Evidence-based answers from the Family Physicians Inquiries Network CLINICAL INQUIRIES ONLINE EXCLUSIVE Allison Lale, MD, MPH; Elise Halajian, DO; Rick Q Which medications work best Guthmann, MD, MPH Advocate Illinois Masonic Medical Center, Chicago for menorrhagia? Joan Nashelsky, MLS Family Physicians Inquiries Network, Iowa City EVIDENCE-BASED ANSWER ASSISTANT EDITOR Four medications have been without reporting MBL. Gary Kelsberg, MD Valley Family Medicine A shown to reduce menstrual No studies compared all effective med- Residency, University of blood loss (MBL) significantly in ical therapies against one another. In head- Washington at Valley in placebo-controlled randomized controlled to-head comparisons, women were more Renton trials (RCTs): the levonorgestrel-releasing likely to experience improvement with the intrauterine system (LNG-IUS), tranexam- LNG-IUS than with tranexamic acid (num- ic acid, nonsteroidal anti-inflammatory ber needed to treat [NNT] = 2 to 6). Both drugs (NSAIDs), and danazol, a synthetic treatments are superior to NSAIDs. Dan- steroid (strength of recommendation: A, azol is also more efficacious than NSAIDs, meta-analyses of RCTs). but its use is limited by its adverse effects, A single trial showed that the LNG- including teratogenicity. IUS reduced MBL by about 100 mL, com- No placebo-controlled trials have pared with placebo. In a meta-analysis of studied oral contraceptive pills (OCPs) or 4 placebo-controlled RCTs, tranexamic acid oral progesterone to treat menorrhagia. reduced MBL by about 53 mL, roughly a However, multiple comparative RCTs have 40% to 50% decrease. The 8 NSAID trials (5 demonstrated that these commonly pre- mefenamic acid, 2 naproxen, 1 ibuprofen) scribed medications significantly decrease demonstrated effectiveness, but the effect MBL. Trials have shown the reduction to size is difficult to quantify. The single dan- be inferior to LNG-IUS and danazol and azol RCT used a subjective scoring system equivalent to NSAIDs. Evidence summary bination or progesterone-only pills. All of the A 2015 Cochrane review of the LNG-IUS for trials excluded women with palpable or large menorrhagia included 1 placebo-controlled (> 5 cm) fibroids. In 3 trials (2 against OCPs RCT; most of the remaining 21 RCTs com- and 1 against a 10-day course of oral proges- pared the LNG-IUS to invasive procedures terone), the LNG-IUS decreased MBL more such as endometrial ablation or hysterecto- than OCPs did. A fourth trial found LNG- my.1 The placebo-controlled trial compared IUS comparable to oral progesterone dosed the LNG-IUS with placebo in 40 women on 3 times a day from Day 5 to Day 26 of each anticoagulation therapy and found a mean menstrual cycle. beneficial difference of 100 mL (95% confi- A recent large RCT (571 patients) that dence interval [CI], –116 to –83) using a sub- compared LNG-IUS with usual medical treat- jective pictorial blood assessment chart. ment (mefenamic acid [MFA], tranexamic acid, norethindrone, OCPs, progesterone-only Women are less likely to withdraw pill, medroxyprogesterone acetate injection) from LNG-IUS treatment found women significantly less likely to with- Four trials (379 patients) included in the Co- draw from LNG-IUS at 2 years (relative risk chrane review compared LNG-IUS with com- [RR] = 0.58; 95% CI, 0.49-0.70).2 CONTINUED MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 7 | SEPTEMBER 2020 | THE JOURNAL OF FAMILY PRACTICE E11 CLINICAL INQUIRIES Estrogen and progestin contraceptives Different NSAIDs, significantly reduce bleeding equivalent efficacy In addition to the trials in the 2015 Cochrane A 2013 Cochrane review of 18 RCTs includ- review comparing OCPs with LNG-IUS, a ed 8 (84 patients) that compared NSAIDs 2009 Cochrane review included a single (5 MFA, 2 naproxen, 1 ibuprofen) with place- 2-month crossover trial of 45 patients.3 This bo.5 In 6 trials, NSAIDs produced a significant RCT compared OCPs with naproxen, MFA, reduction in MBL compared with placebo, and danazol to treat heavy menstrual bleed- although most were crossover trials that ing (assessed using the alkaline haematin couldn’t be compiled into the meta-analysis. method). One trial (11 patients) showed a mean Researchers didn’t analyze the data us- reduction of 124 mL (95% CI, 62-186 mL) ing intention-to-treat. No group was found to in the MFA group. In another trial, women be superior. The OCP group (6 women) had were less likely to report no improvement a 43% reduction in MBL over baseline (no P in the MFA group than in the placebo group value reported). (odds ratio [OR] = 0.08; 95% CI, 0.03-0.18). No NSAID had significantly higher efficacy than Tranexamic acid outperforms the others. oral progesterone and NSAIDs but not ... Danazol was superior to NSAIDs in a A 2018 Cochrane meta-analysis of 13 RCTs meta-analysis of 3 trials (79 patients) with In head-to-head (1312 patients) of antifibrinolytics