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The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids Bala´zs Nagy a,b,*, Gyo¨rgy Tima´r b, Judit Jo´zwiak-Hagyma´sy b, Ga´bor Kova´cs b, Gergo˝ Mere´sz b, Istva´n Va´mossy c, Tama´s A´gh c, A´da´m La´szlo´ d, Zolta´n Voko´ a,b, Zolta´n Kalo´ a,b a
Department of Health Policy & Health Economics, Institute of Economics, Faculty of Social Sciences, Eo¨tvo¨s Lora´nd University, Budapest 1117, Hungary Syreon Research Institute, Budapest 1146, Hungary c Gedeon Richter Plc., Budapest 1103, Hungary d Bajcsy-Zsilinszky Hospital, Budapest 1106, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 July 2013 Received in revised form 18 December 2013 Accepted 21 January 2014
Objectives: Ulipristal acetate is a selective progesterone receptor modulator that has been demonstrated to be an effective 3-month pre-operative treatment for moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The aim of this analysis was to assess the cost-effectiveness of 5 mg ulipristal as an add-on therapy to standard pre-surgical observation and treatment in Hungary. Study design: A Markov model was developed using a 10-year time horizon. Ulipristal was compared with pre-surgical observation and immediate hysterectomy. The model comprised the following mutually exclusive health states: mild, moderate, severe, or persistent severe excessive bleeding disorder; myomectomy; post-myomectomy with mildly to moderately excessive bleeding disorder; post-myomectomy with severely excessive bleeding disorder; hysterectomy; post-hysterectomy; postmenopause; and death. Transition probabilities and utility values were obtained from clinical trials and the scientific literature. Resource utilisation and unit costs were derived from a consensus panel of clinical experts, National Health Insurance Fund tariffs, and publications. Results: Adding a 3-month course of ulipristal to pre-operative observation was predicted to achieve an additional 0.021 quality-adjusted life years (QALYs) at an estimated incremental cost of s397, which would result in an incremental cost of s19,200/QALY. When 3 months of ulipristal therapy was compared with immediate hysterectomy, the incremental cost-effectiveness ratio was reduced to s3575/QALY. The results were most sensitive to the utility value of the post-hysterectomy health state but responsive to changes in other model parameters. Conclusions: The results of this analysis suggest that adding ulipristal treatment to standard pre-surgical therapy represents a good value for money in Hungary. The inclusion of societal benefits may considerably reduce the cost-effectiveness ratio. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ulipristal acetate Economic evaluation Cost-effectiveness Cost-utility analysis
Introduction Uterine fibroids, or leiomyomas, are benign hormone-sensitive tumours that consist of smooth muscle cells and affect approximately 20–40% of women of reproductive age [1,2]. Uterine fibroids are a benign disease, but this condition may have serious pathological consequences. In addition to anaemia caused by abnormal uterine bleeding, dysmenorrhea, pelvic pain, and pelvic pressure are common symptoms that are associated with uterine
* Corresponding author at: Syreon Research Institute, Tho¨ko¨ly Street 119, 1146 Budapest, Hungary. Tel.: +36 1 787 0083; fax: +36 1 220 5768.
fibroids and may significantly reduce quality of life and affect fertility [3–6]. The mainstays of treatment for symptomatic uterine fibroids are surgical and radiological interventions. Uterine fibroids are the most common indication for hysterectomy [2]. Less invasive procedures include myomectomy, uterine artery embolisation and other radiological interventions [3,7]. Additionally, medical therapies are available to manage uterine fibroids. However, most of these therapies, such as gonadotropin-releasing hormone (GnRH) agonists, progestins, and levonorgestrel-releasing intrauterine devices, have limitations. GnRH agonists induce a lowoestrogen state, which effectively reduces fibroid size and bleeding, but they frequently cause hot flushes, and because of safety concerns, such as the loss of bone mineral density, the use of
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Please cite this article in press as: Nagy B, et al. The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.01.022
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these drugs is limited to short-term therapy [8]. Progestins may actually cause fibroids to grow and can result in breakthrough bleeding, which may limit their use [9,10]. Levonorgestrelreleasing intrauterine devices can only be used in women with no uterine distortion caused by fibroids. These devices control menorrhagia only in certain patients, and their effect on fibroid volume remains controversial [11]. Ulipristal acetate 5 mg (Esmya1, manufactured by Gedeon Richter Plc., Budapest, Hungary) is a novel oral therapy for the preoperative treatment of symptomatic uterine fibroids in adult women of reproductive age [12]. Ulipristal acetate is a selective progesterone receptor modulator (SPRM) with a direct action on fibroids and the endometrium through the progesterone receptor [5,6,13]. Its clinical benefits include its ability to reduce fibroidrelated bleeding, anaemia, pain, and fibroid size [5,6]. Ulipristal acetate has been compared with a placebo (Pearl