Effets secondaires du mirabegron 50 mg versus placebo : revue systématique et méta-analyse

03 septembre 2021

Auteurs : J. Hou, F. Xu, H. Du, N. Li
Référence : Prog Urol, 2021, 11, 31, 627-633




 




Introduction


Overactive bladder (OAB) is a syndrome with complex symptoms, characterized by urgency of urination, with or without urgency urinary incontinence, with urinary frequency and nocturia, without lower urinary tract infection [1]. It is estimated that more than 50 million people worldwide suffer from the disease [2]. Antimuscarinic agents are applied as the first-line treatments for patients with OAB; however, patients often give up using the therapies due to serious adverse events (AEs) such as dry mouth, constipation and blurred vision [3]. Mirabegron, a β 3 adrenergic agonist, is the first of a new class of drugs developed for the treatment of OAB [4]. At present, mirabegron 50mg, the most representative of them, is the most widely used therapy. In the recent meta-analysis, no significant difference was found in the safety outcomes between mirabegron and other therapies or placebo [5, 6, 7, 8]. The adverse events induced by mirabegron and placebo were similar, or mirabegron did not increase the risk of adverse events [8]. However, for safety outcomes, nearly all previous meta-analysis were focused on anticholinergic side effects or cardiovascular events (CV), and there were nothing worthy of concern [5, 6, 7, 8, 9]. Whether other safety outcomes deserve our attention remains a question? Thus, it is necessary to comprehensively analysis the research progress of safety and AEs of mirabegron monotherapy for patients with OAB.


In the current study, a systemic review and meta-analysis was designed, versus placebo over a 12-week cycle, aiming to comprehensively evaluate the safety of mirabegron 50mg therapy for OAB patients.


Materials and methods


Search strategy


Cochrane Library, PubMed, and EMBASE were searched for randomized controlled trails (RCTs) (search performed on 3 JUNE 2020 with no date restriction). The search terms that we used were "mirabegron", "overactive bladder", "randomized controlled trials" (Appendix A). We also reviewed the references of relevant articles, and no additional papers were obtained.


Each article identified through the electronic searches was screened by two reviewers for relevance, initially using the title and the abstract, and subsequently by reading the full text to select articles that met inclusion criteria. Records of the selection process were retained and a PRISMA flowchart was generated (Fig. 1). Finally, 10 articles containing 10 RCTs [10, 11, 12, 13, 14, 15, 16, 17, 18, 19] were included; the baseline characteristics of these 10 studies are summarized in Table 1. All disputes arising during the systematic literature review process were resolved by a third reviewer.


Fig. 1
Fig. 1. 

PRISMA flow diagram showing study selection process and rationale for exclusions. EMBASE: Excerpta Medica database; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.




Inclusion and exclusion criteria


Inclusion: (1) patients with OAB, age≥18years; (2) RCTs; (3) mirabegron 50mg monotherapy; (4) placebo controlled; (5) safety outcomes. Exclusion: (1) neurogenic bladder or lower urinary tract symptoms associated with benign prostatic hyperplasia, et al.; (2) conference papers; (3) flexible-dose therapy.


Assessment of quality and baseline characteristics


All 10 RCTs are randomized, double blind, placebo controlled study except Kosilov et al. [16] is single blind. None mentioned allocation concealment, selective report, intention-to-treat (ITT), et al (Table 2). The quality of evidence for retrieved references was determined using the Cochrane risk of bias tool [20]. (1) Was randomization carried out appropriately? (2) Was the baseline between groups was comparable? (3) Was the concealment of treatment allocation adequate? (4) Were the care providers, participants and outcome assessors blind to treatment allocation? (5) Were the lost visit reported and the specific number of missing data? (6) Was there any evidence to suggest that the authors measured more outcomes than they reported? (7) Did the analysis include an ITT analysis?


