Introduction
According to the International Continence Society, overactive bladder (OAB) is defined as urinary urgency, usually with urinary frequency and nocturia, with or without urgency urinary incontinence. Urinary tract infection must have been previously ruled out1,2. OAB is predominant in the African-American race and in the female sex3–5. It presents a 30% prevalence in patients > 60 years. In Latin America, the prevalence in women > 18 years old is 14%, and in women > 40 years is 32%6.
The OAB treatment is a widely debated topic, in which multiple prospective studies have been carried out, allowing different treatments to be compared. Based on these studies, recommendations have changed over time, starting from the premise that a few decades ago, antimuscarinics were the treatment of choice for this pathology7. Since 2010, this has been a debated subject due to the appearance of new treatments such as B3 agonists7. Mirabegron, being a sympathomimetic, does not have the typical effects of antimuscarinics such as dry mouth, urinary retention, or constipation8. In terms of efficacy, in clinical trials conducted to date, mirabegron has shown similar efficacy to that of antimuscarinics, conducting the treatment based on the side effects and tolerability8. In the latest guidelines of the European Association of Urology, it is recommended to start antimuscarinic drugs or beta 3 agonists as an alternative to antimuscarinic drugs if they do not respond to conservative treatment (pelvic floor therapy and adjustment of voiding habits)9.
Darifenacin is one of the few antimuscarinics that does not penetrate the central nervous system, since it does not cross the blood-brain barrier, as well as being a selective M3 receptor (present in the urinary tract). Thus, it is considered the antimuscarinic agent with fewer secondary effects of neural origin. About mirabegron, it is a B3 agonist that does not have penetrance into the central nervous system either, with mainly peripheral side effects such as arterial hypertension. When reviewing the literature, few studies have been found comparing mirabegron versus darifenacin, and none in the Colombian population. A comparative retrospective study was carried out in this population, facilitating the decision on first-line treatment in OAB syndrome (OABS).
Material and methods
A retrospective observational study was carried out in patients with OAB without treatment started. About 3013 medical records of patients with OAB diagnosis from two institutions were reviewed between January 2019 and April 2022. Only patients starting on mirabegron or darifenacin as first-line treatment were included. All patients with incomplete data, combined treatments, or previous treatments were excluded. Having received previous pelvic floor therapy was not an exclusion criteria.
The U Mann-Whitney test was obtained to compare the quantitative variables, and the χ2 for the qualitative ones, considering a significant difference of p < 0.05. To establish the difference between daytime and nighttime urinary frequency before and after treatment, diferencing between darifenacin and mirabegron, the Student’s t-test tool was used. Data were tabulated and calculated using the Statistical Package for the Social Sciences 28. Objective results decreased daytime and nighttime frequency, and subjective results were about the patient-reported improvement after starting medication. In addition, a subanalysis by age and sex was performed.
Results
A total of 234 patients who received mirabegron (66%) or darifenacin (33%) as initial treatment were included. There were no demographic differences in terms of age, sex, comorbidities, or the presence or absence of uninhibited contractions in urodynamics (Table 1).
Table 1. Demographic data according to treatment
| Demographic data | Total, n = 234 (%) | Darifenacin, n = 78 (%) | Mirabegron, n = 156 (%) | p |
|---|---|---|---|---|
| Age | 68 ± 19 | 69 ± 22 | 67 ± 17 | 0.61 |
| Sex | 0.578 | |||
| Female | 129 (55.1) | 41 (52.6) | 88 (56.4) | |
| Male | 105 (44.9) | 37 (47.4) | 68 (43.6) | |
| Comorbidities | ||||
| Neurological disease | 22 (9.4) | 8 (10.3) | 14 (9.0) | 0.756 |
| Obesity | 25 (10.7) | 10 (12.8) | 15 (9.6) | 0.454 |
| Arterial hypertension | 96 (41) | 32 (41) | 64 (41) | 1.000 |
| Radiotherapy | 9 (3.9) | 1 (1.3) | 8 (5.1) | 0.149 |
| Pelvic surgery | 40 (17.1) | 15 (19.2) | 25 (16) | 0.539 |
| Oncological disease | 32 (13.7) | 8 (10.3) | 24 (15.4) | 0.282 |
| Coronary disease | 30 (12.8) | 11 (14.1) | 19 (12.2) | 0.678 |
| Overactive detrusor in urodynamics | 34 (14.5) | 9 (11.5) | 25 (16) | 0.359 |
There was no statistically significant difference related to the subjective improvement referred by the patient. When performing the analysis by subgroups regarding sex and age, there was also no difference in subjective improvement (Table 2).
