Efficacy of Mirabegron in Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Updated Meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-2106647/v1

Abstract

The possibility of using mirabegron as a new medical expulsive therapy agent for ureteral stones has been studied owing to its relaxant effects on the ureteral smooth muscle. The objective of this study was to update the evidence regarding the efficacy of mirabegron in medical expulsive therapy for the management of ureteral calculi. We systematically searched PubMed, Cochrane library and Embase to collect the clinical trials from inception dates to August 2022. Meta-analysis and forest-plot figures were calculated with the software review manager v5.0. Six studies with 462 patients were eligible for inclusion. Mirabegron achieved significantly higher expulsion rate than control (pooled RR: 1.44, 95% CI: 1.12, 1.86; P = 0.004). A subgroup analyses showed that mirabegron has a significantly higher expulsion rate on stone sizes smaller than 5/6 mm (RR 1.4; 95% CI: 1.11–1.77; P = 0.005). The superior effect was not observed on stone sizes > 5/6 mm (RR 1.04; 95% CI: 0.80–1.35; P = 0.77). The pooled data showed no significant difference in the expulsion time between mirabegron and control group (MD: -0.53, 95% CI -5.77–4.71; P = 0.84). There was no significant difference between the mirabegron group and the control group in the episodes of renal colic (MD -0.18; 95% CI -0.39–0.02; P = 0.08). But patients receiving mirabegron had less analgesic consumption. No serious adverse events were reported with mirabegron treatment. This systematic review shows that mirabegron is an effective and safe medical expulsive therapy agent in patients with ureteral stones.

Introduction

Urolithiasis is a common urological condition and the prevalence was reported to be 1%-20%[1, 2]. Ureteral stones account for 22% of all urinary tract stones which result in > 1 million emergency department visits per year in the USA[3, 4]. Most ureteral stones are initially treated with a period of observation as more than half of the stones smaller than 10 mm can pass spontaneously[5]. During this observation period, medical expulsive therapy (MET) is usually used to enhance the expulsion and reduce the need for an interventional procedure. Nowadays, alpha-blockers are the most frequently used and preferable MET agents with proven efficacy in multiple clinical trials[6]. However, alpha-blockers were associated with many complications including retrograde ejaculation, orthostatic hypotension, dizziness and headache. Therefore, seeking a novel and effective agent with lower adverse effects is still warranted.

Previous studies confirmed the presence of beta-adenoreceptors in the ureter[7]. Additionally, in the last decade, the possibility of using mirabegron in MET has been studied owing to its relaxant effects on the ureteral smooth muscle. Cai conducted a meta-analysis demonstrating that mirabegron was effective for the expulsion of ureteral stones[8]. However, only two randomized controlled trials (RCT) evaluating the effect of mirabegron in MET were included which may downgraded the quality of the evidence. In present, the efficacy of mirabegron in MET is still debated. Considering that new studies have been performed, we performed an updated meta-analysis to systematically elucidate the efficacy of mirabegron for ureteral stones in MET.

Materials And Methods

Search strategy

We report this systematic review according to the PRISMA recommendations[9]. We searched PubMed, Cochrane library and Embase for relevant studies. Searches were performed with a number of free words, keywords, and combinations, including “mirabegron”, “beta-3 agonist”, “ureteral stones”, “urolithiasis”, “ureteral calculi” and “medical expulsive therapy”. The last search was in August 2022. Reference lists of each article were checked for additional studies.

Selection criteria

The titles and abstracts of studies obtained by this search strategy were reviewed for inclusion by 2 reviewers (LQ, QYL). Any discrepancies were resolved by a final reviewer (HCY). Studies were included if they met the following criteria: 1) trials comparing mirabegron with placebo or conventional care (hydration and analgesics), 2) an English-language report, 3) ureteral calculi < 10 mm in size, 4) the effect of mirabegron on medical expulsive therapy was measured. The exclusion criteria were as follows: 1) case reports, comments, letters or reviews were excluded, 2) studies containing an incomplete dataset, 3) patients with a history of endoscopic surgery, 4) urinary tract infection, ureteric abnormalities, pregnant or lactating women.

Data extraction

Two authors (LQ, ZSX) independently extracted the data from the original reports using a computerized excel sheet. We included information about number of participants in experimental and control groups, dosage of mirabegron, the follow-up, pain episodes, and other relevant attributes.

