An observational study on the efficacy of mirabegron in medical expulsive therapy of the lower ureteric calculus

Souvik Chatterjee; Vishal Jalan; Dilip Kumar Pal

doi:10.4103/UROS.UROS_19_21

ORIGINAL ARTICLE

Year : 2021 | Volume : 32 | Issue : 3 | Page : 132-136

An observational study on the efficacy of mirabegron in medical expulsive therapy of the lower ureteric calculus

Souvik Chatterjee¹, Vishal Jalan¹, Dilip Kumar Pal²
¹ Department of Urology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
² Department of Urology, SSKM and IPGMER Hospital, Kolkata, West Bengal, India

Date of Submission	20-Jan-2021
Date of Decision	23-Mar-2021
Date of Acceptance	07-Apr-2021
Date of Web Publication	28-Sep-2021

Correspondence Address:
Dilip Kumar Pal
Department of Urology, SSKM and IPGMER Hospital, Kolkata - 700 020, West Bengal
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_19_21

Abstract

Purpose: Medical expulsive therapy (MET) is used in lower ureteric calculus to reduce symptoms, to facilitate passage, and to decrease the requirement of endourological surgical interventions. Alpha-blockers, spasmolytics, and calcium channel blockers have been shown to be effective in clinical trials. Beta-3 receptor stimulation in the ureter has been shown to decrease the intraluminal pressure. Thus, Mirabegron, beta 3 receptor agonist, can be thought as alternative MET agent. Materials and Methods: We have done prospective observational study to see the efficacy of mirabegron for MET of lower ureteric calculus ≤10 mm in size. Patients were divided into two groups: Group A (n = 50) received diclofenac 50 mg twice daily for 5 days then on demand for 4 weeks and Group B (n = 50) received diclofenac 50 mg twice daily for 5 days than on demand and mirabegron 50 mg daily for 4 weeks. Patients were followed up weekly with clinical examination, ultrasound screening of kidney, ureter, and bladder (KUB) and noncontrast computed tomography scan KUB after the 28^th day of therapy. Results: We found that the passage of stone is significantly higher in mirabegron group (Group A: 68% and Group B: 92%; P < 0.05), and this effect is also statistically significant for stones <7 mm size (Group A: 73.91%, Group B: 96.96%, P = 0.01026). Duration of stone expulsion in Group A: 20.29 ± 5.512 days and Group B: 10.65 ± 4.294 days (P = 0.00001) and the relief of storage symptoms are earlier in mirabegron group (Group A: 16.28 ± 5.65 days and Group B: 6.2 ± 2.58 days, P = 0.00001). Conclusion: Our study reveals that Mirabegron is effective for the treatment of lower ureteric stones ≤10 mm size, especially for stone of size <7 mm and it improves the storage symptoms in these patients.

Keywords: Lower ureteric calculus, medical expulsive therapy, mirabegron

How to cite this article:
Chatterjee S, Jalan V, Pal DK. An observational study on the efficacy of mirabegron in medical expulsive therapy of the lower ureteric calculus. Urol Sci 2021;32:132-6

How to cite this URL:
Chatterjee S, Jalan V, Pal DK. An observational study on the efficacy of mirabegron in medical expulsive therapy of the lower ureteric calculus. Urol Sci [serial online] 2021 [cited 2023 Dec 1];32:132-6. Available from: https://www.e-urol-sci.com/text.asp?2021/32/3/132/326932

Introduction

Spontaneous expulsion ratios (SERs) of distal ureteral stones are between 25% and 53% for ≤10 mm stones.^[1],[2] Accordingly, the wait-and-see policy can be applied for ≤10-mm stones with good pain management. The SER of ≤5-mm stones is 71%–98%, whereas this ratio is 25%–51% in 5- to 10-mm stones.^[2] Today, medical expulsive therapy (MET) is more effective and commonly used in distal ureter stones compared with conservative treatments.^[2] Spontaneous expulsion depends on some factors (e.g., stone size, configuration, location, ureter smooth muscle spasm, ureter edema, and anatomic narrowing).^[3] Renal colic attacks, urinary system infection, hydroureteronephrosis, and pyelonephritis are problems that may develop.^[4] Many pharmacological agents have been currently tried to reduce such complications and accelerate stone expulsion.^{[3],[5],[6],[7]} Alpha-adrenergic and calcium channel blockers are the most frequently used medicines for MET. However, ureteroscopic lithotripsy is the gold standard treatment and has a high success rate if the stone does not spontaneously pass out.^[8] In addition, Galli et al. showed that supine position transgluteal extracorporeal shock-wave lithotripsy therapy had an 85.7% success rate.^[9] Furthermore, the intramural ureter is the narrowest segment of the ureter. If the stone is located in this segment, symptoms (e.g., pain, urinary urgency due to vesical irritability, and frequency), which are similar to overactive bladder syndrome, may be observed.^[10] In many trials on animals and humans, the presence of β3 receptors in the ureter and bladder was shown. Matsumoto et al. confirmed the expression of mRNAs of β1, β2, and β3 adrenalin receptors in the ureter with reverse transcription-polymerase chain reaction in their study.^[11] They showed that these receptors were present in both smooth muscles and urothelial cells in the proximal, middle, and lower ureter. With similar findings in the bladder, it could play a role in relaxation by acting on β3 adrenoceptor of urothelial tissue, thus indirectly affecting the muscular tone. Their study also showed that the main relaxation was achieved through β3 receptors. It was noted that the stimulation of these receptors may provide relaxation in the intramural ureteral segment.^{[11],[12],[13],[14]} Thus, mirabegron can be an alternative MET agent because of this mechanism. Moreover, mirabegron is thought to have more advantages than others because it is acting through different pathways and has a low side effect profile. This study observed the efficacy of mirabegron for MET in patients with radiologically defined lower ureteral stone.

