18–50 years with heavy uterine bleeding (PBAC score >100) caused by fibroids; fibroid-related anaemia, at least one myoma measuring ≥3 cm in diameter (but no myoma measuring >10 cm), and a uterine size equivalent to that of a pregnancy of no more than16 weeks of gestation, and eligible for surgery. MBL assessment method Duration of treatment/MBL outcome Adverse effects thrombocytosis, 484,000/μl (n=1), hypokalaemia, 3.4 mEq/l (n=1), and diastolic hypertension, 93 mmHg (n=1). PBAC 13 weeks of treatment (after which patients could have surgery) Median reduction in PBAC score from baseline to wk 9–13: Placebo, 11% 5 mg of ulipristal acetate daily, 100% 10 mg ulipristal acetate daily, 100% Headache: 4%, 4% and 10%, respectively Breast pain/tenderness/ discomfort: 0%, 2%, 6% Abdominal pain: 4%, 2%, 3% Continuation rates (for “other medical therapies”) reported>> Completed study: 98%, 96%, and 94%, respectively Underwent surgery: 40%, 43%, and 50% Pyrexia: 4%, 3%, and 2% Hypercholesterolemia: 2%, 3% and 2% Hypothyroidism: 2%, 3%, and 2% Constipation: 2%, 4% and 0% Hypertriglyceridemia: 2%, 3% and 1% Influenza: 2%, 1%, and 3% Dizziness: 0%, 1% and 66 Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Adverse effects Continuation rates (for “other medical therapies”) 3% Nasopharygitis: 0%, 3%, and 0% Dysmenorrhea: 4%, 0% and 0% Donnez et al. 2012 (Pearl II)(93) Austria, Belgium, France, Germany, Israel, Italy, Netherlands, Poland, and Spain Intramuscular leuprolide acetate 3.75 mg once monthly (n=101) 5 mg oral ulipristal acetate daily (n=97) 10 mg oral ulipristal acetate daily (n=103) Randomized double-blind Leiomyoma Premenopausal women aged 18–50 years with heavy uterine bleeding (PBAC score >100) caused by fibroids, at least one myoma measuring ≥3 cm in diameter (but no myoma measuring >10 cm), and a uterine size equivalent to that of a pregnancy of no more than16 weeks of gestation, and eligible for surgery. PBAC 13 weeks of treatment (after which patients could have surgery) intramuscular leuprolide acetate group; 92% median reduction at 13 weeks 5 mg oral ulipristal acetate group; 94% median reduction at 13 weeks 10 mg oral ulipristal acetate group; 99% median reduction at 13 weeks Moderate-to-severe hot flashes occurred in 11%, 10% and 40% of women, in the three groups respectively. Hot flush: 65%, 26%, and 24% respectively Completed study: 94%, 98%, and 97%, respectively. Underwent surgery: 51%, 52%, and 53% Headache: 29%, 26%, and 18% Procedural pain: 9%, 9%, and 15%, Abdominal pain:14%, 6% and 11% Nausea: 6%, 6%, and 7% Fatigue: 3%,4%, and 7% Anaemia: 5%, 5%, and 3% Breast pain/tenderness: 2%, 5%, and 3% Influenza: 5%, 2%, and 67 Author (year)/Country Comparators Inclusion/Exclusion criteria MBL assessment method Duration of treatment/MBL outcome Adverse effects Continuation rates (for “other medical therapies”) 2% Insomnia: 5%, 2%, and 2% Pharyngitis:2%, 5%, and 0% BID, twice daily; MPA, medroxyprogesterone acetate; PBAC, pictorial blood assessment chart; SERM, selective estrogen receptor modulator; TID, three times daily 68 References 1. Crosignani PG, Vercellini P, Mosconi P et al. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol 1997;90:257-63. 2. Irvine GA, Campbell-Brown MB, Lumsden MA et al. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998;105:592-8. 3. Hurskainen R, Teperi J, Rissanen P et al. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet 2001;357:273-7. 4. Soysal M, Soysal S, Ozer S. A randomized controlled trial of levonorgestrel releasing IUD and thermal balloon ablation in the treatment of menorrhagia. Zentralblatt fur Gynakologie 2002;124:213-9. 5. Barrington JW, Arunkalaivanan AS, Abdel-Fattah M. Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol 2003;108:72-4. 