Assessment of risk of bias

Two independent reviewers (LQ, HCY) assessed risk of bias using the Cochrane Collaboration risk of bias tool. The individual domains included (1) random-sequence generation, (2) allocation sequence concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) completeness of outcome data, (6) selective reporting, and (7) other sources of bias. Two investigators (LQ, HCY) independently classified each domain as either low, unclear, or high risk of bias. Any disagreement was resolved by discussion with a third author.

Data synthesis and analysis

Analyzes were conducted using Review Manager 5.3. The primary outcomes of included studies are the stone expulsion rate and stone expulsion time. Pain episodes, analgesic consumption, and adverse effects were considered secondary outcomes. Heterogeneity between the included studies was analyzed using a Chi² test and the I² test, with p value of 0.05 used for statistical significance. The data were analyzed using the random-effects model when I-square > 50%. When I-square < 50%, a fixed-effects model was applied. We performed subgroup analyses to investigate the effect of mirabegron in patients with different stone size.

Results

Study selection and risk of bias

The search strategy identified 456 articles and 6 trials[1015] (including 5 RCTs) with 462 patients were included in the final analysis. The literature screening process is shown in Fig. 1. The characteristics of the included studies are shown in Table 1. The studies were published in 5 countries: Turkey (2 trials); China, Saudi Arabia, Egypt and United States of America (1 each). In all of these studies a daily dosage of 50 mg of mirabegron was given in the experimental group.

Table 1

Characteristics of individual studies included in the meta-analysis

Study

Country

Study design

experimental group

Sample size

Included population

Follow-up

Medicine BCo 2017

America

RCT

Mirabegron, 50mg/day

33

Ureter stones (4–10 mm)

4 weeks

Solakhan 2019

Turkey

Retrospective

study

Mirabegron, 50mg/day

68

Distal ureter stones (< 10 mm)

2 weeks

Bayar 2020

Turkey

RCT

Mirabegron, 50mg/day

115

Ureter stones (4–10 mm)

4 weeks

Qing 2021

China

RCT

Mirabegron, 50mg/day

90

Distal ureteral stones (≤ 10 mm)

4 weeks

Morsy 2022

Saudi Arabia

RCT

Mirabegron, 50mg/day

96

Ureter stones (5–10 mm)

4 weeks

Abdel-Basir 2022

Egypt

RCT

Mirabegron, 50mg/day

60

distal ureteral stones (≤ 10 mm)

4 weeks


The risk of bias assessment for each included trial is shown in Fig. 2. Most studies had a low risk of bias for random-sequence generation, allocation concealment, incomplete reporting of data and selective outcome reporting.

The expulsion rate of mirabegron for stones

The current meta-analysis included 452 pooled patients after the elimination of the dropouts. The pooling of the data showed favorable results for mirabegron in terms of stone expulsion rates with a risk ratio of 1.44 (95% CI: 1.12, 1.86; P = 0.004)(Fig. 3A).

We conducted subgroup analyses based on stone size (stone size ≤ 5/6 mm vs. >5/6 mm). our results showed that the expulsion rate of mirabegron group was significant higher than that of the control group for ≤ 5/6 mm stones (RR 1.4; 95% CI: 1.11–1.77; P = 0.005). There was no significant difference in the expulsion rate between mirabegron group and control group for > 5/6 mm stones(RR 1.04; 95% CI: 0.80–1.35; P = 0.77)(Fig. 3B).

The expulsion time of mirabegron for stones

3 of the included studies, including 233 participants (118 in the mirabegron group and 115 in the control group), allowed us to analyze the expulsion time of patients with ureteral stones. There was no significant difference in the expulsion time between mirabegron group and control group (MD -0.53; 95% CI -5.77–4.71; P = 0.84)( Fig. 4A).

The episodes of renal colic and analgesic consumption

4 studies including 304 patients were involved in the research for episodes of renal colic. The results revealed that there was no marked difference between the mirabegron group and the control group in the episodes of renal colic for ureteral stones (MD -0.18; 95% CI -0.39–0.02; P = 0.08) (Fig. 4B). Three trials reported analgesic consumption in the articles which showed less analgesic consumption in the mirabegron group[10, 11, 15]. But we could not conduct an overall quantitative analysis of the amount of analgesic consumption due to different types of analgesics used in each study.