Table 2. Subjective improvement assessed, after starting darifenacin versus mirabegron
| Outcomes | Total, n = 234 (%) | Darifenacin, n = 78 (%) | Mirabegron, n = 156 (%) | p |
|---|---|---|---|---|
| Subjective improvement | 157 (67.1) | 48 (61.5) | 109 (69.9) | 0.31 |
| Daytime voiding frequency | ||||
| Onset | 8 ± 4.5 | 7.5 ± 5 | 8 ± 4 | 0.61 |
| Post treatment | 6 ± 4 | 6 ± 5 | 6 ± 4 | 0.21 |
| Nocturnal voiding frequency | ||||
| Onset | 3 ± 2.5 | 2 ± 4 | 3 ± 2 | 0.49 |
| Post treatment | 2 ± 2 | 2 ± 2 | 2 ± 2 | 0.43 |
A significant decrease in overall daytime voiding frequency was evidenced, including darifenacin or mirabegron, finding a difference in daytime frequency of 2.6 urinations per day (95% confidence interval [CI]: 1.5-3.6; p = 0.0001). When discriminating between mirabegron and darifenacin, it was found that mirabegron presented a significant difference in terms of the daytime frequency change, before and after treatment, decreasing 2.87 urinations per day (95% CI: 1.76-3.97; p = 0.0001). On the other hand, darifenacin did not show a statistically significant difference with a decrease of 1.25 micturitions per day (95% CI: 1.8-4.3; p = 0.39).
About nocturnal urination frequency, it also presented a significant global decrease in the number of nocturnal micturitions before and after the medication (1.1 micturitions with 95% CI: 0.7-1.51; p = 0.0001); Alone treatment with darifenacin did not present a significant decrease (0.54 urinations with 95% CI: −0.49-1.57; p = 0.28), unlike mirabegron, which presented a decrease of 1.25 nocturnal urinations (95% CI: 0.8-1.6; p = 0.0001), being statistically significant (Table 3).
Table 3. Adverse events and drug suspension cause
| Demographic data | Total, n = 234 (%) | Darifenacin, n = 78 (%) | Mirabegron, n = 156 (%) | p |
|---|---|---|---|---|
| Treatment suspension causes | ||||
| Arterial hypertension | 4 (1.7) | 2 (2.6) | 2 (1.3) | 0.476 |
| Headache | 5 (2.1) | 4 (5.1) | 1 (0.6) | 0.025 |
| Dry mouth | 5 (2.2) | 3 (3.9) | 2 (1.3) | 0.195 |
| Dry skin | 1 (0.4) | 1 (1.3) | 0 | 0.151 |
| Constipation | 4 (1.7) | 4 (5.1) | 0 | 0.004 |
| Rash | 1 (0.4) | 0 | 1 (0.6) | 0.48 |
| Blurry vision | 1 (0.4) | 1 (1.3) | 0 | 0.16 |
| Drowsiness | 1 (0.4) | 1 (1.3) | 0 | 0.16 |
| Edema | 1 (0.4) | 0 | 1 (0.6) | 0.48 |
| Adverse event | 15 (6.4) | 10 (12.8) | 5 (3.2) | 0.005 |
| Treatment suspension | 16 (6.8) | 10 (12.8) | 6 (3.8) | 0.010 |
Mirabegron was less discontinued than darifenacin (3.8% vs. 12.8% p = 0.01) with fewer adverse events (3.2% vs. 12.8% p = 0.005). Women presented a greater number of side effects (10.1 vs. 1.9% p = 0.011) and tended to quit treatment (10.1 vs. 2.9% p = 0.03) in comparison with men, with a statistically significant difference. When performing the analysis according to age (greater or younger than 65 years), no significant difference was found in terms of secondary events and suspension.
Discussion
“Overactive detrusor” term differs from OAB in that the first is a urodynamic parameter, whereas the latter is a combination of signs and symptoms. Therefore, an overactive detrusor can be one of the many causes of OABS. Among the etiologies of this syndrome, it is found mucosa inflammation, chronic outlet tract obstruction, and idiopathic or neurogenic hyperactive detrusor due to neurological pathologies (Parkinson’s, cerebrovascular disease, transverse myelitis, or spinal cord lesions)1–10. Both, antimuscarinics and B3 adrenergics have been studied and their formulation has been widely applied as first-line drugs in the treatment of OABS, regardless of an overactive detrusor or not10; Patients with this syndrome are more likely to suffer from depression and anxiety, making extremely important to know the effectiveness and safety of the different medications, choosing the best option according to each case11. In this order, the main purpose of this study was to compare two first-line drugs (mirabegron vs. darifenacin) with different mechanisms of action and with little penetration into the central nervous system.