I) [5] and GnRH agonists (Pearl II) [6] in pivotal clinical trials. In several Central-Eastern European countries, including Hungary, GnRH agonists are not reimbursed for the preoperative treatment of symptomatic uterine fibroids. Therefore, in these countries, GnRH agonists are not appropriate comparators for ulipristal acetate in economic evaluations. The aim of this analysis was to assess the cost-effectiveness of ulipristal acetate 5 mg as an add-on therapy to standard pre-surgical observation (i.e., a placebo) or immediate hysterectomy in a Hungarian healthcare setting. Materials and methods A Markov state-transition economic model was developed using a 10-year time horizon to estimate the cost-effectiveness of ulipristal acetate compared with either pre-surgical observation or immediate hysterectomy. The model comprised the following mutually exclusive health states: mild to moderate excessive bleeding disorder, severe excessive bleeding disorder, persistent severe excessive bleeding disorder, myomectomy,
post-myomectomy with mild to moderate excessive bleeding disorder, post-myomectomy with severe excessive bleeding disorder, post-myomectomy with persistent severe excessive bleeding disorder, hysterectomy, post-hysterectomy, post-menopause, and death (Fig. 1). In the ulipristal acetate and pre-surgical observation arms, the patient pathways (Fig. 1) followed the Pearl I clinical trial pattern. Pearl I was a randomised, parallel-group, double-blind, placebocontrolled, phase 3 trial that was conducted to assess the efficacy and safety of ulipristal acetate treatment for up to 13 weeks in women with symptomatic uterine fibroids and excessive uterine bleeding. All patients were eligible to undergo fibroid surgery at the end of the treatment period. Uterine bleeding was evaluated using the Pictorial Blood Assessment Chart (PBAC) [14]. The PBAC is a validated self-reporting tool that is used to estimate menstrual blood loss. The 28-day PBAC scores range from 0 (amenorrhea) to more than 500, and higher scores indicate increased bleeding. In the Pearl I clinical trial, women with a PBAC score >100 during days 1–8 of menstruation were included in the study. The mean 28-day PBAC score for all patients on a placebo and on ulipristal acetate 5 mg was 478.2 at baseline. Additional details on the Pearl I clinical trial’s study design, methods, and results have been previously reported [5]. The patient characteristics that were used in the current study model were consistent with the study population in the Pearl I clinical trial. In the economic model, a minimum 50% reduction in the PBAC score was considered to be a clinically significant outcome. Therefore, ‘‘mild to moderate excessive bleeding’’ was defined by a PBAC score 12 weeks) were differentiated from the patients with recent onset of severe bleeding symptoms. Patients may die in any of these health states; therefore, patient deaths were assessed by obtaining the age-specific mortality rate. The starting age of the cohort was assumed to be 42 years, similar to the mean age of the patients in the Pearl I study. In addition, 50 years was assumed to be the mean age of the patients at menopause. The analysis was performed from the public payer perspective in Hungary. Costs and benefits were discounted at a yearly rate of 3.5%. Transition probabilities were calculated using the Pearl I clinical trial data, published scientific literature [15], and estimates from an international expert panel meeting [20]. The cycle length was 4 weeks in the first and second cycle, 5 weeks in the third cycle and 12 weeks in the fourth cycle, which reflected the measurement points in the clinical trial. After 26 weeks, the length of the Markov cycles was 12 weeks. For the first 13 weeks, transition probabilities were calculated using the individual patient-level data from the Pearl I trial, as depicted in Table 1. After the 13th week, similar to the Pearl I trial, patients could undergo surgical intervention, either myomectomy or hysterectomy. The clinical trial provided limited information on the outcomes of post-surgical treatment; therefore, assumptions were made in the model. Bleeding symptoms could not recur immediately after myomectomy, therefore the transition probability from myomectomy to post-surgical severe excessive bleeding or to hysterectomy was assumed to be 0. The transition from post-surgical severe excessive bleeding to recurrent surgery or to any bleeding-related health state was similar to the transitions from pre-surgical severe excessive bleeding, and transition probabilities were obtained from the Pearl I trial data. The transition probability of recurrent bleeding symptoms after non-definitive surgery, such as myomectomy, was calibrated to reflect the results of Hirst et al. [15] (i.e., the incidence of a subsequent surgery was assumed to be 18.3% within 7 years after myomectomy). The subsequent surgery after myomectomy was assumed to be hysterectomy. This assumption was supported by the international consensus panel that was convened to simplify patient pathways [20]. The probability of surgery for patients with persistent severe excessive bleeding (i.e., severe excessive bleeding for >12 weeks) was assumed to be 25% greater than that for patients with non-persistent severe excessive bleeding (i.e., severe excessive bleeding for a maximum of 12 weeks) in both treatment arms.