Data analysis


Data were analyzed by using RevMan v5.3.0 (Cochrane Collaboration, Oxford, UK). Odds ratio (OR) was employed to assess dichotomous data. We analyzed comparable data using 95% credible intervals (CIs). Heterogeneity among studies was assessed by using the &khgr; 2 test based on the Q and I 2 tests (I 2>50% will be considered of substantial heterogeneity; a P value of Q test<0.10 will be considered statistically significant), an individual study could be characterized as a fixed model if P >0.1, I 2<50%, otherwise a random-effects model was chosen.


Results


Nasopharyngitis


In all, 5 RCTs [11, 12, 13, 15, 17] involving 3646 participants (1819 in the mirabegron group and 2407 in the placebo group) contained data on nasopharyngitis. No obvious between-study heterogeneity (P =0.81, I 2=0%) was found. Using a fixed-effects model, for nasopharyngitis (OR: 1.54 [95%CI: 1.05, 2.25]; P =0.03<0.05; Fig. 2 or Table 3), showing the significant differences between mirabegron 50mg and placebo.


Fig. 2
Fig. 2. 

Forest plots showing changes in 15 safety outcomes.




Other 14 safety outcomes


Dry mouth, hypertension, constipation, headache, dyspepsia, urinary tract infection (UTI), Dizziness, Blurred vision, Nausea, CV, Influenza, electrocardiogram(ECG) QT prolonged, upper respiratory tract infection and high blood pressure, the results of which showed no differences (P >0.05) between mirabegron 50mg and placebo, respectively (Fig. 2 or Table 3).


Discussion


Anticholinergics are the current mainstay of pharmacotherapy for OAB; however, patients, with the therapies, often give up the medication because of their bothering side effects [21]. Mirabegron, a β 3 -adrenoceptor agonist, has a potential to increase blood pressure and heart rate [22]. For all these reasons, safety of drug therapy got widely attention, previous studies as we described, had proved that mirabegron 50mg was safe for patients with OAB. However, the studies usually focused on assessing anticholinergic side effects or CV events as safety outcomes. Other safety outcomes were not analyzed comprehensively, for safety endpoints might be more complex than efficacy in terms of quantities and various definitions. To deep assess the safety of mirabegron 50mg versus placebo for patients with OAB, we selected the data more accurately, and analyzed these data more comprehensively. The key finding of current study is that mirabegron 50mg is nearly as safe as placebo. However, for nasopharyngitis (OR: 1.54 [95%CI: 1.05, 2.25]; P =0.03<0.05; Fig. 2A), showing mirabegron 50mg monotherapy is a remarkable risk of nasopharyngitis for patients with overactive bladder.


Acute nasopharyngitis has been known to cause human work failure, economic loss and even death, but no effective treatment has already been established for the disease [23, 24]. Nasopharyngitis, as a safety outcome, ignored by previous meta-analyses [5, 6, 7, 8], was assessed as a mirabegron related adverse event in our meta-analysis. The mechanisms between mirabegron and nasopharyngitis are not known. The future progression of nasopharyngitis is also needed to be researched.


Our studies showed a higher similarity between mirabegron 50mg and placebo, in terms of wider adverse events assessed as safety outcomes. Those other 14 safety results were consistent with the findings of previous meta-analyses or agreed with the outcomes showed in 10 original documents, which meant the safety of mirabegron 50mg therapy was similar to placebo.


There are some particular merits of our study. First, results of the present study were providing reference for clinical practice; nasopharyngitis, as the drug-related adverse event, the risk of which was remarkably increased by mirabegron 50mg. Second, a greater number of safety outcomes were analyzed in our study compared with previous meta-analyses, enhancing the power of the present study, mirabegron is nearly as safe as placebo. Third, no significant heterogeneity was observed among the studies, and nearly all heterogeneity analysis indicated that no obvious between-study heterogeneity (P >0.1, I 2<50%) was found, this means the results are highly credible. However, some caveats of our report should be taken into consideration. First, the follow-up period of the total studies were 12 weeks, making the long-term safety of mirabegron uncertain. Second, limited information about basic characteristics was provided 5 of 10 included trials (Table 1), leading to potential selection bias and detection bias. More RCTs, longer follow-up periods and larger sample sizes, were recommended to strengthen the credibility of the conclusions of the analysis.