Since then, mirabegron (B3 agonist) has been compared with different antimuscarinics such as tolterodine, imidafine, and solifenacin12–16. However, all of these antimuscarinics have penetrance into the central nervous system and can produce neurological effects such as dizziness, drowsiness, blurred vision, or cognitive defects, which may condition their suspension17. The effectiveness of mirabegron has approached 70% with 50 mg daily compared to 59% with placebo18.
Besides, darifenacin and trospium do not cross the blood-brain barrier, presenting fewer neuronal effects19,20. In addition, darifenacin is the most selective for M3, showing fewer adverse effects on the cardiovascular system (M2 receptors) and the nervous system (M1)20. Solifenacin has been shown to be more effective than the rest of the antimuscarinics but with greater adverse effects since it is not M3 selective21, Its use is contraindicated in patients with angle-closure glaucoma.
On the other hand, mirabegron is a sympathomimetic B3 adrenergic agonist that produces relaxation of the longitudinal detrusor under the influence of norepinephrine. This does not have the typical effects of anticholinergics; however, they can present hypertension, nasopharyngitis, and headaches22. In terms of efficacy, in clinical trials carried out to date, mirabegron has shown similar efficacy to antimuscarinic drugs.
Meek et al. performed a meta-analysis comparing the risk of constipation by the administration of anticholinergics, showing that tolterodine (OR 1.36, 95% CI = 1.01-1.85) and darifenacin (OR 1.93, 95% CI = 1.40-2.66) gets on less constipation. On the other hand, trospium (OR 2.93, 95% CI = 2.00-4.28) and solifenacin produce greater constipation (OR 3.02, 95% CI = 2.37-3.84)23. In another meta-analysis conducted by Cochrane, they conclude that solifenacin is more effective than tolterodine, with a lower risk of dry mouth. Within the reported data, two crossover trials were presented comparing oxybutynin and darifenacin, having the same effectiveness.
In the SOLIDAR study published in 2012, the efficacy and safety profile of darifenacin was compared with solifenacin. There was no significant difference in the reduction of OAB symptoms with overactive detrusor between the two groups; however, solifenacin showed a greater increase in quality of life compared to darifenacin. Adverse effects in both groups were similar (constipation, blurred vision, headache, dizziness, insomnia, concentration, and memory problems) with the exception of dry mouth, which was higher with darifenacin24.
The BLOSSOM clinical trial also compared tolterodine versus placebo versus mirabegron (100/150 mg) in a period of 4 weeks25. Voiding frequency and incontinence frequency were significantly decreased in both mirabegron groups compared to placebo; however, there was no significant difference between tolterodine and placebo. About drug suspension due to adverse effects, 1.5% was discontinued in the placebo group, 4.6% in the mirabegron 100 mg group, 7.7% in the mirabegron 150 mg group, and 3.1% in the tolterodine group. More adverse effects were observed in the mirabegron 150 mg group, consisting of palpitations, vertigo, blurred vision, dry mouth, nausea, dizziness, rash, and fatigue25.
The SCORPIO trial was carried out in 27 countries of Europe and in Australia, a double-blind, randomized controlled phase 3 study, where the efficacy of mirabegron (50, 100 mg) versus placebo and tolterodine 4 mg versus placebo was evaluated for 12 weeks26. A greater reduction in urination and incontinence episodes was found in 12% of patients compared to placebo26. When comparing tolterodine with placebo, there was no significant difference in the reduction of voiding episodes per day, but there was a significant difference in the reduction of incontinence episodes. In this study, tolterodine is not directly compared with mirabegron26. The ARIES study (USA and Canada) followed a similar methodology to the SCORPIO study for 12 weeks, where mirabegron 50/100 mg was compared versus placebo. However, this study did not compare tolterodine versus placebo. Likewise, it showed a significant decrease in micturition frequency and incontinence in both groups of mirabegron versus placebo. The JAPAN and ASIA study, carried out more recently, shows the same results, evidencing a significant decrease in micturition frequency and incontinence with mirabegron than with placebo. However, there is no significant decrease in these parameters with tolterodine27,28.
The TAURUS study (Europe, Australia, South Africa, USA, and Canada) is the continuation of the SCORPIO and ARIES study, whose main outcome was to evaluate the safety profile of mirabegron compared to placebo and tolterodine for 12 months29. The incidence of adverse effects was similar in the mirabegron 50 mg/100 mg and tolterodine groups (59.7% vs. 61.3% vs. 62.6%, respectively)29,30. Most of them were mild-to-moderate adverse effects, including hypertension, headache, dry mouth, or constipation. Of these, the only significant difference between the groups was the incidence of dry mouth, with a higher presentation in the tolterodine group. The rise in systolic blood pressure was only 0.2 and 0.4 mmHg in the mirabegron 50 mg and 100 mg groups, respectively. The drug discontinuation was similar in the three groups (6.4% vs. 5.9% vs. 6.0%). Major adverse events were similar in the three groups. A higher incidence of cardiac arrhythmias and episodes of urinary retention was found with tolterodine.