6. Rauramo I, Elo I, Istre O. Long-term treatment of menorrhagia with levonorgestrel intrauterine system versus endometrial resection. Obstet Gynecol 2004;104:1314-21. 7. Reid PC, Virtanen-Kari S. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. BJOG 2005;112:1121-5. 8. Abdel Malak K, Shawki O. Management of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection. Gynecol Surg 2006;3:275-80. 69 9. Busfield RA, Farquhar CM, Sowter MC et al. A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. BJOG 2006;113:257-63. 10. Shaw RW, Symonds IM, Tamizian O et al. Randomised comparative trial of thermal balloon ablation and levonorgestrel intrauterine system in patients with idiopathic menorrhagia. Aust N Z J Obstet Gynaecol 2007;47:335-40. 11. Kucuk T, Ertan K. Continuous oral or intramuscular medroxyprogesterone acetate versus the levonorgestrel releasing intrauterine system in the treatment of perimenopausal menorrhagia: A randomized, prospective, controlled clinical trial in female smokers. Clin Exp Obstet Gynecol 2008;35:57-60. 12. Endrikat J, Shapiro H, Lukkari-Lax E et al. A Canadian, multicentre study comparing the efficacy of a levonorgestrel-releasing intrauterine system to an oral contraceptive in women with idiopathic menorrhagia. J Obstet Gynaecol Can 2009;31:340-7. 13. de Souza SS, Camargos AF, de Rezende CP et al. A randomized prospective trial comparing the levonorgestrel-releasing intrauterine system with thermal balloon ablation for the treatment of heavy menstrual bleeding. Contraception 2010;81:226-31. 14. Kaunitz AM, Bissonnette F, Monteiro I et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:625-32. 15. Ghazizadeh S, Bakhtiari F, Rahmanpour H et al. A randomized clinical trial to compare levonorgestrel-releasing intrauterine system (Mirena) vs trans- ervical endometrial resection for treatment of menorrhagia. Int J Women's Health 2011;3:207-11. 70 16. Shabaan MM, Zakherah MS, El-Nashar SA et al. Levonorgestrel-releasing intrauterine system compared to low dose combined oral contraceptive pills for idiopathic menorrhagia: A randomized clinical trial. Contraception 2011;83:4854. 17. Sesti F, Piancatelli R, Pietropolli A et al. Levonorgestrel-releasing intrauterine system versus laparoscopic supracervical hysterectomy for the treatment of heavy menstrual bleeding: a randomized study. J Womens Health (Larchmt) 2012;21:851-7. 18. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97:690-4. 19. Milsom I, Andersson K, Andersch B et al. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol 1991;164:87983. 20. Andersch B, Milsom I, Rybo G. An objective evaluation of flurbiprofen and tranexamic acid in the treatment of idiopathic menorrhagia. Acta Obstet Gynecol Scand 1988;67:645-8. 21. Tang GW, Lo SS. Levonorgestrel intrauterine device in the treatment of menorrhagia in Chinese women: efficacy versus acceptability. Contraception 1995;51:231-5. 22. Barrington JW, Bowen-Simpkins P. The levonorgestrel intrauterine system in the management of menorrhagia. Br J Obstet Gynaecol 1997;104:614-6. 23. Xiao B, Wu SC, Chong J et al. Therapeutic effects of the levonorgestrelreleasing intrauterine system in the treatment of idiopathic menorrhagia. Fertil Steril 2003;79:963-9. 71 24. Gupta B, Mittal S, Misra R et al. Levonorgestrel-releasing intrauterine system vs. transcervical endometrial resection for dysfunctional uterine bleeding. Int J Gynaecol Obstet 2006;95:261-6. 25. Kriplani A, Singh BM, Lal S et al. Efficacy, acceptability and side effects of the levonorgestrel intrauterine system for menorrhagia. Int J Gynaecol Obstet 2007;97:190-4. 26. Gorgen H, Api M, Akca A et al. Use of the Levonorgestrel-IUS in the treatment of menorrhagia: assessment of quality of life in Turkish users. Arch Gynecol Obstet 2009;279:835-40. 