Conclusions


In conclusion, evidences from the current study indicate that nasopharyngitis is associated with mirabegron therapy for patients with overactive bladder. With the exception of nasopharyngitis, mirabegron 50mg therapy is nearly as safe as placebo for patients with OAB.


Disclosure of interest


The authors declare that they have no competing interest.


Author contributions


J.H., H.X., F.D., N.L. conceived and designed the studies; J.H., H.X., F.D. performed the studies; J.H., H.X., F.D. reviewed the literatures and analyzed the data; N.L. contributed technical and material support; J.H., N.L. wrote the paper.



Acknowledgments


The research was supported by the educational department of Liaoning Province No.: QN2019018 Grant to Ning Li.



Appendix A. Supplementary data


(22 Ko)
  




Table 1 - Assessment of basic characteristic.
Study  Trial design  Race, n (%) or location  Female, n (%)  Number  Duration, week  Population 
Chapple 2013 [10 Phase II, RCT, double blind  White, 328(90.7)  300 (88.8)  338  12  OAB, ≥ 18years 
Herschorn 2013 [11 RCT, double blind  White, 789(90.3)  604 (69.2)  873  12  OAB, ≥ 18years 
Khullar 2013 [12 RCT, double blind  White, 978(99.1)  713 (72.2)  987  12  OAB, ≥ 18years 
Nitti 2013 [13 Phase III, RCT, double blind  White, 786(87.8)  667 (74.5)  895  12  OAB, ≥ 18years 
Yamaguchi 2014 [14 Phase III, RCT, double blind  Japan  621 (81.9)  758  12  OAB, ≥ 20years 
Abrams 2015 [15 Phase II, RCT, double blind  White, 159(100)  106 (66.7)  159  12  OAB, ≥ 18years 
Kosilov 2015 [16 RCT, single blind  Russia  Unclear  122  12  OAB, ≥ 65years 
Kuo 2015 [17 RCT, double blind  China, Korea, India  453 (61.9)  732  12  OAB, ≥ 18years 
Yamaguchi 2015 [18 RCT, double blind  Japan  346 (82.4)  420  12  OAB, ≥ 20years 
Herschorn 2017 [19 RCT, double blind  White, 677(79.6)  650 (76.4)  851  12  OAB, ≥ 18years 
Total      6135 





Table 2 - Assessment of quality.
Study  Randomization  Allocated  Blinding  Baseline  Loss of follow-up  Selective report results  ITT 
Chapple 2013 [10 Unclear  Yes  Double blind  Comparable  Yes (n =2)  Unclear  Unclear 
Herschorn 2013 [11 Unclear  Yes  Double blind  Comparable  Yes (n =7)  Unclear  Unclear 
Khullar 2013 [12 Computer generated  Yes  Double blind  Comparable  Yes (n =7)  Unclear  Unclear 
Nitti 2013 [13 Computer generated  Yes  Double blind  Comparable  Yes (n =11)  Unclear  Unclear 
Yamaguchi 2014 [14 Unclear  Yes  Double blind  Comparable  Unclear  Unclear  Unclear 
Abrams 2015 [15 Unclear  Yes  Double blind  Comparable  Yes (n =2)  Unclear  Unclear 
Kosilov 2015 [16 Simple probability sampling  Yes  Single blind  Unclear  Unclear  Unclear  Unclear 
Kuo 2015 [17 Computer generated  Yes  Double blind  Comparable  Yes (n =9)  Unclear  Unclear 
Yamaguchi 2015 [18 Unclear  Yes  Double blind  Comparable  Unclear  Unclear  Unclear 
Herschorn 2017 [19 Unclear  Yes  Double blind  Comparable  Yes (n =8)  Unclear  Unclear 





