By Jeffrey T. Jensen, MD, MPH , Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: In a randomized study of women who presented to primary care providers with a complaint of excessive menstrual bleeding, the levonorgestrel intrauterine system was more effective than other medical treatments (tranexamic acid, NSAID, combined oral contraceptives, progestin-only pill, Depo-Provera) in reducing the effect of heavy menstrual bleeding on quality of life.
Source: Gupta J, et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med 2013;368:128-137.
Aalthough the levonorgestrel intrauterine system (LNG IUS) has been shown to be an effective treatment for heavy menstrual bleeding (HMB), previous clinical trials included rigorous criteria focused primarily on measuring the severity of bleeding. These evaluations (that involve the collection of menstrual hygiene products) generally are not used in day-to-day assessment of HMB so the applicability of these studies to clinical practice is in question. Alternatively, the ECLIPSE (Effectiveness and Cost-Effectiveness of Levonorgestrel-Containing Intrauterine System in Primary Care against Standard Treatment for Menorrhagia) study was designed as a pragmatic, multicenter, randomized trial to compare the LNG IUS with other medical treatments for the management of menorrhagia. In primary care clinics in the United Kingdom, women 25-50 years old who presented with self-reported excessive menstrual bleeding involving at least three consecutive menstrual cycles were eligible to participate. Exclusions included intention for pregnancy in the next 5 years, current use of hormonal therapy, irregular bleeding (unless an endometrial biopsy was normal), intermenstrual or postcoital bleeding, findings suggestive of large fibroids (e.g., an abdominally palpable 10-12 week size uterus), contraindications to (or a strong preference for) the LNG IUS, or one of the other usual medical treatments. No further workup or imaging studies were mandated by the protocol.
A total of 571 women with HMB at 67 clinical sites were randomized to treatment with either the LNG IUS or one of several usual medical treatments (tranexamic acid, mefenamic acid, combined oral contraceptives, progestin-only pills, or injectable medroxyprogesterone acetate), according to the preference of each attending physician. Outcomes were assessed over a 2-year period. The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS, ranging from 0 to 100, with lower scores indicating greater severity). The MMAS captures menstrual cycle distress according to several domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health). Secondary outcomes included general quality-of-life measures, sexual-activity scores, and whether surgical intervention occurred during the follow-up interval.
Although MMAS scores improved from baseline to 6 months in both the LNG IUS and usual-treatment groups and were maintained over the 2-year period, the improvements were significantly greater in the LNG IUS group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9-16.9). Moreover, the improvements were significantly greater in the LNG IUS group for all MMAS domains and for seven of the eight general quality-of-life domains. At 2 years, more women continued use of the LNG IUS than the usual medical treatment (64% vs 38%, P < 0.001). However, there were no significant between-group differences in the rates of surgical intervention, sexual-activity scores, or serious adverse events between groups.
HMB is the preferred term for excessive bleeding.1 The normal volume of flow is defined as measured menstrual blood loss of 5-80 mL. The 80 mL threshold comes from detailed studies that determined that women become anemic when blood loss exceeds this amount.2 Although the 80 mL definition makes sense for research, it offers little guidance for clinicians. Not all women who complain of HMB will become anemic and a woman’s perception of her own menstrual loss is the key determinant in her presentation to the clinic for evaluation and therapy. A clinical women-focused diagnosis of HMB is the position endorsed by the National Institute for Clinical Excellence (NICE) in the UK.
The LNG IUS is an approved treatment for heavy menstrual bleeding in many countries, including the United States and throughout Europe. Well-designed randomized, controlled trials have established that the LNG IUS effectively reduces measured menstrual blood loss in women rigorously screened to establish baseline bleeding in excess of 80 mL/cycle.3 Other recently approved therapies in the United States include the estradiol valerate/dienogest (E2V/DNG) oral contraceptive4 and tranexamic acid.5 Although a direct comparison is not available, the published studies show that the proportion of women with a reduction in MBL ≤ 80 mL or at least ≥ 50% reduction from baseline to treatment cycle 7 with E2V/DNG (68.2% and 70%, respectively)6 appears to be much higher than that achieved with tranexamic acid (43% and 35%, respectively).5 Although other combined oral contraceptives (COC) reduce the duration and intensity of menstrual bleeding and are widely used to manage abnormal menstruation, little objective data and no labeling indications exist to support this practice. The effectiveness of oral or injectable progestogens also has not been established with rigorous methodology.7 Nonsteroidal anti-inflammatory drugs are widely available, easy to use, and appropriate for the treatment of menstrual pain. A randomized study by Fraser demonstrated that mefenamic acid reduced measured blood loss by up to 39%; this was not significantly different than the reduction seen with a COC (43%) and danazol (49%) but better than naproxen (12%). In other words, the comparators used in the ECLIPSE study — while generally accepted as usual care — have not been shown to be particularly effective. It’s not a surprise that the LNG IUS is the clear winner.
Still, this study adds to the growing literature that the LNG IUS is a first-line treatment for women with HMB, and is applicable to primary care practice. It is great to see this published in a high-profile journal like the New England Journal of Medicine, as it should encourage your primary care colleagues to send more women with HMB to your office for IUS insertion!
- Fraser IS, et al. Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum Reprod 2007;22:635-643.
- Hallberg L, et al. Menstrual blood loss — A population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966;45:320-351.
- Kaunitz AM, et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: A randomized controlled trial. Obstet Gynecol 2010;116:625-632.
- Jensen JT, et al. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: A randomized controlled trial. Obstet Gynecol 2011;117:777-787.
- Lukes AS, et al. Tranexamic acid treatment for heavy menstrual bleeding: A randomized controlled trial. Obstet Gynecol 2010;116:865-875.
- Fraser IS, et al. Normalization of blood loss in women with heavy menstrual bleeding treated with an oral contraceptive containing estradiol valerate/dienogest. Contraception 2012;86:96-101.
- Lethaby AE, Vollenhoven BJ. An evidence-based approach to hormonal therapies for premenopausal women with fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22:307-331.