Table 1 depicts the transition probabilities of the first 3 model cycles for the ulipristal acetate and pre-surgical observation arms. After the third cycle, the transition probabilities were assumed to be equal in both arms (Table 2). The patient quality of life was not evaluated in the Pearl I trial [5]; therefore, data from the Pearl II trial [6] and the scientific literature were applied to determine the quality of life benefits for each health state in the Markov model. The Pearl II trial was a randomised, parallel-group, double-blind, doubledummy, active comparator-controlled, phase 3 clinical trial that was conducted to assess the efficacy and safety of ulipristal acetate 5 mg compared with leuprolide acetate for the preoperative treatment of symptomatic uterine fibroids. The study protocol and the Pearl II trial results have been previously reported [6]. The Pearl II study measured the patient quality of life using the Uterine Fibroid Symptom and Quality of Life [16] (UFS-QOL) disease-specific questionnaire. The patient-level data from the Pearl II trial were analysed to determine the quality of life of patients in pre-surgical health states (PregLem: A Phase III, randomized, parallel group, double-blind, double-dummy, active comparator-controlled, multi-center study to assess the efficacy and safety of PGL4001 (ulipristal) versus GnRH-agonist (leuprorelin 3.75 mg) for pre-operative treatment of symptomatic uterine myomas, 2010. Data on file at Gedeon Richter Plc.). Rowen and Brazier completed a mapping exercise to transform the UFS-QOL results into EQ-5D data [19]. Based on the analysis of the Pearl II UFS-QOL patient-level data and the transformation of the UFS-QOL data into EQ-5D scores, utility values of 0.830 and 0.718 were applied to the ‘mild to moderate excessive bleeding’ and ‘severe excessive bleeding’ health states, respectively. The same utility values were applied to the bleedingrelated health states (i.e., ‘mild to moderate excessive bleeding’ and ‘severe excessive bleeding’) before and after surgery. The utility of persistent severe excessive bleeding was assumed to be equal to that of severe excessive bleeding because the patients who bled for longer periods of time were expected to ‘feel the same’ on average as the patients who bled for a shorter period of time. No differences between the utility of myomectomy and hysterectomy were assumed, similar to the NICE HOPEFUL study [15]. For women who underwent hysterectomy, the diminishing symptoms of uterine fibroids had a positive impact on utility compared with the severe excessive bleeding symptoms, whereas the loss of fertility and other psychological problems had a negative impact compared with ‘mild to moderate excessive bleeding’. Therefore, the utility after hysterectomy was assumed to be smaller in the state of ‘mild to moderate excessive bleeding’, and the utility value was determined to be 0.777 based on the literature [17,18]. Resource utilisation estimates of the health states and any adverse events were calculated using information from consensus panel meetings with clinical experts [20]. The unit costs were
Please cite this article in press as: Nagy B, et al. The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.01.022
Persistent Severe excessive bleeding disorder (1+ cycles)
Myomectomy
Mild to moderate excessive bleeding disorder, post-myomectomy
Severe excessive bleeding disorder (1 cycle), post-myomectomy
Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy
Hysterectomy
Posthysterectomy
0.31 0.10
0.37 0.00
0.00 0.40
0.22 0.27
0.00 0.00
0.00 0.00
0.00 0.00
0.11 0.23
0.00 0.00
0.10
0.00
0.28
0.34
0.00
0.00
0.00
0.28
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.76 0.99
0.25 0.01
0.00 0.00
0.00 0.00
0.00 0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.40
0.50
0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.28
0.63
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
1.00 1.00
0.60 0.10 0.10
0.07 0.00 0.00
0.00 0.41 0.28
0.22 0.27 0.34
0.00 0.00 0.00
0.00 0.00 0.00
0.00 0.00 0.00
0.11 0.23 0.28
0.00 0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.76 0.99
0.25 0.01
0.00 0.00
0.00 0.00
0.00 0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.40
0.50
0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.28
0.63
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
1.00 1.00
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Severe excessive bleeding disorder (1 cycle)
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4th cycle (weeks 14–26) Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder (1 cycle) Persistent severe excessive bleeding disorder (1+ cycles) Myomectomy Mild to moderate excessive bleeding disorder, post-myomectomy Severe excessive bleeding disorder (1 cycle), post-myomectomy Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy Hysterectomy Post-hysterectomy 5th cycle (week 27 and beyond) Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder (1 cycle) Persistent severe excessive bleeding disorder (1+ cycles) Myomectomy Mild to moderate excessive bleeding disorder, post-myomectomy Severe excessive bleeding disorder (1 cycle), post-myomectomy Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy Hysterectomy Post-hysterectomy
Mild to moderate excessive bleeding disorder
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Table 2 Transition probabilities from week 14 and beyond.
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Table 3 Health utilities and direct medical costs for each health state. Health state
Utility value
Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder Persistent severe excessive bleeding disorder Myomectomy Post-myomectomy mild or moderate excessive bleeding disorder Post-myomectomy severe excessive bleeding disorder Post-myomectomy persistent severe excessive bleeding disorder Hysterectomy Post-hysterectomy Post-menopause Death a b
Cost (EUR)
Source (utility)
a
0.83 0.72 0.72 0.65 0.83 0.72 0.72 0.65 0.78 0.96 –
4.76 25.05a 25.05a 680.33b 0.49a 26.65a 26.65a 596.18b 0.15a – –
[20] [20] [20] [19] [20] [20] [20] [19] [18,19] [19] –
Per month. Per event.
