Objective
The purpose of this study was to compare clinical outcome and health related quality of life (HRQOL) 5 years after uterine artery embolization (UAE) or hysterectomy in the treatment of menorrhagia caused by uterine fibroids.
Study Design
Patients with symptomatic uterine fibroids who were eligible for hysterectomy were assigned randomly 1:1 to hysterectomy or UAE. Endpoints after 5 years were reintervention rates, menorrhagia, and HRQOL measures that were assessed by validated questionnaires.
Results
Patients were assigned randomly to UAE (n = 88) or hysterectomy (n = 89). Five years after treatment 23 of 81 UAE patients (28.4%) had undergone a hysterectomy because of insufficient improvement of complaints (24.7% after successful UAE). HRQOL measures improved significantly and remained stable until the 5-year follow-up evaluation, with no differences between the groups. UAE had a positive effect both on urinary and defecation function.
Conclusion
UAE is a well-established alternative to hysterectomy about which patients should be counseled.
Symptomatic uterine fibroids are disabling and are associated with significant morbidity that affects approximately 20-40% of women of childbearing age. The most common symptom of uterine fibroids for which treatment is sought is heavy or prolonged menstrual bleeding, which may result in iron deficiency anemia. When symptoms progress and pharmacotherapeutic options fail, surgical intervention may be necessary. During the last decade, uterine artery embolization (UAE) has been greeted as a minimally invasive treatment alternative for surgery in the reduction of symptoms of heavy menstrual bleedings caused by fibroids. Several randomized controlled trials compared UAE with hysterectomy and/or myomectomy and found similarly good results for both interventions up to 24 months of follow up. Earlier, we reported on the 2-year results from the embolization vs hysterectomy (EMMY) trial and compared clinical results, health-related quality of life (HRQOL) outcomes, and menopausal symptoms between UAE and hysterectomy. After 2 years the chance to avoid a hysterectomy in the UAE group was 76.5% while menorrhagia and HRQOL improved significantly, similarly in both groups. Both UAE and hysterectomy affected ovarian reserve in women >45 years old. Based on these 2-year follow-up results, UAE was considered to be a good alternative to hysterectomy. Because fibroids may grow back, menorrhagia can recur, or other symptoms that warrant hysterectomy may emerge beyond the 2-years of follow-up period. Herefore, we observed our cohort until 5 years after treatment and investigated clinical and HRQOL results between UAE and hysterectomy as well as outcomes between baseline and 5-year follow-up in patients from the EMMY trial.
See Journal Club, page 186
Materials and Methods
Study design
The EMMY study is a multicenter, randomized controlled trial, that was conducted in The Netherlands. Patients who visited the gynecologic outpatient clinics were invited to participate if they (1) were premenopausal, (2) were diagnosed with uterine fibroids, (3) had menorrhagia, (4) had no other treatment options than a hysterectomy, and (5) had no desire for future pregnancy. After written informed consent was obtained, patients were allocated randomly (1:1) to UAE or hysterectomy. Randomization was computer-based and stratified for participating hospitals. The study was approved by the Central Committee Involving Human Subjects ( www.ccmo.nl ) and by local ethics committees of participating hospitals.
Procedures
UAE and hysterectomy were performed according to professional standards as described earlier ( Table 1 ). In the UAE group, 10 patients (12.3%) underwent unilateral UAE.