Table 3 - Results of safety.
Outcomes  Trials  Total  Model  I2  95%CI  OR  P  
Nasopharyngitis  3646  Fixed  0%  (1.05, 2.25)  1.54  0.03 
Dry mouth  10  6135  Fixed  0%  (0.74, 1.41)  1.02  0.92 
Hypertension  3768  Fixed  0%  (0.80, 1.37)  1.05  0.73 
Constipation  4245  Fixed  0%  (0.87, 2.08)  1.35  0.18 
Headache  3252  Fixed  0%  (0.70, 1.56)  1.05  0.83 
Dyspepsia  1348  Fixed  0%  (0.09, 2.76)  0.50  0.43 
Urinary tract infection  3765  Fixed  14%  (0.82, 1.77)  1.20  0.36 
Dizziness  2224  Fixed  0%  (0.89, 4.46)  1.99  0.09 
Blurred vision  1132  Fixed  23%  (0.19, 3.17)  0.78  0.72 
Nausea  1333  Fixed  0%  (0.27, 1.61)  0.65  0.36 
Cardiovascular events  1070  Random  88%  (0.04, 34.38)  1.18  0.93 
Influenza  1305  Fixed  0%  (0.62, 3.45)  1.46  0.38 
ECG QT prolonged  891  Fixed  0%  (0.10, 2.04)  0.46  0.30 
Upper respiratory tract infection  854  Fixed  0%  (0.51, 1.81)  0.96  0.90 
High blood pressure  1769  Fixed  0%  (0.28, 3.20)  0.94  0.93 