obtained from the National Health Insurance Fund tariffs and local publications. All costs were from 2012 and were expressed in Euros (conversion rate: 279.37 Ft/Euro). The public price of ulipristal acetate was s167.5 per month. For the health utilities and the cost estimates, please see Table 3. To examine the effect of the uncertainty of model parameters on results, deterministic sensitivity analyses were performed. Results Compared with a placebo, the addition of 3-month preoperative ulipristal acetate therapy to the standard pre-surgical observation care of patients with moderate to severe symptoms of uterine fibroids was predicted to achieve an additional 0.021 QALYs at an estimated incremental cost of s397, which would result in an incremental cost of s19,200/QALY. When 3 months of ulipristal acetate therapy was compared with immediate hysterectomy without any observation period, the incremental costeffectiveness ratio (ICER) was s3575/QALY (Table 4). Using the model variables, a series of 1-way deterministic sensitivity analyses were performed both systematically (i.e., adding and subtracting 10% from the base case estimates, Fig. 2) and manually (Table 5). The results were robust to changes in most of the model parameters, excluding the utility values of the posthysterectomy health state. Comments The results of the analysis suggest that adding pre-operative ulipristal acetate to standard pre-surgical therapy for women of reproductive age with uterine fibroids and moderate to severe symptoms of bleeding results in reasonable QALY gains compared with observation. To maximise the allocation efficiency of scarce resources, health care decision makers need information about the health and costconsequences of different interventions. Cost-effectiveness is a key criterion for reimbursement decision making to support the
efficient allocation of health resources. Our analysis provides a practical tool for this process. The incremental cost-effectiveness ratio of ulipristal acetate was less than double that of the gross domestic product (GDP) per capita in Hungary (the GDP per capita was s10,085 in 2011). Therefore, ulipristal acetate represents good value for money according to the lower bound of the cost-effectiveness threshold criterion in Hungary. Ulipristal acetate was highly cost-effective compared with immediate hysterectomy. These results support the case for the reimbursement of ulipristal acetate in Hungary. This conclusion adds an important perspective during the reimbursement procedure of medical technologies, as cost-effective medical technologies are highly desirable in improving health care system efficiency. The generalisability of our findings is limited. The Pearl I clinical trial was not designed to assess how the pre-surgical application of ulipristal acetate could reduce the number and invasiveness of surgical interventions. Therefore, we assumed that the need for surgery was purely based on the severity and persistence of bleeding symptoms, independent of the pre-surgical treatment. To simplify the patient pathways, the post-myomectomy surgery was presumed to be hysterectomy. These assumptions were validated by clinical experts and can be further validated in prospective observational studies. Quality of life was not measured in the Pearl I trial; therefore, the UFS-QOL data could not be directly derived from this trial. The results of the mapping exercise by Rowen and Brazier were used to predict the EQ-5D utility scores of patients in pre-surgical health states based on the UFS-QOL data; however, these results were associated with uncertainty, which was well documented by Rowen and Brazier [19]. Based on their judgment, the most appropriate algorithm was applied. In addition, the model results were highly sensitive to the utility of the post-hysterectomy health state. Further studies are needed to validate the utility values for all postsurgical health states. Immediate hysterectomy is a standard procedure in several jurisdictions. The lack of comparative clinical trial data prevented us from considering immediate hysterectomy as a base case comparator for ulipristal acetate in this analysis. When ulipristal
Table 4 The cost-effectiveness results for ulipristal acetate.
Vs. pre-surgical observation Ulipristal acetate Pre-surgical observation Incremental value Incremental cost per QALY Vs. immediate hysterectomy Ulipristal acetate Immediate hysterectomy Incremental value Incremental cost per QALY
QALY (per patient)
Cost (EUR per patient)
Myomectomy (per 1000 patients)
Hysterectomy (per 1000 patients)
6.32 6.30 0.02 19,200 EUR/QALY
1238 842 397
610.9 580.3 30.6
488.0 513.8 26.9
6.32 6.14 0.18 3575 EUR/QALY
1238 609 630
610.9 0 610.9
487.0 1000.0 513.0
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Fig. 2. Tornado diagram with the 20 most sensitive variables.
Table 5 The sensitivity analysis results for pre-surgical ulipristal acetate therapy compared with pre-surgical observation. Variable (value)
Incremental QALYs
Incremental costs (EUR)
ICER (EUR/QALY)
Discount rate (3.7%) Increased probability of surgery because of persistent excessive bleeding (5%) Increased probability of surgery because of persistent excessive bleeding (40%) Starting year of menopause (48 years) Starting year of menopause (52 years) Starting age of the cohort (18 years) Starting age of the cohort (45 years) Societal perspective (1 child born per 1000 patients treated with ulipristal acetate)
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
397 396 397 396 398 398 395 351
18,913 19,801 18,927 20,834 18,073 17,321 21,953 16,743
acetate was directly compared with immediate hysterectomy in the sensitivity analysis, the cost-effectiveness ratio was significantly reduced. The inclusion of societal benefits may considerably reduce the cost-effectiveness ratio, but further evidence from observational studies is needed to determine the benefits of preoperative ulipristal acetate therapy on fertility. Based on the evidence from this study, the current model translates to only short-term clinical benefits of pre-operative ulipristal acetate therapy (i.e., reduced symptoms) in policy related health outcomes. However, additional scientific evidence on the potential long-term benefits of this therapy (i.e., less invasive treatment and surgery may be avoided) may further strengthen the conclusion of its cost-effectiveness. Condensation Our results support the cost-effectiveness of pre-operative ulipristal acetate therapy compared to observation in Hungarian women with moderate to severe symptoms of uterine fibroids. Acknowledgements The authors acknowledge the contributions of Bala´zs Lintner, Szabolcs Va´rbı´ro´ and La´szlo´ Hagyma´sy during the initial phase of the project. This research was financially supported by Gedeon