| Variable | Uterine artery embolization (n = 88) | Hysterectomy (n = 89) |
|---|---|---|
| Age, y a | 44.6 ± 4.8 | 45.4 ± 4.2 |
| Body mass index, kg/m 2 a | 26.7 ± 5.6 | 25.4 ± 4.0 |
| Parity, n (%) | ||
| 0 | 30 (34.1) | 20 (22.5) |
| ≥1 | 58 (65.9) | 69 (77.5) |
| Ethnicity, n (%) | ||
| Black | 24 (27.3) | 20 (22.5) |
| White | 54 (61.4) | 57 (64.0) |
| Other | 10 (11.4) | 12 (13.5) |
| Marital status, n (%) | ||
| Single | 16 (18.2) | 13 (14.8) |
| Married | 55 (62.5) | 54 (61.4) |
| Together but living apart | 5 (5.7) | 4 (4.5) |
| Divorced | 12 (13.6) | 15 (17.0) |
| Widow | 0 | 2 (2.3) |
| Employment status, n (%) | ||
| Employed | 68 (77.3) | 69 (78.4) |
| Unemployed | 20 (22.7) | 19 (21.6) |
| Smoking status, n (%) | ||
| Current smoker | 21 (23.9) | 23 (25.8) |
| Former smoker | 11 (12.5) | 14 (15.7) |
| Nonsmoker | 56 (63.6) | 52 (58.4) |
| Highest educational level, n (%) | ||
| Elementary school | 3 (3.4) | 6 (6.9) |
| Lower vocational, lower secondary school | 29 (33.0) | 32 (36.8) |
| Intermediate and higher vocational, higher secondary school | 26 (29.5) | 27 (31.0) |
| College/university | 28 (31.8) | 22 (25.3) |
| Other | 2 (2.3) | 0 |
| Previous treatment, n (%) | ||
| None | 11 (12.5) | 15 (16.9) |
| Hormonal | 59 (67.0) | 59 (66.3) |
| Nonsteroidal antiinflammatory drugs/tranexamic acid | 45 (51.1) | 41 (46.1) |
| Iron supplement/blood transfusion | 50 (56.8) | 52 (58.4) |
| Surgical procedures | 17 (19.3) | 11 (12.4) |
| Symptoms, n (%) | ||
| Menorrhagia | 88 (100) | 89 (100) |
| Dysmenorrhea | 47 (53.4) | 50 (56.2) |
| Pain (not during menstruation) | 15 (17.0) | 14 (15.7) |
| Anemia | 43 (48.9) | 42 (47.2) |
| Pressure symptoms | 23 (26.1) | 25 (28.1) |
| Other symptoms | 6 (6.8) | 11 (12.4) |
| Duration of symptoms, mo b | 24 (3–250) | 24 (4–240) |
| No. of fibroid tumors b | 2 (1–20) | 2 (1–9) |
| Uterine volume, cm 3 b | 321 (31–3005) | 313 (58–3617) |
| Fibroid volume: dominant fibroid, cm 3 b | 59 (1–673) | 87 (4–1641) |
| Type of embolization, n | ||
| Target embolization | ||
| Left uterine artery | 65 | — |
| Right uterine artery | 59 | — |
| Selective embolization | ||
| Left uterine artery | 8 | — |
| Right uterine artery | 12 | — |
| Type of hysterectomy, n | ||
| Abdominal hysterectomy | 2 | 63 |
| Vaginal hysterectomy | 1 | 8 |
| Vaginal hysterectomy with morcellator | 1 | 1 |
| LH with morcellator | — | 2 |
| LAVH | — | 1 |
a Data are given as mean ± SD;
Sample size and endpoints of the study
The sample size was based on the primary endpoint of the 2-year clinical study, the elimination of menorrhagia thus avoiding hysterectomy after UAE in at least 75% of the patients after 2 years. To reject the null hypothesis that UAE and hysterectomy are not clinically equivalent, at least 2 × 60 (= 120) analyzable patients had to be included. Endpoints after 5 years were reinterventions, menorrhagia, menopause and menopausal symptoms, quality of life, urinary and defecation function, and satisfaction with the received treatment.
