Levonorgestrel Releasing Intrauterine System (Mirena) versus Endometrial Ablation (Novasure) in Women With Heavy Menstrual Bleeding

A Multicentre Randomised Controlled Trial

Malou C Herman; Marian J van den Brink; Peggy M Geomini; Hannah S van Meurs; Judith A Huirne; Heleen P Eising; Anne Timmermans; Johanna MA Pijnenborg; Ellen R Klinkert; Sjors F Coppus; Theodoor E Nieboer; Ruby Catshoek; Lucet F van der Voet; Hugo WF van Eijndhoven; Giuseppe CM Graziosi; Sebastiaan Veersema; Paul J van Kesteren; Josje Langenveld; Nicol AC Smeets; Huib AAM van Vliet; Jan Willem van der Steeg; Yvonne Lisman-van Leeuwen; Janny H Dekker; Ben W Mol; Marjolein Y Berger; Marlies Y Bongers

Disclosures

BMC Womens Health. 2013;13(32) 

In This Article

Methods/Design

Objective

The aim of this study is to assess the effects and cost-effectiveness of a strategy starting with LNG-IUS versus a strategy starting with endometrial ablation in women with heavy menstrual bleeding. This study will also evaluate QoL, sexual function and as predictors of effect of intervention we also measure level of coagulation factors.

Trial Design

This study is a multicenter randomised controlled trial with an economic evaluation alongside it. It will be performed by the Dutch Consortium for Studies in Women's Health and the department of General Practice of the University Medical Center Groningen. The study will be organized in a network infrastructure in which GPs and gynaecologists collaborate. Participating hospitals can be district, teaching, third referral or university hospitals. The study is conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO) and has been approved by the ethics committee of the Academic Medical Centre Amsterdam (ref. no MEC 10/183). The protocol is registered in the Dutch trial register, number NTR2984.

Eligibility Criteria

Women ≥ 34 years suffering from heavy menstrual bleeding, with a PBAC score exceeding 150 points can participate in the trial.

Women who might want to get pregnant in the future will be excluded as an endometrial ablation is an absolute contraindication for pregnancies. Other exclusion criteria are abnormal cervix cytology in the past 5 years, a sounding length of more than 10 cm, intracavitary fibroids or polyps or large intramural fibroids determined by either a transvaginal ultrasound (TVU) or a bimanual vaginal examination.

Patient Recruitment, Randomization and Collection of Data

Eligible patients are identified by the gynaecologist in the participating hospitals or by participating general practitioners. Before entry into the study, inclusion and exclusion criteria are checked by research nurses and if women are eligible they will also be counseled by these experienced research nurses. They will be informed about the aims, methods, reasonably anticipated benefits and potential hazards of the study. We will ask separate informed consent for taking and analyzing blood on levels of coagulation factors. After given written informed consent women will be randomised to a strategy starting with a LNG-IUS or a strategy starting with endometrial ablation. Randomisation is performed by accessing a web-based randomisation program. We will stratify for inclusion by general practitioner or by gynaecologist. Patients will be randomised into two groups in a ratio of 1:1, using permuted block randomization with a variable block size.

Participants will be given a computer generated numeric code. Data handling will be done anonymously, with the patient code only available to the local investigator and the research nurse working in the local centre. At the local centres, baseline data and follow-up data collection is the responsibility of the specialised research nurse. Data will be collected using a website dedicated to studies in the Dutch Consortium for women's health and reproductive medicine studies (http://www.studies-obsgyn.nl). In accordance with guidelines of the Dutch Federation of University Medical Centres (NFU) the data will be kept for 20 years.

Interventions

The LNG-IUS can be placed either by a GP or by a gynaecologist. In the endometrial ablation group, a second generation bipolar ablation technique (Novasure) will be performed by a gynaecologist.

Measurements and Follow-up

Before randomization patients are asked to fill out a PBAC. Prior to start of the treatment, participating patients will fill in two questionnaires measuring health-related QoL: the Short Form-36 (SF-36), a validated GP and the Shaw heavy menstrual bleeding questionnaire, a disease specific questionnaire, which we validated linguistically. Furthermore, patients are asked to complete questionnaires to measure sexual functioning: the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS) and a questionnaire to measure (indirect) costs. Baseline demographic characteristics, medical history and menstruation pattern are recorded in a Case Record Form (CRF).

Patients will fill in the PBAC and the same questionnaires used at baseline at 3, 6, 12 and 24 months after randomised. Since we compare strategies starting with LNG-IUS or endometrial ablation, patients who are not satisfied with the (randomised) treatment effect can choose another treatment, or opt for hysterectomy. Nevertheless, they will be asked to complete follow-up questionnaires.

Outcome Measures

Primary outcome is the PBAC score at 24 months of follow-up. Secondary outcomes are patient satisfaction, complications, number of re-interventions, menstrual bleeding pattern, including rates of amenorrhea, QoL, sexual function, sick leave and costs and as predictors of effect of intervention we also measure level of coagulation factors.

Statistical Analysis

Sample Size. The study is designed as a non-inferiority study. Based on previous studies, we estimate the mean PBAC score at 24 months of follow-up to be 50 points in the LNG-IUS group and 40 points in the endometrial ablation group, with a SD of 40.[23–26]

Previous studies in women with heavy menstrual bleeding have shown that a 50 point difference in PBAC –score between treatments represents a clinically meaningful difference in reduction of menstrual bleeding. In our study we use a non-inferiority marge of 25 points. With this marge and estimated mean PBAC-scores of 50 and 40 points in resp. the LNG-IUS and endometrial ablation group, the estimated scores in both treatment groups will be far below the upper range of normal menstrual blood loss. Using a dropout rate of 15%, an alpha error of 2.5% and Beta error of 20%, we need to include 266 patients (133 patients per treatment group).

Data Analysis. Data will be analysed according to the intention to treat principle. Statistical analysis will be performed using the software Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA).

Point estimates and 95% confidence intervals will be calculated for different time points.

First, the treatment effect at 24 months of follow-up of a strategy starting with LNG-IUS compared to a strategy starting with endometrial ablation will be investigated. For not normally distributed continuous variables, differences between groups will be tested with the Mann–Whitney U test. Differences between categorical variables will be tested with the Chi-square test or Fisher's exact test. Secondary, to assess the treatment effect over time, and the interaction of the intervention effect, we will use a mixed effects model. Time to re-intervention will be compared with Kaplan Meier analysis and Cox regression.

The analysis of the influence of lower levels of coagulation on the treatment effect of LNG-IUS and endometrial ablation will be explorative.

Economic Evaluation

The economic analysis will be conducted from a societal perspective including direct medical and direct and indirect non-medical costs. Relevant direct costs components that will be taken into account are costs of the LNG-IUS and endometrial ablation, interventions for complications, hospital admission and home care, consisting of both professional care as well as informal care. Sick leave and loss of productivity at work will be taken into account as indirect non-medical costs.

The economic evaluation will be designed as a cost-effectiveness analysis, with the costs per treatment resulting in a reduction of menstrual blood loss as an outcome measure. We will also perform a cost-utility analysis expressing the incremental costs per Quality Adjusted Life Years based on the SF-36. Robustness of the results (costs and health outcomes) for various assumptions and parameter estimates will be explored in sensitivity analyses and visualized in ICER-graphs and cost-effectiveness acceptability curves.

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