Richter Plc., Budapest, Hungary. Istva´n Va´mossy and Tama´s A´gh are full-time employees of Gedeon Richter Plc. A´da´m La´szlo´ was an investigator in the PEARL I trial. The authors take full responsibility for the manuscript. References [1] Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol 2010;202:514–21. [2] Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 2004;104:393–406. [3] Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002;17:1424–30. [4] Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update 2007;13:465–76. [5] Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20. [6] Donnez J, Tomaszewski J, Vazquez F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421–32. [7] Dubuisson JB, Chapron C, Fauconnier A, Babaki-Fard K. Laparoscopic myomectomy fertility results. Ann N Y Acad Sci 2001;943:269–75. [8] Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001;2:CD000547. [9] Scialli AR, Jestila KJ. Sustained benefits of leuprolide acetate with or without subsequent medroxyprogesterone acetate in the nonsurgical management of leiomyomata uteri. Fertil Steril 1995;64:313–20. [10] Carr BR, Marshburn PB, Weatherall PT, et al. An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate
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The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids Bala´zs Nagy a,b,*, Gyo¨rgy Tima´r b, Judit Jo´zwiak-Hagyma´sy b, Ga´bor Kova´cs b, Gergo˝ Mere´sz b, Istva´n Va´mossy c, Tama´s A´gh c, A´da´m La´szlo´ d, Zolta´n Voko´ a,b, Zolta´n Kalo´ a,b a
Department of Health Policy & Health Economics, Institute of Economics, Faculty of Social Sciences, Eo¨tvo¨s Lora´nd University, Budapest 1117, Hungary Syreon Research Institute, Budapest 1146, Hungary c Gedeon Richter Plc., Budapest 1103, Hungary d Bajcsy-Zsilinszky Hospital, Budapest 1106, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 July 2013 Received in revised form 18 December 2013 Accepted 21 January 2014
Objectives: Ulipristal acetate is a selective progesterone receptor modulator that has been demonstrated to be an effective 3-month pre-operative treatment for moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The aim of this analysis was to assess the cost-effectiveness of 5 mg ulipristal as an add-on therapy to standard pre-surgical observation and treatment in Hungary. Study design: A Markov model was developed using a 10-year time horizon. Ulipristal was compared with pre-surgical observation and immediate hysterectomy. The model comprised the following mutually exclusive health states: mild, moderate, severe, or persistent severe excessive bleeding disorder; myomectomy; post-myomectomy with mildly to moderately excessive bleeding disorder; post-myomectomy with severely excessive bleeding disorder; hysterectomy; post-hysterectomy; postmenopause; and death. Transition probabilities and utility values were obtained from clinical trials and the scientific literature. Resource utilisation and unit costs were derived from a consensus panel of clinical experts, National Health Insurance Fund tariffs, and publications. Results: Adding a 3-month course of ulipristal to pre-operative observation was predicted to achieve an additional 0.021 quality-adjusted life years (QALYs) at an estimated incremental cost of s397, which would result in an incremental cost of s19,200/QALY. When 3 months of ulipristal therapy was compared with immediate hysterectomy, the incremental cost-effectiveness ratio was reduced to s3575/QALY. The results were most sensitive to the utility value of the post-hysterectomy health state but responsive to changes in other model parameters. Conclusions: The results of this analysis suggest that adding ulipristal treatment to standard pre-surgical therapy represents a good value for money in Hungary. The inclusion of societal benefits may considerably reduce the cost-effectiveness ratio. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ulipristal acetate Economic evaluation Cost-effectiveness Cost-utility analysis
Introduction Uterine fibroids, or leiomyomas, are benign hormone-sensitive tumours that consist of smooth muscle cells and affect approximately 20–40% of women of reproductive age [1,2]. Uterine fibroids are a benign disease, but this condition may have serious pathological consequences. In addition to anaemia caused by abnormal uterine bleeding, dysmenorrhea, pelvic pain, and pelvic pressure are common symptoms that are associated with uterine
* Corresponding author at: Syreon Research Institute, Tho¨ko¨ly Street 119, 1146 Budapest, Hungary. Tel.: +36 1 787 0083; fax: +36 1 220 5768.
fibroids and may significantly reduce quality of life and affect fertility [3–6]. The mainstays of treatment for symptomatic uterine fibroids are surgical and radiological interventions. Uterine fibroids are the most common indication for hysterectomy [2]. Less invasive procedures include myomectomy, uterine artery embolisation and other radiological interventions [3,7]. Additionally, medical therapies are available to manage uterine fibroids. However, most of these therapies, such as gonadotropin-releasing hormone (GnRH) agonists, progestins, and levonorgestrel-releasing intrauterine devices, have limitations. GnRH agonists induce a lowoestrogen state, which effectively reduces fibroid size and bleeding, but they frequently cause hot flushes, and because of safety concerns, such as the loss of bone mineral density, the use of
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Please cite this article in press as: Nagy B, et al. The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.01.022
