左炔诺孕酮宫内系统控制月经过多效果佳

《新英格兰医学杂志》1月10日在线发表的一项研究显示，释放左炔诺孕酮的宫内系统(Mirena, Bayer HealthCare)在改善月经过多女性患者的生活质量方面，效果优于多种标准常规药物治疗(N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMoa1204724])。

这项临床随机研究由英国伯明翰大学的Janesh Gupta博士及其同事进行，纳入63个英国医学中心4年内由初级保健医生收治的571例25~50岁月经过多女性患者。患者随机接受左炔诺孕酮宫内系统(285例)或药物治疗(286例)，如甲芬那酸、氨甲环酸、炔诺酮、雌激素-孕激素口服避孕药、单纯孕激素避孕药、醋酸甲羟孕酮注射液，或这些药物的一些联合治疗。药物治疗由患者及其医生根据患者的避孕需求及有关激素治疗的意愿进行选择。两组在患者年龄(小于或大于35岁)、体重指数(小于或大于25 kg/m²)、症状持续时间(少于或多于1年)、避孕需求(是或否)及有或无月经疼痛方面无差异。

研究者采用月经过多多属性量表(MMAS)来评估月经过多对日常生活的6个领域的影响，这6个领域包括实际困难、社会生活、心理健康、身体健康、工作和日常生活、以及家庭生活和人际关系。MMAS评分范围为0(“严重受影响”)至100(“完全未受影响”)。研究者还采用医学结局研究组的36项健康调查简表(SF-36，100分制)及欧洲生活质量研究组5维自评问卷(EQ-5D，具有2个100分)来评估与一般健康相关的生活质量。研究者采用性行为问卷来评估与性行为相关的快感和不适以及相对于患者常规水平的性行为频率。

主要结局指标是随访2年后MMAS评分的改善情况。结果显示，所有患者的这些评分均获得改善，但左炔诺孕酮宫内系统组MMAS所有6个领域评分的改善显著大于药物治疗组，不仅随访2年时如此，而且在所评估的各个时间点均如此。

这些患者的最终MMAS评分相对基线时的平均差值为13.4分，这一变化兼具统计学和临床意义。这表明患者由明显受月经过多影响改善至受影响很小，或从受影响很小改善至完全不受影响。

对未从原治疗组交叉至另一不同治疗组的患者进行的敏感性分析显示，左炔诺孕酮宫内系统组的MMAS评分改善17.8分，证实了主要分析的结果。

同样，左炔诺孕酮宫内系统组SF-36简表8个领域中有7个领域的评分在所有时间点的改善均优于药物治疗组。两组在EQ-5D评分或性行为问卷任何指标方面均无显著差异。两组随访期间因月经过多接受手术干预的患者比例也无显著差异：两组进行子宫切除术的患者比例均为6%；左炔诺孕酮宫内系统组和药物治疗组进行子宫内膜消融术的患者比例分别为4%和6%。

研究者表示，鉴于月经过多通常持续多年，因此计划对这些患者进行更长时间的随访。在随访5年和10年时将进行额外的意向治疗分析。

该研究获美国国立卫生研究院卫生技术评估项目支持。Gupta博士声明与Hodder Arnold Publishing、Ethicon Gynecare和Femcare-Nikomed公司存在联系。

随刊述评：美国应批准扩大左炔诺孕酮宫内系统的适应证

Eve Espey博士

新墨西哥大学妇产科的Eve Espey博士表示，目前美国仅批准左炔诺孕酮宫内系统用于治疗需要避孕的女性的月经过多，上述研究支持将适应证范围扩大，即不论有无避孕需求，只要是月经过多即可使用该系统(N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMe1214191])。

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By: MARY ANN MOON, Internal Medicine News Digital Network

The levonorgestrel-releasing intrauterine system is superior to a variety of medical therapies at improving quality of life for women with menorrhagia, according to a report published online Jan. 10 in the New England Journal of Medicine.

In a randomized clinical trial that followed 571 subjects for 2 years, levonorgestrel-IUS (Mirena, Bayer HealthCare) was more effective than the usual medical treatments at combating the adverse effects of heavy menstrual bleeding on women’s daily lives, as well as at improving their psychological and physical well-being, said Dr. Janesh Gupta of the University of Birmingham (England) and his associates for the ECLIPSE (Effectiveness and Cost-Effectiveness of Levonorgestrel-Containing Intrauterine System in Primary Care against Standard Treatment for Menorrhagia) Trial Collaborative Group.