Study measures
Patients received questionnaires at baseline and at fixed intervals for 2 years after treatment. In addition, for logistic reasons, all patients received 1 questionnaire in the autumn of 2007, at a median follow up period of approximately 5 years after primary treatment, which resulted in a variable follow-up evaluation in both groups. In tables and figures, the median of 5 years is depicted as a fixed point in time for both treatment arms, despite this variation within the group. All questionnaires were identical, except for the 5-year questionnaire, which was a condensed version without the Higham Pictorial Chart, Euro-Quality of Life-5, Health Utilities Index Mark 3, sexual activity, and body image questionnaires to optimize the response rate. The following subjects were evaluated in the 5-year questionnaire: additional interventions between 2- and 5-year follow up evaluation (in case of nonrespondents, the patients’ general practitioners were contacted by telephone to check for any additional procedures), menstrual characteristics (intensity and regularity since UAE or no complaints because of menopause; only in the UAE group), and several HRQOL measures that were assessed by validated questionnaires. Menopausal symptoms were queried by the Kupperman score as modified by Wiklund et al. Scores may range from 0–51; higher scores represent more serious menopausal symptoms. In addition we inquired whether patients believed themselves to be in or beyond menopause. Generic HRQOL was assessed by the Medical Outcome Study Short Form 36 (SF-36). The SF-36 can be divided into the physical component summary score (PCS) and the mental component summary score (MCS). Scores may range from 0–100 (100 indicates the optimal score) and were validated for the Dutch population. The Urogenital Distress Inventory (UDI) was used to investigate urinary symptoms. UDI scores range from 0–100; higher scores indicate worse functioning. For defecation complaints, the Defecation Distress Inventory (DDI) was used, with scores ranging from 0–100; higher scores are less favorable. Patients were asked to rate the overall quality of their urinary and stool function as “very good,” “good,” “fairly good,” “not good or bad,” “fairly bad,” “bad,” or “very bad.” Furthermore, the use of pads for urinary incontinence or of laxatives was registered. Patients were asked to indicate how satisfied they were with the received treatment: “very satisfied,” “satisfied,” “fairly satisfied,” “not satisfied or unsatisfied,” “fairly unsatisfied,” “unsatisfied,” or “very unsatisfied.” We also inquired whether patients would recommend the primary treatment to a friend. Finally, we asked women whether they would indeed have chosen the assigned treatment again if they had had the opportunity to do so.
Statistical analysis
Analyses were done with SPSS statistical software (version 16.0; SPSS Inc, Chicago, IL). Study outcomes were analyzed according to original treatment assignment (intention to treat). Reinterventions were also analyzed according to per-protocol analysis. A Kaplan-Meier curve was constructed to show the distribution of the secondary hysterectomies over time. Differences in categoric data were compared with χ 2 test or Fisher’s exact tests, if appropriate. The Student t test (or Mann-Whitney test, when applicable) assessed differences in numeric data. A probability value of < .05 was considered statistically significant. Predictors for failure (secondary hysterectomy) were tested by logistic regression analysis. In this analysis, baseline characteristics ( Appendix ) were included for multiple regression analysis whenever univariate analysis revealed probability values of < .1. In the multiple regression analysis, a probability value of < .05 was considered statistically significant. Repeated measurements analysis was used to evaluate longitudinal differences in MCS, PCS, DDI, UDI, and Wiklund scores between treatment strategies with time as repeated factor. Self-reported quality of urinary and stool function at follow-up evaluation was compared with baseline and yielded 1 of 3 possible answers: worse, the same, or better. Logistic regression analysis was performed to test the impact of improvement in SF-36 MCS and PCS on satisfaction at 5 years (“very satisfied” and “satisfied” vs “moderately satisfied” and “very unsatisfied”). To evaluate the impact of baseline variables ( Appendix ) on the change in MCS, PCS, UDI and DDI at 5 years compared with baseline, multiple linear regression analysis was performed for those variables that yielded probability values of < .1 in the univariate analysis. Nonresponders were not included in the analyses.
Results
Patients
Patients were enrolled between March 2002 and February 2004. In the hysterectomy group, 75 women received the allocated treatment vs 81 in the UAE group. Table 1 lists the baseline characteristics of the participating patients, which include myoma characteristics; all characteristics were not significantly different. Figure 1 shows the flow of patients through the trial: 93% of the mailed 5-year questionnaires were returned, with a median follow-up period of 59 months, ranging from 47-73 months (UAE: median, 60 months [range, 49–73 months]; hysterectomy: median, 58 months [range, 47–71 months]). The median age of all patients when responding to the 5-year questionnaire was 50 years, ranging from 39-63 years (UAE: median, 49 years [range, 39–63 years]; hysterectomy: median, 49 years [range, 40–59 years]).
