GLOBAL VALUE DOSSIER TruClear In myomectomy and … · Figure 5-4 The TruClear™ system 8.0 hysteroscope set..... 51 . Figure 5-5 The TruClear™ system 5C hysteroscope set

GLOBAL VALUE DOSSIER TruClearTM system for hysteroscopic tissue removal

In myomectomy and polypectomy

Global Value Dossier: TruClear™ System 2

Prepared by: Rhodri Saunders

Coreva Scientific

Kaiser-Joseph Str 198-200

79098 Freiburg, Germany

Phone: +49 76 176 999 422

E-mail: [email protected]

Rafael Torrejon Torres

Coreva Scientific

Kaiser-Joseph Str 198-200

79098 Freiburg, Germany

Phone: +49 76 176 999 422

E-mail: [email protected]

Version No. 1.0

Date: March 26, 2018


Contents

1. Disclaimer and scope ....................................................................................................... 10

1.1. Products and aliases ................................................................................................ 10

1.2. Data sources ............................................................................................................ 10

1.3. Data analysis ............................................................................................................ 10

1.4. FDA information ....................................................................................................... 10

2. Executive summary .......................................................................................................... 11

3. Background ...................................................................................................................... 12

3.1. Abnormal uterine bleeding ...................................................................................... 12

3.1.1. Uterine fibroids ................................................................................................. 15

3.1.2. Endometrial polyps .......................................................................................... 17

3.2. Current care paradigm ............................................................................................. 19

3.2.1. Consensus guideline recommendations for non-operative tissue removal .. 27

3.3. Healthcare burden ................................................................................................... 27

3.3.1. Costs associated with treatments for AUB ..................................................... 28

3.3.1. Out-of-pocket costs ........................................................................................ 32

3.3.1. Savings potential .............................................................................................. 32

3.4. Patient burden.......................................................................................................... 33

3.4.1. Quality of life associated with uterine fibroids and endometrial polyps ......... 34

3.4.2. Indirect burden ................................................................................................. 36

3.4.3. Patient satisfaction .......................................................................................... 37

4. Unmet needs .................................................................................................................... 38

4.1. Heterogeneous and delayed patient presentation ................................................. 38

4.2. Treatment selection ................................................................................................ 40

4.3. Patient outcomes .................................................................................................... 40

4.4. High burden of disease ............................................................................................ 41

4.5. Excess costs due to non-optimized care ................................................................ 42

4.6. Unmet needs in guidelines ....................................................................................... 42

4.7. Overview .................................................................................................................. 43

5. Minimally invasive procedures indicated for treatment of abnormal uterine bleeding .. 44

5.1. Hysteroscopic interventions ................................................................................... 44

5.1.1. Dilation and curettage (D&C) ........................................................................... 46

5.1.2. Mechanical tissue resection ............................................................................. 46

5.1.3. Electrosurgical tissue resection ...................................................................... 47

5.2. Efficacy and safety of hysteroscopic tissue removal .............................................. 48

5.3. The TruClear™ system ............................................................................................ 49


5.3.1. The TruClear™ system .................................................................................... 49

5.3.2. The TruClear™ system compared to other hysteroscopic mechanical tissue resection devices ............................................................................................. 52

5.3.3. Hysteroscopic mechanical tissue resection compared to competitor procedures ....................................................................................................... 55

6. Health economic analyses of hysteroscopic tissue removal .......................................... 66

6.1. Introduction to health economic analyses .............................................................. 66

6.1.1. Best practice and data requirements .............................................................. 67

6.2. Published health economic analyses ....................................................................... 69

6.2.1. Real-world cost and outcomes studies ........................................................... 70

6.2.2. Computational analyses .................................................................................. 71

6.3. Review of published computational models............................................................ 72

6.4. A cost-utility model for the TruClear™ system for mechanical hysteroscopic tissue removal ......................................................................................................... 74

6.4.1. Model structure ................................................................................................ 74

6.4.1. Uterine fibroid removal .................................................................................... 77

6.4.2. Endometrial polyp removal .............................................................................. 78

6.4.3. Discussion and conclusions ............................................................................. 79

7. Benefits of hysteroscopic mechanical tissue resection.................................................. 81

7.1.1. Non-invasive surgery ....................................................................................... 81

7.1.2. Improved quality of life ..................................................................................... 81

7.1.3. A high chance of procedure success................................................................ 82

7.1.4. Low rates of recurrence ................................................................................... 83

7.1.5. Regain of fertility .............................................................................................. 83

7.1.6. High patient satisfaction .................................................................................. 84

7.2. Optimization of healthcare resources .................................................................... 84

7.2.1. Shorter operation room time ........................................................................... 84

7.2.2. High physician acceptance............................................................................... 85

7.2.3. Cost-effective intervention ............................................................................. 87

7.3. Summary .................................................................................................................. 87

8. Appendix ........................................................................................................................... 89

8.1. Efficacy data ............................................................................................................. 89

8.2. Level of evidence table ............................................................................................ 94

8.3. Additional fibroid classification systems ................................................................. 95

8.4. Health-economic model development ................................................................... 97

8.4.1. Recurrence data ............................................................................................... 97

8.5. Retained products of conception (RpoC) .............................................................. 101

8.5.1. Hysteroscopic Morcellation Versus Loop Resection for Removal of Placental Remnants: A Randomized Trial ...................................................................... 101


8.5.2. A Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies ................................................................................ 103

9. Extended bibliography ................................................................................................... 104

9.1. TruClear™ system for hysteroscopic tissue removal studies ............................. 104

9.1.1. Long-term outcomes after intrauterine morcellation vs hysteroscopic resection of endometrial polyps .................................................................... 104

9.1.2. The Intra Uterine Morcellator: a new hysteroscopic operating technique to remove intrauterine polyps and myomas ...................................................... 105

9.1.3. Clinical implementation of the hysteroscopic morcellator for removal of intrauterine myomas and polyps. A retrospective descriptive study ........... 106

9.1.4. Removal of Endometrial Polyps: Hysteroscopic Morcellation versus Bipolar Resectoscopy, A Randomized Trial ............................................................... 107

9.1.5. Hysteroscopic Tissue Removal Systems: A Randomized In Vitro Comparison .. ........................................................................................................................ 109

9.1.6. A comparison of hysteroscopic mechanical tissue removal with bipolar electrical resection for the management of endometrial polyps in an ambulatory care setting: preliminary results ................................................. 111

9.1.7. Hysteroscopic morcellation compared with electrical resection of endometrial polyps: a randomized controlled trial ........................................ 113

9.1.8. Hysteroscopic morcellator for removal of intrauterine polyps and myomas: a randomized controlled pilot study among residents in training ................... 115

9.2. Other mechanical tissue resection studies ........................................................... 118

9.2.1. Hysteroscopic morcellation versus bipolar resection for endometrial polyp removal. .......................................................................................................... 118

9.2.2. A prospective study of the use of the MyoSure®* resectoscope to manage endometrial polyps in an outpatient setting ................................................. 119

9.2.3. Hysteroscopic intrauterine morcellation of submucosal fibroids: preliminary results in Hong Kong and comparisons with conventional hysteroscopic monopolar loop resection .............................................................................. 121

9.2.4. A Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies ................................................................................ 123

9.2.5. Hysteroscopic myomectomy with the IBS®* integrated Bigatti Shaver versus conventional bipolar resectoscope ............................................................... 125

9.2.6. Uterine Morcellator versus Resectoscopy in the Management of Heavy Menstrual Flow in Reproductive-Age Women. .............................................. 127

9.2.7. The efficacy, cost and patient satisfaction of classic versus office hysteroscopy in cases with suspected intrauterine space occupying lesions with 3-dimension ultrasound and abnormal uterine bleeding ...................... 129

9.3. Systematic reviews and meta-analyses ................................................................ 131

9.3.1. Hysteroscopic morcellation: Review of the manufacturer and user facility device experience (MAUDE) database ........................................................... 131

9.3.2. Intrauterine Morcellator Devices: The Icon of Hysteroscopic Future or Merely a Marketing Image? A Systematic Review Regarding Safety, Efficacy, Advantages, and Contraindications .............................................................. 133


9.3.3. Hysteroscopic Morcellation Versus Resection for the Treatment of Uterine Cavitary Lesions: A Systematic Review and Meta-analysis .......................... 135

10. References ................................................................................................................. 137

List of Tables Table 3-1 Descriptions of abnormal uterine bleeding ..................................................... 13

Table 3-2 International guidelines related to management of uterine fibroids .............. 22

Table 3-3 International guidelines related to management of endometrial polyps ....... 25

Table 3-4 Unit costs for uterine fibroid treatments in Europe ........................................ 29

Table 3-5 Peer-reviewed adverse event rates for indicated surgical procedures .......... 31

Table 3-6 HCPCS costs per adverse event ...................................................................... 32

Table 3-7 Quality of life reported for women with AUB in Turkey ................................... 33

Table 3-8 EQ-5D health utilities associated with polyp removal .................................... 34

Table 3-9 Health utilities associated with fibroid removal .............................................. 35

Table 4-1 Many women in Europe live with symptoms of uterine fibroids for ≥5 years . 38

Table 4-2 Reasons for patients reporting unmet healthcare need ................................. 39

Table 5-1 Hysteroscopic mechanical tissue resection devices specifications............... 53

Table 5-2 MAUDE adverse events reported .................................................................... 54

Table 5-3 Safety and efficacy of the TruClear™ system for mechanical tissue resection .. .......................................................................................................................... 54

Table 5-4 Adverse events related to fibroid removal ...................................................... 56

Table 5-5 Adverse events related to polyp removal ........................................................ 63

Table 6-1 Myomectomy cost by route ............................................................................. 70

Table 6-2 Real world procedure costs .............................................................................. 70

Table 6-3 Cost-effectiveness outpatient procedures .................................................... 71

Table 6-4 Cost and QALY of fibroid resection in computational models ........................ 71

Table 6-5 Results of the base case for uterine fibroid removal ....................................... 77

Table 6-6 Results of the base case for endometrial polyp removal ................................ 78

Table 7-1 Quality of life associated with endometrial polyp resection ........................... 81

Table 7-2 Quality of life associated with uterine fibroid resection .................................. 82

Table 7-3 Odds ratio of success for endometrial polyp resection .................................. 83

Table 7-4 Odds ratio of success for uterine fibroid resection ......................................... 83

Table 7-5 Experienced pain score during procedure ....................................................... 84

Table 7-6 Procedure duration endometrial polyp resection ........................................... 85

Table 7-7 Procedure duration uterine fibroid resection .................................................. 85

Table 8-1 Complete efficacy data .................................................................................... 89

Table 8-2 Recurrence data published in peer-reviewed literature .................................. 97


Table 8-3 Non-linear regression variables for the Dose-response-Hill curve .............. 100

Table 8-4 Data comparing the TruClear™ system and bipolar resectoscopy (BPR) .... 102

Table 8-5 Data comparing the TruClear™ system and monopolar resectoscopy (MPR) devices ............................................................................................................ 105

Table 8-6 Data on polypectomy and myomectomy using the TruClear™ system ...... 106

Table 8-7 Data comparing the TruClear™ system and bipolar resectoscopy (BPR) .... 107

Table 8-8 Data comparing the TruClear™ system and VERSAPOINT™* devices ....... 114

Table 8-9 Data comparing the TruClear™ system (hysteroscopic morcellation) and resectoscopy .................................................................................................. 116

Table 8-10 Data comparing MyoSureTM* and VERSAPOINT™* devices ........................ 118

Table 8-11 Data reporting polyp removal using the MyoSure TM*device ........................ 120

Table 8-12 Data comparing MyoSure TM*and resectoscopy ........................................... 122

Table 8-13 Data reporting intrauterine pathologies removal using MyoSure TM* devices ……………………………………………………………………………………………………………….124

Table 8-14 Data comparing IBS TM* and VERSAPOINT™* devices ................................. 126

Table 8-15 Data comparing IBS TM* and conventional resectoscopy (Circon ACMY, U.S.) ……………………………………………………………………………………………………………….128

Table 8-16 Data comparing office and classic hysteroscopy .......................................... 130

Table 8-17 Publications comparing the TruClear™ system and other devices .............. 134

List of Figures Figure 3-1 PALM-COEIN classification system ................................................................ 12

Figure 3-2 Abnormal uterine bleeding pane ...................................................................... 13

Figure 3-3 Prevalence of abnormal uterine bleeding by country ...................................... 14

Figure 3-4 Tissue sample from a uterine fibroid ............................................................... 15

Figure 3-5 Fibroid classification system ............................................................................ 16

Figure 3-6 Self-reported prevalence of fibroids by country ............................................. 17

Figure 3-7 Incidence and prevalence of uterine fibroids by age and race ......................... 17

Figure 3-8 Visualization of an endometrial polyp .............................................................. 18

Figure 3-9 Prevalence of endometrial polyps by country ................................................. 18

Figure 3-10 Flowchart endometrial polyp treatment ......................................................... 20

Figure 3-11 Total annual cost invasive fibroid treatment ................................................... 28

Figure 3-12 Number of annual procedures for uterine fibroid treatment .......................... 29

Figure 3-13 Cost of procedures for treatment of AUB ....................................................... 30

Figure 3-14 Estimated total annual procedure costs associated with AUB ....................... 30

Figure 3-15 Absenteeism depending on symptoms ........................................................... 36


Figure 5-1 Locations of pathology within the uterus ........................................................ 45

Figure 5-2 World map of peer-reviewed publications detailing use of mechanical hysteroscopic tissue removal .......................................................................... 45

Figure 5-3 Hysteroscopic mechanical tissue resection scope ......................................... 47

Figure 5-4 The TruClear™ system 8.0 hysteroscope set ................................................. 51

Figure 5-5 The TruClear™ system 5C hysteroscope set ................................................. 51

Figure 5-6 Overview of TruClear™ system mechanical tissue resection devices ........... 52

Figure 5-7 TruClear™ system Indications ......................................................................... 52

Figure 5-8 Comparison of procedure duration between hysteroscopic mechanical tissue resection and resectoscopy ............................................................................ 59

Figure 5-9 Comparison of fluid deficit between hysteroscopic mechanical tissue resection and resectoscopy ............................................................................ 60

Figure 5-10 Comparison procedure duration for resectoscopy and hysteroscopic mechanical tissue resection ............................................................................ 61

Figure 5-11 Comparison fluid deficit between resectoscopy and hysteroscopic mechanical tissue resection ........................................................................... 62

Figure 6-1 Healthcare spending as percentage of GDP .................................................... 66

Figure 6-2 Development of publication numbers ............................................................. 68

Figure 6-3 Complex models of uterine fibroid resection .................................................. 73

Figure 6-4 Simple models for uterine fibroid treatment ................................................... 74

Figure 6-5 Treatment decision tree .................................................................................. 75

Figure 6-6 Markov model for long-term patient progression .......................................... 76

Figure 6-7 Cost effectiveness plane fibroid removal with the TruClear™ system .......... 78

Figure 6-8 Cost-effectiveness plane endometrial polyp removal with the TruClear™ system .............................................................................................................. 79

Figure 7-1 Convenience with procedure of residents in training ..................................... 86

Figure 7-2 Number of procedures which required guidance ............................................ 87

Figure 8-1 Oxford levels of evidence scheme ................................................................... 94

Figure 8-2 Oxford levels of evidence scheme (continued) ............................................... 95

Figure 8-3 STEPW fibroid classification system ............................................................... 96

Figure 8-4 Extrapolation of fibroid recurrence to 50 years post intervention ................. 98

Figure 8-5 Extrapolation of polyp recurrence to 50 years post intervention ................... 99

Figure 8-6 Data comparing the TruClear™ system and MyoSure TM* devices for the removal of surrogate polyps .......................................................................... 110

Figure 8-7 Data comparing the TruClear™ system and MyoSure TM* devices for the removal of fibroid tissue ................................................................................. 110

Figure 8-8 Operating and polypectomy times for each device and depending on the surgery expertise. .......................................................................................... 112

Figure 8-9 Convenience regarding use of instrument by the resident........................... 116

Figure 8-10 Subjective trainer scores on convenience regarding easiness of use by the resident ........................................................................................................... 117


Figure 8-11 Completeness of resection according to fibroid size ................................... 124

Figure 8-12 Pain reported by the patients prior to, during and after office hysteroscopy according to a 10-point visual analog scale (VAS) ......................................... 130

Figure 8-13 Data comparing adverse events for the TruClear™ system and MyoSure TM* devices ............................................................................................................ 132

Figure 8-14 Meta-analysis of the total procedure time .................................................... 136


1. Disclaimer and scope

1.1. Products and aliases

This document focuses on the TruClear™ system, which is a complete hysteroscopy system, including hysteroscope sets, the TruClear™ system 8.0 hysteroscope set and the TruClear™ system 5C hysteroscope set and compatible pathology-optimized tissue removal devices, TruClear™ system INCISOR™*, TruClear™ system INCISOR™* Plus, TruClear™ system ULTRA Plus and TruClear™ system ULTRA Mini.

1.2. Data sources

Data regarding incidence, prevalence and costs of abnormal uterine bleeding, uterine fibroids, and endometrial polyps were derived from searches of published literature in PubMed (April 2017).

For clinical evidence data of the TruClear™ system, structured searches were performed using PubMed (April 2017) and EMBASE (April 2017) for peer-reviewed literature applying consistent exclusion criteria across searches for specific surgical indications. Results were restricted to publications based on data obtained within the most recent 20 years of the search (1997 and onwards), and excluded editorials/commentaries, articles with no abstract, those that did not report relevant clinical data (such as animal or ex vivo studies), those that reported data on fewer than 20 patients, those which were not focused on outcomes related to the technology (that is, no mention of hysteroscopic tissue removal) and articles which did not reference the TruClearTM system or generic TruClearTM system technology (electrosurgical or mechanical hysteroscopic tissue removal).

Structured searches were supported by hand searches of PubMed, Google Scholar, and websites of national regulatory bodies and medical societies. Reference lists from included publications were also used as a source to identify further data.

1.3. Data analysis

Clinical results from individual studies are presented as reported (including indication of statistical significance where determined). Where data are amalgamated from multiple reports, please note that the individual studies will vary in terms of design, protocol, technique and patient population, which may limit conclusions drawn from direct comparison and relevant analysis of statistical significance

1.4. FDA information

On April 17, 2014 a warning regarding laparoscopic power morcellation for hysterectomy and myomectomy was issued. This warning was updated on November 25, 2014. In this update the FDA states that hysteroscopic morcellation is a different procedure and does not pose the same risk.a NICE (UK) stated in their 2015 guideline based upon expert opinion that laparoscopic and hysteroscopic morcellation are different procedures with different risk profile.1 In this guideline it was also concluded that until release date no spread of unrecognized malignant tissue into the peritoneal cavity was reported in the peer-reviewed literature. 1

This dossier is focused on hysteroscopic procedures and data provided on the TruClear™ system is solely related to hysteroscopic use.

a https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM424123.pdf


2. Executive summary Background

Abnormal uterine bleeding (AUB) is a highly prevalent and costly condition. It affects up to 40% of women,2–4 and was reported to have an annual cost of GBP 98 million in the United Kingdom (UK) and USD 2,533 per patient in the United States (US).5,6 AUB is frequently a symptom of uterine fibroids or endometrial polyps, of which the former will affect 70-80% of women by the age of 50 years. 7–9 The total cost associated with uterine fibroids in the US was estimated at USD 4.1–9.4 billion.10 Along with the financial burden on payers, patients with AUB and uterine pathology suffer with substantially reduced quality of life.11–13 Studies have shown that quality of life can often be restored after pathology removal.11–13

Unmet needs in abnormal uterine bleeding

Across countries there are a lack of standardized care pathways. Patients find it difficult to access care, as evidenced by 39.8% of European patients living with symptoms for ≥5 years.14,15 Many AUB treatments are in-hospital procedures, and a switch-of-site to in-office and outpatient procedures could increase the accessibility of treatment. Studies demonstrate the effectiveness of these outpatient procedures, such as hysteroscopic removal of endometrial polyps and uterine fibroids.16–20 Furthermore, increased patient awareness of treatment options is required. Of patients undergoing myomectomy, only 14.4% reported this as the treatment they received, with 60.2% reporting they had undergone hysterectomy.21 A separate study found that many patients would favor living with symptoms over receiving hysterectomy.22 There are clear needs to increase patient access to care, and providing care that is understood by and acceptable to patients.

Efficacy and Safety of hysteroscopic tissue removal

Hysteroscopic removal of polyps and fibroids using mechanical hysteroscopic tissue removal has been shown to be safe and effective. 23–57 In trials assessing the efficacy of the TruClear™ system, on average 97% of endometrial polyps and 90% of uterine fibroids were successfully removed on first attempt.23,24,42,44,47 The odds ratio of success if bipolar resection was used is substantially lower, being 0.15 for endometrial polyp resection and 0.27 for uterine polyp removal.23,24,39,44,47,51,52,58,59 The safety profile of the TruClear™ system is comparable to electrosurgical resection,23,24,42,44 while having no risk of burns. A higher percentage of cases are successful at the first-removal attempt with the TruClear™ system compared with bipolar resection.23,24,42,44

Cost benefit of the TruClear™ system

For uterine pathology removal, the hysteroscopic route has lower costs compared with laparoscopic procedures, which can cost up to 77% more. 60 In clinical studies, myomectomy incurred lower total costs than hysterectomy.60–62 No published cost data specific to the TruClear™ system exist, and so a cost-effectiveness model was developed to quantify its impact on the cost of care and patient outcomes. For polypectomy in the UK setting, The TruClear™ system reduced costs by GBP 700 and marginally improved quality of life compared to use of bipolar resection.

Conclusions

A strong body evidence supports the safety and efficacy of the TruClear™ system.23,24,42,44 It has been shown to be a successful treatment option for endometrial polyps and uterine fibroids. While incurring a comparable number of adverse events, the costs profile and success rate is more beneficial than with bipolar electrosurgical hysteroscopic tissue removal. The opportunity to apply mechanical hysteroscopic tissue removal with the TruClear™ system as in-office, outpatient or day-case scenario may also reduce the resource burden and increase the accessibility of the health care system.


3. Background

Key messages

Abnormal uterine bleeding is a highly prevalent condition affecting up to 40% of women, depending on country, definition, and estimation method.2–4

Frequent causes for abnormal uterine bleeding are uterine fibroids and endometrial polyps, of which the former will affect 70-80% of women by the age of 50.7,8,63

Hysteroscopy is commonly considered the gold standard for the diagnosis of endometrial polyps and uterine fibroids.7,64–67

Endometrial polyps and uterine fibroids substantially reduce patient quality of life.11–13 Hysteroscopic removal of these pathologies has been shown to provide substantial to

significant improvement in patient quality of life.11–13

3.1. Abnormal uterine bleeding

Abnormal uterine bleeding (AUB) can be defined as a change in the pattern or volume of menstrual flow and also includes post-menopausal bleeding.68 Definitions in the literature do, however, vary and research into AUB has historically been hampered by the absence of standardized terminology and nomenclature.69 In 2011, the PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified) classification system (Figure 3-1) was published with the aim of standardizing nomenclature for AUB.69 AUB can present under a number of etiologies, such as heavy menstrual bleeding or amenorrhea (Table 3-1), and differentiation between the etiologies and underlying causes may be complex due the continuum of symptom severity (Figure 3-2).

Figure 3-1 PALM-COEIN classification system

Taken from Munro et al 201170


Table 3-1 Descriptions of abnormal uterine bleeding

Condition Presentation

Heavy menstrual bleeding

Regular vaginal bleeding that is heavy and/or prolonged. It was previously referred to menorrhagia

Intermenstrual bleeding

Vaginal bleeding at any time outside of normal menstruation that is not related to coitus

Irregular bleeding Affected women either have anovulation (no ovulatory cycles) or oligo-ovulation, in which their cycle switches between period of ovulatory cycles and anovulation. This condition is, hence, associated with ovulatory dysfunction

Amenorrhea The absence of bleeding for at least three standard cycle lengths, which can present as a primary (pre-menarche) or secondary (post-menarche) condition

Decreased volume Unusually light menstruation or menstruation of short duration

Regular menses with increased frequency

The days between usual menses decreases to less than 21 days

Post-menopausal bleeding

Vaginal bleeding after menopause

Figure 3-2 Abnormal uterine bleeding pane

Abnormal uterine bleeding can present as disrupted volume, frequency, or timing of menstrual bleeding or some combination of these.

Estimates of disease burden for AUB vary dependent on the definitions and estimation method employed.71 In developing countries, heavy menstrual bleeding has been found to


have a prevalence of between 8% and 27% (Figure 3-3).2 Of approximately 9,600 women presenting at an emergency room in the U.S. with gynecological concerns, 4.3% presented with AUB.4 Nationwide in the U.S., AUB has been estimated to have an incidence of 25%72 and a prevalence of 40%,3 making it a common burden for both pre- and postmenopausal women. Beyond the patient impact of AUB, it is an important concern for healthcare providers and payers, with direct annual costs per patient in the U.S. estimated to be USD 2,533 in 2012.5 For the UK, those costs were estimated to be GBP 98 million in 2006, of which GBP 8.8 million were attributable to general practitioner visits only.6 In Germany, in 2015, there were 22,326 patients discharged with a diagnoses of abnormal uterine bleeding (ICD 10-N91-93) accounting for 65,032 hospital billing days.b In Europe hospitalization costs are incurred by up to 1 in 2 women with AUB. The cost burden is explored in section 3.3.

In general, AUB is, however, a symptom of an underlying condition or conditions. Common causes underlying AUB are uterine fibroids,64,73–76 endometrial polyps,64,74,76,77 adenomyosis,74,75 and endometrial hyperplasia.75,78 Diagnosis of the underlying cause often requires differential diagnosis by exclusion, as bleeding may result from any anatomic site in the lower (vulva, vagina, cervix) or upper (uterine corpus, fallopian tubes, ovaries) genital tract. Compared with dilation and curettage, hysteroscopy has been determined to offer significant advantages in the diagnosis of complications underlying AUB.78 Two independent meta-analyses have also demonstrated the excellent sensitivity and specificity of hysteroscopy in identifying endometrial polyps and uterine fibroids.64,65

Figure 3-3 Prevalence of abnormal uterine bleeding by country

AUB was defined as heavy bleeding by Harlow and Campbell (1)2 and as undiagnosed bleeding symptoms by Downes et al. (2), with prevalence data derived from surveys and literature review (dark blue bars). Light blue bars are the prevalence of AUB in women presenting for gynecological investigations at an Indian outpatient department79 and an emergency room in the U.S.4

b Destatis, Germany. Accessed August 1, 2017


3.1.1. Uterine fibroids

Uterine fibroids are also known by the terms leiomyomata and myomas. A uterine fibroid is defined as a benign neoplasm of the uterine smooth muscle that is “characteristically firm, well-circumscribed, round, and gray-white” (Figure 3-4).80,81 Uterine fibroids are sub-categorized by their position within uterine smooth muscle (Figure 3-5, additional classification systems are available, see section 8.2). Fibroids that grow within the uterine wall are termed intramural, while those extending towards the outside of the uterus are subserosal. The final classification is submucosal; these fibroids extend towards the uterine cavity. In this dossier, uterine fibroids refer to submucosal fibroids, for which hysteroscopic tissue removal is commonly indicated.

