Efectos del acetato de ulipristal en pacientes con miomas uterinos sintom�ticos

Navarro Plazaola, Natalia; Vega Chacana, Marla; Avil�s Dorlhiac, Raimundo

doi:10.5867/medwave.2021.04.8162

Res�menes Epistemonikos

Medwave 2021;21(4):e8162 doi: 10.5867/medwave.2021.04.8162

Efectos del acetato de ulipristal en pacientes con miomas uterinos sintom�ticos

Effects of ulipristal acetate in patients with symptomatic uterine fibroids

Natalia Navarro Plazaola, Marla Vega Chacana, Raimundo Avil�s Dorlhiac

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Palabras clave: ulipristal, uterine fibroids, epistemonikos, GRADE

Abstract

Introduction
Uterine fibroids are frequently encountered in gynecology and are a therapeutic challenge. New therapies, such as ulipristal acetate, could help with symptomatic relief, improve quality of life, and decrease uterine fibroid size. Notwithstanding, there is controversy about adverse effects, especially for hepatotoxicity.

Methods
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach.

Results and conclusions
We identified nine systematic reviews and included ten studies overall, of which five were randomized trials. We conclude that ulipristal increases the likelihood of amenorrhea, improves the quality of life, and decreases menstrual bleeding. However, there is also a likely increase in the risk of adverse effects. Furthermore, ulipristal could decrease the size of fibroids.

Problem

Uterine fibroids have an incidence of 40% in women older than 35 years [1]. They are symptomatic less than 30% of the time, including dysmenorrhea and abnormal uterine bleeding, among the most frequent [2].

Most of the time, these symptoms respond well to medical treatments such as non-steroidal anti-inflammatory drugs or contraceptives. The remaining percentage will eventually require surgery, ranging from myomectomy to hysterectomy. Uterine fibroids account for 60% of major gynecological surgeries [3] and cost between 1,400 and 2,300 USD. When seeking to preserve the patient’s fertility, a myomectomy can be performed, a surgery that generally has high bleeding rates and requires adequate training by the surgeon. Since this technique was described, various preoperative strategies have been tried to reduce bleeding.

Among the different medical alternatives available, ulipristal acetate has been used to reduce bleeding and eventually facilitates surgery [4]. Despite this benefit, there is controversy about its use because adverse events have been described.

Methods

We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), a meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach, and a table of other considerations for decision-making.

Main messages

On the one hand, ulipristal acetate increases the probability of amenorrhea, slightly improves quality of life, and increases the risk of reduced menstruation flow. On the other hand, it increases the risk of adverse effects in patients with symptomatic uterine fibroids.
Ulipristal acetate reduces the size of fibroids; however, the certainty of the evidence is low.
Regarding the risk of adverse effects, it is recommended to monitor liver function before, during, and after using ulipristal acetate.

In relation to the body of evidence to answer these questions

What is the evidence See evidence matrix in Epistemonikos later	We identified nine systematic reviews [1],[4],[5],[6],[7],[8],[9],[10],[11] including 11 studies overall[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] of which five were randomized trials [12],[13],[14],[15],[16],[17]. The table and summary are based on the randomized trials, as the observational studies did neither increase the level of certainty of the evidence nor added any additional relevant information.
What types of patients were included*	All trials included patients with uterine fibroids, which were defined as the presence of at least one fibroid diagnosed by ultrasound [12],[15],[16], or magnetic resonance [13]. One trial did not define the imaging technique for the diagnosis of uterine fibroids [12]. Of these patients, the age range was 18 to 50 years [12],[15],[16],[17], only one trial considered ages 33 to 50 years [13]. Patients in menopause, using progestins or agents that alter ovarian or liver function, as well as a history of previous gynaecological surgery [12],[13],[15],[16],[17], were excluded. In addition, other trials excluded patients using corticosteroids [12],[13],[17], with a history of gynaecological cancer [12],[13],[15],[17], with coagulation disorders [12],[15],[17], a history of polyp and/or endometrial hyperplasia [12],[17], patients with blood transfusions or haemoglobin less than 6 grams per decilitre [12] and use of anticoagulants [12],[17].
What types of interventions were included*	All trials used ulipristal as an intervention and were compared with placebo. Three trials [12],[15],[16] used the drug at doses of 5 and 10 milligrams. Only one trial [13] considered doses of 10 and 20 milligrams. Four trials [13],[15],[16],[17] did not report surgery following ulipristal use. One trial [12] did consider surgery following surgery.
What types of outcomes were measured	All the clinical trials reported multiple outcomes, which were as follows: Amenorrhoea Quality of life Adverse effects Reduction in menstruation Fibroid size Follow-up ranged from 12 [15],[16] to 13 weeks [12]. Only one trial had a follow-up of 90 and 110 days [13].

*Information about primary studies is not extracted directly from primary studies but from identified systematic reviews, unless otherwise stated.

What is the evidence

See evidence matrix in Epistemonikos later

Summary of findings

Information on the effects of ulipristal acetate on uterine fibroids is based on four randomized trials [12],[13],[15],[16], which included 873 patients.

Four trials measured amenorrhea outcome (862 patients) [12],[13],[15],[16], two trials measured quality of life outcome (195 patients) [13],[16], and one trial measured adverse effects outcome (237 patients) [12]. Only one trial measured reduction in menstruation at doses of 5 and 10 mg (289 patients) [12]. Only one trial measured fibroid reduction [12].

None of the systematic reviews reported pregnancy rates and hepatotoxicity outcomes.

