10 February, 2014
Heliövaara-Peippo and colleagues have recently reported on a randomized controlled trial in five Finnish university hospitals to compare the effect of treatment with a levonorgestrel-releasing intrauterine system (LNG-IUS) and the effect of hysterectomy in women with menorrhagia (n = 221) [1]. The studied population that fulfilled the inclusion criteria, initially aged 35–49 years, was monitored for 10 years and the endpoints were health-related quality of life (HRQoL), psychosocial well-being, and cost-effectiveness.
Instruments to measure quality of life and psychosocial well-being were used periodically, including the five-dimensional EuroQoL, the 36-item RAND Health Survey, the Spielberger 20-Item State-Trait Anxiety Inventory, the Beck Depression Inventory and the McCoy Sex Scale. Direct and indirect costs, sick-leave days and out-of-pockets costs were calculated from the time of randomization up to the 10-year follow-up control. There have been several previous publications concerning this trial, including the 12-month and the 5-year follow-up results.
HRQoL and psychosocial well-being were improved during the initial 5 years but diminished between 5 and 10 years; the improved HRQOL returned close to the baseline level without any significant difference between the LNG-IUS-treated and hysterectomy-treated groups. The overall costs in the LNG-IUS group ($ 3423/patient) were lower than in the surgery group ($ 4937/patient), despite the fact that 55 women (46%) assigned to the LNG-IUS group subsequently underwent surgery: 24 (44%) during the first year, 26 (47%) between 12 months and 5 years and five (9%) between 5 and 10 years. The main reasons for hysterectomy were bleeding problems during the first 5 years and fibroids and bleeding problems in the five hysterectomies performed between 5 and 10 years.
At the 10-year follow-up, 44 women had a LNG-IUS in situ; of these 40 women (91%) reported amenorrhea or oligomenorrhea, two hypomenorrhea, one normal menstrual bleeding and one irregular bleeding. In 18 women, the LNG-IUS was removed but hysterectomy was not performed; of these 18 women, 12 women reported amenorrhea or oligomenorrhea, three normal menstrual bleeding, two irregular bleeding, and one woman submitted to thermoablation after reported hypomenorrhea.
Comment
The prevalence of menorrhagia is very high among women in their late pre- and perimenopausal years. These women may have fatigue, iron depletion and anemia, social and job limitations, work loss, anxiety and low quality of life [2, 3]. The assessment of heavy menstrual bleeding is mandatory to select an appropriate treatment [4]. In women in their post-reproductive years, several studies have suggested that the LNG-IUS is among the most cost-effective treatments [5, 6]. Women treated with the LNG-IUS had more effective control of their menorrhagia as compared to other medical treatments, although LNG-IUS users reported side-effects such as unexpected bleeding and breast tenderness which are very disturbing for patients. Hysterectomy is not devoid of some inconvenience and some women do not wish to lose their uterus. On the other hand, some women may prefer hysterectomy as a definitive menorrhagia treatment without any further follow-up after surgery. However, there is limited information concerning long-term costs, well-being and quality of life; some women treated with the LNG-IUS may need further treatment if this first treatment fails, including surgery. Any current clinical or therapeutic intervention should consider several aspects, including clinical solutions, side-effects of intervention, initial treatment failures, economic costs, quality of life and long-term sequelae.
The Heliövaara-Peippo trial [1] has several merits, including the randomization of a large enough population to compare the surgical procedure with a non-surgical treatment, its long-term (10 years) follow-up and its detailed clinical information. The initial population was exhaustively studied to discard organic causes of heavy menstrual bleeding, genital cancer, endocrine disorders and severe depression, as recently recommended by FIGO. Ten years after randomization, the mean cost of LNG-IUS treatment/patient was less in economic terms than the cost of hysterectomy. However, the Finnish study also showed that a significant fraction (46%) of women randomized to the LNG-IUS had a clinical evolution which was not sufficiently satisfactory for them or for medical reasons, thus necessitating a subsequent hysterectomy. These 'rescue' hysterectomies may be considered as failures (mainly due to bleeding) of the initial non-surgical treatment and occurred in the early years after the device insertion.
The measurements of well-being and quality of life have a high subjective component, reaching higher individual values than objective measures; these aspects were also studied by the authors. Although HRQOL and psychosocial well-being improved during the first 5 years, they diminished in later years and returned close to the baseline values in both arms of the study; these may be analogous to age- and menopause-related changes. Thus, in otherwise healthy mid-aged women, quality of life worsens in relation to age, menopausal status and social factors [7]. It is likely that both treatments (initial hysterectomy + rescue hysterectomy vs. LNG-IUS for 10 years) produced similar or comparable levels of well-being and quality of life. However, 46% of the patients randomized to the LNG-IUS group were retreated with hysterectomy due to undesired clinical aspects or for unexpected unsatisfactory results. It is likely that well-being and quality of life would not be sufficiently good in these women who changed to the surgery option.
Circulating levonorgestrel has been detected in women using oral levonorgestrel administration and has been linked with cardiovascular risk. Women using the LNG-IUS for contraceptive purposes have plasma levonorgestrel levels of about 200 pg/ml and these decrease during the recommended period of use, although levonorgestrel may still be detectable in the 8th year after device insertion [8-10]. In young women using the LNG-IUS device for contraceptive purposes, plasma levonorgestrel levels are about 200 pg/ml and are associated with a decrease in endothelium-dependent, flow-mediated dilatation in the brachial artery as compared with the control group (wearing a TCu 380A intrauterine device) during the first year after insertion [10]. There is a need for information about plasma levonorgestrel levels in women using the LNG-IUS to treat menorrhagia and about functional vascular changes or their circulatory consequences, if any, after 10 years of LNG-IUS use.
During the last decade, different new treatments have been proposed for the management of menorrhagia including new steroid hormones, non-hysteroscopic endometrial ablation, and 'second-generation' devices such as balloon, radiofrequency or microwave ablation, which are safe and technically easy to perform under local anesthesia and which involve only a short hospital stay [6,11,12]. This scenario opens new management possibilities to compete with hysterectomy and the LNG-IUS. Pandora's beautiful jar (pithos) is still open to search for new solutions in terms of clinical endpoints, economic costs, quality of life, long-term risks and patients' desires for the such as yet unsolved gynecologic problem of menorrhagia.
Faustino R. Pérez-López
Professor of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain
References
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http://www.ncbi.nlm.nih.gov/pubmed/21535970