Figure 3-4 Tissue sample from a uterine fibroid

Source: Mosby’s Medical Dictionary, ninth edition;80 with referenced source Finkbeiner et al. 2009.82

Uterine fibroids are a common underlying condition of AUB.64,73–76 Baird et al. estimated in 2003 a cumulative prevalence of 70%-80% for fibroids in women up to the age of 50, a value that has been taken as the guideline prevalence in multiple countries.7,8,63 The actual prevalence of uterine fibroids determined in medical practice, varies considerably. The study by Zimmermann et al. assessed self-reported prevalence of uterine fibroids in multiple countries and found that the percentage of women reporting the condition ranged from 4.5% in the UK to 9.8% in Italy (Figure 3-6). In a retrospective study conducted in the UK, 28 of 74 women (37.8%) presenting with AUB were determined to have uterine fibroids.76 Of the 28 women, 2 (7.1%) presented with both uterine fibroids and endometrial polyps.76 An analysis of 100 cases selected at random from women presenting with AUB at a large tertiary hospital in India found that 28% had uterine fibroids.75 Lower prevalence was reported in the U.S., where Matteson et al. found that 9.0% of women presenting in the emergency room with AUB had uterine fibroids.4 This is likely, however, an underestimate given the early findings of Cramer and Patel (1990).83 Their analysis of 100 consecutive hysterectomy samples from Rochester General Hospital, U.S., found that 77 included uterine fibroids.83 Furthermore, in 84% of cases multiple uterine fibroids were present; the total number of fibroids identified being 649.83


Figure 3-5 Fibroid classification system

Taken from Munro et al. 201170

Data available clearly demonstrate the varying prevalence of uterine fibroids by country and setting. The risk factors for uterine fibroids are not commonly reported in peer-reviewed literature, but there are individual studies linking menopause, obesity, and nulliparity to uterine fibroid presence.84,85 Race and age are other factors linked to fibroid incidence, with a 2016 study from Germany finding that the presence of uterine fibroids varied from 21% in women aged 30–35 years to 63% in women aged 46–50 years.86 This variance of uterine fibroids by age is supported by the work of Wise et al., who reviewed the incidence and prevalence data from multiple studies (Figure 3-7).81 The data reported by the authors also compared black and white women, with uterine fibroid prevalence between the races equivalent in women in their early-20s. After this age, prevalence in black women increased beyond that in white women. For women in their late 30s, the prevalence of uterine fibroids in black women was more than double that in white women.81


Figure 3-6 Self-reported prevalence of fibroids by country

Taken from Zimmermann et al. 201287

Figure 3-7 Incidence and prevalence of uterine fibroids by age and race

Circles depict the age-specific prevalence of uterine fibroids in pregnant women in the U.S. Squares are the cumulative incidence in 33 to 46-year old women in a study of hysterectomy. The solid lines and long-dashed lines are cumulative incidence data derived from women aged 35 to 49 years in the U.S. The dotted line shows cumulative incidence data from Italy in 30 to 50-year old women. The single diamond is an estimate from 33 to 40-year old Swedish women. Taken from Wise et al. 201681

3.1.2. Endometrial polyps

A uterine or endometrial polyp is a “pedunculated overgrowth of the endometrium”.80 Pedunculated growths are attached to their tissue of origin via a peduncle, an elongated stalk of tissue. The presence of uterine polyps is a common cause of AUB,64,74,76,77 and they are also often associated with endometrial hyperplasia and uterine fibroids.80 Polyps are, in general, benign growths with a diameter of ≤1 cm (Figure 3-8) and can occur singularly or in


clusters.80 In rare cases, polyp growth can continue and larger polyps have been found to prolapse through the cervix.80 They may also develop into malignancies.88,89

Figure 3-8 Visualization of an endometrial polyp

Source: Mosby’s Medical Dictionary, ninth edition;80 with referenced source Finkbeiner et al. 2009.82

Not all endometrial polyps are symptomatic. Research by Hassa et al. found that 36.1% of postmenopausal and 44.4% of premenopausal women were asymptomatic.90 In 2000, Tjarks and Van Voorhis reviewed the literature and reported that polyps were identified in 13 to 50% of women with AUB.91 At the upper end of this range, data presented in 2015 by Cooper et al. indicated a 48% prevalence of polyps in women presenting with AUB (Figure 3-9).11 Between April 2008 and July 2011, 1,537 women were screened for eligibility as part of a randomized, controlled trial covering 31 centers in the UK National Health Service (NHS).11 Of those screened, 737 patients (48.0%) had evidence of benign polyps.11 Of these 737 patients, 22 (3.0%) were considered to have possible malignant lesions.11 This is in line with estimates from Brazil, where Lenci et al. reported 2% of polyps to be in a pre-malignant state and 0.5% to be malignant.92

Figure 3-9 Prevalence of endometrial polyps by country

Prevalence of endometrial polyps in women undergoing hysteroscopic investigation in Brazil,93 Spain,94 UK11 (women aged >60 years)95, and U.S.96


Age has been shown to be a risk factor for malignancy in uterine polyps. Hileeto et al. determined that 2.5% of uterine polyps were malignant in women aged 25–35 years, and this rose to 32% in those women aged >60 years.97 Across the age range of women assessed, increasing age was significantly (p < 0.001) linked to increased likelihood of malignant polyps.97 Age is also a risk factor for polyp development, with increased age associated with increased polyp prevalence.97,98 In the Turkish setting, Hassa et al. reviewed details on 526 women who were assessed at an outpatient clinic.98 The mean (standard deviation) age of women diagnosed with endometrial polyps was 45.0 (11.4) years compared with 36.0 (11.7) years for those given the all clear.98 The two groups did not differ by body mass index or diabetes status, but those with polyps had significantly higher prevalence of hypertension (13,6% versus 5.4%, p < 0.05).98 Tamoxifen, which is commonly used as a treatment for breast cancer, has been linked to increased risk of endometrial polyps.99 In a prospective study focused on AUB, Bakour et al. found that after adjusting for age, parity, and menopause, the odds of developing polyps were 11.21 (95% confidence interval 2.70–46.46) times higher with use of tamoxifen than without.99 The authors also investigated use of hormone replacement therapy, but no significant correlation was established.99

3.2. Current care paradigm

AUB can have multiple diagnoses underlying. As an initial assessment of the type of AUB, changes in the pattern or the amount of blood lost can be examined.72 For heavy menstrual bleeding, a physical examination, laboratory tests and ultrasound are suggested to determine if an underlying pathology is the cause.100–102

The importance of AUB in current healthcare provision is substantial, and its impact on women’s quality of life is specifically mentioned in the National Institute for Health and Care Excellence (NICE) guideline for the NHS.101 Its importance is also evidenced by the number of guidelines related to the diagnosis and management of AUB, uterine fibroids, and endometrial polyps.1,7,63,85,101–105 For idiopathic AUB, the indicated first-line treatment is medical, with NICE and the French College of Obstetricians & Gynaecologists recommending Levonorgestrel intrauterine devices (LNG-IUS).101,102 This is in line with recommendations issued in the systematic review of Matteson et al., who found that in most comparisons, LNG-IUS was superior to other considered treatments.106

Fibroids occur with varying complexity and size. For women with heavy menstrual bleeding and fibroids of 3 cm or more in diameter, NICE recommends the use of ulipristal acetate as a precursor to operative treatment.101 This pre-operative treatment is approved in both Europe and Canada, and was shown to be effective in the control of symptomatology and fibroid size in a randomized controlled trial by Donnez et al. in 2012.81,107 A study by Ferrero et al. in 2016 was able to show that the completion rate for fibroids of high complexity was significantly increased (92% vs 68%, p<0.05) following 3-month, pre-operative treatment with ulipristal acetate.108

Where endometrial polyps have been diagnosed as the underlying cause of AUB, the AAGL states that medical management is not recommended.7 Similarly, for uterine fibroids a systematic review by Gurusamy et al. in 2016 found that there is insufficient evidence to recommend any medical treatment.109 Nevertheless, medical treatment is indicated for fibroids to reduce bleeding, correcting anemia and reducing the volume of the fibroma.101,102 If the treatment of the symptoms is not sufficient, the preferred indicated treatment for fibroids is hysteroscopic resection.101,102 Before a specific intervention for AUB can be recommended, diagnosis of the underlying condition is required. Imaging is often recommended and ultrasound is the first-line diagnostic methodology within the UK NHS.101 Still, there is general international agreement that hysteroscopy is the gold standard, most appropriate, and most accepted method of diagnosing whether uterine


fibroids or endometrial polyps are the underlying cause of AUB.7,64–66,110 NICE recommend that a biopsy be performed to exclude the potential for endometrial cancer or atypical hyperplasia.101 There is, in addition, agreement that treatment should be individualized and based upon the patients’ needs.1,111 The Norwegian Society of Obstetrics and Gynecology released a suggested care pathway that explicitly incorporates patients’ wishes in the treatment decision (Figure 3-10). This focus on patient needs is similar to the recommendations for uterine fibroids issued by NICE.1,111

Figure 3-10 Flowchart endometrial polyp treatment

SIS, Saline-infusion sonography; *TCRP: Transcervical resection of polyp **TCRE: Transcervical resection of endometrium; Taken from the Norwegian Society of Obstetrics and Gynecology111

Following differential diagnosis to exclude other possibilities for AUB, with either uterine fibroids or endometrial polyps identified as the cause, there are six main treatment options available:

1. No (immediate) intervention - In asymptomatic women, no immediate intervention and regular follow up,

so-called watchful waiting, may be the most appropriate action.112 2. Blind removal

- Dilation and curettage is the most commonly performed blind technique. For dilation and curettage, the cervix is dilated and a curette is inserted through the cervix and into the uterus to scrape away the target tissue. As the target tissue cannot be visualized, the extracted tissue must be examined for possible pathology.

3. Hysteroscopic removal - The fibroid or polyp is visualized via use of a hysteroscope that is inserted

through the vagina and cervix. Tissue removal, generally using either a


cutting blade or loop, is then performed under direct visual observation. The HTR device can be separate or combined with the hysteroscope.

4. Uterine artery embolization - This is a minimally invasive procedure that treats uterine fibroids via artificial

blocking of the blood supply 5. Laparoscopic removal

- Minimally invasive surgery allows access to the uterus from the abdomen via trocars. Target tissue can then be removed using a cutting blade or loop.

6. Hysterectomy - Complete or partial removal of the female reproductive organ.

Intervention is recommended for symptomatic uterine fibroids and endometrial polyps.7,101,104,105 In selecting an intervention, guidelines indicate that focus should be on selection of the appropriate action to reduce symptomatology and restore quality of life.101,112 Historically, hysterectomy was the mainstay of management,112 and may still be considered the most effective option.104 It is, however, an extreme option that can impact on women’s psychological health and sexual functioning.113–115 Hysteroscopic tissue removal preserves the reproductive organs and many studies have shown the efficacy of these procedures in ameliorating fibroid- and polyp-related symptoms.12,50,116 After the introduction and establishment of hysteroscopic techniques, there is consensus that hysteroscopic options should be considered as a first-line therapy for women requiring surgical treatment.7,104,105 With respect to endometrial polyps, Jayaprakasan et al. (2012) concluded during the conduct of the latest available Cochrane review that “due to the lack of available randomised evidence, the authors of this review are unable to draw any conclusions on the routine removal of endometrial polyps prior to treatments for infertility. To answer this question, large and well designed studies are required.”117 To date, still only a low number of small studies has addressed this data gap. As such, although hysteroscopic interventions are indicated, there is little evidence to guide an informed choice between different options for hysteroscopic tissue removal. Key recommendations from international guidelines are here summarized for management of uterine fibroids (Table 3-2) and endometrial polyps (Table 3-3).

`


Table 3-2 International guidelines related to management of uterine fibroids

American association of gynecological laparoscopists

Society of Obstetricians and Gynaecologists of Canada

NICE guidelines French College of Obstetricians & Gynaecologists

Local published guidelines

Pati

ent

fact

ors For women wishing to

preserve fertility, every effort should be made to minimize thermal damage to adjacent tissue.7

Concern about possible complications related to fibroids in pregnancy is not an indication for myomectomy except in women who have had a previous pregnancy with complications related to these fibroids.63 Treatment of women with uterine leiomyomas must be individualized.63

Treatment depends on whether the leiomyomas cause symptoms, and on the woman's desire for future childbearing.1

When pregnancy is desired, hysteroscopic removal of fibroids <4 cm in length is recommended.104

The choice of therapy is influenced by the following factors: severity of symptoms (pain, bleeding), infertility related to myomas, tumor characteristics, age, wish to preserve uterus, and wish to preserve fertility.118 (Belgium)

Asy

mpt

omat

ic

‘‘Watchful waiting’’ is an option but it is difficult to counsel women as to expected outcomes.7

Women with asymptomatic fibroids should be reassured that there is no evidence to substantiate major concern about malignancy and that hysterectomy is not indicated. 63

Fertility can be improved by hysteroscopic treatment for women with asymptomatic submucosal fibroids that deform the uterine cavity but are asymptomatic. 104

Current evidence does not support the treatment of fibroids in asymptomatic women.85 (US)

Expectant management is the treatment of choice for women with asymptomatic uterine fibroid tumors.85 (US)






Hys

tero

scop

y

Effective hysteroscopic myomectomy of larger lesions requires a system designed to morcellate the tumor.7

Where possible, transcervical or hysteroscopic myomectomy is preferred because of its efficacy, and the reduction in surgical morbidity afforded by the absence of abdominal incisions.7

Hysteroscopic myomectomy with the removal of the entire myoma is effective for the relief of AUB.7

Myomectomy is an option in those wishing preserve their uterus or enhance fertility, but carries the potential for further intervention.63

Hysteroscopic myomectomy should be considered first-line conservative surgical therapy for the management of symptomatic intracavitary fibroids.63

When morcellation is necessary to remove the specimen, the patient should be informed about possible risks and complications.63

The use of power morcellator is contraindicated in the presence of (suspected) malignancy.63

Myomectomy is recommended for women with AUB associated with uterine fibroids and who want to retain their uterus.101

Hysteroscopic morcellation of uterine fibroids should only be done by clinicians with specific training in this technique.1

Hysteroscopic morcellation is intended to reduce the risk of traumatic injury to the uterus and the risk of inadvertent fluid overload associated with traditional procedures.1

Hysteroscopic morcellation is most useful for small or pedunculated fibroids.1

Current evidence on the efficacy of hysteroscopic morcellation of uterine leiomyomas (fibroids) is limited in quality and quantity. Evidence on safety shows potential for serious complications. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.1

Hysteroscopic treatment for asymptomatic submucosal fibroids that deform the uterine cavity may improve fertility.104

First-line treatment for the myomas of level 0, 1, and 2 (<4 cm) is surgical treatment, specifically, hysteroscopic resection.102

Hysteroscopic myomectomy can be considered for women with symptomatic submucosal uterine fibroids.85 (US)

Hysteroscopic myomect-omy is indicated in cases of submucosal myomas ≤5 cm in size.118 (Belgium)

For class 0 myomas, cutting the pedicle by hysteroscopy is indicated. 118 (Belgium)

For class 1 myomas <3 cm, hysteroscopic myomect-omy is an option.118 (Belgium)






Ope

rati

ve The role of uterine artery

embolization for management of uterine fibroids is controversial and should be used with caution.7

Hysterectomy is the most effective treatment for symptomatic uterine fibroids.63

Hysterectomy should not be a first-line treatment solely for AUB, and only considered after other options have failed.101

Hysterectomy is the most effective treatment for symptomatic fibroids.104

Morcellation within a containment bag minimizes the risk of iatrogenic tissue seeding.119 (U.S.)


Table 3-3 International guidelines related to management of endometrial polyps



The Norwegian society of Obstetrics and Gynecology

French College of Obstetricians & Gynaecologists


Pati

ent

fact

ors

The high prevalence of endometrial polyps in infertile women suggests a causative relationship between the presence of endometrial polyps and infertility. However, a causal relationship between endometrial polyps and infertility appears to have been confirmed in only one randomized trial.120

Previous studies have reported that the prevalence of endometrial polyps is increased in infertile women, and the results of a randomized controlled trial indicates that removal of endometrial polyps may improve fertility in infertile women.111

Asy

mpt

omat

ic Conservative

management, such as watchful waiting, is reasonable, particularly for small polyps and if asymptomatic.120

Small polyps in asymptomatic women without increased risk of malignancy may be left untreated.111

Most endometrial polyps are asymptomatic. 111




The Norwegian society of Obstetrics and Gynecology

French College of Obstetricians & Gynaecologists


Hys

tero

scop

y

Hysteroscopic polypectomy remains the gold standard for treatment and the mainstay of management.120

Hysteroscopic removal is to be preferred to hysterectomy because of its less-invasive nature, lower cost, and reduced risk to the patient.120

Where possible, hysteroscopic polypectomy combined with resectoscopic endometrial ablation should be used for women with symptomatic intracavitary pathology.121

If significant intracavitary pathology is present, resectoscopic endometrial ablation combined with hysteroscopic polypectomy should be considered in a non-fertility-sparing setting.121

Endometrial polyps should be removed by transcervical resection (hysteroscopy). Curettage is not recommended for removal of endometrial polyps.111

Hysteroscopic resection of the polyp is recommended.102

Blind curettage without hysteroscopic control is not recommended.102

Studies suggest a positive role of hysteroscopic polypectomy in improving pregnancy rate.122 (Italy)

Morcellation within a containment bag minimizes the risk of iatrogenic tissue seeding.119 (US)

Specific treatments, such as hysteroscopy with D&C, polypectomy, or myomectomy, may be required if structural abnormalities are suspected as the cause of acute AUB.123 (US)

Ope

rati

ve

Hysterectomy guarantees no polyp recurrence and no potential for malignancy; however, it is a major surgical procedure, with significantly greater costs and potential for morbidity. It should be used judiciously and only after discussion with the patient about its implication.120


3.2.1. Consensus guideline recommendations for non-operative tissue removal

Literature review revealed a large volume of guidelines focused on hysteroscopy. Many focused on hysteroscopy in general, its use as a diagnostic, or were specific to areas such as fluid management. There was, though, a relative paucity of publications with reference to hysteroscopic myomectomy or polypectomy. These guidelines are summarized in Table 3-2 and Table 3-3.

Overall, there is agreement between guidelines that blind curettage is not a recommended intervention for either myomectomy or polypectomy, and the American Association of Gynecologic Laparoscopists (AAGL) and NICE contraindicate its use.7,101 Hysterectomy, the removal of all or part of the uterus, is commonly seen as the most effective option for amelioration of symptomatology associated with AUB, uterine fibroids, and endometrial polyps.7,101,102,104 It is, though, a major procedure and should not be used as a first-line option.7,101 Guidelines are in agreement that asymptomatic patients can be assigned to watchful waiting, whereas symptomatic patients require treatment.7,85

3.2.1.1. Gold-standard hysteroscopic tissue removal

In general, hysteroscopic procedures are recommended where treatment is indicated. The strength and specifics of the recommendation varies.7,63 The AAGL considers hysteroscopic polypectomy as the gold-standard treatment, and suggests referral to another provider if hysteroscopy cannot be offered.120 The method of hysteroscopic intervention is rarely specified. In guidelines that refer specifically to mechanical hysteroscopic tissue removal, it is contraindicated in cases where there is suspected malignancy.1,63,119 The advantage of such mechanical hysteroscopic tissue removal is that it reduces the risk of traumatic injury to the uterus and the risk of fluid overload associated with traditional procedures.1 The target patient for mechanical hysteroscopic tissue removal is, however, debated. NICE present patients with small or pedunculated fibroids as the group most likely to benefit,1 while the AAGL conclude that effective hysteroscopic myomectomy of larger lesions requires a system designed to morcellate the tumor.7

3.3. Healthcare burden

The consistently high incidence and prevalence of AUB across the globe suggests that it places a substantial strain on healthcare services and due to specific pathologies a number of studies have been undertaken to quantify the burden of AUB. An estimation from Flynn et al. determined the costs associated with uterine fibroids in the US to be 2.15 billion USD in the year 2000.124 A more recent estimate by Cardozo et al. put the burden in the US at USD 4.1–9.4 billion in 2010 (Figure 3-11).10 Within this, medical management cost USD 3.27–5.1 billion, approximately twice that associated with medical management of breast cancer in the US.10 Furthermore, the estimated cost of obstetric outcomes related to uterine fibroids were substantial, ranging from USD 238 million to USD 7.76 billion.10 The direct cost of AUB was conservatively estimated at USD 1 billion in the US in 2005.71 In terms of resource use, the burden placed on healthcare services by AUB is also high. Wise et al. estimated that uterine fibroids resulted in 27.5 inpatient stays every 10,000 person years in women in the US.81 Such inpatient stays may add to the care and cost burden associated with uterine fibroids.

Outside of the US, the burden of AUB is similarly large. In the German setting, Fernandez et al. reported that fibroid-related admissions cost payers 212.3 million euros in 2005.125 For France and England this was EUR 73.3 million and EUR 52.7 million, respectively.125 In a survey of 1,756 women covering France, Germany, Italy, Spain, and the UK, the number of


women reporting a hospitalization due to AUB ranged from 1 in 2 for Germany to 1 in 10 for France.14

Figure 3-11 Total annual cost invasive fibroid treatment

Total annual costs for myomectomy, including hysterectomy, laparoscopic, and hysteroscopic procedures. Logarithmic scale. *10 **125

3.3.1. Costs associated with treatments for AUB

AUB has a substantial impact on patient quality of life and can increase the burden imposed by out-of-pocket expenses.126 In terms of overall costs, however, it is the cost of treatment that dominates. Historically, hysterectomy was one of the most common treatments for AUB and, in particular, uterine fibroids. Keshavarz et al. estimated in 2002 that one third of the approximately 600,000 hysterectomies performed each year between 1994 and 1999 in the US were attributable to uterine fibroid treatment.127 This is consistent with the trends reported by Wright et al., who found that hysterectomies due to uterine fibroids in the US peaked at 373,629 in 2002, and then declined to 195,735 hysterectomy procedures in 2010 (Figure 3-12).128 Given data from the US Census Bureau,129 this translates to 1.25 uterine-fibroid hysterectomies per 1,000 women in the U.S. In addition to these hysterectomies, many hysterectomies were performed due to AUB; in 2010, these totaled 195,231.128

The uterine-fibroid related hysterectomies estimated for the U.S. are aligned to those reported for European countries. In 2009, Fernandez et al. reported that the number of uterine-fibroid-related hospital procedures ranged from 0.71 per 1,000 women in England to 1.53 per 1,000 women in Germany.125 The percentage of these procedures that included hysterectomy was also highest in Germany (84.9%).125 For France and England, these percentages were 59.7% and 64.1%, respectively.125


Figure 3-12 Number of annual procedures for uterine fibroid treatment

Total number of annual procedures. Due to the large number of procedures reported in the United States, the y-axis has a logarithmic scale. *128 **130 ***125.

The approximate cost of hysterectomy procedures was reported by Carls et al. to be USD 9,954 in 2005 (Figure 3-13).60 Given the volume of procedures, the direct costs for hysterectomy attributable to uterine fibroids are therefore in the region of USD 1.88 billion (Figure 3-14). When accounting for inpatient stays and other services, the mean total charge to the patient/payer per hysterectomy in the US was reported as USD 43,622 for abdominal, USD 31,934 for vaginal, USD 38,312 for laparoscopic, and USD 49,526 for robotic.131 In Germany, Fernandez et al. found that hysterectomies — accounting for EUR 190 million — formed the major component of the EUR 212 million in costs associated with uterine fibroid treatment.125 The cost of a single hysterectomy in Germany was reported to be in the range of EUR 3,316 to EUR 4,310 in 2008 (Table 3-4).125 Other interventions for treatment of uterine fibroids in the German setting were reported at an average cost of EUR 2,260.125 Prices for both hysterectomies and other interventions were similar in other European countries studied.

Table 3-4 Unit costs for uterine fibroid treatments in Europe

Country, currency Hysterectomy cost Other intervention cost

England, EUR125 3,440 1,056–3,440

France, EUR125 3,404–4,664 842–2,734

Germany, EUR125 3,316–4,310 2,260

English prices are provided in EUR as per the cited publication.


Figure 3-13 Cost of procedures for treatment of AUB

Single procedure costs. All costs in local currency units. *60 **125 ***132 ****133 *****134

Figure 3-14 Estimated total annual procedure costs associated with AUB

Data presented are estimated total costs for procedures calculated as the product of the procedure costs (Figure 3-13) and the procedure volume (Figure 3-12). Estimates are on a logarithmic scale

3.3.1.1. Reported adverse events and their costs

The occurrence of adverse events during healthcare interventions can result in substantial costs and resource use. A 2009 Dutch study found that avoidable adverse events accounted for 1% of total national health service spending.135 Of the ICD9 primary groups

*** ****

*****

**

*


analyzed, avoidable complications during genitourinary interventions had the second highest cost per case, with each adverse event costing EUR 6,640.135 These results are reflected in a study from the U.S. that reported that for every 1,000 admissions for women’s health surgery USD 90 was paid in indemnity.136 Although in 69% of cases no legal claim was made, the majority of claims were either settled pre-trial or found for the plaintiff, with mean legal payments ranging from USD 1,900 for minimal disability (<1 month) to USD 7.6 million for disability >6 months or death.136

Although relatively rare (Table 3-5), adverse events associated with procedures for the treatment of AUB can add substantially to care costs (Table 3-6). In a randomized trial by Volkers et al. in 2008, approximately 10% of hysterectomy costs were attributable to complications.132 Major adverse events, though more costly, were not the main driver of overall costs, with minor complications having a nearly five-fold higher influence.132 Adverse events are an even more costly aspect of uterine artery embolization, where their contribution to costs is 30%.132 Retrospective analysis has, however, reported lower contributions of adverse events to costs for hysterectomy, with Oderda et al. finding that 6.6% of hysterectomy procedure costs were attributed to complications.137

Table 3-5 Peer-reviewed adverse event rates for indicated surgical procedures

Adverse event Hysterectomy138

Hysteroscopic myomectomy 139

Hysteroscopic polypectomy12

Endometrial ablation138

Cystostomy 1% 1.3%139

Ureteral injury 0.1%

Bowel injury 0.3% 0.5% Uterine perforation

0-5% 44,140* <1%-2%

Hemorrhage 1.3%139 Need for transfusion

2.4% 0.7%

Cardiorespiratory event

0.4% 1.3%139

Thrombotic event

0.3%

Pelvic or vaginal vault hematoma

3.9% 1.6%141

Wound hematoma or rupture

3.5% 0.9%

Ileus 0.7% 1.3%139 Infection 8.8% 2.6%139 3.9%

Fluid overload 0.2% (mHTR) 23,24,44,142,143†- 3.4% (eHTR) 144

0.2% (mHTR) 23,24,44,142,143† -3.4% (eHTR) 144

4.0%

HCPCS, Healthcare common procedure coding system. Adverse events reported for different methods of fibroid and polyp treatment. *Highest (with VERSAPOINT™* and lowest (with the TruClear™ system) reported fraction of patients experiencing a uterine perforation. †In these trials, a total of 1 event (1 procedure aborted due to imminent fluid overload) was reported from a total of 444 (37+278+27+28+30+44) patients


Table 3-6 HCPCS costs per adverse event

Adverse event Costs 2014 USD (HCPCS code)

Cystostomy 2,373 (51900)

Ureteral injury 3,377 (51800)

Bowel injury 2,169 (44620)

Uterine perforation 1,816 (58520)

Hemorrhage 408 (46430) *

Need for transfusion 408 (46430)

Thrombotic event 1,780 (34101)

Infection 780 (10180)

Average charge submitted for facility based procedures. Taken from Medicare 2014 national HCPCS aggregate report. *Assumed as cost for blood transfusion

3.3.2. Out-of-pocket costs

Women with AUB also experience higher out-of-pocket costs for hygiene products compared to matched controls.145 In a case control study in Turkey, Gokyildiz et al. found that the number of hygiene pads used by women with AUB was increased compared with controls.126 The cost to patients was quantified by Frick et al. in 2009, and the authors attributed USD 333 (95% CI USD 263–403) to excess pharmaceuticals, pads, and tampons.146 In addition to this, the authors calculated a mean annual financial loss of USD 842 due to missed workdays.146 The overall loss attributable to uterine fibroids summed to an average of USD 2,291 USD per patient per year.146 In Taiwan, Chang reports that patient out-of-pocket expenses total USD 344 and USD 696.35 for open and laparoscopic myomectomy, respectively.147

3.3.3. Savings potential

The costs associated with AUB and its treatment are a substantial burden on healthcare providers. Furthermore, lost productivity due to AUB can impact on the economy, with Cardozo et al. estimating that the total cost burden of lost work in 2010 was between USD 1.55 billion and USD 17,20 billion in the US.10 With optimization of treatment, there is likely potential to reduce the cost burden on patients, providers, and nations.