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these drugs is limited to short-term therapy [8]. Progestins may actually cause fibroids to grow and can result in breakthrough bleeding, which may limit their use [9,10]. Levonorgestrelreleasing intrauterine devices can only be used in women with no uterine distortion caused by fibroids. These devices control menorrhagia only in certain patients, and their effect on fibroid volume remains controversial [11]. Ulipristal acetate 5 mg (Esmya1, manufactured by Gedeon Richter Plc., Budapest, Hungary) is a novel oral therapy for the preoperative treatment of symptomatic uterine fibroids in adult women of reproductive age [12]. Ulipristal acetate is a selective progesterone receptor modulator (SPRM) with a direct action on fibroids and the endometrium through the progesterone receptor [5,6,13]. Its clinical benefits include its ability to reduce fibroidrelated bleeding, anaemia, pain, and fibroid size [5,6]. Ulipristal acetate has been compared with a placebo (Pearl I) [5] and GnRH agonists (Pearl II) [6] in pivotal clinical trials. In several Central-Eastern European countries, including Hungary, GnRH agonists are not reimbursed for the preoperative treatment of symptomatic uterine fibroids. Therefore, in these countries, GnRH agonists are not appropriate comparators for ulipristal acetate in economic evaluations. The aim of this analysis was to assess the cost-effectiveness of ulipristal acetate 5 mg as an add-on therapy to standard pre-surgical observation (i.e., a placebo) or immediate hysterectomy in a Hungarian healthcare setting. Materials and methods A Markov state-transition economic model was developed using a 10-year time horizon to estimate the cost-effectiveness of ulipristal acetate compared with either pre-surgical observation or immediate hysterectomy. The model comprised the following mutually exclusive health states: mild to moderate excessive bleeding disorder, severe excessive bleeding disorder, persistent severe excessive bleeding disorder, myomectomy,
post-myomectomy with mild to moderate excessive bleeding disorder, post-myomectomy with severe excessive bleeding disorder, post-myomectomy with persistent severe excessive bleeding disorder, hysterectomy, post-hysterectomy, post-menopause, and death (Fig. 1). In the ulipristal acetate and pre-surgical observation arms, the patient pathways (Fig. 1) followed the Pearl I clinical trial pattern. Pearl I was a randomised, parallel-group, double-blind, placebocontrolled, phase 3 trial that was conducted to assess the efficacy and safety of ulipristal acetate treatment for up to 13 weeks in women with symptomatic uterine fibroids and excessive uterine bleeding. All patients were eligible to undergo fibroid surgery at the end of the treatment period. Uterine bleeding was evaluated using the Pictorial Blood Assessment Chart (PBAC) [14]. The PBAC is a validated self-reporting tool that is used to estimate menstrual blood loss. The 28-day PBAC scores range from 0 (amenorrhea) to more than 500, and higher scores indicate increased bleeding. In the Pearl I clinical trial, women with a PBAC score >100 during days 1–8 of menstruation were included in the study. The mean 28-day PBAC score for all patients on a placebo and on ulipristal acetate 5 mg was 478.2 at baseline. Additional details on the Pearl I clinical trial’s study design, methods, and results have been previously reported [5]. The patient characteristics that were used in the current study model were consistent with the study population in the Pearl I clinical trial. In the economic model, a minimum 50% reduction in the PBAC score was considered to be a clinically significant outcome. Therefore, ‘‘mild to moderate excessive bleeding’’ was defined by a PBAC score 12 weeks) were differentiated from the patients with recent onset of severe bleeding symptoms. Patients may die in any of these health states; therefore, patient deaths were assessed by obtaining the age-specific mortality rate. The starting age of the cohort was assumed to be 42 years, similar to the mean age of the patients in the Pearl I study. In addition, 50 years was assumed to be the mean age of the patients at menopause. The analysis was performed from the public payer perspective in Hungary. Costs and benefits were discounted at a yearly rate of 3.5%. Transition probabilities were calculated using the Pearl I clinical trial data, published scientific literature [15], and estimates from an international expert panel meeting [20]. The cycle length was 4 weeks in the first and second cycle, 5 weeks in the third cycle and 12 weeks in the fourth cycle, which reflected the measurement points in the clinical trial. After 26 weeks, the length of the Markov cycles was 12 weeks. For the first 13 weeks, transition probabilities were calculated using the individual patient-level data from the Pearl I trial, as depicted in Table 1. After the 13th week, similar to the Pearl I trial, patients could undergo surgical intervention, either myomectomy or hysterectomy. The clinical trial provided limited information on the outcomes of post-surgical treatment; therefore, assumptions were made in the model. Bleeding symptoms could not recur immediately after myomectomy, therefore the transition probability from myomectomy to post-surgical severe excessive bleeding or to hysterectomy was assumed to be 0. The transition from post-surgical severe excessive bleeding to recurrent surgery or to any bleeding-related health state was similar to the transitions from pre-surgical severe excessive bleeding, and transition probabilities were obtained from the Pearl I trial data. The transition probability of recurrent bleeding symptoms after non-definitive surgery, such as myomectomy, was calibrated to reflect the results of Hirst et al. [15] (i.e., the incidence of a subsequent surgery was assumed to be 18.3% within 7 years after myomectomy). The subsequent surgery after myomectomy was assumed to be hysterectomy. This assumption was supported by the international consensus panel that was convened to simplify patient pathways [20]. The probability of surgery for patients with persistent severe excessive bleeding (i.e., severe excessive bleeding for >12 weeks) was assumed to be 25% greater than that for patients with non-persistent severe excessive bleeding (i.e., severe excessive bleeding for a maximum of 12 weeks) in both treatment arms.