Adverse events

Four studies[1012, 15] reported the adverse events during treatment. Bayar reported that one patient experienced an episode of hypertension in the mirabegron group. The remaining studies did not report any adverse events.

Discussion

Ureteral stones account for 22% of all urinary tract stones[3]. The spontaneous passage of ureteral stones depends on several factors, which include stone size, localization, ureter spasm, edema, and anatomic structure. MET exerts its effects via relaxation of the ureter smooth muscles and augmentation of the hydrostatic physical force proximal to the stones. In recent years, MET has proven to be an effective method of facilitating spontaneous passage of ureteral stones and have gained popularity in the management of ureteral stones smaller than 10 mm. Nowadays, alpha-adrenergic blockers and calcium channel blockers are the most widely-used MET agents. However, Approximately 4–15% of patients experience adverse effects due to the underlying mechanism of action[16, 17]. Patients using these drugs may suffer from retrograde ejaculation, dizziness, palpitation, and orthostatic hypotension[18, 19]. Therefore, seeking an effective MET agent with lower complication profiles is still warranted. Mirabegron is a selective β3 AR agonist which has recently been introduced as a new MET agent. Beta-3 adrenoreceptors (β3 AR) are detected in the ureteral smooth muscles, mediating the adrenergic stimulation for ureteral relaxation[20]. Previous studies have confirmed the presence of β1, β2, and β3 adrenoceptors in both smooth muscle and urothelial layers of the whole ureter. The ureter smooth muscle relaxation was reached by stimulating β-3 receptors which supported the potential role for mirabegron as a medical expulsive therapy[21].

A few studies have been carried out to investigate the efficiency of mirabegron in the MET with conflicting results. A recent meta-analyses which included four trials demonstrated that mirabegron had a significant effect in improving the stone expulsion rate[8]. But in one included RCT, mirabegron was used as an adjunctive therapy for patients before ureterolithotripsy. This may lead to high heterogeneity of the outcomes due to different inclusion criteria. In present study, this RCT was excluded and six trials finally met the standards. Our study showed that mirabegron was superior to control as MET, achieving a 21% increase in the probability of expulsion. In the subgroup analysis, mirabegron showed a significant effect in MET for patients with a stone size of < 5/6 mm. Previous studies have demonstrated that MET agents had a higher expulsion rate for distal ureteral stones[22, 23]. In our included studies, however, there is insufficient data available to summarize the evidence in a quantitative analysis. Our results demonstrated that mirabegron had no effect in decreasing the time to expulsion of the ureteral stones. Three trials reported analgesic consumption in the articles which showed less analgesic consumption in the mirabegron group, but we did not conduct an overall quantitative analysis of the amount of analgesic consumption due to the massive heterogeneity between studies.

One advantage of mirabegron as a MET agent is the lower rate of complication. The adverse events of mirabegron included mouth dryness, constipation, tachycardia, and urine retention, but the incidence of which was similar to that of the placebo[24, 25]. In our included studies, Bayar reported that one patient experienced an episode of hypertension in the mirabegron group[11]. The remaining studies did not report any adverse events.

This meta-analysis has several limitations. The first limitation is the small number of included studies. In our study, only articles published in English were included, resulting in potential publication bias. As to the secondary outcomes, we were unable to conduct a meta-analysis for analgesic consumption due to the massive heterogeneity between studies. Moreover, substantial heterogeneity was detected in our analysis. The heterogeneity possibly originated from variations in inclusion criteria, follow-up periods, and outcome measurements. We used the random-effects model and conducted subgroup analyses to minimize the heterogeneity among the included studies. Apart from the above limitations, the findings of this meta-analysis remain crucial for proving the efficacy and safety of mirabegron in the treatment of ureteral stones. We suggest that high quality and more robust trials are needed to learn more about the efficacy of mirabegron in MET.

Conclusion

In conclusion, our study provide evidence that mirabegron may be an effective and promising MET agent for the management of ureter stones. Given the small sample sizes, different intervention protocols in different studies and heterogeneity, larger, high-quality RCTs are needed to provide firm conclusions regarding the effectiveness of mirabegron.

Declarations

Statement of Ethics

The authors have no ethical conflicts to disclose.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive any funding sources.

Author Contributions

LQ collected and analyzed the data, and wrote drafts of the paper. ZSX collected and analyzed the data, and revised the paper. HCY analyzed the data and revised the paper.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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