Many of the currently conducted treatments for AUB are inpatient procedures, although outpatient and in-office procedures for both myomectomy and polypectomy are available. Switch of site away from hospital day procedures is gaining momentum, as evidenced by the number of studies conducted to investigate the suitability of shifting to either an outpatient12,19,116,148,149 or an in-office116,134,150 setting. Where costs have been reported, outpatient and in-office procedures are generally cost saving and cost effective.17,19,134,151 It is also possible that these faster,19,134 out-of-hospital procedures result in patients spending less time away from work. Similarly, inpatient stays associated with hysterectomy can be substantial. A trial by Volkers et al. found hysterectomy to be associated with an inpatient stay of 5.1 days.132 As well as the time away from normal activities, this inpatient stay had direct costs of USD 2,952.132 For minimally invasive hysteroscopic procedures


Camanni et al. reported a stay of only 4 hours on average.152 From the perspective of cost and time burden, it may be prudent to first consider hysteroscopic approaches before hysterectomy in patients with pathology accessible by hysteroscopy. The cost consequences and potential savings related to treatment choices are detailed in Section 6.

3.4. Patient burden

As well as a cost burden (see Section 3.3.1), medical conditions and disease can be a cause of reduced physical, mental, and social wellbeing for patients. The complete utility of interventions and treatments cannot be wholly described by defined efficacy and safety endpoints. The interventions impact on a patient and a patient’s preference should also be considered. Although required for cost-effectiveness analyses, measuring and defining health-related quality of life can be controversial.153,154 Commonly used surveys to assess health-related quality of life are the Medical Outcomes Study 36-item Short-Form Survey (SF36) and the EuroQOL 5-dimensions survey (EQ-5D). These two surveys are considered generic and can be used in almost all health settings, which can facilitate comparison between different medical conditions. Due to their generic nature, however, they can be considered insufficient to capture all aspects of patient burden and disease-specific indices are also often available. In their review of the literature, Matteson et al. found that 50 different instruments were used to evaluate health-related quality of life in women with AUB.4

The reduced quality of life associated with AUB was directly referenced by NICE guidelines,101 and underpinned the need for intervening appropriately in affected women. In 2016, Laberge et al. reported that AUB is associated with a high patient burden with prolonged menstrual period and reduced time between consecutive menstrual periods.145 During a case controlled study in Turkey, this impact was quantified, with the authors showing significant decreases in quality of life associated with AUB (Table 3-7).126 Compared with controls, women with AUB had significantly reduced quality of life in all aspects measured with the short-form 36 (SF36) survey.126 The largest decrements were found in physical function (minus 4.15 units) and mental health (minus 4.09 units).126

Table 3-7 Quality of life reported for women with AUB in Turkey

Dimension of the SF36 survey

AUB cases (n=138) Controls (n=157) Significance

Physical function 24.39 (5.06) 28.54 (2.37) P<0.001

Social functioning 7.26 (1.87) 8.68 (1.58) P<0.001

Mental health 17.21 (4.15) 21.30 (3.74) P<0.001

General health 15.35 (3.82) 18.58 (3.18) P<0.001

Role physical 1.72 (1.44) 2.92 (1.47) P<0.001

Role emotional 1.49 (1.16) 2.06 (1.18) P<0.001

Energy/Fatigue 12.99 (3.82) 16.82 (3.79) P<0.001

Pain 6.25 (2.06) 8.27 (1.80) P<0.001

Values presented are means (standard deviation), with significance tested using the Mann-Whitney U test. Source: Gokyikidz 2013.126


Another important factor contributing to the patient burden of disease is intervention failure; that is continued AUB, intervention termination, and the recurrence of pathology. Each of these can result in a repeat procedure. Guidelines recommend to focus on the needs and quality of life of the patient, rather than on complete cessation of symptoms.101 Hysteroscopic removal of endometrial polyps and uterine fibroids has been shown to be effective in the treatment of AUB and its associated symptoms.12,13,22 Furthermore, Chen et al. were able to show the value of hysteroscopic tissue removal as a fertility treatment for patients affected by intrauterine pathology.155 Nevertheless, there is a risk of recurrence and adverse events associated with hysteroscopy which varies numerically by technology used, pathology addressed, and patient characteristics.

Patient safety is also influenced by the technology used. For electrosurgical hysteroscopic tissue removal, comparative trials reported that on average 2-7 insertions during the procedure were necessary.24,51,156 In a study by Hamerlynck et al., two such reinsertions led directly to uterine perforation.44 For mechanical hysteroscopic tissue removal a maximum of 2 insertions were reported, even for residents in training.24,51,156 In those studies, no perforation was linked to reinsertions.24,51,156 With regard to efficacy, the recurrence rate of abnormal uterine bleeding after 4 years was similar between both methods, at 20.3% after 4 years.142

Although, by definition, hysterectomy eliminates the cause of AUB and the risk of recurrence, it has other patient burden associated with it. It renders the patient infertile, which, for instance, may be an issue for many pre-menopausal women.22 Comparing hysterectomy with uterine fibroid removal (mixed access methods), You et al. have shown a similar quality of life for both methods after 5 years, but with a substantial difference in direct costs (see section 6).133 The main difference in efficacy between hysterectomy and hysteroscopy is a low risk of recurrence associated with hysteroscopy.142 Irrespective of this difference in the recurrence risk, patient satisfaction with endometrial polyp and uterine fibroid removal was found to be very high (see section 3.4.3).11,12

3.4.1. Quality of life associated with uterine fibroids and endometrial polyps

In normalizing data to allow for cross study comparison, perfect quality of life is given a value of 1.0 while death has a value of 0.0.22 Studies in populations of healthy individuals generally return a quality of life utility in the range of 0.80 to 0.99, dependent on age. In the German setting, Huber et al. found that women aged 40–49 years who reported no health problems had a quality of life utility of 0.916 as measured by EQ-5D.157 This dropped to 0.773 if ≥1 health problem was present.157

Patients with uterine fibroids or endometrial polyps are at risk for decreased quality of life. A randomized controlled trial by Clark et al. in 2015 showed that the quality of life in women with endometrial polyps was 0.78 as measured by the EQ-5D (Table 3-8).11,12 Following polypectomy this value increases to 0.87 within 6 months. A similar study, also performed in the UK, reported quality of life with endometrial polyps to be in the range of 0.72 to 0.79.149

Table 3-8 EQ-5D health utilities associated with polyp removal

Setting Baseline 6 months 1 year 2 years

UK12 0.78 0.87 0.86 0.84

UK office149 0.79 0.82

UK inpatient149 0.72 0.81

Clark et al. 201512; The p-value between different timepoints was not assessed in the presented studies.


Compared with endometrial polyps, uterine fibroids have an even greater impact on the quality of life. Fennessy et al. found that 197 women with uterine fibroids had EQ-5D scores of between 0.525 and 0.569.22 It is also clear that intervention to remove uterine fibroids can results in substantial increase in patient quality of life. The patients followed by Fennessy et al. reported quality of life as high as 0.934 (p-value <0.001) following treatment.22 Likewise, Spies et al. showed that for 274 patients uterine fibroid removal with either method greatly restored the patient’s quality of life, and in many categories of the SF-36 it was almost comparable to that in controls (Table 3-9).13 Despite improved quality of life following intervention, the interventions themselves are not without patient burden. The patients followed by Fennessy et al. would be willing to wait significantly longer with symptoms to avoid undergoing hysterectomy than they would for other available interventions.22

Table 3-9 Health utilities associated with fibroid removal

Uterine fibroids Control at baseline n=101

Cases at baseline n=274

p-value baseline

Control at 1 year

Cases at 1 year post intervention

p-value 1 year

SF-36

Physical functioning 93.2 74.8 <.001 95.4 91 .013

Role physical 93.4 48.0 <.001 93.8 83.7 .001

Bodily pain 86 48.2 <.001 85.9 77.0 <.001

General health 83.3 66.9 <.001 81.3 75.5 .014

Vitality 62.8 37.8 <.001 66.1 61.7 NS

Social functioning 90.3 58.0 <.001 93.7 83.7 <.001

Role emotional 89.3 51.9 <.001 89.0 80.3 .016

Mental health 78.8 62.2 <.001 80.6 76 .012

Physical component score 54.7 43.4 <.001 54.7 52 .001

Mental component score 51.3 40.4 <.001 52.3 49.6 0.013

NS, not significant. Spies et al. 2010, a prospective study in the U.S.13

3.4.1.1. Condition-specific measures (UFS-Qol)

In 2002, Spies et al. introduced the uterine fibroid symptom quality of life questionnaire (UFS-Qol).158 Using 37 questions, this survey addresses events and symptoms related to uterine fibroids. It has been validated over several studies and shown to be a useful instrument to determine fibroid symptomatology and changes in severity159–162. Harding at al. assessed the responsiveness of the UFS-QoL in 2008 showing that between 38 patients with same or worsening of symptoms and 61 patients with an improvement of symptoms the p-value for the difference between both populations ranged between 0.001 and 0.03.160


3.4.2. Indirect burden

Lifestyle changes or impairments can put an indirect burden on patient’s families and employers. From a regulatory perspective, these issues are rarely considered as part of the licensing and reimbursement pathway. Their importance to patients and their family, friends, and employees should not, though, be underestimated. As such, countries with a national/state health insurance system are more likely to consider indirect burden. Indirect burden is recommended to be included for cost-effectiveness analyses in Sweden. NICE (UK) also has specific guidance for when to include indirect costs in cost analysis, although in most cases inclusion of productivity is not recommended.163

In the study by Frick et al., it was reported that leisure activity is at a minimum severely affected in 43% of patients with AUB.146 The ability to work for one or more days was impaired in 47% of patients.146 In addition, 37% of those patients were confined to bed for one or more days during their menstrual period.146 Overall, in 2009 women with AUB in the U.S. missed 4.5 hours of work time per cycle.146 Uterine fibroids, and the degree of symptomatology, was correlated to time missed from work (Figure 3-15).146 While the majority of patients with mild uterine fibroid symptoms do not miss work, over 20% of those with moderate/severe symptomatology miss more than 8 hours of work per month.146

Figure 3-15 Absenteeism depending on symptoms

Missed working hours due to uterine fibroid symptomatology.145

Missed work is a common occurrence in women suffering from AUB and uterine fibroids. In a study by Downes et al. that covered five European countries the absenteeism related to uterine fibroids was from 4.3% of missed worktime in France up to 9.3% in Germany.14 Except for France in all countries of interest more than 33% of women reported a degree of absenteeism.14


3.4.3. Patient satisfaction

Following interventions for both uterine fibroids and endometrial polyps, patient quality of life has been demonstrated to improve substantially.12,13,22 The 2014 National Heavy Menstrual Bleeding Audit in the UK found that women receiving surgical treatment were more frequently satisfied with their care at 1-year follow-up compared with other treatment options, such as medical treatment.21 That, however, does not mean that patient satisfaction with every treatment option is high, and the work of Fennessy et al. found that patients would choose to live longer with symptoms rather than undergo hysterectomy.22 In general, procedures for myomectomy and polypectomy are well received by patients.

For inpatient polypectomy, Clark et al. reported a 95% acceptance and 97% chance that the method will be recommended to friends.11,12 For the outpatient scenario, an acceptance of 81% and a recommendation rate of 93% were reported by the authors.11,12 Similar values were reported by McIlwaine et al., who found a 92.5% satisfaction rate for outpatient polypectomy specific to hysteroscopic tissue removal.164 Higher satisfaction rates of 97% (good–totally acceptable) were reported by Smith et al. for in-office mechanical hysteroscopic tissue removal.42 For procedures done using electrical resection outcomes acceptance was 78%, with 2% finding the procedure “unacceptable”.42

A study by Rubino and Lukes, published 2014, showed similar satisfaction for hysteroscopic tissue removal of uterine fibroids.116 For the outpatient scenario, 93% of patients were at least satisfied, while in the office scenario 89% of patients were satisfied.116 The recommendation rate was the same for both inpatient and office settings at 95%.116 Looking at both hospital and outpatient settings, Kulbersh and Rubino reported satisfaction with uterine fibroid removal to be 92.7% and 100%, respectively.165 It is clear, that the general trend is for excellent patient satisfaction following hysteroscopic polypectomy and myomectomy. There is little difference between, and no general trend in, patient preference for hospital, outpatient, or in-office procedures.


4. Unmet needs

Key messages

Up to 39.8% of European patients live with symptoms for ≥5 years.14 In the US, 7.4% of insured and 38.4% of patients uninsured for over one year cannot

access treatment due to costs.15 There is no definite gold-standard issued by guidelines, but it is recommended to

determine treatments based on patient presentation, severity of the underlying condition, and patient wishes. 63,101

Women who wish to preserve their fertility are recommended to undergo hysteroscopic treatment.63,104

Multiple studies have shown that outpatient and office scenarios are cost-saving and cost-effective compared to inpatient scenarios.16–20

Only 14.4% of patients receiving myomectomy were aware of the treatment used.21

To provide value-based healthcare from both the patient and provider perspective requires an understanding of the data gaps, unmet needs, and opportunities for process and outcome optimization. Within the setting of uterine health, and with specific focus on uterine fibroids and endometrial polyps, the potential for improvement stretches all the way from patient awareness and diagnosis through to treatment and outcomes.

4.1. Heterogeneous and delayed patient presentation

In a survey of women diagnosed with or experiencing uterine-fibroid-related symptoms from five European countries, Downes et al. found that although most women had sought a diagnosis within the first year of symptoms, a substantial number had been affected for ≥5 years (Table 4-1).14 All countries showed a bimodal distribution, but this was most extreme in the UK, where more women had symptoms for ≥5 years compared with ≤1 year. Women in the UK were also much less likely to have visited a healthcare provider regarding their condition in the last 12 months, with only 38.1% reporting having done so.14 This was significantly less than the 75.9% of women in Germany (p < 0.002) who reported a relevant visit with a healthcare provider in the last year.14 These data call in to question two aspects fundamental to healthcare provision: patient education and service accessibility. The data presented by Downes et al. do not allow for these two items to be dissected, although the authors hypothesized that social and cultural reasons might play a role in women seeking help later in Italy and the UK compared with other countries.14 Perhaps informative, is that the most common first healthcare provider in all countries was an obstetrician/gynecologist, except in the UK where a general practitioner dominated.14 It may be that limited access to specialists hinders patient willingness to seek help or results in a longer period of diagnosis.

Table 4-1 Many women in Europe live with symptoms of uterine fibroids for ≥5 years

Duration of symptoms

France Germany Italy Spain UK

Women, N 136 108 176 162 113

≤1 year, n (%) 64 (47.0) 60 (55.5) 85 (48.2) 105 (64.8) 41 (36.2) 2 years, n (%) 16 (11.8) 15 (13.9) 18 (10.2) 20 (12.3) 11 (9.7) 3 years, n (%) 11 (8.1) 8 (7.4) 10 (5.7) 7 (4.3) 10 (8.8)

4 years, n (%) 10 (7.4) 2 (1.9) 12 (6.8) 2 (1.2) 6 (5.3) ≥5 years, n (%) 35 (25.7) 23 (21.2) 51 (28.9) 28 (17.2) 45 (39.8)

Source: Downes et al. (2010)14


Both factors (education and access) have been previously reported in peer-reviewed literature.166–168 An analysis of women with menstrual disorders in Leicestershire, UK, also found that 46% of women had symptoms for over 1 year before receiving a secondary care consultation.168 In New Zealand, Lawton et al. examined post-menopausal bleeding and found that 25% of women were not aware that they should see a general practitioner about this.166 For Maori women the percentage was higher, with 44% unaware that post-menopausal bleeding should necessitate a healthcare visit.166 Furthermore, the authors noted that only 23% of women were referred to a specialist with an appointment within the 28 day target; 67% waited more than 6 weeks.166 In Taiwan, Lai et al. determined that women with no local access to a gynecologist were less likely to have gynecological disorders on their health records.167 Those women that did visit a gynecologist did so less frequently than women living in a town with a gynecologist present.167 The authors also presented data indicating that many women are unlikely to discuss gynecological issues with their general practitioner, with only 23.3% having consulted a non-gynecologist in their town.167 Over two-thirds of women choose to travel out of town to see a specialist.167 Access to specialist healthcare advice is, therefore, likely to be important in a timely and accurate diagnosis of AUB and its underlying conditions.

In assessing the reasons why patients report unmet needs in local healthcare provision, data suggest that 6.7% of patients in the European Union (EU, range: 0.3% in Austria to 19.2% in Latvia) report problems.3 This is in line with estimates from Canada, where 7% reported problems with healthcare accessibility or acceptibility.169 Of those reporting problems, up to 8.2% reported not knowing where to obtain help and up to 87.2% indicated that access to healthcare was prohibitively expensive (Table 4-2).170,3 In the U.S., 7.4% of insured patients could not access healthcare when required in the last year due to cost reasons.15 This rose to 38.6% in those uninsured for over 1 year.15

Table 4-2 Reasons for patients reporting unmet healthcare need

Reason for unmet healthcare need

Patients reporting problems, %

Unknown where to get help

Not available in the area, %

Waiting time too long, %

Too costly, %

Canada169 7 3.9 7.0 22.9 11.4

France 6.3 NR 1.6 6.3 36.5

Germany 6.4 NR 1.6 14.1 9.4

Greece170 9.9 (10.7) 8.2 3.0 12.7 25.4

Italy 7.8 NR 1.3 10.3 87.2

Spain NR NR 0 1.9 9.3

UK 4.1 NR 0 48.8 2.4

NR Not reported.

3 Data from EuroStat (http://ec.europa.eu/eurostat/statistics-explained/)


4.2. Treatment selection

There are a multitude of treatment options available for AUB, uterine fibroids, and endometrial polyps. Selecting the optimal treatment for a patient involves consideration of patient needs and wishes, and treatment properties. In reviewing treatment options, Miller suggests that the optimal therapy for uterine fibroids is “easy to perform, minimally invasive, cost effective, preserves fertility, preserves the uterus, efficacious, acceptable tolerability and durability, and low incidence of myoma recurrence”.171 Each option has, though, its drawbacks. Non-surgical options may provide only temporary relief, with myoma regrowth after cessation of therapy.171 Newer options such as laparoscopic uterine artery occlusion, magnetic resonance imaging–guided focused ultrasound surgery, and uterine artery embolization are costly, come with the risk of potentially severe complications, and have insufficient long-term follow-up data.171 The Uterine Artery Embolization in the Treatment of Symptomatic Uterine Fibroid Tumors (EMMY) randomized, controlled trial undertaken in the Netherlands found that uterine artery embolization resulted in higher rates of major complications (4.9% vs. 2.7%), readmissions (11.1% vs. 0%), and minor complications (58% vs. 40%) compared with hysterectomy.172 Hysterectomy is the definitive treatment but comes with high costs, loss of fertility, and risk of mortality. Hysteroscopic myomectomy can preserve fertility, but has a risk of surgical morbidity and uterine fibroid recurrence.171

Multiple treatment guidelines are available (see Section 3), 7,101 but there is a lack of a definitive gold-standard treatment. Guidelines specify the need to determine treatments based on patient presentation, severity of the underlying condition, and patient wishes.63,101 In only one instance, though, was a patient treatment pathway or decision tree presented to standardize the decision making process.111 In specifying the need for individual, patient-led treatment decisions but failing to provide guidance in how to achieve this may result in treatment recommendations being highly heterogeneous across patients with similar disease profiles. Furthermore, recommendations for the same technology can be contradictory between guidelines. For example, hysteroscopic tissue removal with a morcellator is recommended for large uterine fibroids by the AAGL but is specified for small or pedunculated uterine fibroids by NICE.1,7 In 2010, Julian et al. also identified that women menstrual disorders were often unaware that guidelines for their care existed and were confused as to how they would influence their care.168 The authors highlighted the need for patient-centric guidelines that could allow women to understand their condition and the treatment decision process.168 This is also evident considering the number of patients within the UK who were able to correctly report the type of the treatment used, which was only true in 14.2% of myomectomy cases, but 95.4% of hysterectomy procedures.21

4.3. Patient outcomes

Outcomes of an intervention, both intended and unintended, must be a key determinant of the final treatment decision. For pre-menopausal women, continued or return of fertility is likely to be a major consideration. Unfortunately, many interventions available are lacking long-term follow-up on this and other outcomes.171,173 Reviewing the literature, Miller reported 56 completed pregnancies in 1,200 women (4.7%) who underwent uterine artery ablation.171 Although expected to impair future fertility, term pregnancies after endometrial ablation (15 of 74, 20.3%) have been reported.172 Increasing the potential for pregnancy and successful term delivery would likely be an important driver of patient preference for an intervention. Currently, women wishing to maintain fertility are recommended to undergo hysteroscopic procedures.63,104 Guidelines shy away from making recommendations for specific hysteroscopic interventions, as the AAGL recommend avoidance of thermal devices for maintenance of fertility and NICE states that hysteroscopic tissue removal with a morcellator is designed to reduce damage to the uterus,1,7 it could be interpreted that


mechanical hysteroscopic tissue removal is well positioned as a treatment for women wishing to maintain or recover their fertility.

Patient perception of outcomes following intervention is generally high. There is, though, room for improvement in some settings. For inpatient mechanical hysteroscopic polypectomy, 97% of women reported that they would recommend the method to friends.12 For mechanical hysteroscopic tissue removal of uterine fibroids between 89% and 93% of women were satisfied with their treatment.116 In one study reporting on electrical resection, the satisfaction was lower with 78% happy and 2% finding the procedure “unacceptable”.42 Patient satisfaction with treatment is likely correlated with reductions in symptomatology, recurrence rates, and adverse event incidence. Hysterectomy, by definition, removes the source of AUB symptoms and many hysteroscopic methods have excellent efficacy. In a study with 12-month follow up, pathology removal, using mechanical hysteroscopic tissue removal, was considered complete in 99.9% of cases for polyps and 95.9% of cases for uterine fibroids.116 After reviewing the literature, Miller reported that uterine fibroids recurred in 9% of women receiving laparoscopic uterine artery occlusion, compared with 18.2% and 18.5% in women undergoing myomectomy via a laparoscopic and laparotic route, respectively.171 For hysteroscopic procedures, AlHilli et al. showed 10.6% and 3.1% polyp recurrence after electrosurgical and mechanical hysteroscopic tissue removal, respectively.142 For women receiving uterine artery embolization, 2.9% required subsequent hysterectomy.171 Uterine artery embolization has also been demonstrated to have a high rate of readmissions and complications.172 For hysteroscopic tissue removal, Arnold et al. reported that 6% of patients required a subsequent hysterectomy.50 Of these hysterectomies, 80% were attributable to uterine fibroids not indicated for hysteroscopic tissue removal.50 Most options for pathology removal are effective, but with the optimization of treatment selection there is scope for reducing both the recurrence and adverse event rates.

4.4. High burden of disease

Although the majority of uterine fibroids and endometrial polyps can be completely removed in a single, minimally invasive procedure, the burden of disease, for both patients and providers, remains high. The cost of medical management for AUB in the U.S., which is frequently associated with uterine fibroids and endometrial polyps, has been estimated at USD 3.27–5.1 billion.10 That is approximately twice the cost associated with medical management of breast cancer in the U.S.10 The scope for reducing the cost burden is clear. Options for reducing the cost burden could also result in substantial improvement in healthcare resource utilization.

From the patient perspective, uterine fibroids and endometrial polyps result in reduced quality of life. In 2015, Clark et al. found that women with endometrial polyps had a quality of life index of 0.78 on average.12 This deficit is, however, reversible and the authors demonstrated that after undergoing polypectomy the patients’ quality of life improved to a mean of 0.87 within 6 months.12 Given the evidence that hysteroscopic myomectomy and polypectomy are safe and effective treatments for uterine fibroids and endometrial polyps, respectively, the fact that these indications underlie the majority of hysterectomies is concerning.125,127 Hysterectomy is a major, invasive, and expensive procedure that results in infertility. It is not recommended as a first-line treatment option, 7,101 and so early and correct identification of patients suitable for hysteroscopic techniques is required to optimize treatment decisions and potentially reduce numbers of hysterectomies performed.


4.5. Excess costs due to non-optimized care

Ensuring that patients receive the most suitable treatment option is crucial for cost-effective healthcare provision. It is unclear to what extent cost-effectiveness is achieved in management of AUB. It is possible that the lack of clarity in guidelines (see Section 4.6) exacerbates the problem of providing optimal care for patients that seek treatment. Evident, though, is the potential to improve care. In a study comparing hysteroscopic myomectomy using either the Integrated Bigatti Shaver (IBS™*) or VERSAPOINT™*, the authors found that 21 of 131 procedures (13.9%) could not be completed on the scheduled day.39 A second procedure needed to be scheduled in the subsequent two months due to either a fluid deficit of 2,000 ml reached during the procedure or the procedure requiring more than one hour.39 Beyond the patient burden, repeat procedures will also double the costs of care. Such repeat procedures are also required for recurrence. In an analysis of hysteroscopic polypectomy in 240 women, polyp recurrence was noted in 5% of women undergoing polypectomy with microscissors, 15% with grasping forceps, and 2% with electrical probe.174 There was no recurrence identified in women receiving polypectomy with a resectoscope,174 indicating that there is potential for improvement by moving clinical practice toward more recent and complete technologies.

Excess costs are also incurred when indicated procedures are unnecessarily performed in a high cost setting. Inpatient procedures have historically been the norm for myomectomy and polypectomy. There is a substantial body of evidence supporting the use of these hysteroscopic procedures in an outpatient or office setting. Within the UK OPT trial Diwakar et al. estimated that the average total cost after 12 months for a polypectomy is GBP 938 and GBP 1482 for an outpatient or inpatient procedure, respectively.19 In Turkey, Filiz et al. determined that office procedures (both myomectomy and polypectomy) cost on average TLY 193 (EUR 91), whereas classic in hospital procedures cost TLY 679 (EUR 323).134 Patient satisfaction was high and outcomes equivalent compared with inpatient procedures.149 The cost and patient advantages of outpatient and office procedures relative to inpatient procedures is supported by works in the U.S., UK, and Italy.16–20

Access to such outpatient procedures is an ongoing issue. The availability of surgical methods by sites-of-service was reported in the UK.21 This report released by the Royal College of Obstetricians and Gynecologists showed that hysteroscopic procedures were only available in 94% of gynecology departments, whereas hysterectomies were available almost ubiquitously.21 Furthermore, the type of hysteroscopic procedures varied with only 83% of hospitals offering hysteroscopic myomectomy. Providing access to the optimal form of intervention may be an important factor in improving patient care.