Table 1 depicts the transition probabilities of the first 3 model cycles for the ulipristal acetate and pre-surgical observation arms. After the third cycle, the transition probabilities were assumed to be equal in both arms (Table 2). The patient quality of life was not evaluated in the Pearl I trial [5]; therefore, data from the Pearl II trial [6] and the scientific literature were applied to determine the quality of life benefits for each health state in the Markov model. The Pearl II trial was a randomised, parallel-group, double-blind, doubledummy, active comparator-controlled, phase 3 clinical trial that was conducted to assess the efficacy and safety of ulipristal acetate 5 mg compared with leuprolide acetate for the preoperative treatment of symptomatic uterine fibroids. The study protocol and the Pearl II trial results have been previously reported [6]. The Pearl II study measured the patient quality of life using the Uterine Fibroid Symptom and Quality of Life [16] (UFS-QOL) disease-specific questionnaire. The patient-level data from the Pearl II trial were analysed to determine the quality of life of patients in pre-surgical health states (PregLem: A Phase III, randomized, parallel group, double-blind, double-dummy, active comparator-controlled, multi-center study to assess the efficacy and safety of PGL4001 (ulipristal) versus GnRH-agonist (leuprorelin 3.75 mg) for pre-operative treatment of symptomatic uterine myomas, 2010. Data on file at Gedeon Richter Plc.). Rowen and Brazier completed a mapping exercise to transform the UFS-QOL results into EQ-5D data [19]. Based on the analysis of the Pearl II UFS-QOL patient-level data and the transformation of the UFS-QOL data into EQ-5D scores, utility values of 0.830 and 0.718 were applied to the ‘mild to moderate excessive bleeding’ and ‘severe excessive bleeding’ health states, respectively. The same utility values were applied to the bleedingrelated health states (i.e., ‘mild to moderate excessive bleeding’ and ‘severe excessive bleeding’) before and after surgery. The utility of persistent severe excessive bleeding was assumed to be equal to that of severe excessive bleeding because the patients who bled for longer periods of time were expected to ‘feel the same’ on average as the patients who bled for a shorter period of time. No differences between the utility of myomectomy and hysterectomy were assumed, similar to the NICE HOPEFUL study [15]. For women who underwent hysterectomy, the diminishing symptoms of uterine fibroids had a positive impact on utility compared with the severe excessive bleeding symptoms, whereas the loss of fertility and other psychological problems had a negative impact compared with ‘mild to moderate excessive bleeding’. Therefore, the utility after hysterectomy was assumed to be smaller in the state of ‘mild to moderate excessive bleeding’, and the utility value was determined to be 0.777 based on the literature [17,18]. Resource utilisation estimates of the health states and any adverse events were calculated using information from consensus panel meetings with clinical experts [20]. The unit costs were
Please cite this article in press as: Nagy B, et al. The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.01.022
Persistent Severe excessive bleeding disorder (1+ cycles)
Myomectomy
Mild to moderate excessive bleeding disorder, post-myomectomy
Severe excessive bleeding disorder (1 cycle), post-myomectomy
Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy
Hysterectomy
Posthysterectomy
0.31 0.10
0.37 0.00
0.00 0.40
0.22 0.27
0.00 0.00
0.00 0.00
0.00 0.00
0.11 0.23
0.00 0.00
0.10
0.00
0.28
0.34
0.00
0.00
0.00
0.28
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.76 0.99
0.25 0.01
0.00 0.00
0.00 0.00
0.00 0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.40
0.50
0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.28
0.63
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
1.00 1.00
0.60 0.10 0.10
0.07 0.00 0.00
0.00 0.41 0.28
0.22 0.27 0.34
0.00 0.00 0.00
0.00 0.00 0.00
0.00 0.00 0.00
0.11 0.23 0.28
0.00 0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.76 0.99
0.25 0.01
0.00 0.00
0.00 0.00
0.00 0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.40
0.50
0.00
0.00
0.00
0.00
0.00
0.10
0.00
0.28
0.63
0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
1.00 1.00
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Severe excessive bleeding disorder (1 cycle)
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4th cycle (weeks 14–26) Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder (1 cycle) Persistent severe excessive bleeding disorder (1+ cycles) Myomectomy Mild to moderate excessive bleeding disorder, post-myomectomy Severe excessive bleeding disorder (1 cycle), post-myomectomy Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy Hysterectomy Post-hysterectomy 5th cycle (week 27 and beyond) Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder (1 cycle) Persistent severe excessive bleeding disorder (1+ cycles) Myomectomy Mild to moderate excessive bleeding disorder, post-myomectomy Severe excessive bleeding disorder (1 cycle), post-myomectomy Persistent severe excessive bleeding disorder (1+ cycles), post-myomectomy Hysterectomy Post-hysterectomy
Mild to moderate excessive bleeding disorder
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Table 2 Transition probabilities from week 14 and beyond.
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Table 3 Health utilities and direct medical costs for each health state. Health state
Utility value
Mild to moderate excessive bleeding disorder Severe excessive bleeding disorder Persistent severe excessive bleeding disorder Myomectomy Post-myomectomy mild or moderate excessive bleeding disorder Post-myomectomy severe excessive bleeding disorder Post-myomectomy persistent severe excessive bleeding disorder Hysterectomy Post-hysterectomy Post-menopause Death a b
Cost (EUR)
Source (utility)
a
0.83 0.72 0.72 0.65 0.83 0.72 0.72 0.65 0.78 0.96 –
4.76 25.05a 25.05a 680.33b 0.49a 26.65a 26.65a 596.18b 0.15a – –
[20] [20] [20] [19] [20] [20] [20] [19] [18,19] [19] –
Per month. Per event.