Clinical outcome
Reinterventions
In addition to the 19 secondary hysterectomies (23.5%) that were performed in the UAE group in the first 2 years, another 4 hysterectomies were required between 2 and 5 years, all because of insufficient improvement of bleeding complaints ( Table 2 ). This adds up to a total of 23 secondary hysterectomies after a median follow up of 5 years (28.4%). Distribution over time is presented in Figure 2 . Per protocol analysis showed that, after a technically successful UAE, 19 of 77 patients underwent a secondary hysterectomy (24.7%). Of the 10 women who underwent unilateral UAE, 3 women underwent a hysterectomy, all within the first 2 years of follow up. Multiple regression analysis of failures within 5 years revealed only a higher body mass index to be associated with failed UAE (odds ratio, 1.12; 95% confidence interval [CI], 1.02–1.24; P = .02). All additional interventions that were performed after UAE, including hysterectomies, are listed in Table 2 . Twelve women in the UAE group used medication (tranexamic acid/oral contraception/levonorgestrel intrauterine device) to remedy still symptomatic menorrhagia ( Table 3 ). After 5 years 8 of 75 of the women (10.7%) in the hysterectomy group needed reintervention ( Table 2 ).
| Primary intervention | Secondary intervention | Reason for intervention | Time since primary intervention, mo |
|---|---|---|---|
| UAE | |||
| 1 | Abdominal hysterectomy | Bilateral failure UAE | <1 |
| 2 | Abdominal hysterectomy | Bilateral failure UAE | <1 |
| 3-1 | Abdominal hysterectomy | Bilateral failure UAE | <1 |
| 3-2 | Laparoscopic reconstruction surgery | Incisional hernia | 9 |
| 4 | Vaginal hysterectomy with morcellation | Bilateral failure UAE | <1 |
| 5-1 | Failed attempt to hysteroscopically remove fibroid | Persistent abdominal pain/myoma nascens | 1 |
| 5-2 | Hysteroscopic myoma resection converted to vaginal hysterectomy | Menorrhagia | 20 |
| 6 | Manual resection fibroid | Discharge, fever, persistent abdominal pain/myoma nascens | 2 |
| 7 | Abdominal hysterectomy | Menorrhagia, persistent abdominal pain | 5 |
| 8 | Abdominal hysterectomy | Menorrhagia | 6 |
| 9 | Abdominal hysterectomy | Menorrhagia, persistent abdominal pain, bulk complaints | 7 |
| 10 | Abdominal hysterectomy | Menorrhagia | 7 |
| 11 | Abdominal hysterectomy | Persistent abdominal pain, irregular menstruation | 10 |
| 12 | Vaginal hysterectomy | Menorrhagia, persistent abdominal pain, dyspareunia | 12 |
| 13-1 | Diagnostic hysteroscopy with curettage | Postmenstrual blood loss | 12 |
| 13-2 | Abdominal hysterectomy | Irregular cycle, pain, bulk complaints | 13 |
| 14 | Abdominal hysterectomy | Menorrhagia, bulk complaints | 13 |
| 15 | Abdominal hysterectomy | Menorrhagia | 13 |
| 16 | Laparoscopic-assisted vaginal hysterectomy | Menorrhagia | 15 |
| 17 | Abdominal hysterectomy | Menorrhagia | 17 |
| 18 | Vaginal hysterectomy | Menorrhagia | 17 |
| 19 | Abdominal hysterectomy | Menorrhagia | 20 |
| 20 | Abdominal hysterectomy | Menorrhagia | 24 |
| 21 | Laparoscopic myomectomy | Menorrhagia | 25 |
| 22 | Abdominal hysterectomy | Menorrhagia | 36 |
| 23 | Curettage | Menorrhagia | 37 |
| 24 | Abdominal hysterectomy | Menorrhagia | 44 |
| 25 | Endometrium ablation | Menorrhagia | 47 |
| 26 | Hysteroscopic polypectomy | Menorrhagia | 48 |
| 27 | Abdominal hysterectomy | Menorrhagia | 48 |
| 28 | Abdominal hysterectomy | Menorrhagia | 63 |
| Hysterectomy | |||
| 1-1 | Adhesiolysis by laparotomy | Persistent abdominal pain | 4 |
| 1-2 | Bilateral adnextirpation | Persistent abdominal pain | 11 |
| 2 | Fistula repair with Latzko technique | Vesicovaginal fistula | 7 |
| 3 | Reconstruction surgery | Incisional hernia | 9 |
| 4 | Adhesiolysis and cystectomy by laparotomy | Persistent abdominal pain | 23 |
| 5 | Diagnostic laparoscopy | Persistent abdominal pain | 24 |
| 6 | Ovariectomy | Persistent abdominal pain | 38 |
| 7 | Suburethral sling procedure | Stress incontinence | 50 |
| 8 | Reconstruction surgery | Cosmetic | 54 |
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