4.6. Unmet needs in guidelines

The current guidelines represent an opportunity to improve care provision for patients with uterine fibroids and endometrial polyps. Although extensive, the guidelines have a paucity of specific recommendations on the recommended patient pathway or gold-standard treatment. As an example, guidelines recommend focusing on the patient quality of life and individualized treatment.63,101 The same guidelines note that hysterectomy is the most effective treatment for symptomatic uterine fibroids,63 but that it should not be a first-line treatment.101 Instead hysteroscopic procedures are the first-line conservative surgical therapy.63 The inconsistencies between guidelines may derive from where the treatment focus is placed, as the more efficacious interventions are generally more invasive and have higher risk of adverse events. Furthermore, the individual needs of the patient may eliminate options, as the potential for future fertility excludes hysterectomy. Notably, few guidelines include a recommended patient pathway, and none provide informative questions to be answered in order to fully understand the patient’s experience and wishes.


The vagaries of the guidelines will not facilitate standard practice across settings and geographies.

4.7. Overview

In real-world practice AUB is dominated by heterogeneity. Women present at different stages of the condition, with individual symptomatology, and in varying life situations. The aims and needs of the patients vary and there is no ubiquitous treatment available. It is likely that this heterogeneity underlies the lack of optimized healthcare provision for conditions that are otherwise treatable with minimally invasive techniques. Early identification of affected women and their aims and needs may allow for more effective, individualized treatment. Treatment selection would be further aided by improved guidelines, with one or more suggested treatment pathways. In the current situation, it may be pertinent to question whether treatment options are putting patient requirements first or whether uncertainty is promoting the status quo. Historically, hysterectomy was the procedure of choice. That it still so common given hysteroscopic options available is cause for concern.


5. Minimally invasive procedures indicated for treatment of abnormal uterine bleeding

Key messages

Hysteroscopy should facilitate accurate and appropriate treatment because it enables direct visualization of the pathology.80

The TruClear™ system offers a complete technology platform for the diagnosis and removal of a range of intrauterine pathologies

The TruClear™ system is the only system that uses mechanical energy to remove pathology such as polyps and fibroids with pathology-optimized devices.

The TruClear™ system for hysteroscopic tissue removal has been optimized to enhance hysteroscopic tissue removal and contribute to added patient safety.

Key benefits of the TruClear™ system

Patient friendly hysteroscope design, requiring little to no dilation with the TruClear™ system 5C hysteroscope

Continuous flow through the uterine cavity during diagnostic and operative procedures to maintain a clear field of view

Hysteroscopic fluid management system, designed with patient safety in mind

5.1. Hysteroscopic interventions

Hysteroscopy is the visualization of the uterus with an endoscope.80 This enables direct visualization of the pathology and sites of interest, which should facilitate accurate and appropriate treatment. Hysteroscopic tissue removal is an extension of diagnostic hysteroscopy, whereby operative instruments are inserted through the working channel of the hysteroscope. To maintain a dilated and clear working area, the uterus is filled with isotonic or non-conductive fluid during the procedure. A fluid management system may be used to automate maintenance of distension during the procedure and monitor fluid deficit to avoid fluid overload.

The main areas of therapy for hysteroscopic interventions are submucosal and endometrial pathologies (Figure 5-1). Hysteroscopic tissue removal is indicated for the removal of intrauterine pathology such as endometrial polyps and submucosal uterine fibroids. More specifically, the AAGL guidelines recommend hysteroscopic tissue removal for uterine fibroids of type 0–2 of the FIGO classification. 7 Additional indicated areas of therapy for hysteroscopic tissue removal are evacuation of retained products of conception (see Section 8.5), hysteroscopic adhesiolysis, and endometrial biopsy.


Figure 5-1 Locations of pathology within the uterus

Fibroids and polyps within the uterus.

Hysteroscopic tissue removal is a common procedure, with literature review (see Appendix, Section 9) identifying published evidence of its efficacy for 11 countries (Figure 5-2). By indication covered in this dossier, use of hysteroscopic tissue removal for uterine fibroids was identified in 5 countries and endometrial polyps were the target pathology in 8 countries.

Figure 5-2 World map of peer-reviewed publications detailing use of mechanical hysteroscopic tissue removal

Publications about hysteroscopic tissue removal were found for colored countries.


5.1.1. Dilation and curettage (D&C)

Dilation and curettage is the traditional approach to removing uterine pathologies. It can be conducted in a tactile manner (“blind”) or supported by a hysteroscope. While the blind approach is generally contraindicated,7 dilation and curettage under hysteroscopic guidance is still used to remove intrauterine pathologies as indicated in a 2015 health technology assessment.12 Dilation and curettage can also be used for the removal of retained products of conception and submucosal and endometrial pathologies within the uterus.

The procedure is usually conducted with a speculum widening the vagina and dilators to open the cervix. The required flexible or rigid instruments are then inserted to manually resect the pathology.80 Using forceps, the resected tissue is removed from the uterus. Numerous dilation and curettage sets are available. In general, a set is composed of specula, dilators, curettes, and forceps for varying purposes (dissecting, sponge holder, needle holder, towel clip).

5.1.1.1. Grasping forceps/scissors

Another manual method related to dilation and curettage for the removal of endometrial polyps and uterine fibroids is the hysteroscopy guided use of forceps and scissors.7 For endometrial polyps, the pathology is grasped by the forceps and cut at the base. Uterine fibroids are resected by cutting the surrounding tissue to release the fibroid.

5.1.2. Mechanical tissue resection

Mechanical tissue resection uses a blade to cut tissue that is then removed through the device and captured in a specimen trap.80 (Figure 5-3). The system accesses the pathology through the dilated cervix. On visualization of the pathology, tissue resection can be achieved using either rotating, pivoting, or reciprocating devices which continually cut and remove tissue. Continual tissue removal, when used with a suitable fluid control system to maintain a clear operative field, makes removal and reinsertion of operative instruments only rarely necessary.24,51


Figure 5-3 Hysteroscopic mechanical tissue resection scope

Manufactures of systems and devices for mechanical hysteroscopic tissue resection include:

Medtronic: TruClear™ system Hologic: MyoSure™*system Karl Storz: Intrauterine BIGATTI shaver (IBS™*) system Boston Scientific: Symphion™* system Boston Scientific: Resectr™* devices

5.1.3. Electrosurgical tissue resection

Hysteroscopic electrical tissue resection, or in short ‘resectoscopy’, is a common method for performing myomectomy and polypectomy in many geographies.175 Two different forms of resectoscopy are available: monopolar and bipolar. Both systems use a fluid management system, resectoscope, and electrosurgical instruments. Resection is often performed using a cauterization loop, although alternative designs are also used (e.g., roller ball). During the procedure, resected tissue needs to be removed regularly from the cavity to maintain visualization of the target pathology. This is achieved by removing the electrosurgical instrument and inserting forceps or other mechanical instruments through the port or removing the entire resectoscope.


5.1.3.1. Monopolar resectoscopy

Monopolar resectoscopy uses the patient body as the grounding electrode. This makes the use of non-conductive fluid, e.g. glycine or sorbitol, imperative. Use of non-conductive, hypotonic fluids has been shown to cause cerebral edema or hypotonic hyponatremia if absorbed in excess.7 Therefore the AAGL recommend a 1,000mL maximum fluid deficit for hypotonic solutions instead of the 2,500mL maximum fluid deficit for isotonic solutions.7

During monopolar resectoscopy, the pathology is dissected and coagulated using heat. Forceps are required to remove the loose tissue from the uterus. As the vision can be blocked by the tissue, monopolar resectoscopy in general needs multiple insertions before the pathology is removed completely.

5.1.3.2. Bipolar resectoscopy

In bipolar resectoscopy, both electrodes are incorporated in the device. The current is solely focused between these electrodes, avoiding discharges to the body. Bipolar resectoscopy can therefore use isotonic fluid. As with monopolar resectoscopy, resected tissue needs to be regularly removed using forceps. Therefore multiple insertions are necessary in order to remove the full pathology.44

Available bipolar resectoscopic systems are:

ETHICON GYNECARE VERSAPOINT™* KARL STORZ TROPHYSCOPE™* OLYMPUS OES Pro™* RICHARD WOLF RESECTION MASTER™* RICHARD WOLF Princess™* TEKNO™* BIPOLAR RESECTOSCOPE SOPRO COMEG™* Bipolar resectoscope Stryker™* resectoscope Bissinger PLASMALOOP™*

5.1.3.3. Combination resectoscopy and mechanical tissue removal

A combination device that performs resection of the endometrium and mechanical degradation of the resected chips has been reported.176–178 Morcellation of the removed chips allows them to be removed through the hysteroscope and prevents the need to pass the resectoscope in and out of the cervix.

5.2. Efficacy and safety of hysteroscopic tissue removal

There are three major methods available for the removal of uterine pathologies: hysterectomy, laparoscopic procedures, and hysteroscopic procedures. Hysterectomy can be used to treat all classes of uterine fibroids and there were 195,735 hysterectomies related to uterine fibroids in 2010 in the U.S.128 Hysterectomy is a major operation, associated with an average inpatient length of stay of 5.1 days.137 As previously shown (Table 3-5), it is also associated with severe adverse events and a relatively high infection rate. Laparoscopic surgery can also address the majority of uterine pathologies, however it is not recommended for uterine fibroid types 0–2 and comes at double the cost of hysteroscopic tissue removal.60,125 Hysteroscopic procedures offer treatment at reduced risk and cost, and for these reasons they are often strong candidates for first-line treatment in patients indicated for removal of uterine pathology.

Hysteroscopic tissue removal is indicated for fibroids of FIGO type 0-2 and endometrial polyps. It is a well-established method to treat uterine pathologies. A survey by van Dijk in 2012 showed that hysteroscopy is the dominant technique for endometrial polyp removal


for gynecologists in the Netherlands.179 Blind dilation and curettage was only performed by nine percent of surgeons, with the remaining 91% utilizing hysteroscopy.179 Safety may be a driving factor in this. A systematic review of 8 trials by Noventa et al. reported that adverse event rates with hysteroscopic mechanical tissue removal occurred in 0.02% of patients.180 For hysteroscopic electrical tissue removal, the percentage of patients experiencing an adverse event was 0.4%.180 Recurrence is also low following mechanical hysteroscopic tissue removal, with recurrence of endometrial polyps reported in 15.1% of cases after 4 years of follow-up.142 The efficacy of hysteroscopic tissue removal in the resection of intra-uterine pathology is high and comparable to that of hysterectomy. While hysterectomy removes all of the pathology, mechanical hysteroscopic tissue resection has been reported to remove between 92% and 100% of the pathology during the procedure.44,140 A distinct advantage of the hysteroscopic approach is the potential for future pregnancy by leaving the uterus intact. Chen et al. reported in 2015 that 46% of women who were considered infertile due to intrauterine pathology, successfully delivered on-term after hysteroscopic mechanical tissue resection of uterine fibroids.155

5.3.The TruClear™ system

5.3.1. The TruClear™ system

The TruClear™ system is a complete mechanical operative hysteroscopy system and part of our gynecologic portfolio. The system consists of

The TruClear™ system 5C hysteroscope (Figure 5-5), which is the newest hysteroscope to the family of products and offers several advantages:

- Enables both operative and diagnostic procedures in the office, clinic, ambulatory surgery center (ASC) and operating room, eliminating the need for scope changes

- Patient-friendly instrumentation, with an anatomically-designed distal end for gentle introduction into the cervical canal and uterine cavity with little to no dilation

- Longer hysteroscope length means access to the entire uterine cavity, including the fundal wall and cornua

- Used with the TruClear™ system INCISOR™ device and the TruClear™ system ULTRA Mini device

The TruClear™ system 8.0 hysteroscope set (Figure 5-4), which is most frequently utilized in the operating room / theatre or ASC setting and offers several benefits:

- Large working channel offers capability to use additional hysteroscopy instruments

- Option to use TruClear™ system obturator for gentle introduction of the sheath into the uterine cavity

- Used with the TruClear™ system INCISOR™ Plus device and the TruClear™ system ULTRA Plus device

The family of TruClear™ system devices includes pathology-optimized devices in two different sizes that allow simultaneous tissue cutting with mechanical energy and aspiration to meet your needs for a full spectrum of procedures (Figure 5-6 and Figure 5-7)

- The TruClear™ system INCISOR™ devices are optimized for treatment of soft tissue such as polyps or adhesions

- The TruClear™ system ULTRA devices are optimized for treatment of dense tissue such as fibroids

- Both styles of devices use mechanical energy which offers several advantages to the surgeon and patient


- Mechanical tissue removal eliminates the risk of electrical energy discharge and minimizes the risk of gas emboli inside the uterus

- Uses normal saline instead of glycine or sorbitol, which allows a higher deficit limit without increasing patient risk

- Mechanical tissue removal has been shown to be easier to learn and shown to have a shorter operating time compared to electrical resection

The Hysteroscopic fluid management system, which can be used in most hysteroscopic procedures, was designed with patient safety in mind

- High maximum flow rate contributes to optimized visualization and facilitates maintained uterine distension

- High speed response to changes in uterine pressure - Continuous deficit monitoring for accurate measurement with +/-3%

accuracy - Flexible suction contributes to clear visualization and maintained distension - Reliable audible alarms for patient safety, including over pressure, under

pressure and fluid deficit thresholds The TruClear™ system and TruClear™ system devices are intended for intrauterine

use by trained gynecologists to hysteroscopically resect and remove tissue such as submucous myomas, endometrial polyps and retained products of conception. The TruClear™ system enables a full spectrum of procedures, including:

- Polypectomy - Myomectomy - RPOC evacuation - Diagnostic visual D&C - Endometrial biopsy

The TruClear™ system has consistently been shown to be successful in the treatment of polypectomy, myomectomy and RPOC evacuation.156,181 The TruClear™ system meets demands for an easy-to-use, effective treatment of intrauterine pathology while simultaneously improving the treatment safety when compared with earlier procedures such as electrical resection.

The TruClear™ system also fulfils women’s preferences for uterine-saving, office procedures and might be able to reduce the frequency of hysterectomies which, although often not clinically indicated, expensive and disliked by women, continue to be widely used.7,149,182–184 The TruClear™ system is therefore in a good position to satisfy patient preferences and reduce both the clinical and economic burden associated with AUB and intrauterine pathology.


Figure 5-4 The TruClear™ system 8.0 hysteroscope set

Devices shown: TruClear™ system operative hysteroscope 8.0, TruClear™ system sheath 9.0, TruClear™ system obturator, TruClear™ system calibration insert

Figure 5-5 The TruClear™ system 5C hysteroscope set

Devices shown: TruClear™ system operative hysteroscope 5C, TruClear™ system sheath 5C, TruClear™ system calibration insert


Figure 5-6 Overview of TruClear™ system mechanical tissue resection devices

* Available TruClear™ system tissue removal devices as of June 2017

Figure 5-7 TruClear™ system indications

Range of indications for the various TruClear™ system tissue removal devices.

5.3.2. The TruClear™ system compared to other hysteroscopic mechanical tissue resection devices

Compared to competitor products, the TruClear™ system offers the most extensive range in devices. Products in the TruClear™ system family have the smallest and largest range diameters for the both the hysteroscopic system and the device itself (Table 5-1). The cutting window provided by TruClear™ system devices ranges from a high-accuracy, small window of 8 mm3 to a window of 72 mm3 to address larger uterine pathologies. The maximum flow for the fluid control system and the range of intrauterine pressures accommodated are in line with other available products.


Table 5-1 Hysteroscopic mechanical tissue resection devices specifications

Characteristic TruClear™ system

MyoSure™* BIGATTI Shaver

Symphion™* Resectr™*

No. scopes 2 2 1 1 0

No. devices 4 4 2 1 2

No. styles 2 1 1 1 1

Range diameter (mm)

… system 5.7-9 6-7 8 6.3

… device 2.9-4.0 3-4 4 3.6 1.65-3

Device length (mm) 357 320 320 350

RPM range 100-2500 <=8075 <=5000

Cutting window range

… length (mm) 5-10 10.2-14 5-7.5

… size (mm3) 8-72 31-98

Fluid control

Max flow (ml/min) 700 800 450

Intrauterine pressure range (mmHg)

15-125 40-150 <=95 45-125

mL, Mililiters; Mm, Milimeters; mmHG, Milimeters of mercury; RPM, Rotations per minute. Sources: Meulenbroeks et al,185 and manufacturer-provided product information available on websites.4,5,6,7

The FDA requires adverse events or malfunctions to be reported by manufacturers. Reported events are accessible via the MAUDE database. A study by Haber et al., published in 2015, searched for reported adverse events by the TruClear™ system and MyoSureTM* in the MAUDE database.186 Between 2005 and 2014 there were 23 reported events related to the TruClear™ system.186 The authors estimated that 1 out of 5,000 procedures with the TruClear™ system is complicated by an adverse events.186 This is five time safer than with MyoSureTM*, where the authors estimated that 1 in 1,000 procedures is complicated by an adverse event.186 The limitation of this study was that it could only include adverse events submitted to the MAUDE database and, as stated by the authors, it is likely “[…] adverse events reported to the MAUDE database were underreported and lacked relevant details, the

4 Myosure: Physician brochure 5 Intrauterine Bigatti Shaver: Product information 6 Symphion: System instructions 7 Resectr: http://www.bostonscientific.com/en-US/products/uterine-tissue-removal-systems/resctr.html

http://www.hologic.com/sites/default/files/white-papers/PB-00280-001%20Rev.%20001_MyoSure_Physician_Brchr_LowRes.pdf

https://www.karlstorz.com/cps/rde/xbcr/karlstorz_assets/ASSETS/3210338.pdf

https://www.bostonscientific.com/content/dam/bostonscientific/uro-wh/sites/symphion/pdfs/System_Instructions.pdf

http://www.bostonscientific.com/en-US/products/uterine-tissue-removal-systems/resctr.html


number of procedures performed was estimated […]”.186 As of May 31, 2017 the count of adverse events in the MAUDE database associated with hysteroscopic mechanical tissue removal are reported in Table 5-3. For the TruClear™ system, the simple count was 165 adverse event reports over 14 years, or 11.4 reports per year. In comparison, MyoSure™* was associated with 40.7 reports per year and Symphion™* with 9.1.

Table 5-2 MAUDE adverse events reported

Device name Adverse events reported

First FDA clearance

Adverse events/year

TruClear™ system 165 2003/02/12 11.4

MyoSureTM* 314 2009/10/23 40.7

Symphion™* 30 2014/03/24 9.1

Resectr™* N/A N/A N/A

Intrauterine BIGATTI shaver (IBSTM*)

N/A N/A N/A

Source: MAUDE database

Safety data from clinical trials and studies are favorable for hysteroscopic tissue removal, with only single or minor events being reported (Table 5-3). 44,51,52 The completion rate is also above 90% for all trials reporting on hysteroscopic tissue removal23,24,42,44,47. Recurrence of pathology and symptomatology was investigated by AlHili et al in 2013. The authors found that the cumulative incidence of endometrial polyp recurrence after 2 years was 4.5% (95% CI, 1.2%–7.7%) with resectoscopy and 0.8% (95% CI, 0%– 2.3%) with the TruClear™ system.142 This difference was maintained at 10 years, at which point 10.6% (95% CI, 5.3%–15.6%) of patients receiving resectoscopy had recurrence, compared with 3.1% (95% CI, 0%–6.7%) of patients receiving the TruClear™ system.142 The cumulative incidence of symptom recurrence after 5 years, measured by AUB, was reported as 23% (95% CI, 17.0%– 28.5%).142

In the following sections, the safety and efficacy of hysteroscopic mechanical tissue resection is discussed for both uterine fibroids and endometrial polyps. Data are included from multiple hysteroscopic mechanical tissue resection devices and competitors. Full data is available in the appendix (Table 8-1).

Table 5-3 Safety and efficacy of the TruClear™ system for mechanical tissue resection

Study Treated pathology

Completion rate (patients)

Used instrument

Procedure duration (minutes)

Adverse events

Emanuel (2005) 23 Fibroid type 0-1, polyps

93% myoma 100% polyps (28/27)

Intra-uterine morcellator (IUM)

16.4 myoma 8.7 polyps

None reported

Van Dongen (2008) 24 Fibroid type 0-1, polyps

87.5% myoma 100% polyps (10/20)

The hysteroscopic morcellator

10.6 One imminent but avoided fluid overload


Hamerlynck (2011)27 Fibroid type 0-2, polyps

NS TruClear™ system

18.2 myoma 6.6 polyps

None reported

Mathiopoulos (2011)28 Fibroids, polyps

NS TruClear™ system

32 myoma 9 polyps

None reported

Smith (2014) 42 Polyps 98% (62)

TruClear™ system 5.0

5.5 One vasovagal episode

Hamerlynck (2015) 44 Polyps >1cm

100% (44)


9.5 One perforation during dilation

Pampalona (2015) 47 Polyps 92% (63)


6.8 None reported

Torres (2016)56 Polyps NS TruClear™ system

13 None reported

Summary of data available from published TruClear™ system trials; NS: Not specified

5.3.3. Hysteroscopic mechanical tissue resection compared to competitor procedures

5.3.3.1. Fibroid removal

Studies have generally compared hysteroscopic mechanical tissue resection with resectoscopy in uterine fibroid removal. Many studies, though, include a mixed patient population, reporting on both uterine fibroids and endometrial polyps. Overall, patient safety with hysteroscopic mechanical tissue resection is generally equivalent or superior to that with resectoscopy (Table 5-4). In 10 trials with 429 patients only two bleedings and one fluid overload where reported during the procedure. In seven comparative trials using resectoscopy five bowel perforations, one uterine perforation and three fluid overloads were reported in 586 patients.

Comparing outcomes among 50 patients, Borg and Shehata found that none of 25 patients undergoing hysteroscopic mechanical tissue resection required reoperation, whereas 3 of 25 receiving resectoscopy underwent a second procedure (P = 0.07).51 In 2014, Bigatti et al reported that the number of patients requiring a second procedure for complete removal of pathology was significantly higher with resectoscopy than it was with hysteroscopic mechanical tissue resection (p=0.007).39


Table 5-4 Adverse events related to fibroid removal

Study Level of evidence (patients)

Pathology mHTR mHTR adverse events Resectoscope Resectoscope adverse events

Emanuel (2005) 23

2b (271)

Fibroid type 0-1, polyps

Intra-uterine morcellator (IUM) [Precursor TruClear™ system]

None reported Monopolar resectoscope

None reported

Van Dongen (2008) 24

1b (214)



One imminent but avoided fluid overload

Olympus monopolar resectoscope

One Bowel perforation

Bigatti (2010)^ 25

4 (44)

Fibroid type 0-2, polyp IBSTM* Two overloads None -

Lukes (2010) ^ 26

4 (13)

Fibroid, polyp MyoSureTM* No serious adverse events None -

Hamerlynck (2011) 27

2b (315)

Fibroid type 0-1, polyp

TruClear™ system None None -

Mathiopoulos (2011) ^ 28

4 (NS)

Fibroid, polyp TruClear™ system None reported None -

Rubino (2011) ^ 29

4 (41)


Lukes (2012) ^ 31

4 (37)



Lukes (2012) ^ 32

4 (30)



4 (50)

Fibroid, polyp MyoSureTM* None reported None -

Bigatti (2012) 30

2b (95)

Fibroid, Polyp IBSTM* None VERSAPOINT™* Two bowel perforations

Bigatti (2013) ^ 34

4 (NS)

Fibroid IBSTM* None reported VERSAPOINT™* None reported

Lukes (2013) ^ 37

4 (76)


Lukes (2013) ^ 36

4 (17)


Harari (2013) ^ 35

4 (220)

Fibroid, polyp MyoSureTM* LITE, MyoSureTM* XL

None reported None -

Lukes (2014) ^ 40

4 (23)

Fibroid, polyp MyoSureTM* None None -


4 (100)


Bigatti (2014) ^ 38

4 (NS)

Fibroid IBSTM* None reported None -

Bigatti (2014) 39

2b (289)

Fibroid type 0-2 Intrauterine BIGATTI Shaver (IBSTM*)

None reported Bipolar VERSAPOINT™* resectoscope

None reported


Scheiber (2014) ^ 43

4 (55)

Polyps, Fibroids MyoSureTM* None reported None -

Krishnamurthy (2015) ^ 45

4 (95)



4 (140)


Reddy (2015) ^ 48

4 (26)


Arnold (2016) 50

2b (255)


MyoSureTM* and MyoSureTM* XL

None None -

Borg (2016) 51

2b (50)


Intrauterine BIGATTI Shaver (IBSTM*)

Bleeding Circon ACMY monopolar resectoscope

3 fluid overload, 1 needing ICU admission

Lee (2016) 44

2b (29)

Submucosal fibroids MyoSureTM* None Monopolar loop resection

1 Uterine perforation

Ms (2016) ^ 53

4 (50)

Fibroids MyoSureTM* None reported None -

Palinska-Rdzka (2016) ^ 54

4 (130)

Fibroids, polyps MyoSureTM* 2 ongoing bleeding None -

Scheiber (2016) 55

2c (278)

Fibroids, polyps MyoSureTM* 4 mild cervical traumas, 1 postoperative pedal edema

None -

Rubino (2017) ^ 57

4 (26)

Fibroids, polyps MyoSureTM* 1 minor nausea 2 abdomino-pelvic crampings

None -

HMTR, Hysteroscopic mechanical tissue resection; ICU, Intensive Care Unit. The IUM is the precursor of TruClear™ system; Level of evidence taken from: OCEBM Levels of Evidence Working Group^. "The Oxford 2011 Levels of Evidence". Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653


Procedure statistics are mostly in favor of hysteroscopic mechanical tissue resection. There is consistent evidence that hysteroscopic mechanical tissue resection is a faster procedure to complete than is resectoscopy (Figure 5-8). Only one study, that by Bigatti et al and reporting on the intrauterine Bigatti Shaver (IBSTM*), found hysteroscopic mechanical tissue resection and resctoscopy to be of equivalent time (mean 21.12 vs. 21.13 minutes for uterine fibroids <3cm).39 In contrast, Borg and Shehata determined that the time taken to remove uterine fibroids was 9.33 (±1.23) minutes using hysteroscopic mechanical tissue resection and 29.32 (±3.23) minutes using resectoscopy (p<0.05).51 The overall reported average procedure duration for mechanical hysteroscopic fibroid removal was 21.17 minutes while monopolar and bipolar resectoscopic procedures took 40.78 minutes and 30 minutes, respectively. One aspect factoring in to reduced procedure time may be the need for fewer insertions of the hysteroscopic mechanical tissue resection device. Van Dongen et al. (2008) and Borg and Shehata (2006) both reported that the number of insertions needed for monopolar resectoscopy was seven, whereas hysteroscopic mechanical tissue resection required normally one, maximally two, insertions.24,51

Figure 5-8 Comparison of procedure duration between hysteroscopic mechanical tissue resection and resectoscopy

Trials comparing procedure duration for resectoscopy and hysteroscopic mechanical tissue resection. †mean procedure time for both fibroid and polyp removal #bipolar resectoscope, otherwise monopolar; Sources: Emanuel and Wamsteker (2005)23; Van Dongen et al (2008)24; Bigatti et al (2014)39; Hamidouche et al (2015)58; Borg and Shehata (2016)51; Lee and Masuzono (2016)52

Five studies reported on fluid deficit, with outcomes balanced between the two procedures. Three studies, of which two were reporting on the TruClear™ system, found reduced mean fluid deficit with hysteroscopic mechanical tissue resection,23,24,51 and two reported mean fluid deficit to be higher with hysteroscopic mechanical tissue resection.39,52 In all studies, fluid deficit comprising a patient safety event was rare.