The summary of results is as follows:

The use of ulipristal increases the likelihood of amenorrhea in patients with symptomatic uterine fibroids.
The use of ulipristal slightly improves the quality of life in patients with symptomatic uterine fibroids.
The use of ulipristal probably increases the risk of side effects.
The use of ulipristal acetate increases the risk of reduced menstrual flow in patients with symptomatic uterine fibroids.
It is not possible to clearly establish whether the use of ulipristal acetate decreases the size of fibroids, as the certainty of the existing evidence has been assessed as low.
No studies were found that evaluated pregnancy rates.
No studies were found evaluating hepatotoxicity.

Follow the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

This evidence applies to women of childbearing age, considered between 18 and 50 years of age, who present at least one symptomatic uterine myoma diagnosed by ultrasound or magnetic resonance imaging.
Postmenopausal women who use drugs such as corticosteroids, progestins, or agents that alter ovarian or liver function are excluded, as well as a history of previous gynecological surgery or suspicion of malignant disease.

About the outcomes included in this summary

The outcomes included in the summary of findings table are those considered critical for decision-making, according to the opinion of the authors of this summary, and in general, coincide with the systematic reviews identified.
The outcome “myoma size” was included in the results summary table because it is a relevant outcome for clinical experts, even though it is a surrogate outcome. The reduction of the size of the myoma facilitates the management, surgical technique and reduces the intraoperative bleeding rates.
The authors consider relevant outcomes for decision-making are hepatotoxicity and pregnancy rates, which were not reported in the systematic reviews.

Balance between benefits and harms, and certainty of the evidence

The benefit/risk ratio of ulipristal acetate is positive in terms of clinical improvement. It presents a high level of certainty of the evidence regarding the reduction of menstruation and amenorrhea, in addition to improving the quality of life, despite presenting a slight increase in adverse effects.
On the other hand, regarding the reduction in the size of the fibroids, we consider that it is relevant as it could facilitate surgery; however, it is not possible to make an adequate balance of risks and benefits on the use of ulipristal in this outcome, because the certainty of the evidence is low.
No information was reported regarding the pregnancy rate and hepatotoxicity after the use of ulipristal, which we consider to be relevant outcomes when using this drug; this balance may not be entirely favorable concerning these aspects.

Resource considerations

None of the included studies performed a resource analysis; however, ulipristal acetate has a high economic cost: Nevertheless, it provides benefits in terms of symptomatic relief with decreased menstrual bleeding, thus improving the quality of life. Likewise, it must be considered that it is not free of adverse effects. Its cost-effectiveness must be evaluated directly in each patient.
The economic cost of ulipristal acetate is around 200 to 600 USD per month for a treatment that varies between 3 and 6 months. On the other hand, myomectomy ranges from 1,400 to 2,300 USD according to private health institutions adjusted to the FONASA code of Chile [23]; however, these prices can vary significantly depending on the medical center.

What would patients and their doctors think about this intervention

Among medical treatments, ulipristal acetate is accepted among physicians as an alternative for surgery to manage the symptoms produced by uterine fibroids in the face of the failure of other first-line medical treatments such as contraceptives and non-steroidal anti-inflammatory drugs.
Regarding patient opinion, although this treatment reduces bleeding, they could eventually reject it due to hepatotoxicity and its high economic cost.

Differences between this summary and other sources

The conclusions of this summary are consistent with the identified systematic reviews.
The National Institute for Health Care and Excellence (NICE) guidelines [24] recommend ulipristal acetate 5 mg as a treatment option for women with symptomatic fibroids with a diameter of 3 cm or greater for the management of heavy menstrual bleeding.
The Food and Drug Administration (FDA) [25] initially rejected the use of ulipristal acetate as a treatment for uterine fibroids due to its hepatotoxicity; therefore, the European Pharmacovigilance Risk Assessment Committee (PRAC) [26] initiated an investigation that concluded that ulipristal might have contributed to the development of some cases of severe liver injury. Consequently, new measures such as monitoring of liver function and contraindication in women with an underlying liver disorder were generated.
The Spanish Society of Gynecology and Obstetrics (SEGO) [27] reports that ulipristal acetate 5 mg has a favorable safety and tolerability profile and is the only treatment indicated for the intermittent repeat treatment of uterine fibroids. In addition, they state that it is useful for women of childbearing age who want to preserve their uterus, preserve fertility, improve their quality of life, achieve pregnancy, and delay or avoid surgery. Also, the drug has been shown to rapidly control and reduce uterine bleeding and fibroids volume, improving pain and quality of life for women with this condition.

Could this evidence change in the future?

Given the certainty of the evidence, the probability that future research changes the conclusions of this summary is low in relation to increased amenorrhea, reduced menstruation, quality of life, and adverse events; however, there is still uncertainty in relation to other relevant outcomes.
The International Prospective Register of Systematic Reviews (PROSPERO) identified three ongoing systematic reviews that include the use of ulipristal to treat uterine fibroids [28],[29],[30].
In the International Clinical Trials Registry Platform of the World Health Organization, we identified two ongoing studies on the use of ulipristal in uterine fibroids [31],[32].

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and present it as a matrix of evidence.

Follow the link to access the interactive version: Ulipristal for uterine fibroids.

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time the new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, denominated Friendly Summary of Body of Evidence using Epistemonikos (FRISBEE), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a not-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is the Epistemonikos database.

Roles and contributions
RAD: Conceptualization, investigation, writing (review and editing), and supervision. NNP and MVC: Conceptualization, methodology, analysis, investigation, data curation, writing (review and editing), manuscript preparation (original draft preparation), and visualization.

Competing interests
The authors who completed the ICMJE conflict of interest declared that they did not receive funds for completion of this article; they do not have financial relationships with an organization that may have an interest in the published article and they do not have other relationships or activities that may influence the publication of the article.

Funding
The authors declare Universidad Finis Terrae supported this study.

Ethics
This study was not presented to the ethics committee because the source of information for this review was secondary, and the articles were public.

Language of submission
Spanish.

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