Methodology

RAC No.: IPGME and R/RAC/090.

Date of RAC approval: November 16, 2019.

Institute name: Institute of Post Graduate Medical Education and Research (IPGME&R).

The Institutional Ethics Committee (IEC) approval takes time in the institute of this study. This study was conducted for 1 year after taking Institutional Recombinant DNA Advisory Committee approval on November 16, 2019. Meanwhile, the IEC approved this study on October 21, 2020.

IEC (ETHICAL) No.: IPGME&R/IEC/2020/681.

Date of IEC approval: October 21, 2020.

Institute ethical committee name: IPGME&R Research Oversight Committee.

This was a prospective, observational study conducted for 1 year (November 16, 2019–November 15, 2020) at a tertiary care hospital in India. Patients >12 years old with a unilateral single lower ureteric stone of up to 10 mm were included. As per the inclusion and exclusion criteria (mentioned below), patients prescribed diclofenac (50 mg twice/day for an initial 5 days then on demand) by their treating physician were included in Group A and those prescribed diclofenac (50 mg twice/day for initial 5 days then on demand) and mirabegron (50 mg/day) for 28 days were included in Group B. Patients of both groups were advised to drink plenty of clear fluids and prescribed to take levofloxacin 500 once daily for an initial of 5 days. During the study period, the treatment outcomes in the patients of Groups A and B had been prospectively observed. Written informed consent was taken from every participant. Detailed medical history and physical examination, biochemical tests, urine analysis, and urine culture sensitivity were performed on all patients. Lower ureteral stone was diagnosed using kidney–ureter–bladder (KUB) X-ray/urinary system ultrasonography, and a noncontrast computed tomography scan (NCCT KUB) was performed to confirm the diagnosis on suspected patients. Age, gender, stone size, laterality, and hydronephrosis severity were recorded. Only patients with a single stone of up to 10 mm that are located in the lower ureteral segment were included in this study. Patients were followed up with clinical examination, weekly screening of USG KUB, and NCCT KUB after day 28 of therapy (earlier if the stone passage was documented by patients). Patients were asked to look for stone passage in urine during 28 days of MET and to note down the day if they found a stone in the urine. However, surgical intervention (ureteroscopic lithotripsy) is planned if the stone is still found in the ureter after 28 days of therapy. During that 28 days of MET, patients who developed fever with chills, uncontrolled pain abdomen, increment of hydronephrosis grade, or developed pyonephrosis were taken for immediate surgical intervention. The exclusion criteria for this study were multiple or bilateral stone; >10-mm stones; pregnancy; previous ureter or bladder surgery; anatomic abnormality of the urinary system; uncontrolled hypertension (systolic blood pressure, ≥180 mmHg and diastolic blood pressure, ≥110 mmHg); taking a diuretic, calcium channel blocker and/or alpha-blocker; features of distal obstruction; history of acute urinary retention; stroke; paraplegia; neurological conditions such as parkinsonism, solitary kidney status, or ipsilateral nonfunctioning kidney; transplanted kidney; known case of chronic renal disease; and serum creatinine >1.5 mg/dL and patients who had not given consent.

Statistical analysis

The IBM Corp. (2019). IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp.[Computer SoftWare].was used for the statistical calculations. Moreover, data were expressed as arithmetic mean and standard deviation. Categorical variables were analyzed by the Chi-square test, and numeric variables were analyzed with t-tests.

Results

No statistically significant difference was noted between Groups A and B in terms of age, gender, stone size, laterality, hydronephrosis severity, and Charlson comorbidity index [Table 1].

Table 1: Demographic data (n=50)

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The SER is 68% (34 of 50) and 92% (46 of 50; P < 0.05) in Groups A and B, respectively. A subgroup analysis found that SER is higher and statistically significant in Group B having <7 mm calculus (Group A – 73.91% and Group B – 96.96%; P < 0.05). Moreover, the SER for 7- to 10-mm stones was comparable in two groups [Group A – 62.96%, Group B – 82.35%; P = 0.1698; [Figure 1] and [Table 2]].