Figure 5-9 Comparison of fluid deficit between hysteroscopic mechanical tissue resection and resectoscopy

Resectoscopy versus hysteroscopic mechanical tissue resection †mean fluid deficit for both fibroid and polyp removal; #bipolar resectoscope, otherwise monopolar; ‡No comparator used; Sources: Emanuel and Wamsteker (2005)23; Van Dongen et al (2008)24; Bigatti et al (2014)39; Borg and Shehata (2016)51; Lee and Masuzono (2016)52

5.3.3.2. Polypectomy

Multiple trials have shown the suitability of hysteroscopic mechanical tissue resection for endometrial polyp removal. Hamerlynck et al (2015), Pampalona et al (2015) and Smith et al. (2014) have shown that the percent of successful removals with hysteroscopic mechanical tissue resection is higher than with resectoscopy.42,44,47 Polyp recurrence has also shown to be lower following hysteroscopic mechanical tissue resection compared with resectoscopy.142 Bipolar resectoscopy was associated with a hazard ratio 3.3 (95% CI, 0.94–11.49) for polyp recurrence (p=0.06).142 In addition to these beneficial outcomes, hysteroscopic mechanical tissue resection was consistently found to have a shorter mean procedure time than resectoscopy (Figure 5-10). The average reported time was 7.27 minutes for mechanical hysteroscopic polyp removal while the average reported duration for monopolar and bipolar resectoscopic procedures was 20.15 and 16.84 minutes, respectively.23,24,30,42,44,47,51 As with myomectomy, polypectomy procedures undertaken with hysteroscopic mechanical tissue resection require fewer insertions (one) than does resectoscopy (two).44 This will factor into differences in procedure time, but is unlikely to account for the differences upwards of 15 minutes reported.23,51


Figure 5-10 Comparison procedure duration for resectoscopy and hysteroscopic mechanical tissue resection

†mean procedure time for both fibroid and polyp removal; #bipolar resectoscope, otherwise monopolar; Sources: Emanuel and Wamsteker (2005)23; Van Dongen et al (2008)24; Bigatti et al (2012)30; Lobo Abascal et al (2014)187; Hamidouche et al (2015)59; Pampalona et al (2015)47; Hamerlynck et al (2015)44; Borg and Shehata (2016)51

The four studies reporting on fluid deficit all found it to be lower for hysteroscopic tissue removal procedures compared with resectoscopy (Figure 5-11). In fact, one of the three fluid overloads reported by Borg and Shehata (2016) for resectoscopy required the patient to be admitted to the intensive care unit.51 In general, safety data for hysteroscopic mechanical tissue resection are favorable relative to resectoscopy (Table 5-5). For resectoscopic procedures in 7 trials three bowel perforations, two uterine perforations, three fluid overloads and 6 minor adverse events were reported within 639 patients. 24,30,42,44,49,51 For mechanical hysteroscopic tissue removal 13 trials with 945 patients reported two fluid overloads, one endometritis, three bleeds and six minor adverse events. 25,42,51,54,55

This is partly due to shorter procedures and reduced instrument insertions. For example, the study by Hamerlynck et al. included two uterine perforations when using resectoscopy, and the authors associated this with reinsertion of the instruments.44


Figure 5-11 Comparison fluid deficit between resectoscopy and hysteroscopic mechanical tissue resection

†mean fluid deficit for both fibroid and polyp removal; #bipolar resectoscope, otherwise monopolar; Sources: Emanuel and Wamsteker (2005)23; Van Dongen et al (2008)24; Bigatti et al (2012) 30; Hamerlynck et al (2015)44; Borg and Shehata (2016)51

Global Value Dossier: TruClear™ System © 2018 Medtronic. All rights reserved. Medtronic logo and Further, Together are trademarks of Medtronic. ™ This party brands are trademarks of their respective owners. All other brands are trademarks of a Medtronic company, US180165 03/2018

63 Global Value Dossier: TruClear™ System

63

Table 5-5 Adverse events related to polyp removal

Study Level of evidence (patients)

Pathology mHTR mHTR adverse events

Resectoscope Resectoscope adverse events

Emanuel (2005) 23

2b (271)



None reported Monopolar resectoscope

None reported

Van Dongen (2006) 24

1b (214)


The hysteroscopic morcellator [Precursor TruClear™ system]

None reported Olympus monopolar resectoscope

One Bowel perforation

Bigatti (2010)^ 25

4 (44)

Fibroid type 0-2, polyp IBSTM* Two overloads None -

Lukes (2010) ^ 26

4 (13)

Fibroid, polyp MyoSureTM* No serious adverse events

None -


2b (315)

Fibroid type 0-1, polyp

TruClear™ system None None -


4 (NS)

Fibroid, polyp TruClear™ system None reported None -

Rubino (2011) ^ 29

4 (41)


None -

Lukes (2012) ^ 31

4 (37)


None -

Lukes (2012) ^ 32

4 (30)


None -


4 (50)


Bigatti (2012) 30

2b (95)

Fibroid, Polyp IBSTM* None VERSAPOINT™* Two perforations

Lukes (2013) ^ 37

4 (76)


Lukes (2013) ^ 36

4 (17)




64

Harari (2013) ^ 35

4 (220)

Fibroid, polyp MyoSureTM* LITE, MyoSureTM* XL

None reported None -

Lobo Abascal (2014) ^187

4 (217)

Polyp TruClear™ system None reported None -

Lukes (2014) ^ 40

4 (23)



4 (100)


None -

Scheiber (2014) 43

4 (55)


Smith (2014) 42

1b (121)

Polyps TruClear™ system 5.0 1 Vasovagal episode 1 Endometritis

VERSAPOINT™* bipolar resectoscope

6 Vasovagal episodes


1b (84)

Polyps >1cm TruClear™ system 8.0 None reported Karl Storz bipolar resectoscope

2 Uterine perforations

Krishnamurthy (2015) ^ 45

4 (95)



4 (140)


Pampalona (2015) 47

1b (133)

Polyps TruClear™ system 5.0 None reported VERSAPOINT™* bipolar resectoscope

None reported

Reddy (2015) 48

4 (26)


Stoll (2015) 49

4 (22)

Polyps IBSTM* None Unspecified resectoscope

1 Operative Hysteroscopy Intravascular Absorption syndrome

Arnold (2016) 50

2b (255)


MyoSureTM* and MyoSureTM* XL

None None used -



65

Borg (2016) 51

2b (50)


Intrauterine BIGATTI Shaver (IBSTM*)

1 Hemorrhage Circon ACMY† monopolar resectoscope

3 Fluid overloads

Palinska-Rdzka (2016) 54

4 (13)

Fibroids, polyps

MyoSureTM* 2 ongoing bleeding None -

Scheiber (2016) 55

2c (278)

Fibroids, polyps MyoSureTM*

4 mild cervical traumas, 1 postoperative pedal edema

None -

Torres (2016) 56

4 (NS)

Polyps TruClear™ system None reported Bipolar VERSAPOINT™* resectoscope

None reported

Rubino (2017) 57

4 (26)

Fibroids, polyps MyoSureTM*

1 minor nausea, 2 abdominopelvic crampings

None -

HMTR, Hysteroscopic mechanical tissue resection; NS, Not specified. †Device as described in the published manuscript, generally referred to as ACMI; Level of evidence taken from: OCEBM Levels of Evidence Working Group^. "The Oxford 2011 Levels of Evidence". Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653


6. Health economic analyses of hysteroscopic tissue removal

Key messages

Laparoscopic procedures have a 77% increased cost compared to hysteroscopic procedures.60

Real-world cost-collection studies have shown that myomectomy incurs lower total costs than hysterectomy.60–62

In computational models, myomectomy was shown to be dominant compared to uterine artery embolization.133,188

The de-novo developed cost-utility analysis showed that the TruClear™ system reduces care costs and improves patient quality of life compared to bipolar resectoscopy for polypectomy in the UK.

6.1.Introduction to health economic analyses

Health economics is the quantification of the value and efficiency offered by a procedure or treatment. Health economics determine whether the procedure or treatment is cost-effective and/or affordable. The goal of these analyses is the optimization of healthcare resource allocation. This is of importance because healthcare expenditures have been increasing across the globe (Figure 6-1). The expectation is for this to continues in the future, for example, an annual increase in healthcare spending of 5.6% between 2016 and 2025 was forecast for the US.189 Therefore for many countries health economic evaluations have become mandatory prior to market entry and guidelines for health economic have been issued by authorities and specialist committees.190–193

Figure 6-1 Healthcare spending as percentage of GDP

Source: https://data.worldbank.org/indicator/SH.XPD.TOTL.ZS?contextual=default&end=2014&locations=DE-CN-GB-US-ZA-RU-FR&start=1995&view=chart&year=2014


To ensure results that are both relevant to expenditure and healthcare practice, health economics considers both costs and health outcomes. The analysis should include all costs and health outcomes relevant to the product/procedure in question, rather than a subset thereof that are influenced directly. This approach ensures that not only short-term effects are captured, but also mid- and long-term benefits and implications.

6.1.1. Best practice and data requirements

Since Nobel-prize winner Kenneth Arrow described modern health economics in the mid-20th century it has continually grown in importance. This is evidenced by the increase in health economic peer-reviewed publications over the last few decades (Figure 6-2).194,195 The growth of health economics has resulted in many countries formulating their own requirements and guidelines for health economic assessment.8 In addition, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) provides a global perspective on best practice and standardization of health economic analyses. 9

8 https://www.ispor.org/PEguidelines/COUNTRYSPECIFIC.asp 9 https://www.ispor.org/


Figure 6-2 Development of publication numbers

Taken from Wagstaff and Culyer 2012195; A: Health economics articles 1969-89; B: Health economics articles 1990-2009

A common requirement in countries with developed healthcare systems is cost-effectiveness analysis, which assesses the costs and health consequences of introducing a new product.194 In line with good practice, a cost-effectiveness analysis is an unbiased comparison between two treatments or interventions, that considers all relevant costs, health outcomes and inputs. The compared characteristics include efficacy, safety, resource use, costs, and life expectancy amongst others. The direct costs of intervention (eg. purchase and processing) are always considered; some countries, such as Canada and Sweden, also recommend that indirect costs like time off work and lost productivity be included.10 The outcome of this analysis is the incremental cost effectiveness ratio (ICER), which describes how much an increase in the change of the measured outcome would cost.

One form of the cost-effectiveness analysis is the cost-utility analysis. It focuses on how the health outcome influences patient quality of life.194 Each event in the model can increase or decrease the patients quality of life. The outcome is quality adjusted life and expectancy

10 Canada: https://www.ispor.org/PEguidelines/countrydet.asp?c=5&t=1 Sweden: https://www.ispor.org/PEguidelines/countrydet.asp?c=21&t=1


measured in QALYs. The primary outcome of this analysis is the cost per QALY gained. In many countries a standard threshold is applied, e.g. £20,000 - £30,000 per QALY gained in the UK, below this value the intervention is considered cost-effective.

Cost-effectiveness studies are patient focused and balance costs with outcomes. This means, though, that they do not give insight in overall costs to the payer. Therefore, for institutions and organizations focused on budgetary constraints another form of evaluation exists, the budget impact model. This model focuses on the cost implications of the whole target population. A method can be cost-effective, but on a large scale too expensive to afford. As evidenced by a recent discussion within the UK, which was sparked by a hepatitis C medication that was cost effective, but had a high budget impact and substantially impacted NHS spending.11

6.2. Published health economic analyses

The health economics of uterine fibroid and endometrial polyp removal using mechanical hysteroscopic tissue removal has to date not been assessed by publications so far. This evidence gap has been identified as an unmet need by publications, with authors recommending such an analysis be undertaken. Published cost analysis from cohort or database studies in this area focus on the comparison of uterine fibroid or endometrial polyp removal irrespective of the route.60–62,133,188 That is, the hysteroscopic removal of uterine fibroids combined with abdominal and laparoscopic removal to provide a single analysis group for myomectomy. Carls et al. showed in 2008 that this is not entirely justifiable as the vaginal route was associated with substantially lower costs than the abdominal or laparoscopic route (Table 6-1).60

11 https://pharmaphorum.com/views-and-analysis/budget-impact-cost-effectiveness-alternatives-nice-nhse-proposals/


Table 6-1 Myomectomy cost by route

Route Myomectomy cost (USD) Percentage increase over hysteroscopic

Vaginal (hysteroscopic) 6,553 NA

Abdominal 8,971 +37%

Laparoscopic 11,602 +77%

Carls et al. 200860

The literature review showed that two questions were addressed in the published health economic analysis:

1. The cost-effectiveness of the resection method. 2. The feasibility of outpatient or in-office scenarios.

To answer the first question, publications were comparing the different methods to treat uterine fibroids: Hysterectomy, Magnetic Resonance-guided Focused Ultrasound (MRgFUS), and uterine artery embolization.60–62,133,188,196 The second question is of interest as the vaginal route allows for day-case or outpatient procedures without the need for an associated inpatient stay, thus providing potential to reduce overall resource usage.152

6.2.1. Real-world cost and outcomes studies

Literature review identified 5 studies assessing real-world costs and outcomes associated with myomectomy or polypectomy.12,60–62,148 No study evaluated the cost-effectiveness of mechanical hysteroscopic tissue removal compared to any other method. In general, only uterine fibroid and endometrial polyp removal irrespective of the route was assessed. In two out of the three real-world studies focusing on fibroid treatment uterine fibroid removal via myomectomy was the lowest cost method (Table 6-2). For example, Dembek et al. found in 2008 that the total costs of fibroid treatment with myomectomy are USD 11,768 compared to USD 12,775 with hysterectomy and USD 13,270 with uterine artery embolization.61

Table 6-2 Real world procedure costs

Procedure costs

Post-operative costs

Indirect costs Total costs

Myomectomy (I) 7,605 (II) 8,890 (III) 3,579

(II) 5,257*

(III) 2,097

(I) 11,768 (II) 14,726* (III) 5,676

Hysterectomy (I) 8,211 (II) 9,594 (III) 3,591

(II) 4,961*

(III) 2,115

(I) 12,775 (II) 15,180* (III) 5,707

Uterine artery embolization

(I) 8,293 (II) 10,696 (III) 2,084

(II) 5,049*

(III) 623

(I) 13,270 (II) 16,430* (III) 2,707

Endometrial ablation

(I) NR (II) 4,110 (III) NR

(II) 7,345*

(II) 12,096*

No surgical treatment

(II) 7,460*

(I) Dembek et al. 200861, (II) Carls et al. 200860, (III) Goldberg et al. 200762 – all US; *At one year; NR: Not reported


Two studies assessed the feasibility of outpatient and in-office procedures.12,148 A cost-effectiveness evaluation of polypectomy procedures by Clark et al. in 2015 for the UK showed that outpatient procedures would be considered as cost-effective compared to inpatient procedures (Table 6-3).12 This outcome was also supported by the work of Penketh et al., who found that the costs for outpatient procedures (£482-£901) were lower than for inpatient procedures (£1,018-£1,702).148

Table 6-3 Cost-effectiveness outpatient procedures

Cost QALY

Patient reported effectiveness

ICER

Outpatient £937.612 £482-£901148

0.833812 0.8112 445,867£ saved per QALY lost 12

Inpatient £1,606.312 £1,018-£1,702148

0.835312 0.8512 Reference

Clark et al. 201512, Penketh et al. 2014148

6.2.2. Computational analyses

Real-world analyses give a general overview of actual cost and health differentials. These studies, however, generally have a limited number of patients and a follow-up time of one year or less. The economic and health impact of an intervention may though, be realized over many years and could be impacted by the rare but important outcomes unlikely to be observed in a small cohort. Due to such limitations of real world data collection, computational models are an instrument to predict the health economic impact of an intervention.

As with real-world data, to date there is no computational analysis assessing the cost-effectiveness of mechanical hysteroscopic tissue removal. Three publications have assessed the cost-effectiveness of uterine fibroid removal, all with different verdicts (Table 6-4). Cain-Nielsen et al. showed in 2014 that myomectomy is cost-effective compared to MRgFUS and dominant (lower cost and more effective) compared to UAE. You et al. showed in 2009 that hysterectomy is dominant compared to both myomectomy and UAE, if indirect costs are included. Zowall et al. on the other hand claimed in 2008 that MRgFUS is dominant or at least cost effective compared to any other method.197 This analysis did not consider hysterectomy and myomectomy to be two different procedures, assigning them the same cost and safety profile.

Table 6-4 Cost and QALY of fibroid resection in computational models

Intervention Outcome Cain Nielsen et al.188 (USD) 5 years

You et al.133 (HKD converted to USD) 5 years

Wu et al.196 (GBP) 12 years

Uterine artery embolization (reference)

Cost QALY

18,653 3.943

8,174* 4.245

2,536 8.203

Myomectomy Cost (∆ vs UAE) QALY (∆ vs UAE) ICER vs UAE

15,459 (-3,194) 3.957 (+0.014) Dominant

7,504* (-670) 4.273 (+0.028) Dominant

- - -

Hysterectomy Cost (∆ vs UAE) QALY (∆ vs UAE) ICER vs UAE

- - -

8,418* (+244) 4.368 (+0.123) 1,984/QALY

3,282 (+746) 8.241 (+0.038) 19,632/QALY

MRgFUS Cost (∆ vs UAE) QALY (∆ vs UAE) ICER vs UAE

15,274 (-3,379) 3.953 (+0.01) Dominant

- - -

- - -

*Reported indirect costs were excluded from total costs


6.3.Review of published computational models

Four models of myomectomy and of varying complexity are currently published.133,188,196,197 The models, though, do have similarities. All models start with the respective treatment and assess for related adverse events before evaluating treatment success. If treatment fails or recurrence occurs, the treatment is repeated and/or a different method is used. Similarly, if pathology recurrence occurs patients undergo a repeat procedure. Except for the model by Cain-Nielsen et al, all models end in hysterectomy if multiple treatments fail.

As the models all differ in the currency used, it is difficult to directly compare the costs between the analyses. Common nevertheless is, that myomectomy was assigned the lowest unit cost of the considered treatments. QALY is a more universal measurement, allowing for comparison between studies. Here, the base case assumption of annual quality of life seems to differ between the analysis by Cain-Nielsen et al. and You et al., introducing a 0.3 difference in QALY over the whole time horizon. The difference in quality of life after 5 years between myomectomy and uterine artery embolization is similarly low in both models, being 0.014 (3.957 vs. 3.943) in the Cain-Nielsen model and 0.028 (4.273 vs. 4.245) in the You model (Table 6-4).133,188

The model by Zowall et al. (Figure 6-3A) addressed the cost-effectiveness of MRgFUS as first-line treatment. The comparator was the current standard of care, a mixture of myomectomy, uterine artery embolization, and hysterectomy. The model type is a mixed Markov decision tree model. After the selection of treatment, complications and procedure success are assessed. If the treatment failed, an alternative treatment is used: myomectomy or uterine artery embolization. The evaluation is repeated until the treatment is a success or hysterectomy is performed. An advantage of the model design is the long time horizon possible and that all procedures are accessible. The disadvantage is the focus on MRgFUS and the bias regarding input parameters as myomectomy and hysterectomy are considered equal in costs and efficacy.

The model by You et al. (Figure 6-3B) compares between myomectomy, uterine artery embolization and hysterectomy for their cost-utility. The chosen modelling approach is a mix of Markov and decision tree models. At initiation, the patients are distributed between hysterectomy, myomectomy and uterine artery embolization. For myomectomy and uterine artery embolization, the treatment can be either successful or relapse occurs. On relapse, the procedure will be repeated until the patient enters remission or a hysterectomy is performed. The strength of their model is the inclusion of relapse and remission, allowing to also account for these in patients’ quality of life. In addition, the model by You et al. provides an estimate on the indirect costs. A disadvantage is the limited time horizon (5 years), which does not allow for investigation of long-term progression.


Figure 6-3 Complex models of uterine fibroid resection

A: Model by Zowall et al. 2008197 B: Model by You et al. 2009133

The model by Cain-Nielsen et al. (Figure 6-4 A) considers uterine preserving procedures. The aim of this study was to determine which procedures were cost-effective. At initiation, the patient is assigned a treatment modality. If the treatment is a success, the patient stays in adequate relief until recurrence. In cases of recurrence and treatment failure, the patient will be treated again, with myomectomy as second line treatment. On one hand, the model is simple and does account for multiple lines of treatment, as well as major adverse events and productivity costs. On the other hand, the time horizon is only 5 years and the model schemata is overly simplified.

The model by Wu et al. (Figure 6-4 B) is a cost-utility analysis of uterine artery embolization. It compares hysterectomy and uterine artery embolization as first-line treatments. The chosen modelling approach is a decision tree model. The model does not include states but only direct procedure success or technical failure. If first-line uterine artery embolization results in a technical failure, the second-line procedure may be repeat uterine artery embolization, hysterectomy, or myomectomy. This decision tree repeats until the patient receives a hysterectomy or the procedure is considered a success. The model design is simple and based upon a cohort study, which is an advantage of the chosen approach. Also, the chosen time horizon of, at maximum, 21 years is accounting for long-term progression. Nevertheless, there are a number of disadvantages. First, recurrence is not well described. Second, the only procedure failure is “Technical failure”. Third, only using uterine artery embolization as second line treatment in case of unresolved symptoms is unique as the other three models directly consider the more invasive options. Lastly, the comparison of only hysterectomy and uterine artery embolization is questionable give that other possible methods are available.


Figure 6-4 Simple models for uterine fibroid treatment

A: Model by Cain-Nielsen et al. 2014188 B: Model by Wu et al. 2007196

6.4. A cost-utility model for the TruClear™ system for mechanical hysteroscopic tissue removal

6.4.1. Model structure

The developed cost-utility analysis for the TruClear™ system consists of two parts. The first part is a decision tree, determining the treatment related to pathology and assessing adverse events, outcomes and time (Figure 6-5). For each intervention, there is a probability of using sedation and/or anesthesia. Subsequently, procedure time and adverse events are evaluated including if the procedure was a success, failure, or resulted in an unlikely event of patient death. Initially all patients are eligible for hysteroscopic procedures, therefore hysterectomy and laparoscopic procedures are not used. In line with other published models in this area, after the decision tree enter a Markov model.


Figure 6-5 Treatment decision tree

The decision tree begins with assessment of the pathology and then the choice of procedure, then device, and then sedation. Subsequently, the characteristics of the chosen approach are tested via sampling against probabilities. Each patient is exposed to the risk of all adverse events individually and outcomes as competing risk. Patients enter the Markov model at either success, failure or death. AE, Adverse event; MAC, Monitored anesthesia care

The Markov model assesses long-term patient progression (Figure 6-6). This is simulated using a Markov model. The Markov model has health states that reflect real-world patient states. That is, the patient can be symptom free, develop pathology recurrence and/or symptom recurrence. Patients with recurrence of target pathology can re-enter the decision tree. At this stage, hysterectomy and laparoscopy are also potential treatments.

At each cycle (every three months) the Markov reevaluates if the patient stays in the current health state or progresses to a new one. In essence, thinking of a patient in the “success” health state, the patient can remain symptom free, develop symptom, have pathology recurrence or die. The probability of death is informed by WHO life tables.


Figure 6-6 Markov model for long-term patient progression

Patients enter the model from the decision tree at either Success, Failure, or Death. At each time point in the model, there is a probability of staying in the same health state or moving to one of the subsequent health states. If there are no subsequent health states depicted, they are identical to the left-most equivalent health state in the branch. Death is a terminal state from which no other health states can be accessed. AUB, Abnormal uterine bleeding.


Each health state is associated with both costs and patient quality of life modulators. For example the cost of “hysterectomy” is GBP 4,897.15 while the cost of “Treatment of pain” is 27.59.198 Each patient with pain loses 0.06 units of quality of life, compared to a loss of 0.1 units for abnormal uterine bleeding.146 By running up costs and quality of life over time the cost and health impact of interventions can be quantified. The model is run once with mechanical hysteroscopic tissue removal data and once with competitor to assess the cost-effectiveness of hysteroscopic mechanical tissue removal. Full details of input data are in the appendix.

6.4.2. Uterine fibroid removal

6.4.2.1. Base case data

The base case result of the cost-effectiveness model for the TruClear™ system considers a 50 year time horizon and a pathology distribution of 18.5% type 0 fibroids, 64.1% type 1 fibroids and 17.4% type 2 fibroids. The population has a mean age of 51 years and 45% are post-menopausal. The country for which incidences, prevalences and costs are used is the United Kingdom (UK). As comparator, bipolar resection was identified as the most relevant to UK healthcare practice.

6.4.2.2. Base case results

The model showed that the TruClear™ system is cost-effective compared to bipolar resection (Table 6-5). The overall associated costs were lower and the quality of life was higher with the TruClear™ system. The TruClear™ system showed a decrease in costs of GBP 1,340 and an increase in the quality adjusted life expectancy of 0.28 QALYs.

Table 6-5 Results of the base case for uterine fibroid removal

Bipolar resection TruClear™ system Difference

Total cost (GBP) 4,337 2,997 -1,340

Life expectancy 34.56 34.56 0

Total QALE 30.57 30.85 0.28

Hysteroscopic procedures

2.33 1.69 -0.64

6.4.2.3. Sensitivity analyses

Sensitivity analysis is an instrument to assess the uncertainty of the base case analysis. Using the standard deviation of input data, different scenarios are sampled and assessed for their individual cost-effectiveness. For the cost-effectiveness analysis here, 1,000 runs performed.

6.4.2.4. Quantifying uncertainty in the model results

Sensitivity analysis showed that the TruClear™ system was at least cost-effective in 77.6% of all scenarios assuming a GBP 10,000 willingness-to-pay threshold (Figure 6-7). Only in 22.4% of scenarios was the TruClear™ system considered as non-cost-effective. In general, the TruClear™ system led to both an increase in QALY and a decrease in costs.


Figure 6-7 Cost effectiveness plane fibroid removal with the TruClear™ system

Cost-effectiveness plane for uterine fibroid removal using the TruClear™ system compared to bipolar resection. The willingness-to-pay threshold was assumed as GBP 10,000.

6.4.3. Endometrial polyp removal

6.4.3.1. Base case data

The base case result of the cost-effectiveness model for the removal of endometrial polyps with the TruClear™ system considers a 50-year time horizon. The population has a mean age of 51 years and 45% are post-menopausal. The comparator is bipolar resection.

6.4.3.2. Base case results

The model showed that the TruClear™ system is cost-effective compared to bipolar resection (Table 6-6). The overall associated costs were lower and the quality of life was higher with the TruClear™ system. The TruClear™ system showed a decrease in costs of GBP 708 and an increase in the quality adjusted life expectancy of 0.08 QALYs.

Table 6-6 Results of the base case for endometrial polyp removal

Bipolar resection

TruClear™ system Difference

Total cost (GBP) 3,338 2,629 -708

Life expectancy 34.56 34.56 0

Total QALE 31.04 31.12 0.08

Hysteroscopic procedures

1.84 1.48 -0.37

6.4.3.3. Sensitivity analyses

For the cost-effectiveness analysis here, 1,000 runs performed.


6.4.3.4. Quantifying uncertainty in the model results

Sensitivity analysis showed that the TruClear™ system was at least cost-effective in 90% of all scenarios assuming a GBP 10,000 willingness-to-pay threshold (Figure 6-8). Only in 10% of scenarios was the TruClear™ system considered as non-cost-effective. In general, the TruClear™ system led to both an increase in QALY and a decrease in costs.

Figure 6-8 Cost-effectiveness plane endometrial polyp removal with the TruClear™ system

Cost-effectiveness plane for endometrial polyp removal using the TruClear™ system compared to bipolar resection. The willingness-to-pay threshold was assumed as GBP 10,000.

6.4.4. Discussion and conclusions

Considering the presented evidence hysteroscopic tissue removal may be considered as cost-effective. Most real-world cost-collection studies have shown that uterine fibroid resection is a cost-saving and cost-effective strategy. Those studies were irrespective of the route and it was shown that the abdominal and hysteroscopic routes were 37% and 77%, respectively, more expensive than the hysteroscopic route (Table 6-1).60 Therefore, the reported costs may be an overestimate for the hysteroscopic route, thus increasing its potential cost-effectiveness.