27. Chattopdhyay B, Nigam A, Goswami S et al. Clinical outcome of levonorgestrel intra-uterine system in idiopathic menorrhagia. Eur Rev Med Pharmacol Sci 2011;15:764-8. 28. Kriplani A, Awasthi D, Kulshrestha V et al. Efficacy of the levonorgestrelreleasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet 2012;116:35-8. 29. Kingman CE, Kadir RA, Lee CA et al. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG 2004;111:1425-8. 30. Choudry A, Malik A, Choudry H et al. Effectiveness and safety of levonorgestrel releasing intrauterine system in treatment of menorrhagia secondary to oral anticoagulations and chronic liver disease. Rawal Med J 2009;34:187-90. 31. Kilic S, Yuksel B, Doganay M et al. The effect of levonorgestrel-releasing intrauterine device on menorrhagia in women taking anticoagulant medication after cardiac valve replacement. Contraception 2009;80:152-7. 72 32. Grigorieva V, Chen-Mok M, Tarasova M et al. Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril 2003;79:1194-8. 33. Mercorio F, De Simone R, Di Spiezio Sardo A et al. The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia. Contraception 2003;67:277-80. 34. Soysal S, Soysal ME. The efficacy of levonorgestrel-releasing intrauterine device in selected cases of myoma-related menorrhagia: a prospective controlled trial. Gynecol Obstet Invest 2005;59:29-35. 35. Murat Naki M, Tekcan C, Ozcan N et al. Levonorgestrel-releasing intrauterine device insertion ameliorates leiomyoma-dependent menorrhagia among women of reproductive age without a significant regression in the uterine and leiomyoma volumes. Fertil Steril 2010;94:371-4. 36. Shawki O, El-Sherbiny W, Saber W et al. Treatment of heavy menstrual bleeding associated with uterine leiomyoma with the levonorgestrel-releasing intrauterine system. Gynecol Surg 2009;6:331-7. 37. Sayed GH, Zakherah MS, El-Nashar SA et al. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynecol Obstet 2011;112:126-30. 38. Socolov D, Blidaru I, Tamba B et al. Levonorgestrel releasing-intrauterine system for the treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine leiomyoma. Eur J Contracept Reprod Health Care 2011;16:480-7. 73 39. Jindabanjerd K, Taneepanichskul S. The use of levonorgestrel - IUD in the treatment of uterine myoma in Thai women. J Med Assoc Thai 2006;89 Suppl 4:S147-51. 40. Xie ZW, Zhang YN, Wan S et al. Levonorgestrel-releasing intrauterine device is an efficacious contraceptive for women with leiomyoma. J Int Med Res 2012;40:1966-72. 41. Fedele L, Bianchi S, Raffaelli R et al. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril 1997;68:426-9. 42. Cho S, Nam A, Kim H et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol 2008;198:373 e1-7. 43. Istre O, Trolle B. Treatment of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection. Fertility and Sterility 2001;76:304-9. 44. Kittelsen N, Istre O. A randomized study comparing levonorgestrel intrauterine system (LNG IUS) and transcervical resection of the endometrium (TCRE) in the treatment of menorrhagia: Preliminary results. Gynaecol Endosc 1998;7:615. 45. Fraser IS, McCarron G. Randomized trial of 2 hormonal and 2 prostaglandininhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol 1991;31:66-70. 46. Fraser IS, Romer T, Parke S et al. Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: A randomized, double-blind Phase III trial. Hum Reprod 2011;26:2698-708. 74 47. Jensen JT, Parke S, Mellinger U et al. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: A randomized controlled trial. Obstet Gynecol 2011;117:777-87. 48. Abu Hashim H, Alsherbini W, Bazeed M. Contraceptive vaginal ring treatment of heavy menstrual bleeding: A randomized controlled trial with norethisterone. Contraception 2012;85:246-52. 