Authors' objectives: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Endometriosis, which affects up to 1 in 10 women, is characterised by the proliferation of endometrial cells outside the uterus, usually within the pelvis. These endometriotic deposits undergo cyclical proliferation in response to ovarian oestrogen, resulting in internal bleeding, scarring and adhesion formation, which causes pain and has a serious impact on quality of life in affected women. Surgical removal or destruction of endometriotic tissue is currently the preferred treatment but the risk of recurrence is high. Recurrence can be controlled by post-surgical hormonal treatment to reduce circulating levels of oestrogen but there is uncertainty as to the clinical and cost-effectiveness of two commonly used modalities: long-acting reversible contraceptive (LARC) and the combined oral contraceptive pill (COCP). Progestogen-based LARCs used in the trial were the levonorgestrel-releasing intrauterine system (LNG-IUS) or depot medroxyprogesterone acetate injection (DMPA). To evaluate the clinical and cost-effectiveness of LARCs compared with COCP in preventing recurrence of endometriosis-related pain and quality of life.

Authors' results and conclusions: Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: −0.8, 95% confidence interval −5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval −0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. A total of 405 women were allocated to receive either LARC (N = 205) or COCP (N = 200) following laparoscopic surgery for endometriosis. The two randomised groups were comparable in terms of age [29.6 years (6.7 years) vs. 29.3 years (6.6 years)]; body mass index [27.0 kg/m2 (10.6 kg/m2) vs. 26.3 kg/m2 (5.5 kg/m2)]; early-stage endometriosis: stages I and II (79% vs. 79%); complete surgical excision (92% vs. 90%); white ethnicity (91% vs. 92%) and previous hormonal treatment (27% vs. 23%). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no statistically significant difference between LARC and COCP at 3 years [adjusted mean difference: −0.8; 95% confidence interval (CI) −5.7 to 4.2; p = 0.76]. The choice of LARC (LNG-IUS or DMPA) did not alter these findings. Most of the other domains of the EHP-30 were improved in both groups at all time points compared with preoperative scores, with no consistent evidence of any difference between groups when estimates of uncertainty were considered. Women in the LARC group had fewer surgical procedures or second-line treatments compared with those taking COCP (73 vs. 97 events, occurring in 50 vs. 61 women due to repeat interventions), translating to a 33% reduction in time to treatment failure [hazard ratio (HR) 0.67, 95% CI 0.44 to 1.00]. Participants in the LARC group had a slightly higher mean EQ-5D-5L score at 36 months compared with those in the COCP arm (0.693 and 0.686, respectively). The mean adjusted imputed QALY difference between the two arms was 0.043 (95% CI −0.069 to 0.152) in favour of COCP, where participants in LARC group had a lower QALY value than those randomised to COCP (1.937 and 1.976, respectively). Despite this, the COCP group was estimated to be more expensive than the LARC group by £533 (95% CI 52 to 983) per woman over 36 months of follow-up. At 36 months, women allocated to LARCs or COCP had comparable levels of pain, with both groups showing around 40% improvement from presurgical levels. Although COCP is likely to be considered more cost-effective at a threshold of £20,000 per QALY, the difference between the two is marginal. LARCs may be preferred by some women as they are associated with lower rates of surgery, particular hysterectomy and operations for recurrence of endometriosis.

Authors' methods: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Thirty-four United Kingdom hospitals. Women of reproductive age undergoing conservative surgery for endometriosis. Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Thirty-four NHS hospitals within the UK. Women of reproductive age undergoing laparoscopic surgery for pelvic pain due to endometriosis were eligible if they fulfilled the following criteria: Inclusion criteria: Aged 16–45 years. No immediate plans to conceive. Scheduled for laparoscopic conservative surgery, or diagnostic laparoscopy with concurrent surgery if endometriosis is found, for pelvic pain associated with endometriosis. Willing to be randomised to one long-acting progestogen (LNG-IUS or DMPA) and COCP. The following women were also eligible if they had recurrent pain and were to have conservative surgery for endometriosis: Had one or more previous diagnostic laparoscopies. Had previous laparoscopic conservative surgery for endometriosis, provided that this did not involve rectovaginal dissection or bowel resection. Used postoperative medical treatment, including the treatment options included in the trial. Previous use of treatment options included in the trial as contraceptives. Use of preoperative gonadotropin-releasing hormone analogues (GnRHa), provided that this was stopped at least 4 weeks prior to laparoscopy. Exclusion criteria: No endometriosis identified at diagnostic laparoscopy. Infertility. Any plans for further elective endometriosis surgery (for deep disease or endometrioma). Contraindications to the use of hormonal treatment with oestrogen or progestogens. Suspicion of malignancy. Four hundred and five women were randomised in a one-to-one ratio via secure internet facility to either LARCs or COCP. The LARC was either 150 mg DMPA or 52 mg LNG-IUS. The COCP formulation contained 30 µg ethinylestradiol and 150 µg levonorgestrel. The LARC (LNG-IUS or DMPA) was selected before randomisation by the patient if a preference was apparent (or alternatively allocated randomly if there was no opinion). In the absence of a no-treatment arm, we were unable to demonstrate the effect of surgery alone on preventing recurrence of pain symptoms. While we are able to comment on the effectiveness of a strategy of postoperative prescription of LARC versus COCP, the true impact of these interventions is difficult to gauge as the prolonged duration of follow-up meant that many women had discontinued their allocated treatments. The predominance of white women in the recruited sample limits our ability to be confident about how our results might apply to women from other ethnic backgrounds. Use of telephone follow-up to collect primary outcome data in those who failed to return full questionnaires resulted in missing data for some of the secondary outcomes. While all patients were recruited prior to the COVID-19 pandemic, the number of women who required further surgery may be underestimated, given the negative impact of COVID-19 on waiting lists for elective surgery throughout the UK. It is possible that this may have led to an increase in the use of GnRHa treatment by women who were unable to access surgery for their symptoms.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/11/114/01

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/SQWY6998

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: United Kingdom

DOI: 10.3310/SQWY6998

Organisation Name: NIHR Health and Social Care Delivery Program

Contact Name: Rhiannon Miller

Contact Email: rhiannon.m@prepress-projects.co.uk