Regarding models, the evidence is mixed. Uterine fibroid removal has the lowest associated costs in studies assessing its cost-effectiveness (Table 6-4). QALYs were reported to be both higher and lower with uterine fibroid resection compared to hysterectomy.60–62,133,188 It is important to take into consideration that this comparison lacked the impact of the loss of fertility, which may irrespective of the quality adjusted life years shift the patients’ preference to uterine fibroid resection. The assessed comparator, uterine artery embolization, was dominated by uterine fibroid resection in both analyses assessing its cost-effectiveness.133,188

The cost-effectiveness of mechanical hysteroscopic tissue removal has been noted as an evidence gap.133,188 To address this, a cost-effectiveness model for direct comparison of electrosurgical and mechanical hysteroscopic tissue removal was developed. The results of this model showed that while both methods are efficient in the removal of the pathology, the TruClear™ system reduced the need for reinterventions and therefore reduced the costs of care (Table 6-5). The lower need for further surgical procedures also had a positive


impact on patient quality of life, increasing the quality adjusted life expectancy by more than one year over the 50-year time horizon.

Overall, there is good evidence supporting the cost-effectiveness of myomectomy.133,188 The analysis presented here extents that to mechanical hysteroscopic tissue removal specifically, indicating that the TruClear™ system could be considered as an effective and cost-effective option for healthcare provider.


7. Benefits of hysteroscopic mechanical tissue resection

Key messages

Hysteroscopic mechanical tissue removal procedures are suitable for day-case, outpatient, and in-office procedures.152

Both, endometrial polyp resection and uterine fibroid removal result in improved patient quality of life.12,13

Up to 100% of procedures with the TruClear™ system were reported to successfully remove all target pathology.23,24

After 4 years, only 3.1% of patients had recurrence of endometrial polyps.142 Residents in training reported a substantially higher convenience with hysteroscopic

tissue removal compared to electrosurgical procedures.24

7.1.1. Non-invasive surgery

Removal of uterine fibroids and endometrial polyps requires access to the uterus. This is possible via various routes, of which hysteroscopic tissue removal is the least invasive. Use of the vaginal route requires that no additional artificial opening to the body be made, which facilitates recovery and reduces the need for inpatient stay. The average length of stay was reported to be as low as 4 hours, making the hysteroscopic tissue removal even suitable for day-case procedures.152 This is likely favorable in all countries as in-office or outpatient procedures can generally be performed at lower cost compared to inpatient procedures.12,14 Furthermore, the non-invasive nature of a hysteroscopic procedure leaves the uterus intact and does not result in the need for suturing and the potential for visible scars. Both of these may be perceived as a benefit for patients.

7.1.2. Improved quality of life

The quality of life of patients with abnormal uterine is reduced compared to healthy individuals.71,146 Likewise, patients with uterine fibroids and endometrial polyps have been shown to have reduced quality of life.12,13 In the UK, NICE guidelines have made improving patient quality of life the driving factor in treatment decisions.101 For uterine fibroids and endometrial polyps a variety of trials have shown that hysteroscopic tissue removal is effective in recovering patients quality of life.12,13,151 For having endometrial polyp resection, quality of life improved substantially after 6 months (Table 7-1). For uterine fibroids significant improvements in all subcategories of the patients’ health perception were achieved one year after the procedure (Table 7-2).13

Table 7-1 Quality of life associated with endometrial polyp resection

baseline 6 months 1 year 2 years healthy157

Polypectomy 0.78 0.87 0.86 0.84 0.916*

Clark et al. (2015)12; Huber et al. (2015)157; *QoL for women between 40 and 49 years used.


Table 7-2 Quality of life associated with uterine fibroid resection

Uterine fibroids Control at baseline n=101

Control at 1 year

Cases at baseline n=274

Cases at 1 year post intervention

Cases 1 year difference post-procedure

p-value 1 year

SF-36

Physical functioning 93.2 95.4 74.8 91 +16.2 .013

Role physical 93.4 93.8 48.0 83.7 +35.7 .001

Bodily pain 86 85.9 48.2 77.0 +28.8 <.001

General health 83.3 81.3 66.9 75.5 +8.6 .014

Vitality 62.8 66.1 37.8 61.7 +23.9 .077

Social functioning 90.3 93.7 58.0 83.7 +25.7 <.001

Role emotional 89.3 89.0 51.9 80.3 +28.4 .016

Mental health 78.8 80.6 62.2 76 +13.8 .012

Physical component score 54.7 54.7 43.4 52 +8.6 .001

Mental component score 51.3 52.3 40.4 49.6 +9.2 0.013

Spies et al. 201013

7.1.3. A high chance of procedure success

The primary outcome of importance during pathology-removal procedures is the completeness of the removal. It has been shown that upon successful removal of these pathologies, the quality of life of the patients increases quickly over the next year.12,13,149 Therefore it is of high interest to both the physician and the patient that the pathology is removed completely. Hysterectomy, by definition removes all uterine fibroids and endometrial polyps, but renders the patient infertile. Fennessy at al. showed that patients favor living with symptoms longer over undergoing hysterectomy.22 Hysteroscopic options maintain patient fertility and have high rates of success. In 20 trials assessing outcomes in over 1,000 patients the success rate of mechanical hysteroscopic tissue removal was determined to be 97% for endometrial polyp and 81% for uterine fibroid resection (Table 7-3 and Table 7-4). Considering only the TruClear™ system related trials, the success rate for uterine fibroid resection rises to over 90%. Comparative trials assessing the outcomes of electrosurgical and mechanical hysteroscopic tissue removal also showed that the mechanical approach was at least equivalent if not even superior to electrosurgical resection. The odds of successful removal of endometrial polyps with the TruClear™ system significantly increased compared to bipolar resectoscopy (OR: 6.67; 95% CI: 2.7 – 16.49).23,24,39,44,47,51,52,58,59


Table 7-3 Odds ratio of success for endometrial polyp resection

TruClear™ system

All mHTR devices

Monopolar eHTR devices

Bipolar eHTR devices

Studies, N 5 18 2 4

Patients, N 226 754 31 182

Successful, N 220 733 31 154

Efficacy, % success

97.22 97.21 100 84.54

OR of success

(95% CI)

Ref 0.95 (0.38-2.39)

1.86 (0.10–33.77)

0.15 (0.06-0.37)

Table 7-4 Odds ratio of success for uterine fibroid resection

TruClear™ system

All mHTR devices



Studies, N 2 7 2 2

Patients, N 58 266 24 100

Successful, N 52 215 20 70

Efficacy, % success

90.15 80.86 84.3 69.81

OR of success

(95% CI)

Ref 0.49 (0.20-1.19)

0.58 (0.15-2.26)

0.27 (0.10-0.69)

7.1.4. Low rates of recurrence

Endometrial polyps and uterine fibroids are a frequent cause of infertility and can have a substantial impact on patients’ quality of life.12,13 The recurrence rate of the pathology is therefore of high interest. Hysterectomy eliminates the risk for recurrence, but is also a major surgical procedure associated with the loss of fertility. Hysteroscopic tissue removal is beneficial in this context, as it leaves the uterus intact. It has also been associated with a low rate of symptom recurrence (18% over 4 years) by AlHilli et al.142 The same study reported that endometrial polyps recur in 3.1% of patients treated by mechanical hysteroscopic tissue removal and 10.6% of the electrosurgically treated patients after 4 years.142 A second trial by Preutthipan and Herabutya did not even detect any recurrence of endometrial polyps 9 years after using hysteroscopic removal.174

7.1.5. Regain of fertility

Endometrial polyps and uterine fibroids can cause infertility in some patients.199 To regain fertility the removal of those pathologies is recommended. In guidelines, hysteroscopic tissue removal is recommended as a method intended to reduce damage to the uterus or


even directly referred to as an option to maintain or enhance fertility.1,7,63,104 Two trials have reported the on-term life-birth rate after treatment with hysteroscopic tissue removal, both showing similar success rates of 45% and 46%.155,200

7.1.6. High patient satisfaction

Procedure outcomes as well as the experience during the procedure are important for patients. Compared to alternatives, mechanical hysteroscopic tissue removal is a less invasive, shorter procedure that lowers the burden on patients. Being associated with an average length of stay of 4 hours mechanical hysteroscopic tissue removal does not require a long absence from normal daily activities. These benefits are reflected in reported patient satisfaction rates. Smith et al. reported that 97% of patients treated by mechanical hysteroscopic tissue removal found the procedure at least generally acceptable.42 This was only true for 78% of patients being treated with electrosurgical hysteroscopic tissue removal.42 An underlying cause for this discrepancy may be found in the experienced pain due to the procedure, which was reported both during and after the procedure as significantly lower with mechanical hysteroscopic tissue removal (Table 7-5).42 Kulbersh and Rubino assessed if patients would recommend mechanical hysteroscopic tissue removal to their friends and found that 92.7% would recommend it in the hospital setting and 100% in the outpatient setting.165

Table 7-5 Experienced pain score during procedure

Pain Score Hysteroscopic Morcellation

Electrical Resection

Mean Difference (95% CI)

p-value

Baseline 8.1 ± 9.4 5.1 ± 9.7 -3.0 (-6.4 — 0.5) .1

During procedure

35.9 ± 23.5 52.0 ± 23.5 16.1 (7.6 — 24.7) <.001

After procedure

23.9±21.2 31.0±23.9 6.1 (-11 — 15.3) .09

7.2.Optimization of healthcare resources

Abnormal uterine bleeding and treatment of uterine fibroids and endometrial polyps can place a large burden on healthcare providers. In the US, pre- and postmenstrual women are affected by abnormal uterine bleeding with an incidence of 25% and a prevalence of 40%. 3,72 Uterine fibroids alone accounted for 195,735 hysterectomies within the US in 2010.128 This adds substantially to the healthcare burden within the US and demonstrates why efficient usage of healthcare resources is imperative.

7.2.1. Shorter operation room time

The operation room is one of the most resource intensive areas of a hospital. The cost of operation room time has been reported at GBP 16.35 per minute.201 As such, operation room time is an important factor in the healthcare utilization associated with uterine fibroid and endometrial polyp removal. Reducing the procedure time would positively impact resource usage. Comparative trials have shown that the procedure time with mechanical hysteroscopic tissue removal is substantially reduced compared to electrosurgical resection (Table 7-6 and Table 7-7).23,24,39,44,47,51,52,58,59 The average procedure duration with mechanical hysteroscopic tissue removal was reported as 7.32 minutes for polyps and 21.17 minutes for fibroids. These time reductions could save GBP 225.79 per procedure in operation room time alone, or allow for increased throughput for the provider.39,42,44,47


Table 7-6 Procedure duration endometrial polyp resection

TruClear™ system

All mHTR devices



Studies, N 5 8 2 4

Patients, N 442 510 31 340

Procedure duration

7.32 ± 1.45 7.27 ± 1.32 20.15 ± 5.23 16.84 ± 6.22

Significance Reference NS P<0.05 P<0.05

NS: Not significant

Table 7-7 Procedure duration uterine fibroid resection

TruClear™ system

All mHTR devices



Studies, N 3 6 4 2

Patients, N 95 193 210 100

Procedure duration

15.27 ± 3.99 21.17 ± 8.23 40.79 ± 8.36 30 ± 1.38

Significance Reference P<0.05 P<0.05 P<0.05

NS: Not significant

7.2.2. High physician acceptance

An important aspect influencing uptake and use of new technology is acceptance by the physician conducting the procedure. Multiple studies have addressed the acceptability of hysteroscopic mechanical tissue resection. Van Dongen et al. (2008) reported on the difference in convenience for residents in training between hysteroscopic electrosurgical tissue resection and mechanical tissue resection.24 The convenience was generally higher for hysteroscopic mechanical tissue resection. In the main, mHTR was assigned with the highest convenience rating by the participants (Figure 7-1), and was the only method to receive scores of 9 and 10 out of 10 on the scale used.


Figure 7-1 Convenience with procedure of residents in training

Difference in convenience for electrosurgical tissue resection (white) and mechanical tissue resection (black). Taken from Van Dongen et al.24

Another trial by Pampalona at al. in 2015 reported on the need of residents in training to receive practical guidance in order to complete the procedure. While for resectoscopy a takeover by the trainer was necessary in every case, 5/23 procedures with the TruClear™ system were manageable without physical guidance (Figure 7-2).47 This is similar to findings by Van Dongen et al., who reported that only 3% of hysteroscopic mechanical tissue resection procedures were taken over by trainer compared to 17% with resectoscopy.24 Beside easier handling of hysteroscopic tissue removal devices, the duration of the procedures was reduced compared to resectoscopy.23,24,39,44,47,51,52,58,59 Together with the reduced need for reinsertion, physicians found that this positively influenced the procedure complexity.24,44,51


Figure 7-2 Number of procedures which required guidance

VS = VERSAPOINT™* system, TS = TruClear™ system. 1 = inability to perform the procedure, 2 = need for practical and verbal guidance during more than 50% of the procedure, 3 = need for practical and verbal guidance during less than 50% of the procedure, 4 = need for verbal assistance and support, and 5 = no help of any kind. Taken from Pampalona et al. 47

7.2.3. Cost-effective intervention

Hysteroscopic tissue removal is a cost-effective intervention to treat AUB related to endometrial polyps and uterine fibroids. A variety of trials assessing the costs and cost-effectiveness of various treatment modalities showed that uterine fibroid resection was mostly the lowest cost modality and associated with better long-term outcomes.60–62,133,188 All these studies investigated myomectomy as a mix of hysteroscopic, laparoscopic and abdominal surgery.60 As hysteroscopy is of lower cost than the other two, it is likely that its cost effectiveness is improved relative to that published. Therefore, it is likely that those studies underestimate the benefits of hysteroscopic tissue removal.

Mechanical hysteroscopic tissue removal with the TruClear™ system can be performed as a day-case, outpatient, or in-office procedure. Compared to the inpatient setting, these settings were found to be both cost-saving and cost-effective in studies. Therefore, the TruClear™ system may help to reduce the burden on the health system.12,148

Compared to electrosurgical hysteroscopic tissue removal, the TruClear™ system was found to be cost-effective in analyses presented in sections 6.4.1 and 6.4.2. The TruClear™ system reduced the reintervention rate and was associated with both lower costs and a higher quality of live over patients’ lifetime (See sections 6.4.1 and 6.4.2).


7.3. Summary

Mechanical hysteroscopic tissue removal is beneficial for endometrial polyp and uterine fibroid removal. It has been shown that the procedure is faster and more efficient than electrosurgical hysteroscopic tissue removal. Patients and physician acceptance of the procedure was also found to be higher with mechanical hysteroscopic tissue removal then with competitors. This can be related to patients experiencing significantly lower experienced pain during and after the procedure, and improved handling and fewer insertions for physicians.

Compared to hysterectomy mechanical hysteroscopic tissue removal is associated with lower costs. This is attributable to the minimally invasive manner of hysteroscopic tissue removal which is in most cases does not require an inpatient stay. Cost-effectiveness analysis has found that mechanical hysteroscopic tissue removal will likely provide a cost-benefit to healthcare payers and providers.

Where data are available for the TruClear™ system devices specifically, these studies have consistently found that the TruClear™ system is faster and more efficient than competitor technology. As such, TruClear™ system devices may offer additional economic and health benefits over other methods of mechanical hysteroscopic tissue removal.



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8. Appendix

8.1.Efficacy data

Table 8-1 Complete efficacy data

Type Device Patients Completion rate fibroid

Completion rate polyp

Procedure time fibroid

Procedure time polyp

Fluid deficit fibroid

Fluid deficit polyp

Level of Evidence

Emanuel (2005)23


IUM 55 93 100 16.4 8.7 660 220.4 2b

Van Dongen (2008)24


IUM 30 87.5 100 10.6 10.6 409 409 1b

Bigatti (2010)Ѳ25


IBS™* 44 66.67 100 14 3.28 4

Lukes (2010) Ѳ26

Fibroids, polyps

MyoSure™* 13 92.31 92.31 1.4 (RT) 1.4 (RT) 4

Hamerlynck (2011)27


TruClear™ system

315 18.2 6.6 440 2b

Mathiopoulos (2011) Ѳ 28

Fibroids, polyps

TruClear™ system

Not specified

32 9 4



90

Rubino (2011) Ѳ 29

Fibroids, polyps

MyoSure™* 41 98 98 3.2 (RT) 3.2 (RT) 4

Bigatti (2012)30 Fibroid type 0-2, polyps

IBS™* 50 100 100 27.41 6.76 666.66 124.2 2b

Lukes (2012) Ѳ 31


MyoSure™* 37 1.2 (RT) 1.2 (RT) 4

Lukes (2012) Ѳ 32

Fibroid type 0, polyps

MyoSure™* 30 4


Fibroid type 0-1

MyoSure™*,TruClear™ system

50 4

Bigatti (2013) Ѳ 34

Fibroids, polyps

IBS™* 76 93.5 4

Harari (2013) Ѳ 35


MyoSure™* LITE, MyoSure™* XL

220 98 (LITE) / 92 (XL)

98 (LITE) / 92 (XL)

2.3 (LITE) / 5.8 (XL) (RT)

2.3 (LITE) / 5.8 (XL) (RT)

301 (LITE)/1066 (XL)

301 (LITE)/1066 (XL)

4

Lukes (2013) Ѳ 36


MyoSure™* 76 96 98 4



91

Lukes (2013) Ѳ 37


MyoSure™* 17 4

Bigatti (2014) Ѳ 38

Fibroid type 0-2

IBS™* Not specified

4

Bigatti (2014)39 Fibroid type 0-2

IBS™* 76 90.1 29.12 406.9 2b

Lukes (2014) Ѳ 40


MyoSure™* 23 4

Lobo Abascal (2014) Ѳ 187

Polyps TruClear™ system

Not

specified

12.35 4



MyoSure™* XL

100 17.16 7 985 290 4

Smith (2014)42 Polyps TruClear™ system 5.0

62 98 1b

Scheiber (2014) Ѳ 43


MyoSure™* 55 4

Hamerlynck (2015)44

Polyps TruClear™ system 8.0

44 100 9.5 165 1b



92

Krishnamurthy (2015) Ѳ 45


MyoSure™* 95 95 500 500 4


Fibroids type 0-2, polyps

MyoSure™* 140 17.16 7 985 290 4

Pampalona (2015)47

Polyps TruClear™ system 5.0

63 92 6.8 1b

Reddy (2015)48 Fibroids, polyps

MyoSure™* 26 92.3 92.3 5-54 5-54 100-705 100-705 4

Stoll (2015) Ѳ 49 Polyps IBS™* 22 6.5 430 4

Arnold (2016)50 Fibroid type 0-2, polyps

MyoSure™* LITE, MyoSure™* XL

255 66 92 4.33 (RT) 0.28 (RT) 800 200 2b

Borg (2016)51 Fibroid type 0-1, polyps

IBS™* 50 90 100 9.33 8.13 356.8 356.8 2b

Lee (2016)52 Fibroids MyoSure™* 29 36.6 1005 2b

Ms (2016) Ѳ 53 Fibroids MyoSure™* 50 3.37-6.44 830-1050 4

Palinska-Rdzka (2016) Ѳ 54

Fibroids, polyps

MyoSure™* 130 75 99.2 4



93

Scheiber (2016)55

Fibroids, polyps

MyoSure™* 278 86.8 99.3 6 (RT) 6 (RT) 287 287 2c

Torres (2016) Ѳ 56

Polyps TruClear™ system

Not specified

13 4

Rubino (2017) Ѳ 57


MyoSure™* 26 96 96 19 19 4

Ѳ Congress abstract; RT indicates resection time, not the complete procedure duration; IUM: Intra-uterine morcellator [Precursor TruClear™ system]


8.2. Level of evidence table

There are multiple sources of data available for TruClear™ system devices and other hysteroscopic interventions. Not all these data are of equivalent quality, as features such as study design and patient numbers influence the degree to which results can be generalized. To address the variation in study design and quality, the Oxford level of evidence classification scheme was developed (Figure 8-1 & Figure 8-2). This scheme has a set of quality levels from 1a (best, trial was well-conducted and the result can be considered as strong evidence) to 5 (lowest). The quality of a study is determined by considering a set of conditions specific to the aim of the study.

Figure 8-1 Oxford levels of evidence scheme

Level Therapy / Prevention, Aetiology / Harm

Prognosis Diagnosis Differential diagnosis / symptom prevalence study

Economic and decision analyses

1a SR (with homogeneity) of RCTs

SR (with homogeneity) of inception cohort studies; CDR” validated in different populations

SR (with homogeneity) of Level 1 diagnostic studies; CDR” with 1b studies from different clinical centres

SR (with homogeneity) of prospective cohort studies

SR (with homogeneity) of Level 1 economic studies

1b Individual RCT (with narrow Confidence Interval”)

Individual inception cohort study with > 80% follow-up; CDR validated in a single population

Validating cohort study with good reference standards; or CDR tested within one clinical centre

Prospective cohort study with good follow-up

Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses

1c All or none All or none case-series

Absolute SpPins and SnNouts

All or none case-series

Absolute better-value or worse-value analyses

2a SR (with homogeneity) of cohort studies

SR (with homogeneity) of either retrospective cohort studies or untreated control groups in RCTs

SR (with homogeneity) of Level >2 diagnostic studies

SR (with homogeneity) of 2b and better studies

SR (with homogeneity) of Level >2 economic studies

2b Individual cohort study (including low quality RCT; e.g., <80% follow-up)

Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR or validated on split-sample only

Exploratory cohort study with good reference standards; CDR after derivation, or validated only on split-sample or databases

Retrospective cohort study, or poor follow-up

Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses

2c “Outcomes” Research; Ecological studies

“Outcomes” Research

Ecological studies Audit or outcomes research

See footnote for Figure 8-2 for details.


Figure 8-2 Oxford levels of evidence scheme (continued)

3a SR (with homogeneity) of case-control studies




3b Individual Case-Control Study

Non-consecutive study; or without consistently applied reference standards

Non-consecutive cohort study, or very limited population

Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations.

4 Case-series (and poor quality cohort and case-control studies)

Case-series (and poor quality prognostic cohort studies)

Case-control study, poor or non-independent reference standard

Case-series or superseded reference standards

Analysis with no sensitivity analysis

5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”

Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”



Expert opinion without explicit critical appraisal, or based on economic theory or “first principles”

CDR, Clinical decision rule (algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category); RCT, Randomized, controlled trial; SR, Systematic review. Taken from: http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/

8.3. Additional fibroid classification systems

In addition to the PALM-COEIN system a few other fibroid classification systems have been established. In 1993 Wamsteker et al. published the ESGE classification scheme.202 Within this system, uterine fibroids are classified as three types:

• Type 0: Entirely within endometrial cavity, no myometrial extension • Type I: <50% myometrial extension, <90-degree angle of myoma surface to uterine

wall • Type II: ≥50% myometrial extension, ≥90-degree angle of myoma surface to uterine

wall

A more specific classification system, the STEPW system, was introduced by Lasmer et al. in 2005, assigning a scoring system to estimate the complexity of the present fibroid and appropriate treatment options (Figure 8-3).203


Figure 8-3 STEPW fibroid classification system

Taken from Lasmer et al. 2011.204



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8.4. Health-economic model development

8.4.1. Recurrence data

No single, recent study provided sufficient data on the recurrence of pathology after hysteroscopic surgery. Hand searches were performed in PubMed to identify further studies to inform the modelling process. The studies reporting on pathology recurrence are summarized in Table 8-2.

Table 8-2 Recurrence data published in peer-reviewed literature

Time Derman 1991 Emanuel 1999 Henriquez 2007 AlHilli 2013 Paradisi 2014 Ulubay 2015 Yang 2015

Post surgery, years

Surgery free post-fibroid, %

Surgery free post-fibroid, %

Surgery free, % Polyp free, % Polyp

recurrence, % Polyp

recurrence, % Polyp

recurrence, %

0.5 1.5

1 90.4 67.6 35.3

2 86.9 90.5 95.5

3 85.5 35.6

4 83.9 41.1 89.4

5 83.9 79.5 50.0

6 83.9 13.3* 58.8

7 83.9

8 83.9 73.3

9 83.9

10 83.9

11 83.9

12-16 62.9

* Average follow-up time was 26.3 months +/- 19.7. For 95% of patients, recurrence would have occurred by the mean time plus two standard deviations, a total of 5.5 years



98

8.4.1.1. Fibroid recurrence

Two papers reported on myomectomy,205,206 with both reporting surgery-free survival that was taken as a proxy for fibroid recurrence. In Figure 8-4, the data points are seen as dark blue points. Using Curve Expert Pro software, non-linear regression fitting was undertaken and the Dose-Response-Hill Curve (red line) found to be the best approximation to the data that did not break the rules of cumulative incidence. That is, that the extrapolated cumulative incidence did not pass 100% within patient lifetimes and did not decrease over time. Using the regression equation, it is expected that just over 60% of patients would experience fibroid recurrence over a 50-year period.

Figure 8-4 Extrapolation of fibroid recurrence to 50 years post intervention

Data are taken from Derman 1991 and Emanuel 1999, both of whom reported surgery-free survival following myomectomy. This was taken to be a proxy for fibroid recurrence. Data (dark blue points) were available to 16 years post surgery, and were extrapolated using a Dose-Response-Hill curve with zero background (DR-Hill-Zerobackground, red line). The Dose-Response-Hill curve with zero background was found to be the best fit to the data (that did not break rules for cumulative incidence) using Curve Expert Pro software. The zero background means that the recurrence rate id only linked to the years post-surgery and no other factor.

8.4.1.2. Polyp recurrence

The data available to inform the long-term recurrence polyps varied greatly between sources, with Yang et al. indicating 14.8% (25 of 168 women) recurrence after 1-year follow-up compared with AlHilli reporting a 4.5% recurrence after 2 years.142,207 Three studies that reported similar levels of



99

polyp recurrence were selected for data analysis,142,208,209 with the study by Yang et al. rejected as an outlier. As with the fibroid recurrence data, the Dose-Response-Hill curve was found to be the best fit to the data that did not break the rules of cumulative incidence (Figure 8-5). After 50 years, extrapolation of the published data suggests that 38% of patients would have recurrence.

Figure 8-5 Extrapolation of polyp recurrence to 50 years post intervention

Data points (dark blue points) and the best fit regression line, a Dose-Response-Hill curve (red line).



100

8.4.1.3. Abnormal uterine bleeding recurrence

A similar approach was taken for the recurrence of symptomatology, with data for abnormal uterine bleeding (AUB) taken from the study performed by AlHilli et al.142 The authors found that AUB was reported by 4.8%, 10.2%, 15.9%, and 23.0% of patients 1, 2, 3, and 5 years after hysteroscopic removal of polyps, respectively.

8.4.1.4. Calculating the annual recurrence rate

The expected cumulative incidence in the model was determined by solving the equation for the regression line (Equation 1). Where Yn is the year for which the cumulative incidence is to be determined. The other variables: 𝚹𝚹, 𝛂𝛂, and 𝛅𝛅 are defined by the regression equation, and their values for fibroid and polyp recurrence are provided in Table 8-3. Within the model, the actual expected cumulative incidence is adjusted to the specified input data. For example, if the user input was 10% fibroid recurrence after 5 years then the estimate provided by the regression curve would be multiplied by a factor of circa 0.5, because the current baseline estimate is a recurrence rate of approximately 20% after 5 years (Figure 8-4). A factor is used to adjust the regression equation as opposed to addition or subtraction of an absolute value in order to prevent negative numbers from being returned.

The annual recurrence rate for the model population is calculated via solving Equation 1 first with the current year (Y1) and previous year (Y0) as input variables to give CI1 and CI0, respectively. The percentage of patients expected to have recurrence (PR) in the year from Y0 to Y1 is then given by Equation 2.