49. Larsson G, Milsom I, Lindstedt G et al. The influence of a low-dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992;46:327-34. 50. Nilsson L, Rybo G. Treatment of menorrhagia with an antifibrinolytic agent, tranexamix acid Acta Obstet Gynecol Scand. 1967;46:572-80. 51. Edlund M, Andersson K, Rybo G et al. Reduction of menstrual blood loss in women suffering from idiopathic menorrhagia with a novel antifibrinolytic drug (Kabi 2161). Br J Obstet Gynaecol 1995;102:913-7. 52. Preston JT, Cameron IT, Adams EJ et al. Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. Br J Obstet Gynaecol 1995;102:401-6. 53. Bonnar J, Sheppard BL. Treatment of menorrhagia during menstruation: Randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid. BMJ 1996;313:579-82. 54. Kriplani A, Kulshrestha V, Agarwal N et al. Role of tranexamic acid in management of dysfunctional uterine bleeding in comparison with medroxyprogesterone acetate. J Obstet Gynaecol 2006;26:673-8. 75 55. Lukes AS, Moore KA, Muse KN et al. Tranexamic acid treatment for heavy menstrual bleeding: A randomized controlled trial. Obstet Gynecol 2010;116:865-75. 56. Najam R, Agarwal D, Tyagi R et al. Comparison of traneximic acid with a combination of traneximic acid and mefenamic acid in reducing menstrual blood loss in ovulatory dysfunctional uterine bleeding (DUB). J Clin Diagn Res 2010;4:3020-5. 57. Freeman EW, Lukes A, Van Drie D et al. A dose-response study of a novel, oral tranexamic formulation for heavy menstrual bleeding. Am J Obstet Gynecol 2011;205. 58. Gleeson NC, Buggy F, Sheppard BL et al. The effect of tranexamic acid on measured menstrual loss and endometrial fibrinolytic enzymes in dysfunctional uterine bleeding. Acta Obstet Gynecol Scand 1994;73:274-7. 59. Srinil S, Jaisamrarn U. Treatment of idiopathic menorrhagia with tranexamic acid. J Med Assoc Thai 2005;88 Suppl 2:S1-6. 60. Kouides PA, Byams VR, Philipp CS et al. Multisite management study of menorrhagia with abnormal laboratory haemostasis: A prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol 2009;145:212-20. 61. Chimbira TH, Anderson AB, Naish C et al. Reduction of menstrual blood loss by danazol in unexplained menorrhagia: lack of effect of placebo. Br J Obstet Gynaecol 1980;87:1152-8. 62. Cameron IT, Leask R, Kelly RW et al. The effects of danazol, mefenamic acid, norethisterone and a progesterone-impregnated coil on endometrial 76 prostaglandin concentrations in women with menorrhagia. Prostaglandins 1987;34:99-110. 63. Dockeray CJ, Sheppard BL, Bonnar J. Comparison between mefenamic acid and danazol in the treatment of established menorrhagia. Br J Obstet Gynaecol 1989;96:840-4. 64. Higham JM, Shaw RW. A comparative study of danazol, a regimen of decreasing doses of danazol, and norethindrone in the treatment of objectively proven unexplained menorrhagia. Am J Obstet Gynecol 1993;169:1134-9. 65. Dunphy BC, Goerzen J, Greene CA et al. A double-blind randomised study comparing danazol and medroxyprogesterone acetate in the management of menorrhagia. J Obstet Gynaecol 1998;18:553-5. 66. Chimbira TH, Cope E, Anderson AB et al. The effect of danazol on menorrhagia, coagulation mechanisms, haematological indices and body weight. Br J Obstet Gynaecol 1979;86:46-50. 67. Chimbira TH, Anderson AB, Cope E et al. Effect of danazol on serum gonadotrophins and steroid hormone concentrations in women with menorrhagia. Br J Obstet Gynaecol 1980;87:330-6. 68. Cameron IT, Haining R, Lumsden MA et al. The effects of mefenamic acid and norethisterone on measured menstrual blood loss. Obstet Gynecol 1990;76:85-8. 