Following this, few studies have been carried out comparing antimuscarinics with mirabegron in monotherapy or as an enhancement to anticholinergic therapy. In 2016, the BESIDE study was carried out, in which solifenacin was compared versus mirabegron is associated with solifenacin. The results showed superiority of the combination of mirabegron 50 mg associated with solifenacin 5 mg over the administration of solifenacin 5 mg in monotherapy. In addition, the non-inferiority of this combination is shown with solifenacin 10 mg in monotherapy.
However, few studies comparing directly darifenacin with mirabegron were found. In 2014, Maman and associates combined the results of different studies evaluating the efficacy of antimuscarinic drugs with placebo and compared them with the results of Mirabegron versus placebo. In this way, possible results of hypothetical direct comparison studies between B3 adrenergic and antimuscarinic drugs were simulated31. It was found that there would be no statistically significant difference between mirabegron compared to tolterodine, darifenacin, fesoterodine, oxybutynin, solifenacin 5 mg, and trospium. However, solifenacin 10 mg was the only one showing possibly greater efficacy than mirabegron31.
The only prospective study carried out in 2020 by Bhangu et al. analyzed 60 patients with mirabegron and 60 patients with darifenacin, finding that darifenacin had comparable results to mirabegron, with a slightly greater improvement in symptoms than mirabegron. The improvement in voiding frequency at 4 weeks was 63% for mirabegron and 91% for darifenacin (p = 0.001); however, at 12 weeks, 90% of patients improved with mirabegron and 98% improved with darifenacin, without significant differences. These results differ from our study, where comparable results were found but with a significant decrease in daytime and nighttime urinary frequency32.
On the other hand, Vasudeva et al. conducted a randomized clinical trial comparing these two drugs in the neurogenic bladder and stroke population, finding comparable effectiveness and safety. In both medications, there was a significant decrease when comparing pre- and post-treatment symptoms, such as incontinence, nocturia, and micturition frequency. However, there was no significant difference between the two drugs in terms of these parameters33.
In our study, we did a retrospective comparison of efficacy and side effects between mirabegron and darifenacin as first-line treatment in patients with OAB. Both groups presented similar demographic characteristics with no significant difference in terms of age, sex, comorbidities, or presence of hyperactive destructor in urodynamics. As previously mentioned in studies, there was no significant difference between mirabegron and antimuscarinic in terms of subjective symptom improvement, even when performing a subanalysis by gender and age. However, in terms of daytime and nighttime micturition frequency, a significant difference was seen when comparing the pre- and post-treatment frequency with mirabegron. This difference was not significant for darifenacin. However, it is important to highlight that the number of patients included in mirabegron´s group was double than of darifenacin, which could have affected the result. Now, when comparing daytime and nighttime micturition frequencies, both pre- and post-treatments were comparable.
In terms of safety, darifenacin showed a worse safety profile than mirabegron, with a higher rate of adverse events and suspension, with a significant difference. Constipation and headache were the secondary events presented in the darifenacin group, with a significant difference when compared to mirabegron. This differs from what has been reported in the literature, given that headache and hypertension were the most frequent events with mirabegron. No comparative studies of this medication with mirabegron were found. As expected, no differences were found in neurological side events. Women presented a greater number of side effects and discontinuation of treatment than men, without a difference when discriminating by age (greater or younger than 65 years).
One of this study’s limitations is its retrospective nature, with a difference between the number of patients in each group, doubling the number of cases treated with mirabegron. The results were based on subjective aspects recorded by the specialist in clinical history. Given that urodynamics are not routinely performed in clinical practice before and after the start of treatment in OAB, it was not possible to use this parameter to compare both drugs.
Conclusion
The subjective improvement between mirabegron and darifenacin is comparable; however, a significant decrease in daytime and nighttime micturition frequency was observed in mirabegron related to darifenacin. In addition, darifenacin showed a higher rate of secondary events and drug discontinuation, with constipation prevailing in this group. Constipation and headache were the secondary events with a significant difference between both groups, favoring the patients treated with mirabegron. Based on the above, the door is opened to carry out a prospective comparison that allows a more objective analysis of the symptomatic and urodynamic parameters in the Colombian population, including a larger number of patients.
Funding
The authors declare that this work was carried out with the authors’ own resources.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical considerations
Protection of humans and animals. The authors declare that no experiments on humans or animals were performed for this research.
Confidentiality of data. The authors declare that they have followed their center’s protocols on the publication of patient data.
Right to privacy and informed consent. The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This document is in the possession of the corresponding author.