Equation 1: Equation 2:

Table 8-3 Non-linear regression variables for the Dose-response-Hill curve

Variable Fibroids Polyps

𝚹𝚹 3,357.89 44.18

𝛂𝛂 0.53 10.79

𝛅𝛅 82,324.58 1.22


8.5. Retained products of conception (RpoC) Retained products of conception are potential, partial remnants following from birth, miscarriage, or termination of pregnancy.210 The condition can result in uterine bleeding and infection, and may present as AUB. Over the long term and if left untreated, RpoC can develop into uterine adhesions (Asherman’s syndrome), which may affect future pregnancy outcomes.211 The incidence of RpoC has been reported as 6.3 cases per 100 deliveries or miscarriages.212 In patients undergoing medical abortion, the incidence increases to 15 cases per 100 procedures.213 RpoC are indicated for hysteroscopic tissue removal and a study by Hamerlynck et al. reported that in 94.3% of all cases the pathology was completely removed in the first approach.214

8.5.1. Hysteroscopic Morcellation Versus Loop Resection for Removal of Placental Remnants: A Randomized Trial

Citation

Hamerlynck TW, van Vliet H, Beerens AS, Weyers S, Schoot BC. Hysteroscopic Morcellation Versus Loop Resection for Removal of Placental Remnants: A Randomized Trial. J Minim Invasive Gynecol. 2016; 23(7): 1172–1180.

Country Belgium, Holland

Setting Day surgery setting of a teaching and a university hospital. Operating room. Spinal or general anesthesia.

Design Open-label randomized controlled trial

Enrolment Between May 2011 and July 2015

Follow-up Data on persistence of symptoms or intrauterine pathologies at 6- to 8 weeks follow-up

TruClear™ system

TruClear™ system 8.0 for tissue removal

Comparators Loop resection with a rigid 8.5-mm bipolar resectoscope (Karl Storz GmbH, Tuttlingen, Germany).

Patients 86 women diagnosed with placental remnants after pregnancy requiring operative removal. 46 with the TruClear™ system and 40 with resectoscope

Endpoints Operating time, fluid deficit, number of insertions, adverse events, and postoperative adhesions

Publication Journal article

Hamerlynck et al. compared theTruClear™ system 8.0 with bipolar resectoscopy (BPR) for removal of placental remnants in terms of operating time, fluid deficit, number of insertions, adverse events, and postoperative adhesions. For 63 of the 86 enrolled women, abnormal uterine bleeding was the reported preoperative symptom. Removal of placental remnants required general anesthesia in 85% of procedures using the TruClear™ system for hysteroscopic tissue removal compared with 87.5 % using bipolar resectoscopy (BPR).

Operating time was defined as the time from visual introduction of the hysteroscope until completion of the procedure, meaning definite removal of the hysteroscope from the uterine cavity. After controlling for the diameter of removed placental remnants, the median operating time was significantly reduced with the TruClear™ system, a reduction of 40% (95% CI: 15%–58%, p = .005), compared with resectoscopy. Additionally, the number of insertions using the TruClear™ system was significantly reduced (p < .001) and the tissue removal procedure in both techniques was successful and complete in 93% (77 out of 83 patients) of cases.


The authors reported a relatively high number of perforations (9%) caused by dilation but none during insertion in either technique. They also reported the absence of adverse events during the hysteroscopic part of tissue removal with the TruClear™ system compared with two serious adverse events for patients in the resection group (allergic reaction to antibiotics and postoperative superficial thrombophlebitis at the intravenous infusion site in the arm). At follow-up, office second-look hysteroscopy was performed in 68 of 83 patients (82%). De novo intrauterine adhesions was reported in 3% of patients treated for removal of placental remnants with either technique: 1 of 35 patients in the TruClear™ system group vs 1 of 30 patients in the resection group.

Conversion to another technique took place in 3 of 44 patients (7%) of the hysteroscopic morcellation group (electric vacuum aspiration: n = 2 [bad visibility ± poor distention/rapid fluid loss], office hysteroscope: n =1 [hemiuterus, perforation at dilation]) and 1 of 39 patients (3%) of the resection group (electric vacuum aspiration: n = 1 [remnants too adherent])

Table 8-4 Data comparing the TruClear™ system and bipolar resectoscopy (BPR)

Technique Age (yr) Mean operating time, minutes (IQR)

Mean fluid deficit, mL (IQR)

Number of insertion(IQR)

TruClear™ system 32±6 6.2 (4.0–11.2) 165 (138.1–302.7) 1 (1–1)

BPR 31±4 10.0 (5.8–16.4) 200 (110–290) 3 (1–4)

Improvement with TruClear™ system, p-value

p=0.72 p=0.023 p=0.45 p<0.001

IQR= interquartile range [25th to 75th percentile]


8.5.2. A Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies

Citation Arnold A, Ketheeswaran A, Bhatti M, Nesbitt-Hawes E, Abbott JA. Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies. J Minim Invasive Gynecol. 2016; 23(3): 435–441.

Country Australia

Design Prospective cohort study

Device MyoSureTM* Lite or MyoSureTM* XL (Hologic, Bedford, MA)

Comparators None

Endpoints Activation time of the device, size of intrauterine pathology, fluid deficit, complications

Patients 244 patients with intrauterine pathologies (fibroid, polyp, pregnancy tissue, mixed or pre-invasive or invasive pathologies) but 255 MyoSure®* procedures. 68 % have pre-menopausal status (median 44 yrs; range 22-82 yrs). Fibroids were classified according to the International Federation of Gynecology and Obstetrics classification scheme (see Appendix 8.3).

Setting Operating room. Type of anesthesia not reported.

Follow-up Median follow-up of 3.6 months (217 patients)

Enrolment Between January 2013 and June 2015


Arnold et al. undertook an investigation of the MyoSureTM* system on intrauterine pathologies (fibroid, polyp, pregnancy tissue, mixed or pre-invasive or invasive pathologies) in term of activation time of the device, size of intrauterine pathology, fluid deficit and complications. The authors performed inpatient procedures because “The Australian healthcare system does not reimburse for outpatient/office procedures.”

For additional information, please go to section 9.2.4.


9. Extended bibliography

9.1. TruClear™ system for hysteroscopic tissue removal studies

9.1.1. Long-term outcomes after intrauterine morcellation vs hysteroscopic resection of endometrial polyps

Citation AlHilli MM, et al. Long-term outcomes after intrauterine morcellation vs hysteroscopic resection of endometrial polyps. J Minim Invasive Gynecol. 2013; 20(2): 215–21.

Country U.S.

Setting Polypectomy; Operating room; General anesthesia.

Design Retrospective cohort study

Enrolment Between January 1, 2004 and December 31, 2009

Follow-up Post-procedure outpatient follow-up clinic visits were reviewed through March 5, 2012.

TruClear™ system

Not specified, 9-mm rigid hysteroscope in which a 4.5-mm morcellation device is placed (Smith & Nephew, Andover, MA)

Comparators Hysteroscopic resection (HSR) using microscissors, micrograspers, and the Gynecare VERSAPOINT™* system (Ethicon, Inc., Somerville, NJ).

Patients 311 patients (TruClear™ system, 139 of which 53 have premenopausal status; HSR, 172 of which 70 have premenopausal status).

Endpoints Recurrent abnormal uterine bleeding (AUB); Recurrent polyps


Al Hilli et al. investigated long-term outcomes after hysteroscopic polypectomy using either the TruClear™ system or VERSAPOINT™*. There were no significant differences in characteristics between the two groups receiving polypectomy, except that the size of the resected polyp was larger in women treated with the TruClear™ system compared with VERSAPOINT™*: 2.2 cm vs. 2.0 cm (p = 0.004). 17.6% of women treated with the TruClear™ system had ≥3 polyps compared with 7.5% of VERSAPOINT™*-treated women, but this difference was not reported to be significant. Long-term outcomes were superior with the TruClear™ system:

• AUB recurrence: 15.1% vs. 20.9%

• Polyp recurrence: 2.2% vs. 9.9%

The authors also determined that resection of 2 or more polyps was more successful using the TruClear™ system than using the electrical tissue resection.


9.1.2. The Intra Uterine Morcellator: a new hysteroscopic operating technique to remove intrauterine polyps and myomas

Citation Emanuel MH, Wamsteker K. The Intra Uterine Morcellator: A new hysteroscopic operating technique to remove intrauterine polyps and myomas. J Minim Invasive Gynecol. 2005; 12(1): 62–66.

Country Holland

Setting Operating room. General or regional anesthesia. University-affiliated teaching hospital.

Design Retrospective case-control study

Enrolment Between May 1999 and December 2002

Follow-up 3-month postoperative visit

TruClear™ system

Prototype of 35cm length inserted into 90-mmm hysteroscope (Smith & Nephew Endoscopy, Andover, MA)

Comparators Monopolar resectoscopy (MPR)

Patients 55 patients for hysteroscopy (27 endometrial polyps and 28 uterine fibroids type 0 or I, ESGE classification, see Appendix 8.3) and 216 patients for MPR (44 endometrial polyps and 172 uterine fibroids type 0 or I, ESGE classification, see Appendix 8.3)

Endpoints Operating time, fluid loss


Emanuel and Wamsteker compared a prototype of the TruClear™ system to monopolar resectoscopy for removal of intrauterine pathology in terms of operating time and fluid deficit. They found that outcomes with the TruClear™ system were favourable, with reduced operating time and fluid deficit for both removal of endometrial polyps and uterine fibroids.

For polyps, the mean operating time and fluid loss with the TruClear™ system were 8.7 min and 220.4 ml, compared with 30.9 min and 648.6 ml for conventional monopolar resectoscopy. The mean operating time for myomectomy was also substantially lower with the TruClear™ system (16.4 minutes) than with conventional monopolar resectoscopy (42.2 minutes).

The tissue removal procedure using the new hysteroscopic operating technique was successful and complete in all but two patients (with type I fibroids). No intraoperative or postoperative bleeding was reported. No symptom was found at the 3-month postoperative visit. A statistically significant correlation between operating time and fluid deficit was also reported for any tissue removal using the new technique.

Table 8-5 Data comparing the TruClear™ system and monopolar resectoscopy (MPR) devices

Pathology Mean operating time, minutes (95% CI)

Mean fluid deficit, mL (95% CI)

Patients number (Age range, yrs)

Polyps

TruClear™ system 8.7 (7.3–10.1) 220.4 (138.1–302.7) 27 (30-80)

MPR 30.9 (27.0–34.8) 648.6 (512.8–784.4) 44 (28-86)

Fibroids

TruClear™ system 16.4 (12.6–20.2) 660.0 (418.6–901.4) 28 (33-72)

MPR 42.2 (39.7–44.7) 741.8 (645.9–837.7) 172 (20-53)


9.1.3. Clinical implementation of the hysteroscopic morcellator for removal of intrauterine myomas and polyps. A retrospective descriptive study

Citation

Hamerlynck TW, Dietz V, Schoot BC. Clinical implementation of the hysteroscopic morcellator for removal of intrauterine myomas and polyps. A retrospective descriptive study. Gynecol Surg. 2011; 8(2): 193–196.

Country Holland

Setting Operating room. Spinal or general anesthesia.

Design A retrospective descriptive study

Enrolment Between 2006 and 2009

Follow-up Not reported

TruClear™ system Not specified, 9-mm rigid hysteroscope in which a 4-mm morcellation device is placed (Smith & Nephew, Andover, MA)

Comparators None

Patients 315 women.

Endpoints Operating time, fluid deficit, complications


Hamerlynck et al. undertook a retrospective investigation of removal of intrauterine pathology, polyps and fibroids, using the TruClear™ system (device version not specified). myomectomy was performed in 37 patients (aged 26–49 years) and polypectomy in 278 patients (23–81 years). Spinal anesthesia occurred in 68% for polypectomy and 72% for myomectomy. Each procedure was successful, except for the type II myoma cases, which needed conversion to resectoscopy. Mean operating time for polypectomy and myomectomy were 6.6 minutes and 18.2 minutes, respectively. Mean installation time for both procedures were also short, being 7.3 minutes and 8.7 minutes, respectively. No complications occurred. No evidence of significant bleeding during or after the procedure was reported.

Table 8-6 Data on polypectomy and myomectomy using the TruClear™ system

Pathology Mean operating time, minutes (SD)

Mean installation time, minutes (SD)

Median fluid deficit, mL

Patients number (Age range, yrs)

Type of Polyp

0 1 2

Polyps 7.3 (2.5) 2.0 (0.7) 40 (0–300) 278 (23–81) – – –

Fibroids 8.7 (1.4) 2.0 (0.4) 440 (100–890) 37 (26–49) 23 11 3

SD= standard deviation. Installation and Operating times not defined.


9.1.4. Removal of Endometrial Polyps: Hysteroscopic Morcellation versus Bipolar Resectoscopy, A Randomized Trial

Citation

Hamerlynck TW, Schoot BC, van Vliet HA, Weyers S. Removal of Endometrial Polyps: Hysteroscopic Morcellation versus Bipolar Resectoscopy, A Randomized Trial. J Minim Invasive Gynecol. 2015; 22(7): 1237–43.

Country Belgium, Holland

Setting Day surgery setting of a teaching and a university hospital. Operating room. Spinal or general anesthesia.

Design Multicenter, open label, randomized controlled trial

Enrolment Between July 2011 and January 2014

Follow-up Data on persistence of symptoms or intrauterine pathologies at the 6-week follow-up

TruClear™ system TruClear™ system 8.0 for tissue removal

Comparators Rigid 8.5-mm bipolar resectoscope, BPR (Karl Storz GmbH, Tuttlingen Germany), equipped with a 12 or 30 degree optic

Patients 84 Women with larger (≥1 cm) endometrial polyps. 44 for TruClear ™and 40 for BPR.

Endpoints Operating time, fluid deficit, number of insertions, completeness of tissue removal, adverse events,


Hamerlynck et al. compared the TruClear™ system 8.0 to bipolar resectoscopy for removal of endometrial polyps in terms of operating time and adverse events. For 60 of the 84 enrolled women, abnormal uterine bleeding was the reported preoperative symptom.

Polypectomy required general anesthesia in 66% of procedures using the TruClear™ system for hysteroscopic tissue removal compared with 77.5 % using bipolar resectoscopy (BPR). Operating time was defined as the time from visual introduction of the hysteroscope until completion of the procedure, meaning definite removal of the hysteroscope from the uterine cavity. After controlling for the diameter of removed polyps, the median polypectomy operating time was significantly reduced with the TruClear™ system, a reduction of 39% (95% CI: 5%–61%, p = .029), compared with resectoscopy. Additionally, the number of insertions using the TruClear™ system was significantly

reduced and the polyp removal procedure was successful and complete in 100% cases (Table 8-7).

Adverse events occurred in 3 patients using the TruClear™ system: 1 perforation at dilation but the procedure was completed; 2 patients with a urinary tract infection diagnosed 1 and 2 weeks after the operation. On the other hand, 3 serious adverse events occurred in patients who underwent resectoscopy, in each case a perforation: 2 requiring the procedure to be aborted and 1 resulting in an inpatient hospital stay. There were no differences between the two techniques in term of persisting abnormal uterine bleeding at follow-up.


Table 8-7 Data comparing the TruClear™ system and bipolar resectoscopy (BPR)

Technique

Mean operating time, minutes (IQR)

Mean fluid deficit, mL (IQR)

Post-menopausal number (%)

Insertion, N (IQR)

Complete polyp removal (%)

Perforation (%)

TruClear™ system

4.0 (2.5–7.1) 165 (138.1–302.7)

20 (45.5) 1 (1–1) 44 (100) 1 (2)

BPR 6.0 (3.8–11.7)

200 (110–290)

20 (50) 2 (2–5) 38 (95) 3 (7.5)


p=0.028 p=0.115 p=0.83 p<0.001 p=0.224 p=0.34

IQR= interquartile range [25th to 75th percentile]


9.1.5. Hysteroscopic Tissue Removal Systems: A Randomized In Vitro Comparison

Citation Meulenbroeks D, Hamerlynck TW, Saglam-Kara S, Van Rijssel NK, Van Vliet H, Schoot BC. Hysteroscopic Tissue Removal Systems: A Randomized In Vitro Comparison. J Minim Invasive Gynecol. 2017; 24(1): 159–164.

Country Holland, Belgium

Setting In vitro

Design Prospective randomized in vitro trial

Enrolment Not applicable


TruClear™ TruClear™ system using the TruClear™ system INCISOR 2.9 (TI), TruClear™ system INCISOR Plus (TIP), or TruClear™ system ULTRA Plus (TUP) device

comparators MyoSureTM* system (MyoSureTM* (Hologic, Bedford, MA) using the MyoSureTM* Lite (ML), MyoSureTM* Classic (MC), or MyoSureTM* XL (MXL) device.

Patients 42 fragments of umbilical cord weighing 5 g, as a surrogate for polyps and 18 pieces of fibroid tissue

Endpoints Polyp resection time and fibroid resection rate


Maulenbroeks et al. performed a prospective, in vitro comparison of two hysteroscopic tissue removal systems. The primary endpoints were polyp resection time (minutes) and fibroid resection rate (g/min). To represent polyps in vitro the authors used umbilical cord samples as a surrogate.

For the removal of surrogate polyps, the evaluation of durability of each device was done by testing it three consecutive times (3 runs) before using the next device. The authors show that the TruClear™ system (TIP) device performed significantly better than the MyoSureTM* (ML) device, with a 78 % reduction (95% CI, 58%–89%; p<.001) in resection time in the third run. Moreover, the MyoSureTM* device performed significantly worse, with a reduction of 74% (95% CI, 56%–85%; p,.001) between the first run and the third run (Figure 8-6).

Concerning the myoma tissue resection rate, for a mean myoma volume of 18ml, the TruClear™ system device (TUP) was 24% faster than the MyoSureTM* device (MXL), 2.96g/min and 2.39g/min respectively (Figure 8-7).


Figure 8-6 Data comparing the TruClear™ system and MyoSure™* devices for the removal of surrogate polyps

Resection time, defined as the interval from the time when the device was first activated until the time when the tissue was completely removed.

Figure 8-7 Data comparing the TruClear™ system and MyoSure™* devices for the removal of fibroid tissue

0

1

2

3

4

5

6

250 mmHg 475 mmHg

Fibroid resection rate, g/min,median (IQR)

TruClear™ system ULTRA Plus (TUP) MyoSure™* XL (MXL)


9.1.6. A comparison of hysteroscopic mechanical tissue removal with bipolar electrical resection for the management of endometrial polyps in an ambulatory care setting: preliminary results

Citation

Pampalona RJ, et al. A Comparison of Hysteroscopic Mechanical Tissue Removal With Bipolar Electrical Resection for the Management of Endometrial Polyps in an Ambulatory Care Setting: Preliminary Results. J Minim Invasive Gynecol. 2015; 22(3): 440–445.

Country Spain

Setting Ambulatory care. No anesthesia or sedation of any sort.

Design A randomized controlled clinical trial

Enrolment Between March 2013 and May 2014


TruClear™ system


Comparators Gynecare VERSAPOINT™* system (Ethicon, Inc., Somerville, NJ). Standard forceps with a polyp grip were used as the auxiliary instrument with the VERSAPOINT™* for extracting intrauterine tissue.

Patients 133 patients diagnosed with endometrial polyp(s). 63 patients with TruClear™ system and 64 patients with VERSAPOINT™*.

Endpoints Operating time, polypectomy time, pain experienced by patients, and learning curve of staff in training.


Rovira Pampalona et al. compared, in an outpatient setting, the TruClear™ system 5.0 to the VERSAPOINT™* system for removal of endometrial polyps. The operating and polypectomy times and the reason for any failures were recorded for analysis. The split of menopausal women between use of the two devices was comparable: 54 % (34) for the TruClear™ system and 59.4 % (38) for VERSAPOINT™*.

The average total operating and polypectomy times were significantly in favour of the TruClear™ system, which did not differ if results were stratified by provider: senior surgeon or resident in training (Figure 8-8). Furthermore, a higher success rate for full polyp resection and excision occurred using the TruClear™ system for tissue removal (92% or 58 out of 63 patients) versus the VERSAPOINT™* system (77% or 49 out of 64 patients). The reason for failure for each group was investigated by Rovira Pampalona and al. For the TruClear™ system, 4 out of 5 failures were due to the provider being unable to access the endometrial cavity. Of the 15 failures with VERSAPOINT™*, most were due to incomplete polyp resection or polyp size:

• polyp resection was partial or incomplete in 40%

• the complete tissue extraction was impossible in 26.7%

• the size of the polyp was non-operable in 26.7%

Concerning pain experienced by the patient, no significant difference between the two systems was reported. No complication occurred during this outpatient setting procedure using either system.


Figure 8-8 Operating and polypectomy times for each device and depending on the surgery expertise.

0

2

4

6

8

10

12

14

16

Senior surgeon Resident

Mean operating and polypectomy times, minutes

TruClear™ system 5.0 operating time VERSAPOINT™* operating time

TruClear™ system 5.0 polypectomy time VERSAPOINT™* polypectomy time

Total operating time defined by the authors as the time elapsed from the moment the hysteroscope was inserted until it was removed and the procedure was declared complete (accepted maximum procedure time =30 minutes, according to hospital protocol). Polypectomy time defined by the authors as the time required for total resection and excision of endometrial polyp(s) (single or multiple).


9.1.7. Hysteroscopic morcellation compared with electrical resection of endometrial polyps: a randomized controlled trial

Citation Smith PP, Middleton LJ, Connor M, Clark TJ. Hysteroscopic Morcellation Compared With Electrical Resection of Endometrial Polyps. Obstet Gynecol. 2014; 123(4): 745–751.

Country UK

Setting In-office polypectomy. No general anesthesia or conscious sedation.

Design A multicenter, single-blind, randomized, controlled trial

Enrolment Between July 2012 and May 2013.


TruClear™ system

TruClear ™ system 5.0

Comparators Gynecare VERSAPOINT™* system (Ethicon, Inc., Somerville, NJ).

Patients 121 patients for polyp removal (62 patients for the TruClear™ system vs 59 patients for VERSAPOINT™*)

Endpoints Operating time, completeness of polyp removal, procedural pain and patient acceptability.


Smith et al. compared, in an office setting, the TruClear™ system 5.0 to the VERSAPOINT™* system for removal of endometrial polyps in terms of operating time, completeness of polyp removal, and patient acceptability. The indication for surgery was most commonly bleeding (82% or 51 patients for the TruClear™ system and 88% or 52 patients for VERSAPOINT™*).

Time taken to complete the endometrial polypectomy was defined as the time from insertion to removal of vaginal instrumentation. The median operating time to complete polypectomy was significantly reduced with the TruClear™ system compared with VERSAPOINT™*, 5.28 minutes and 10.12 minutes respectively (p<0.001). The polyp removal procedure was also more likely to be

successful with the TruClear™ system compared with VERSAPOINT™* (Table 8-8).

Surgical complications, only vasovagal reactions, occurred non-significantly (p=0.08) more with the VERSAPOINT™* system. One serious adverse event with the TruClear™ system was reported, a patient admitted two weeks after treatment because of vaginal bleeding and pain.

The authors also investigated the pain scores during the procedure measured on a 100-point Visual Analog Scale (VAS), with higher values reflecting higher pain perception. The mean VAS-pain score reported was 35.9 ±23.5 for the TruClear™ system versus 52.0 ±23.5 for VERSAPOINT™*, leading to a mean difference of 16.1 reduction (95% CI, 7.6–24.7; p<.001) significantly in favor of the TruClear™ system.


Table 8-8 Data comparing the TruClear™ system and VERSAPOINT™* devices

Technique

Pre-menopausal, N (%)

Post-menopausal, N (%)

Complica-tions, N (%)

Complete polyp removal, N (%)

Patient acceptability, N (%)

TruClear™ system

26 (42) 35 (56) 1 (2) 61 (98) 44 (72)

BPR 28 (47) 31 (53) 6 (10) 49 (83) 33 (57)


NR NR NS, p=0.08 p=0.02 p=0.009

The total number of patients reporting for each endpoint varied. NR: not reported. NS: not significant.


9.1.8. Hysteroscopic morcellator for removal of intrauterine polyps and myomas: a randomized controlled pilot study among residents in training

Citation

van Dongen H, Emanuel MH, Wolterbeek R, Trimbos JB, Jansen FW. Hysteroscopic morcellator for removal of intrauterine polyps and myomas: a randomized controlled pilot study among residents in training. J Minim Invasive Gynecol. 2008; 15(4): 466–71.

Country Holland

Setting Operating room. General or spinal anesthesia.

Design A randomized controlled pilot study

Enrolment Between January 2005 and April 2006


TruClear™ system

Not specified, 9-mm rigid hysteroscope in which a 4.5-mm morcellation device is placed (Smith & Nephew, Andover, MA)

Comparators Conventional resectoscopy with a rigid 9 mm resectoscope (Olympus Winter & Ibe, Hamburg, Germany) equipped with a 12- degree optic. Sorbitol (4%) was used for distension and irrigation of the uterine cavity

Patients 60 patients (18 with polyps and 12 with fibroids for the TruClear™ system and 20 with polyps and 10 with fibroids for conventional resectoscopy)

Endpoints Operating time, convenience of technique


Van Dongen et al. compared the TruClear™ system to conventional resectoscopy for removal of intrauterine pathology. Indication for surgery was mostly AUB (83 % or 25 patients for the TruClear™ system and 73% or 27 patients for conventional resectoscopy). Key comparisons were operating time, fluid deficit, and convenience of technique. They found that outcomes with the TruClear™ system were favorable, with reduced operating time and fluid deficit for both removal of endometrial polyps and uterine fibroids.

For the removal of polyps or fibroids (type 0 or 1, ESGE classification, see Appendix 8.3), the mean operating time with the TruClear™ system was significantly shorter (10.6 minutes) compared with conventional resectoscopy (17 minutes). Fluid deficit with the TruClear™ system was non-significantly lower, 409 ml versus 545ml for conventional resectoscopy. Procedures with the TruClear™ system required significantly fewer device insertions compared with conventional resectoscopy (Table 8-9).

The surgeon VAS (0-10) scores regarding use of instrument and the subjective trainer VAS scores for easiness of use by the resident were found to favor the TruClear™ system device (Figure 8-9, Figure 8-10).


Table 8-9 Data comparing the TruClear™ system (hysteroscopic morcellation) and resectoscopy

Technique

Mean operating time, minutes (95% CI)

Mean fluid deficit, mL (95% CI)

Pre-menopausal number (%)

Post-menopausal number (%)

Compli-

cations

Take control by trainer (%)

TruClear™ system

10.6 (7.3–14.0)

409 (229–589)

21 (73) 9 (27) 1 (1–2) 1 (3)

Resectoscopy

17.0 (14.1–19.9)

545 (406–684)

22 (73) 8 (27) 7 (3–50) 5 (17)


p=0.008 NS, p=0.224 NR NR p=0.009 p<0.001

Trainers were requested to take control of the procedure to avoid incomplete removal or fluid overload

Figure 8-9 Convenience regarding use of instrument by the resident


Figure 8-10 Subjective trainer scores on convenience regarding easiness of use by the resident


9.2. Other mechanical tissue resection studies

9.2.1. Hysteroscopic morcellation versus bipolar resection for endometrial polyp removal.

Citation Hamidouche A, et al. Morcellement hystéroscopique versus résection à l’anse bipolaire pour les polypes endométriaux. Gynecol Obstet Fertil. 2015; 43(2): 104–108.

Country France

Setting Operating room. General or spinal anesthesia.