obtained from the National Health Insurance Fund tariffs and local publications. All costs were from 2012 and were expressed in Euros (conversion rate: 279.37 Ft/Euro). The public price of ulipristal acetate was s167.5 per month. For the health utilities and the cost estimates, please see Table 3. To examine the effect of the uncertainty of model parameters on results, deterministic sensitivity analyses were performed. Results Compared with a placebo, the addition of 3-month preoperative ulipristal acetate therapy to the standard pre-surgical observation care of patients with moderate to severe symptoms of uterine fibroids was predicted to achieve an additional 0.021 QALYs at an estimated incremental cost of s397, which would result in an incremental cost of s19,200/QALY. When 3 months of ulipristal acetate therapy was compared with immediate hysterectomy without any observation period, the incremental costeffectiveness ratio (ICER) was s3575/QALY (Table 4). Using the model variables, a series of 1-way deterministic sensitivity analyses were performed both systematically (i.e., adding and subtracting 10% from the base case estimates, Fig. 2) and manually (Table 5). The results were robust to changes in most of the model parameters, excluding the utility values of the posthysterectomy health state. Comments The results of the analysis suggest that adding pre-operative ulipristal acetate to standard pre-surgical therapy for women of reproductive age with uterine fibroids and moderate to severe symptoms of bleeding results in reasonable QALY gains compared with observation. To maximise the allocation efficiency of scarce resources, health care decision makers need information about the health and costconsequences of different interventions. Cost-effectiveness is a key criterion for reimbursement decision making to support the
efficient allocation of health resources. Our analysis provides a practical tool for this process. The incremental cost-effectiveness ratio of ulipristal acetate was less than double that of the gross domestic product (GDP) per capita in Hungary (the GDP per capita was s10,085 in 2011). Therefore, ulipristal acetate represents good value for money according to the lower bound of the cost-effectiveness threshold criterion in Hungary. Ulipristal acetate was highly cost-effective compared with immediate hysterectomy. These results support the case for the reimbursement of ulipristal acetate in Hungary. This conclusion adds an important perspective during the reimbursement procedure of medical technologies, as cost-effective medical technologies are highly desirable in improving health care system efficiency. The generalisability of our findings is limited. The Pearl I clinical trial was not designed to assess how the pre-surgical application of ulipristal acetate could reduce the number and invasiveness of surgical interventions. Therefore, we assumed that the need for surgery was purely based on the severity and persistence of bleeding symptoms, independent of the pre-surgical treatment. To simplify the patient pathways, the post-myomectomy surgery was presumed to be hysterectomy. These assumptions were validated by clinical experts and can be further validated in prospective observational studies. Quality of life was not measured in the Pearl I trial; therefore, the UFS-QOL data could not be directly derived from this trial. The results of the mapping exercise by Rowen and Brazier were used to predict the EQ-5D utility scores of patients in pre-surgical health states based on the UFS-QOL data; however, these results were associated with uncertainty, which was well documented by Rowen and Brazier [19]. Based on their judgment, the most appropriate algorithm was applied. In addition, the model results were highly sensitive to the utility of the post-hysterectomy health state. Further studies are needed to validate the utility values for all postsurgical health states. Immediate hysterectomy is a standard procedure in several jurisdictions. The lack of comparative clinical trial data prevented us from considering immediate hysterectomy as a base case comparator for ulipristal acetate in this analysis. When ulipristal
Table 4 The cost-effectiveness results for ulipristal acetate.
Vs. pre-surgical observation Ulipristal acetate Pre-surgical observation Incremental value Incremental cost per QALY Vs. immediate hysterectomy Ulipristal acetate Immediate hysterectomy Incremental value Incremental cost per QALY
QALY (per patient)
Cost (EUR per patient)
Myomectomy (per 1000 patients)
Hysterectomy (per 1000 patients)
6.32 6.30 0.02 19,200 EUR/QALY
1238 842 397
610.9 580.3 30.6
488.0 513.8 26.9
6.32 6.14 0.18 3575 EUR/QALY
1238 609 630
610.9 0 610.9
487.0 1000.0 513.0
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Fig. 2. Tornado diagram with the 20 most sensitive variables.
Table 5 The sensitivity analysis results for pre-surgical ulipristal acetate therapy compared with pre-surgical observation. Variable (value)
Incremental QALYs
Incremental costs (EUR)
ICER (EUR/QALY)
Discount rate (3.7%) Increased probability of surgery because of persistent excessive bleeding (5%) Increased probability of surgery because of persistent excessive bleeding (40%) Starting year of menopause (48 years) Starting year of menopause (52 years) Starting age of the cohort (18 years) Starting age of the cohort (45 years) Societal perspective (1 child born per 1000 patients treated with ulipristal acetate)
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
397 396 397 396 398 398 395 351
18,913 19,801 18,927 20,834 18,073 17,321 21,953 16,743
acetate was directly compared with immediate hysterectomy in the sensitivity analysis, the cost-effectiveness ratio was significantly reduced. The inclusion of societal benefits may considerably reduce the cost-effectiveness ratio, but further evidence from observational studies is needed to determine the benefits of preoperative ulipristal acetate therapy on fertility. Based on the evidence from this study, the current model translates to only short-term clinical benefits of pre-operative ulipristal acetate therapy (i.e., reduced symptoms) in policy related health outcomes. However, additional scientific evidence on the potential long-term benefits of this therapy (i.e., less invasive treatment and surgery may be avoided) may further strengthen the conclusion of its cost-effectiveness. Condensation Our results support the cost-effectiveness of pre-operative ulipristal acetate therapy compared to observation in Hungarian women with moderate to severe symptoms of uterine fibroids. Acknowledgements The authors acknowledge the contributions of Bala´zs Lintner, Szabolcs Va´rbı´ro´ and La´szlo´ Hagyma´sy during the initial phase of the project. This research was financially supported by Gedeon
Richter Plc., Budapest, Hungary. Istva´n Va´mossy and Tama´s A´gh are full-time employees of Gedeon Richter Plc. A´da´m La´szlo´ was an investigator in the PEARL I trial. The authors take full responsibility for the manuscript. References [1] Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol 2010;202:514–21. [2] Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 2004;104:393–406. [3] Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002;17:1424–30. [4] Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update 2007;13:465–76. [5] Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20. [6] Donnez J, Tomaszewski J, Vazquez F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421–32. [7] Dubuisson JB, Chapron C, Fauconnier A, Babaki-Fard K. Laparoscopic myomectomy fertility results. Ann N Y Acad Sci 2001;943:269–75. [8] Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001;2:CD000547. [9] Scialli AR, Jestila KJ. Sustained benefits of leuprolide acetate with or without subsequent medroxyprogesterone acetate in the nonsurgical management of leiomyomata uteri. Fertil Steril 1995;64:313–20. [10] Carr BR, Marshburn PB, Weatherall PT, et al. An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate
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