Previous studies gauging the effectiveness of various treatments for menorrhagia have focused on their control of menstrual blood loss, but there is great discordance between objective measures of blood loss and women’s perception of the amount they bleed. "Only about half the women with menorrhagia who present to health care providers have blood loss greater than the traditional threshold of 80 mL per menstrual cycle," the investigators wrote.

Moreover, the amount of bleeding doesn’t correlate with a woman’s experience of what is burdensome for her. "Clinical guidelines now advocate a shift in emphasis from the amount of menstrual blood loss to the more patient-centered definition of heavy menstrual bleeding that interferes with a woman’s physical, emotional, and social life," they noted.

Dr. Gupta and his colleagues compared levonorgestrel-IUS with standard medical therapies using these factors rather than the amount of blood loss as the primary outcome measures. They assessed the effect of menorrhagia on six domains of daily life – practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships – using the condition-specific Menorrhagia Multi-Attribute Scale (MMAS). Scores on the MMAS can range from 0 ("severely affected") to 100 ("not affected at all").

The researchers also assessed general health-related quality of life using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which also has a 100-point scoring system, and the EuroQOL Group 5-Dimension Self-Report Questionnaire (EQ-5D), which has two 100-point scores. They used the Sexual Activity Questionnaire to measure pleasure and discomfort associated with sex, as well as the frequency of sexual activity, relative to the patient’s usual levels.

The study subjects were women aged 25-50 years who presented with menorrhagia to their primary care physicians at 63 U.K. medical centers during a 4-year period. These women were randomly assigned to receive either levonorgestrel-IUS (285 subjects) or medical therapies (286 subjects) such as mefenamic acid, tranexamic acid, norethindrone, estrogen-progestogen OCs, progesterone-only OCs, medroxyprogesterone acetate injections, or some combination of these. The medical treatments were chosen by the patient and her physician according to her contraceptive needs and wishes regarding hormonal therapy.

The two study groups were balanced with respect to subject age (younger than or older than 35 years), body-mass index (over or under 25), duration of symptoms (less than or more than 1 year), need for contraception (yes or no), and the presence or absence of menstrual pain.

The primary outcome measure was improvement on MMAS scores after 2 years of follow-up. These scores improved in all patients, but the improvement in all six domains of the MMAS was significantly greater among women in the levonorgestrel-IUS group, not just at 2 years but at every time point that was assessed.

The mean difference between baseline and final MMAS scores was 13.4 points for these women, a change that was both statistically significant and clinically meaningful. This represents an improvement from being substantially affected to minimally affected by menorrhagia, or from being minimally affected to being completely unaffected.

A sensitivity analysis was performed that included only study subjects who did not cross over from their assigned treatment to a different treatment. This analysis confirmed the findings of the main analysis, showing an improvement of 17.8 points in MMAS scores in women given levonorgestrel-IUS.

Similarly, scores on the SF-36 favored levonorgestrel-IUS over standard medical therapy at all time points in seven of the eight domains assessed, the investigators said (N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMoa1204724]).

The two study groups did not differ significantly on EQ-5D scores or on any factor in the Sexual Activity Questionnaire.

The frequency of surgical interventions for menorrhagia during follow-up also did not differ significantly, with 6% of both study groups undergoing hysterectomy; endometrial ablation was performed in 4% of the levonorgestrel-IUS patients and 6% of the medical treatment–group patients.

Given that menorrhagia often persists for years, longer follow-up of these study subjects is planned. Additional intention-to-treat analyses will be done at 5 and 10 years, Dr. Gupta and his associates said.

This study was supported by the National Institute of Health Research Health Technology Assessment Programme. Dr. Gupta reported ties to Hodder Arnold Publishing, Ethicon Gynecare, and Femcare-Nikomed.

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Approval of levonorgestrel-IUS should be broadened in U.S.

At present, the levonorgestrel-IUS is approved for the indication of heavy menstrual bleeding in the United States only among women who first choose to use it as a contraceptive method, said Dr. Eve Espey.

"The data from the study by Gupta et al support broadening its approval to include menorrhagia more generally, whether or not contraception is needed," she said.

Dr. Espey is with the department of obstetrics and gynecology at the University of New Mexico, Albuquerque. She reported no financial conflicts of interest. These remarks were taken from her editorial accompanying Dr. Gupta’s report (N. Engl. J. Med. 2013 Jan. 10 [doi:10.1056/NEJMe1214191]).