Design A single-center observational retrospective comparative study

Enrolment Between January 2012 and December 2013

Follow-up 6 to 8 weeks after surgery

Device MyoSure™* Lite device (Hologic, Bedford, MA )


Patients 25 patients (12 with MyoSure™* and 13 with VERSAPOINT™*)

Endpoints Operating time, completeness of polyp removal, reported size for polyp, complication


Hamidouche et al. compared the MyoSure™* system to the VERSAPOINT™* system for removal of

endometrial polyps in terms of operating time, completeness of polyp removal, and complications.

Infertility was the main cause for surgery with 50 % in the MyoSure™* group and 69 % in the

VERSAPOINT™* group. The reported size for polyp was 9.2 mm (from 9.2 to 25 mm) using the

MyoSure™*system compared with 12.5 mm (from 5 to 30 mm) using the VERSAPOINT™* system.

General anesthesia was used in over 90% of procedures.

Both techniques were successful with 100% completion. The mean operating time (starting at the

beginning of the cervical dilation) for the removal of polyps was similar using the MyoSure™*system

or the VERSAPOINT™* system, 16 minutes and 17 minutes respectively. No intra- or post-operative complication occurred, although follow-up at 6 to 8 weeks after surgery was only completed in 40% of patients.

Table 8-10 Data comparing MyoSureTM* and VERSAPOINT™* devices

MyoSure™* (N=12) VERSAPOINT™* (N=13) p value

Age (yrs) 41.1±8.2 41.1±8.2 0.954

Polyp size 9.2±5.6 12.5±5.7 0.06

Operating time (minutes)

16.4±6.5 17.8±10.8 0.766

Complication 0 0

Complete resection 12 (100%) 13 (100%)

follow-up control 5 (41,6 %) 5 (38.4%) 0.870

Intrauterine adhesion 0 0

Mean ±Standard deviation. N: number of patients


9.2.2. A prospective study of the use of the MyoSure®* resectoscope to manage endometrial polyps in an outpatient setting

Citation McIlwaine P, McElhinney B, Karthigasu KA, Hart R. A prospective study of the use of the MyoSureTM* resectoscope to manage endometrial polyps in an outpatient setting. Aust N Z J Obstet Gynaecol. 2015; 55(5): 482–486.

Country Australia

Setting Outpatient setting. Local anesthesia.

Design A prospective case study

Enrolment Between September 1, 2013 and August 31, 2014


Device MyoSure™* Lite device (Hologic, Bedford, MA)

Comparators None

Patients 42 patients with polyps under local anesthesia, of which 25 in menopausal state (59.5%). Median polyp size 13 mm.

Endpoints Resection time, completeness of polyp removal, complications, pain scores, patient satisfaction


Mcllaine et al. undertook a prospective investigation of the MyoSure™* Lite device for removal of

intrauterine pathology, such as endometrial polyps, in the outpatient setting. Outcomes were resection time, completeness of polyp removal, and complications. The mean size of removed pathology was 12.9 +/- 4.4 mm (range from 7 to 25 mm).

The technique was completed successful in 95.2% of cases. The time taken to resect the polyp was

measured from insertion of the Myosure™* device until the polyp was completely excised. The

mean resection time and fluid deficit for the removal of polyps using the MyoSure™* technique were

39.4 sec and 143 ml, respectively. Minor complications occurred in 2 cases (rate of 4.8%): one vasovagal episode and one small cervical tear that required a suture.

The 10-point pain VAS scores showed a higher median score for premenopausal (median 3.2; range 0.8 - 7.3) versus postmenopausal patients (median 2.5; range 0.7–7.5), although the ranges overlapped substantially. Satisfaction rates were reported with a score of 92.5%, with no significant

differences between pre- and postmenopausal patients (Table 8-11). Of patients, 97.6% would

recommend the procedure to a friend with a similar problem, and 88.1% would be happy to have the procedure again.


Table 8-11 Data reporting polyp removal using the MyoSureTM*device

MyoSure™* Range

Resection time (sec) 39.4±49.7 4–230

Fluid deficit (ml) 143±114.9 11–615

Complete resection, N 40 (95.2%)

Complication rate, N 2 (4.8%)

Pain score, median (all) 2.7 (IQR 1.9–3.8) 0.7–7.5

Satisfaction rate (all) 9.25

Time to discharge, N

Immediately 40 (95.2%)

< 2 hours 2 (4,8 %)

Mean ±Standard deviation. N: number of patients. IQR: Interquartile range


9.2.3. Hysteroscopic intrauterine morcellation of submucosal fibroids: preliminary results in Hong Kong and comparisons with conventional hysteroscopic monopolar loop resection

Citation

Lee MM, Matsuzono T. (2016). Hysteroscopic intrauterine morcellation of submucosal fibroids: preliminary results in Hong Kong and comparisons with conventional hysteroscopic monopolar loop resection. Hong Kong Med J. 2016; 22(1) 56–61.

Country China (Hong Kong)


Design Retrospective review

Enrolment Between January 1, 2011 and December 31, 2014

Follow-up 3 months

Device MyoSure™*(Hologic, Bedford, MA) but system type not specified

Comparators Conventional hysteroscopic monopolar loop resection (MPR)

Patients 29 patients with submucosal fibroids. Age or menopausal status not mentioned.

Endpoints Operating time, fibroid size, fluid deficit, complications, patient satisfaction, hemoglobin level


Lee and Matsuzono performed a retrospective comparison of the MyoSure™*system and the

conventional monopolar resectoscopy for removal of intrauterine fibroids in terms of operating time, fibroid size and complications. Mean uterine fibroid size was equivalent between groups, being 3.5 cm

(Myosure™*) and 3.3 cm (resectoscopy).

Operating time was measured from the time the patient was anaesthetised to completion of the operation. Hence operating time included the time required to position the patient, cleaning, draping, and the time for setting up equipment. The mean operating time was in favor of

MyoSure™*compared with resectoscopy, 36.6 minutes versus 53.6 minutes respectively.

Considering only uterine fibroids <3 cm, the operating time was significantly reduced with

MyoSure™*: 27.6 minutes versus 53.6 minutes (p = 0.019). MyoSure™*though was associated with

increased fluid deficit (1,005 mL; range, 40-2600 mL) compared with the resectoscopy (225 mL; range, 0-1000 mL). One complication occurred (uterine perforation) with the conventional resectoscopy technique.

At 3-month postoperative visit, the overall patient satisfaction was higher for MyoSure™*than for

conventional resectoscopy: 93.3% and 84.6% respectively.


Table 8-12 Data comparing MyoSureTM*and resectoscopy

MyoSure™* MPR p value

Overall N=13 N=12

Operating time, minutes

36.6 (17–72) 53.6 (39–102) 0.005

Mean fluid deficit, mL

1005 (40–2600) 225 (0–1000) 0.003

Satisfaction Outcome

93.3% 84.6% 0.841

Fibroid (≤ 3 cm) N=9 N=5


27.6 (14–45) 53.4 (29–76) 0.019


634.4 (40–1600) 80 (0–200) 0.019

Patient Satisfaction

9 (100%) 4 (80%) 0.797

Fibroid (≥ 3 cm) N=4 N=7


57 (40–66) 53.4 (29–76) 0.527


1839 (556–2600) 225 (0–1000) 0.024

Patient Satisfaction

3 (75%) 6 (85.7%) 0.788

N: number of patients.


9.2.4. A Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies

Citation

Arnold A, Ketheeswaran A, Bhatti M, Nesbitt-Hawes E, Abbott JA. Prospective Analysis of Hysteroscopic Morcellation in the Management of Intrauterine Pathologies. J Minim Invasive Gynecol. 2016; 23(3): 435–441.

Country Australia


Design Prospective cohort study

Enrolment Between January 2013 and June 2015

Follow-up Median follow-up of 3.6 months (217 patients)

Device MyoSure™*Lite or MyoSure™*XL (Hologic, Bedford, MA)

Comparators None

Patients 244 patients with intrauterine pathologies (fibroid, polyp, pregnancy tissue, mixed or pre-invasive or invasive pathologies) underwent 255 MyoSure®*procedures.

Endpoints Activation time of the device, size of intrauterine pathology, Fluid deficit, complications


Arnold et al. undertook a prospective investigation of the MyoSure™*system on intrauterine

pathologies (fibroid, polyp, pregnancy tissue, mixed or pre-invasive or invasive pathologies) in term of activation time of the device, size of intrauterine pathology, fluid deficit and complications. The authors performed inpatient procedures because “The Australian healthcare system does not reimburse for outpatient/office procedures.”

Different types of intrauterine pathologies were treated using MyoSure™*devices in a total of 255 procedures. Senior physicians and residents in training performed the surgery in 39% and 61% of cases, respectively.

Procedure success varied by pathology, with 92% of polyps and 66% of leiomyomas being completely resected.

For patients with mixed pathology, resection was complete in 76% of cases. Completion success was 87% for pregnancy tissue and 88% for pre-invasive or invasive pathology.

Complete removal of fibroid occurred in in 63 of 95 cases (66%) and varies according to their size (Table 8-13, Figure 8-11).

In 3 cases (1%), complications occurred after surgery and fibroid removal was incomplete. It was noted that in each case a prolapsed submucosal fibroid at 2 to 12 weeks after surgery sustained.

Note: Three women underwent a repeat MyoSure™* hysteroscopic procedure at 12 to 18 months after an initial procedure completely resected pathology, after new pathology had been demonstrated. An additional 6 women had a repeat procedure scheduled after incomplete removal of pathology at the first

operation, and 1 woman underwent 3 MyoSure™* procedures over an 8-week period to completely

resect pathology


Table 8-13 Data reporting intrauterine pathologies removal using MyoSure™* devices

Fibroid (N=102) Polyp (N= 98) Pregnancy Tissue (N=

16) p value

Age, yr, median (range)

43 (26–69) 48 (22–77) 33 (25–39) NR

Premenopausal, %

84 50 100 NR

Indication for procedure

92% AUB, 5.5% infertility, 2.5% NR

73% AUB, 4% infertility,

23% NR

31% AUB, 64% RPoC,

5% NR

NR

Median fluid deficit, mL (range)

880 (20–2536) 200 (10–2500)

900 (70–2500)

<0.001

Size of combined pathology, cm, median (range)

4(1–15) 2 (0.3–7) 2.5 (0.8–4.5) <0.001

Complete resection, N

18 (62) type 0

27 (71) type 1

11 (65) type 2

91 (92) 13 (87) NR

N: number of patients. NR: not reported

Figure 8-11 Completeness of resection according to fibroid size


9.2.5. Hysteroscopic myomectomy with the IBS™* integrated Bigatti Shaver versus conventional bipolar resectoscope

Citation

Bigatti G, Franchetti S, Rosales M, Baglioni A, Bianchi S. Hysteroscopic myomectomy with the IBS™* Integrated Bigatti Shaver versus conventional bipolar resectoscope: A retrospective comparative study. Gynecol Surg. 2014; 11(1): 9–18.

Country Italy

Setting Operating room. General or a regional anesthesia

Design A retrospective comparative study

Enrolment Between June 2011 and June 2013


Device IBS™* integrated Bigatti Shaver


Patients 76 patients (42 pre- and 34 post-menopausal) with 88 fibroids for IBS™* vs 51 patients (29 pre- and 22 post-menopausal) with 56 fibroids for VERSAPOINT™*.

Endpoints Resection time, fluid balance, complete single-stage removal of the fibroid


Bigatti et al. compared the IBS™* integrated Bigatti Shaver to the VERSAPOINT™* system for

myomectomy in terms of resection time, fluid deficit and completeness of single-stage tissue removal.

The mean resection time (from the moment the active shaver tip or the resectoscope loop was visible inside the uterine cavity, until the resection was completed) for myomectomy was similar

using IBS™* compared with VERSAPOINT™*: 29.12 minutes versus 29.05 minutes respectively.

Fluid deficit was reported lower after resectoscopy than after using the IBS™* device but the results

were not significant . The volume of fluid used for the procedure was significantly lower with VERSAPOINT™* (mean 5,885 ml; range, 1,000–17,000 ml) for fibroids of ≥3.0 cm compared with

IBS™* (mean 11,583 ml; range, 400–20,000 ml).

The IBS™* technique successfully removed fibroids of ≤3.0 cm in 93.5% of cases. For type 2 fibroids,

62.5% were successfully removed. Values for VERSAPOINT™* were not provided in the paper, but

did not differ significantly from IBS™*, with p-values reported being 0.37 and 0.55 for fibroids of ≤3.0

cm and of type 2, respectively. No major complication or bleeding occurred using the IBS™*

technique.

The authors reported that a number of procedures could not be completed and required a follow-up procedure to be planned two months later. These were required if a fluid deficit of >2,000 occurred or the procedure lasted >60 minutes. The number of second-step procedures was significantly reduced

in the IBS™* group (7/76 patients, 9.2 %) compared with the VERSAPOINT™* group (15/51 patients,

29.4 %), mostly due to differences in procedure time. For nine (out of the 76) patients in the IBS™*

group, a conversion to VERSAPOINT™* was required.


Table 8-14 Data comparing IBS™* and VERSAPOINT™* devices

IBS™* VERSAPOINT™* p value

Age, yr, mean 47.55 48.04 0.8011

Premenopausal, N ( %) 42 (55.3) 29 (56.9) 0.9966

Premenopausal, N ( %) 34 (44.7) 22 (43.1) NR

Fibroids <3 cm N=61 N=35

Mean resection time, minutes

21.12 (3–60) 21.13 (10–45) 0.8715

Mean fluid used, mL (range)

3,765 (800–15,000) 2,655 (500–10,000) 0.0998

Mean fluid deficit, mL (range)

342 (0–1,500) 240 (0–600) 0.1486

Fibroids >3 cm N=27 N=21

Mean resection time, minutes

47.19 (15–109) 42.25 (25–85) 0.4333

Mean fluid used, mL (range)

11,583 (400–20,000) 5,885 (1,000–17,000) 0.0001

Mean fluid deficit, mL (range)

907 (0–1,500) 685 (100–1,500) 0.2352

N: number of patients. NR: not reported


9.2.6. Uterine Morcellator versus Resectoscopy in the Management of Heavy Menstrual Flow in Reproductive-Age Women.

Citation Borg HM, Shehata A. Uterine Morcellator versus Resectoscopy in the Management of Heavy Menstrual Flow in Reproductive-Age Women. J Gynecol Res. 2016; 2(2): 1–8.

Country Egypt

Setting Operating room. General anesthesia.

Design A Prospective randomized controlled study

Enrolment Between January 1, 2015 and June 30, 2016


Device IBS™* integrated Bigatti Shaver (Storz, GERMANY)

Comparators Conventional monopolar resectoscopy (Circon ACMI, U.S.) equipped with a wire-loop electrode using an electro-surgical technique and use (Glycine) electrolyte-free solutions for distension and irrigation.

Patients 50 pre-menopausal patients suffering from heavy menstrual flow, dysmenorrhea or infertility. Endometrial polyps (28 cases) and submucousal fibroids (22 cases) type 0, and type I and fibroids less than 30 mm in diameter according to STEPW Classification (see appendix 8.3)

Endpoints Resection time, fluid balance, complete single-stage removal of the fibroid


Borg et al. compared the IBS™* integrated Bigatti Shaver to conventional resectoscopy for

intrauterine pathology such as polyps and fibroids in terms of resection time, fluid deficit and completeness of single-stage tissue removal.

The mean operating time (not defined) for removal of polyps was significantly reduced using the

IBS™* technique compared with resectoscopy, mean 8.13 ± 0.88 minutes versus 24.50 ± 2.17

minutes respectively. Likewise, the mean operating time for the removal of fibroids was significantly

shorter using IBS™*, mean of 9.33 ± 1.22 minutes versus 29.32 ± 3.23 minutes respectively. Fluid

deficit was also significantly reduced with use of IBS™* (mean 356.80 ± 119.49 ml) compared with

resectoscopy (mean of 586.4 ± 153.06 ml). Likewise, a significantly smaller volume of distension fluid

was required with IBS™* (mean of 3,374 ± 849.47 ml) compared with resectoscopy (5,203 ± 672.44

ml). The number of device insertions was lower with IBS™* than with resectoscopy (Table 9.17).

Complications occurred in three patients undergoing resectoscopy (all fluid overloading) compared

with one complication in the IBS™* group (bleeding treated by cauterization using resectoscope).


Table 8-15 Data comparing IBS™* and conventional resectoscopy (Circon ACMY, U.S.)

IBS™* N=25 Resectoscopy N=25 p value

Age, yr, mean±SD 27.72±3.361 28.44±3.163 0.439

Mean operating time, minutes, mean±SD

8.56±1.16 28.16±3.64 <0.0001

Mean fluid used, mL mean±SD 3,374±849.47 5,203±672.44 <0.0001

Mean fluid deficit, mL mean±SD

356.8±119.46 586.4±153.06 <0.0001

Number of Insertions

mean±SD

1.08±0.28 6.96±3.75 <0.0001

Polyps N=15 N=13


8.13±0.88 24.50±2.17 <0.0001

Fibroids N=10 N=12


9.33±1.23 29.32±3.23 <0.0001

N: number of patients. SD: standard deviation


9.2.7. The efficacy, cost and patient satisfaction of classic versus office hysteroscopy in cases with suspected intrauterine space occupying lesions with 3-dimension ultrasound and abnormal uterine bleeding

Citation

Filiz T, Doǧer E, Çorakçi A, Özeren, S, Çalişkan E. The efficacy, cost and patient satisfaction of classic versus office hysteroscopy in cases with suspected intrauterine space occupying lesions with 3-dimension ultrasound and abnormal uterine bleeding. J Turk Ger Gynecol Assoc. 2009; 10(4): 189–193.

Country Turkey

Setting In-office hysteroscopy without general anesthesia or cervical dilatation versus classic hysteroscopy with general anesthesia and cervical dilatation.

Design A prospective study

Enrolment Between January 1, 2006 and Mai 30, 2008

Follow-up 6 months

Device For office hysteroscopy, a 2.7 mm in diameter telescope with a 30º angle was used within a hysteroscope of 5.5 mm in total diameter (RZMedizin- Technik, Germany). After speculum examination and cervico-vaginal washing a teneculum was used to grasp the cervix from 11 and 1 o’clock positions.

Comparators For classic hysteroscopy, a 4 mm diameter telescope with a 12º angle was used with an operative sheath 10 mm in total diameter (Storz, Germany).

Patients 123 women with AUB (66 patients for office hysteroscopy vs 57 patients for classic hysteroscopy)

Endpoints Operating time, cost, complications, VAS pain scores


Filiz et al. compared the effectiveness and cost of an office hysteroscopic procedure with a classic hysteroscopic procedure for removal of intrauterine pathology in terms of operating time, a 10-point VAS pain scores, and cost. Only seven patients (11.6%) needed anesthesia for the office hysteroscopic procedure. Polyp was the most common intrauterine pathology removed with 81

(65.8%) patients diagnosed, versus fibroid with only 9 (7.3%) patients diagnosed (Table 8-16).

Office hysteroscopy was completed successful in 87.3% of cases. The technique could not be performed in nine patients (13.6%) at the first attempt but was successful a few hours later. The office procedure was also incomplete in six patients (9%) due to various reasons. The procedure was repeated again in 2 to 4 days later and was successfully accomplished in all patients. The mean operating time for the removal of intrauterine pathology was significantly shorter in the office setting compared with the classic hospital setting, 11 minutes and 43 minutes respectively.

No procedure related complication occurred in any setting, although follow-up at 6 months after surgery showed that all 34 (100%) postmenopausal women were symptom free (no more with abnormal uterine bleeding). On the other hand, 7 (7.8%) premenopausal women were still with abnormal uterine bleeding, 4 out of 47 in the office setting compared with 3 out of 42 in the classic hospital setting. Overall the efficacy of the hysteroscopy treatment was 92.4% in the office setting and 96.4% in the classic hospital setting.

The pain reported by the patients prior to, during and after office hysteroscopy according to a 10-

point visual analog scale (VAS) is presented in Figure 8-12. Costs (diagnosis and treatment) were

also reported by Filiz et al. The mean cost was significantly in favour of the office setting compared with the classic hospital setting, 193 Turkish Lira and 696 Turkish Lira respectively.


Table 8-16 Data comparing office and classic hysteroscopy

Office hysteroscopy N=66

Classic hysteroscopy N=57

p value

Age, yr, mean±SD 46±10.9 42±10.4 0.06

Post-menopausal, N (%)

19 (28.8) 15 (26.3) 0.76

Polyps, N (%) 44 (66.7) 37 (64.9) 0.83

Fibroids, N (%) 5 (7.6) 4 (7) 0.89


11±5.6 42.6±18.4 <0.0001

Cost, Turkish Lira (range)

193 (152–203) 696 (389–1277) <0.0001

Treatment efficacy at 6 months, %

92.4 96.4 NR

N: number of patients. SD: standard deviation. NR: not reported.

Figure 8-12 Pain reported by the patients prior to, during and after office hysteroscopy according to a 10-point visual analog scale (VAS)

Taken from Filiz et al. 2009.134


9.3. Systematic reviews and meta-analyses

9.3.1. Hysteroscopic morcellation: Review of the manufacturer and user facility device experience (MAUDE) database

Citation Haber K, Hawkins E, Levie M, Chudnoff S. Hysteroscopic morcellation: Review of the manufacturer and user facility device experience (MAUDE) database. J Minim Invasive Gynecol. 2015; 22(1): 110–114.

Country U.S.

Setting Not applicable

Design Systematic review of Manufacturer and User Device Experience (MAUDE) database

Enrolment Between 2005 and June 2014


TruClear™ system

System type not specified

Comparators MyoSure™*(Hologic, Bedford, MA) but system type not specified

Patients Women undergoing hysteroscopic surgery for removal of intrauterine polyps or fibroids with use of a reciprocating morcellator. Interventions: The MAUDE database was searched for the key words "Hysteroscope," "Hysteroscopic reciprocating morcellator," "Interlace," "MyoSure," "Smith & Nephew," and " TruClear”, to identify reported incidences of device malfunction, injury, or death

Endpoints Adverse events


Haber et al. compared in a systematic review of Manufacturer and User Device Experience (MAUDE)

database the TruClear™ system for hysteroscopic tissue removal and MyoSure™*, in terms of

adverse events.

In the United States, adverse events appear in 1 per 1000 cases among patients treated with the

MyoSure™*device and 1 per 5000 cases with the TruClear™ system for hysteroscopic tissue

removal.

From 2005 to June 2014, major complications occurred in 6 cases for the TruClear™ system and

from 2010 to June 2014 in 31 cases for the MyoSure™*device. Minor complications, on the other

hand, were reported in 17 and 65 adverse events.

Among the 119 adverse events noted in the MAUDE database, the hysteroscopic mechanical tissue

resection TruClear™ system and MyoSure™*devices have a total of 23 and 87 adverse events

respectively.

Uterine perforation was the most reported. Injury to the bowel was reported in 12 patients (3 and 9

using the TruClear™ system and MyoSure™*devices respectively) and in 11 cases additional surgery

was noted.


Figure 8-13 Data comparing adverse events for the TruClear™ system and MyoSure™*devices

0

10

20

30

40

50

60

70

MyoSure™* TruClear™ system

Adverse Events

Major complications Minor complications

05

101520253035404550

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Adverse events reported to MAUDE database

MyoSure™* TruClear™ system


9.3.2. Intrauterine Morcellator Devices: The Icon of Hysteroscopic Future or Merely a Marketing Image? A Systematic Review Regarding Safety, Efficacy, Advantages, and Contraindications

Citation Noventa M, Ancona E, Quaranta M, Vitagliano A, Cosmi E, D’Antona D, Gizzo S. Intrauterine Morcellator Devices. Reprod Sci. 2015; 22(10): 1289–1296.

Country Global

Setting Polypectomy, myomectomy, RPoC. Operating room or office.

Design A Systematic Review

Enrolment Between January 2005 and August 2014

Comparison Mechanical tissue resection (TruClear™ system 8.0 or 5.0 or MyoSure™*system)

vs electrical tissue resection (VERSAPOINT™* system or conventional resectoscope)

Patients 1185 patients (8 studies)

Endpoints Operating time, fluid deficit, complications


Noventa et al. compared in a systematic review the mechanical and electrical tissue resection devices in terms of operating time, fluid deficit and complications.

Four TruClear™ system studies versus VERSAPOINT™* (Alhilli et al., 2013; Smith et al., 2014) or other conventional resectoscope (Emanuel and Wamsteker, 2005; van Dongen et al., 2008) were identified for the removal of polyps, fibroids. Those studies can be found in the section 9.1. Operating time for polyp or fibroid removal using the TruClear™ system was faster than using a resectoscope or the VERSAPOINT™* system. Fluid deficit was reported lower after hysteroscopy using the TruClear™ system than after conventional resectoscopy.

Two additional retrospective cohort TruClear™ system studies both from Hamerlynck et al. in 2011 and 2013 for the removal of polyps, fibroids or placental remnants were also identified by Noventa et al.

Two MyoSure™* case reports for the removal of fibroids (Greenberg et al., 2006) or placental

remnants (Harpham and Abbott, 2014) were also analyzed by Noventa et al. Those later studies are not presented in the extended bibliography as they did not compare results with another tissue resection device.

Overall the authors concluded that for the removal of intrauterine pathologies (except for fibroids type 2, classification ESGE) mechanical tissue resection system:

Is safe and effective tool

Can be used in operating room or office setting


Table 8-17 Publications comparing the TruClear™ system and other devices


9.3.3. Hysteroscopic Morcellation Versus Resection for the Treatment of Uterine Cavitary Lesions: A Systematic Review and Meta-analysis

Citation Shazly SA, Laughlin-Tommaso SK, Breitkopf DM, et al. Hysteroscopic

Morcellation Versus Resection for the Treatment of Uterine Cavitary Lesions: A Systematic Review and Meta-analysis. J Minim Invasive Gynecol. 2016; 23(6): 867–77.

Country Global

Setting Polypectomy, myomectomy. Operating room or outpatient or office.

Design A systematic review and meta-analysis

Enrolment A search of Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science was conducted through August 18, 2015, for randomized controlled trials (RCTs) and prospective and retrospective studies, regardless of surgical indication and study language or sample size

Comparison Mechanical tissue resection (TruClear™ system 8.0 or 5.0 or MyoSure™*system)

vs electrical tissue resection (VERSAPOINT™* system or conventional resectoscope)

Patients 650 women (4 RCTs and 3 retrospective observational studies)

Endpoints Comparison of hysteroscopic morcellation with electrosurgical resection to treat uterine cavitary lesions


Shazly et al. investigated in a systematic review and meta-analysis the mechanical and electrical tissue resection devices.

Seven studies and 650 patients (238 using mechanical tissue resection and 412 using electrical tissue resection) were included in the meta-analysis. Five TruClear™ system studies versus VERSAPOINT™* (Rovira Pampalona et al., 2015; Smith et al., 2014) or other conventional resectoscope (Emanuel and Wamsteker, 2005; van Dongen et al., 2008; Hamerlynck et al., 2015) were identified for the removal of polyps, fibroids. Those studies can be found in the section 9.1. Two

MyoSure™*retrospective comparative studies versus VERSAPOINT™* from Hamidouche et al.

were also identified by Shazly et al.

Abnormal uterine bleeding was noted as the most common pre-operative symptom followed by infertility. The reported size for polyp and fibroid varies from 9.2 to 17 mm and from 9.7 to 25.4 mm, respectively. Meta-analysis of the total procedure time based on the lesion type (polyp, fibroid or both) or on study design was in favour of mechanical tissue resection.

The two randomized controlled trials from Hamerlynck et al. and Rivera Pampalona were meta-analyzed and showed significant less fluid deficit and incomplete polyp removal for the TruClear™ system vs VERSAPOINT™*. Shazly et al. found no significant result for the all studies or the observational studies comparison.


Figure 8-14 Meta-analysis of the total procedure time


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