Figure 1: Stone expulsion ratios, according to size, in two groups

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Table 2: Follow-up results of both the groups (n=50)

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The stone expulsion duration was significantly lower in Group B (Group A – 20 ± 5.512 days, Group B – 10.65 ± 4.294 days; P < 0.05). Moreover, a subgroup analysis found that the stone expulsion duration was significantly low in Group B with <7-and 7- to 10-mm stones (P < 0.05 in both subgroups). No statistically significant difference in pain reduction (after an initial of 5 days) between the two groups (Group A, 10.83 ± 3; Group B, 9.56 ± 3.52; P = 0.55) was noted. Furthermore, storage symptoms subsided earlier in Group B [Group A, 16.28 ± 6.65 days; Group B, 6.2 ± 2.58 days; P < 0.05; [Figure 2] and [Table 2]].

Figure 2: Average duration of stone expulsion (in days) between two groups

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Discussion

Alpha-blockers are classically used for MET. They have their adverse effects due to their mechanism of action, such as retrograde ejaculation, nausea, dizziness, and orthostatic hypotension. The therapeutic dose of mirabegron (50 mg) is not associated with changes in blood pressure, QT time, or heart rate.^[15] Thus, mirabegron seems to be safer to use in terms of sexual and cardiovascular adverse effects.

Matsumoto et al. confirmed the mRNA expressions of β1, β2, and β3 adrenalin receptors in the ureter with reverse transcription polymerase chain reaction in their study.^[11] Moreover, they showed that these receptors were present in both smooth muscles and urothelial cells in the proximal, middle, and lower ureter. Their study showed that the main relaxation was achieved through β-3 receptors. The stimulation of these receptors may provide relaxation in the intramural ureteral segment.^{[11],[12],[13],[14]} Despite activating the beta-3 receptors at the ureter, relaxing the ureteric smooth muscle and regulating the ureteral peristalsis, a few research or clinical trials are done in terms of its use as MET.

In many studies and meta-analyses, alpha-blockers and calcium channel blockers increased spontaneous stone expulsion, shortened expulsion time, and reduced colic pain during distal ureteric stone treatments.^{[3],[5],[6],[7]} The current study observed that stone expulsion was statistically increased with mirabegron (Group A – 68% and Group B – 92%; P = 0.0027), especially in <7-mm stones (P = 0.01026). Although no significant SER difference of 7-to 10-mm stones was noted between the two groups (Group A – 62.96% and Group B – 82.357%; P = 0.1698), a significant difference between the two groups was noted when the expulsion duration (7- to 10-mm stones) was considered (P = 0.00001).

Sayed et al. showed that 88.9% of the patients in the tamsulosin group having distal ureteral stone had passed stone (40 of 45).^[16] Furthermore, Zhangqun et al., in their randomized, multicenter, double-blind, placebo-controlled trial, showed that 86% of the patients in the tamsulosin group had passed stone.^[17] This is comparable with the current finding in which 92% (46 of 50) of patients in the mirabegron group had passed a stone. Sayed et al. also showed that the average time to expulsion in the tamsulosin group was 7.32 ± 0.78 days whereas patients in the mirabegron group in the current study had passed stone at a slightly longer time of 10.65 ± 4.294 days.

A study of Solakhan et al. showed that the spontaneous distal ureteric stone expulsion was 73.53% in the mirabegron group.^[18] However, the current study was 92% in the mirabegron group. Furthermore, any statistically significant difference in terms of stone expulsion time (P = 0.979) was not found in their study. However, patients in the mirabegron group in the current study had passed stone on 10.65 ± 4.294 days, which was almost half the duration taken by the diclofenac-only group (20.29 ± 5.512 days). In their study, the SER of >5-mm stone was not significant (0.238). Conversely, patients with 7- to 10-mm stone have no significant difference in either group (P = 0.1698). This means that the efficacy of mirabegron as MET decreases as the stone size increases.

In one study, 4% of patients receiving alpha-adrenergic for MET were observed with adverse effects (e.g., transient hypotension, ejaculation disorder, dizziness, and asthenia).^[6] One study observed that hypotension and palpitation may occur in approximately 15% of patients receiving calcium channel blockers.^[7] Thus, new therapeutic substances that can facilitate stone expulsion and reduce colic pain with a different mechanism of action and fewer adverse effects are needed. In few studies, during mirabegron treatment on patients with overactive bladder syndrome, adverse effects (e.g., constipation, mouth dryness, dyspepsia, and nausea) were observed to be similar between the placebo and mirabegron groups.^[19],[20] Moreover, in the current study, nausea and dry mouth occurred in 2% (one patient) of patients in Group B (Grade I, as per Clavien–Dindo classification) which was managed with antiemetics.

All 20 of 100 patients who had failed to pass a stone at the end of 28 days (Group A, 16 patients; Group B, four patients) were treated with ureterorenoscopic lithotripsy.

Conclusion

The current study showed that mirabegron is an effective treatment modality for the expulsion of lower ureteric calculus, especially if the stone size is <7 mm. In addition, lower urinary tract symptoms (e.g., frequency and urgency), associated with these stones, respond well with mirabegron and improve the quality of life of these patients during treatment.

Limitations of this study

This study had few limitations. This study was an observational study, and no medicine was prescribed to the enrolled patients. Moreover, they were treated by their treating physician. These patients were just observed during the treatment course. This study was conducted in a single institute. Furthermore, the width of the stones was not taken into consideration, and only the maximum dimension (in millimeters) was noted down.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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