for re- a mean difference of 45 mL (95% CI, 19-71 comparisons, productive-age women with regular heavy mL), as was tranexamic acid in a single trial women were periods and no known underlying pathol- (48 patients) with a mean difference of 73 mL 5 more likely to ogy included 4 RCTs (565 patients) that (95% CI, 22-124 mL). Comparisons with 4 improve with used placebo as a comparator. Therapy with OCPs, oral progesterone, and an older the LNG-IUS tranexamic acid decreased blood loss by model of LNG-IUS showed no significant than tranexamic 53 mL per cycle (95% CI, 44-63 mL), a 40% to differences. The most common adverse -ef 50% improvement compared with placebo. fects were gastrointestinal. acid for reducing Three of the RCTs (271 patients) reported the menstrual blood percent of women improving on tranexam- Danazol linked to weight gain loss. ic acid as 43% to 63%, compared with and other adverse effects 11% for placebo, resulting in an NNT of 2 A 2010 Cochrane review evaluated 9 RCTs, to 3. including 1 (66 patients) comparing dan- One trial (46 patients) found tranexamic azol 200 mg with placebo that showed a sig- acid superior to luteal phase oral progester- nificant decrease in subjectively assessed one, and another study (48 patients) demon- MBL in the danazol group.6 The study, which strated superiority to NSAIDs, with a mean only 22 women finished, didn’t address decrease in MBL of 86 mL compared with intention-to-treat and used an unidentified 43 mL (P < .0027). scoring system. Patients also reported a sig- On the other hand, tranexamic acid nificant 6.7-kg weight gain (95% CI, 1-12.4) compared unfavorably with LNG-IUS (1 RCT, after 3 months of treatment. 42 patients), showing a lower likelihood of In addition to the 2013 meta-analysis improvement (RR = 0.43; 95% CI, 0.24-0.77). showing danazol to be superior to NSAIDs, Whereas 85% of women improved with LNG- several studies6 compared danazol favorably IUS, only 20% to 65% of women improved with oral progesterone, although not all re- with tranexamic acid (NNT = 2 to 6). sults reached significance. One study (37 pa- No statistical difference was found in tients) showed that women were more likely gastrointestinal adverse effects, headache, to rate the efficacy of danazol as moderate or vaginal dryness, or dysmenorrhea.4 Only high compared with progesterone (OR = 4.3; 1 thromboembolic event occurred in the 95% CI, 1.1-17.0), but the mean difference in 2 studies that reported this outcome, a known MBL (–36 mL; 95% CI, −102 to 31 mL) wasn’t risk that prohibits its concomitant use with statistically significant. combination OCPs. Of note, both a meta-analysis of 4 of the E12 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2020 | VOL 69, NO 7 studies (117 patients) and another study com- Editor’s takeaway paring danazol with NSAIDs (20 patients) I was taught to use combination OCPs as first- found significantly more adverse effects in line treatment for menorrhagia, but better evi- the danazol group. Commonly reported ad- dence supports using any of these 4: LNG-IUS, verse effects were acne, weight gain, head- tranexamic acid, danazol, or NSAIDs. In the ache, nausea, and tiredness. absence of clear evidence demonstrating dif- ferences in efficacy, I would use them in the reverse order for cost-effectiveness reasons. JFP Recommendations A comparative effectiveness review by the References Agency for Healthcare Research and Qual- 1. Lethaby A, Hussain M, Rishworth JR, et al. Progesterone or pro- gesterone-releasing intrauterine systems for heavy menstrual ity concluded that evidence showed efficacy bleeding. Cochrane Database Syst Rev. 2015;(4):CD002126. for 4 primary care interventions for heavy cy- 2. Gupta J, Kai J, Middleton L, et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia N Engl J Med. clic bleeding: LNG-IUS, NSAIDs, tranexamic 2013;368:128-137. 7 acid, and combination OCPs. 3. Farquhar C, Brown J. Oral contraceptive pill for heavy menstrual The United Kingdom’s National Institute bleeding. Cochrane Database Syst Rev. 2009;(4):CD000154. 4. Bryant-Smith AC, Lethaby A, Farquhar C, et al. Antifibrinolyt- for Health Care and Excellence (NICE) rec- ics for heavy menstrual bleeding. Cochrane Database Syst Rev. ommends pharmaceutical treatment when 2018;(4):CD000249. 5. Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflamma- no structural or histologic abnormality is tory drugs for heavy menstrual bleeding. Cochrane Database Syst present or when fibroids are < 3 cm in diam- Rev. 2013;(1):CD000400. 6. Beaumont HH, Augood C, Duckitt K, et al. Danazol for heavy eter.8 NICE advises considering pharmaceu- menstrual bleeding. Cochrane Database Syst Rev. 2010;(1): tical treatments in the following order: first, CD00107. 7. Hartmann KE, Jerome RN, Lindegren ML, et al. Primary Care LNG-IUS if long-term use (at least 12 months) Management of Abnormal Uterine Bleeding.