69. Shravage J, Mekhala D, Bellad MB et al. Ormeloxifene versus medroxyprogesterone acetate (MPA) in the treatment of dysfunctional uterine bleeding: A double-blind randomized controlled trial. J S Asian Fed Obstet Gynecol 2011;3:21-4. 70. Fraser IS. Treatment of ovulatory and anovulatory dysfunctional uterine bleeding with oral progestogens. Aust N Z J Obstet Gynaecol 1990;30:353-6. 77 71. Fraser IS, Pearse C, Shearman RP et al. Efficacy of mefenamic acid in patients with a complaint of menorrhagia. Obstet Gynecol 1981;58:543-51. 72. Fraser IS, McCarron G, Markham R et al. Long-term treatment of menorrhagia with mefenamic acid. Obstet Gynecol 1983;61:109-12. 73. Muggeridge J, Elder MG. Mefenamic acid in the treatment of menorrhagia. . Research and Clinical Forums 1983;5:83–8. 74. Makarainen L, Ylikorkala O. Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen. British Journal of Obstetrics & Gynaecology 1986;93:974-8. 75. Ylikorkala O, Pekonen F. Naproxen reduces idiopathic but not fibromyomainduced menorrhagia. Obstet Gynecol 1986;68:10-2. 76. Hall P, Maclachlan N, Thorn N et al. Control of menorrhagia by the cyclooxygenase inhibitors naproxen sodium and mefenamic acid. Br J Obstet Gynaecol 1987;94:554-8. 77. Tsang BK, Domingo MT, Spence JE et al. Endometrial prostaglandins and menorrhagia: influence of a prostaglandin synthetase inhibitor in vivo. Can J Physiol Pharmacol 1987;65:2081-4. 78. Vargyas JM, Campeau JD, Mishell DR, Jr. Treatment of menorrhagia with meclofenamate sodium. Am J Obstet Gynecol 1987;157:944-50. 79. Chamberlain G, Freeman R, Price F et al. A comparative study of ethamsylate and mefenamic acid in dysfunctional uterine bleeding. Br J Obstet Gynaecol 1991;98:707-11. 80. van Eijkeren MA, Christiaens GC, Geuze HJ et al. Effects of mefenamic acid on menstrual hemostasis in essential menorrhagia. Am J Obstet Gynecol 1992;166:1419-28. 78 81. Anderson AB, Haynes PJ, Guillebaud J et al. Reduction of menstrual blood-loss by prostaglandin-synthetase inhibitors. Lancet 1976;1:774-6. 82. Haynes PJ, Flint AP, Hodgson H et al. Studies in menorrhagia: (a) mefenamic acid, (b) endometrial prostaglandin concentrations. Int J Gynaecol Obstet 1980;17:567-72. 83. Nilsson L, Rybo G. Treatment of menorrhagia with epsilon aminocaproic acid. A double blind investigation. Acta Obstet Gynecol Scand 1965;44:467-73. 84. Harrison RF, Cambell S. A double-blind trial of ethamsylate in the treatment of primary and intrauterine-device menorrhagia. Lancet 1976;2:283-5. 85. Turnbull AC, Rees MC. Gestrinone in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97:713-5. 86. Kriplani A, Kulshrestha V, Agarwal N. Efficacy and safety of ormeloxifene in management of menorrhagia: a pilot study. J Obstet Gynaecol Res 2009;35:74652. 87. Edlund M, Blomback M, Fried G. Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time. Blood Coagul Fibrinolysis 2002;13:225-31. 88. Kadir RA, Lee CA, Sabin CA et al. DDAVP nasal spray for treatment of menorrhagia in women with inherited bleeding disorders: a randomized placebo-controlled crossover study. Haemophilia 2002;8:787-93. 89. Rose SS, Faiz A, Miller CH et al. Laboratory response to intranasal desmopressin in women with menorrhagia and platelet dysfunction. Haemophilia 2008;14:571-8. 79 90. Bagaria M, Suneja A, Vaid NB et al. Low-dose mifepristone in treatment of uterine leiomyoma: a randomised double-blind placebo-controlled clinical trial. Aust N Z J Obstet Gynaecol 2009;49:77-83. 91. Ragni MV, Jankowitz RC, Jaworski K et al. Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia. Thromb Haemost 2011;106:641-5. 92. Donnez J, Tatarchuk TF, Bouchard P et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. NEJM 2012;366:409-20. 93. Donnez J, Tomaszewski J, Vazquez F et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. NEJM 2012;366:421-32. 80