References



Abrams P., Cardozo L., Fall M., Griffiths D., Rosier P., Ulmsten U., et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society Urology 2003 ;  61 : 37-49 [inter-ref]
Abrams P., Andersson K.E., Buccafusco J.J., Chapple C., de Groat W.C., Fryer A.D., et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder Br J Pharmacol 2006 ;  148 : 565-578 [cross-ref]
Takasu T., Ukai M., Sato S., Matsui T., Nagase I., Maruyama T., et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function J Pharmacol Exp Ther 2007 ;  321 : 642-647 [cross-ref]
Sexton C.C., Coyne K.S., Kopp Z.S., Irwin D.E., Milsom I., Aiyer L.P., et al. The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS BJU Int 2009 ;  103 (Suppl. 3) : 12-23 [cross-ref]
Athanasiou S., Pitsouni E., Grigoriadis T., Zacharakis D., Salvatore S., Serati M. Mirabegron in female patients with overactive bladder syndrome: What's new? A systematic review and meta-analysis Eur J Obstet Gynecol Reprod Biol 2020 ;  251 : 73-82 [cross-ref]
Chen H.L., Chen T.C., Chang H.M., Juan Y.S., Huang W.H., Pan H.F., et al. Mirabegron is alternative to antimuscarinic agents for overactive bladder without higher risk in hypertension: a systematic review and meta-analysis World J Urol 2018 ;  36 : 1285-1297 [cross-ref]
Lozano-Ortega G., Walker D.R., Johnston K., Mickle A., Harrigan S., Rogula B., et al. Comparative safety and efficacy of treatments for overactive bladder among older adults: a network meta-analysis Drugs Aging 2020 ;  37 : 801-816 [cross-ref]
Wang J., Zhou Z., Cui Y., Li Y., Yuan H., Gao Z., et al. Meta-analysis of the efficacy and safety of mirabegron and solifenacin monotherapy for overactive bladder Neurourol Urodyn 2019 ;  38 : 22-30 [cross-ref]
Kelleher C., Hakimi Z., Zur R., Siddiqui E., Maman K., Aballéa S., et al. Efficacy and tolerability of mirabegron compared with antimuscarinic monotherapy or combination therapies for overactive bladder: a systematic review and network meta-analysis Eur Urol 2018 ;  74 : 324-333 [cross-ref]
Chapple C.R., Dvorak V., Radziszewski P., Van Kerrebroeck P., Wyndaele J.J., Bosman B., et al. A phase II dose-ranging study of mirabegron in patients with overactive bladder Int Urogynecol J 2013 ;  24 : 1447-1458 [cross-ref]
Herschorn S., Barkin J., Castro-Diaz D., Frankel J.M., Espuna-Pons M., Gousse A.E., et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the beta3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder Urology 2013 ;  82 : 313-320 [inter-ref]
Khullar V., Amarenco G., Angulo J.C., Cambronero J., Hoye K., Milsom I., et al. Efficacy and tolerability of mirabegron, a beta3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial Eur Urol 2013 ;  63 : 283-295 [cross-ref]
Nitti V.W., Auerbach S., Martin N., Calhoun A., Lee M., Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder J Urol 2013 ;  189 : 1388-1395 [cross-ref]
Yamaguchi O., Marui E., Kakizaki H., Homma Y., Igawa Y., Takeda M., et al. Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50=mg once daily, in Japanese patients with overactive bladder BJU Int 2014 ;  113 : 951-960 [cross-ref]
Abrams P., Kelleher C., Staskin D., Rechberger T., Kay R., Martina R., et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony) Eur Urol 2015 ;  67 : 577-588 [cross-ref]
Kosilov K., Loparev S., Ivanovskaya M., Kosilova L. A randomized, controlled trial of effectiveness and safety of management of OAB symptoms in elderly men and women with standard-dosed combination of solifenacin and mirabegron Arch Gerontol Geriatr 2015 ;  61 : 212-216 [cross-ref]
Kuo H.C., Lee K.S., Na Y., Sood R., Nakaji S., Kubota Y., et al. Results of a randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter study of mirabegron, a beta3-adrenoceptor agonist, in patients with overactive bladder in Asia Neurourol Urodyn 2015 ;  34 : 685-692 [cross-ref]
Yamaguchi O., Marui E., Igawa Y., Takeda M., Nishizawa O., Ikeda Y., et al. Efficacy and safety of the selective β3 -adrenoceptor agonist mirabegron in japanese patients with overactive bladder: a randomized, double-blind, placebo-controlled, dose-finding study Low Urin Tract Symptoms 2015 ;  7 : 84-92 [cross-ref]
Herschorn S., Chapple C.R., Abrams P., Arlandis S., Mitcheson D., Lee K.S., et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study) BJU Int 2017 ;  120 : 562-575 [cross-ref]
Higgins J.P., Altman D.G., Gøtzsche P.C., Jüni P., Moher D., Oxman A.D., et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials Bmj 2011 ;  343 : d5928
Benner J.S., Nichol M.B., Rovner E.S., Jumadilova Z., Alvir J., Hussein M., et al. Patient-reported reasons for discontinuing overactive bladder medication BJU Int 2010 ;  105 : 1276-1282 [cross-ref]
Rosa G.M., Ferrero S., Nitti V.W., Wagg A., Saleem T., Chapple C.R. Cardiovascular safety of β3-adrenoceptor agonists for the treatment of patients with overactive bladder syndrome Eur Urol 2016 ;  69 : 311-323 [cross-ref]
Regoli M., Chiappini E., Bonsignori F., Galli L., de Martino M. Update on the management of acute pharyngitis in children Ital J Pediatr 2011 ;  37 : 10 [cross-ref]
Wu Y.Q., Xi H.X., Zhang Y., Sun K.X., Zhou Z.Y., Hu Y.H. [Utilization of antibacterial agents for emergency patients with acute upper respiratory infections in tertiary hospitals in Beijing] Beijing Da Xue Xue Bao Yi Xue Ban 2014 ;  46 : 435-439






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