- Email: [email protected]
A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder
european urology 54 (2008) 740–764
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Review – Neuro-urology
A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder Giacomo Novara a, Antonio Galfano b, Silvia Secco b, Carolina D’Elia b, Stefano Cavalleri b, Vincenzo Ficarra b, Walter Artibani b,* a b
I.R.C.C.S. Istituto Oncologico Veneto (I.O.V.), Padova, Italy Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Italy
Article info
Abstract
Article history: Accepted June 25, 2008 Published online ahead of print on July 9, 2008
Context: Anticholinergic drugs are commonly used in patients with overactive bladder (OAB) who do not achieve symptom relief and quality of life improvement with conservative management. Several drugs, with different doses, formulations, and routes of administration are currently available, making the choice quite difficult. Objective: To evaluate efficacy and safety of different doses, formulations, and route of administration of the available anticholinergic drugs. Evidence acquisition: A systematic review of the literature was performed in August 2007 using Medline, Embase, and Web of Science. Efficacy (micturitions per 24 h, volume voided per micturition, urgency urinary incontinence episodes per 24 h, incontinence episodes per 24 h) and safety (mainly, adverse events and withdrawal rates) end points were evaluated in the randomized control trials (RCTs) assessing the role of anticholinergic drugs in non-neurogenic OAB. Meta-analysis of RCTs was conducted using the Review Manager software 4.2 (Cochrane Collaboration). Evidence synthesis: Our systematic search identified 50 RCTs and three pooled analyses. Tolterodine immediate release (IR) had a more favorable profile of adverse events than oxybutynin IR. Regarding different dosages of IR formulations, dose escalation might yield some limited improvements in the efficacy but at the cost of significant increase in the rate of adverse events. In the comparisons between IR and extended-release (ER) formulations, the latter showed some advantages, both in terms of efficacy and safety. With regard to the route of administration, use if a transdermal route of administration does not provide significant advantage over an oral one. Conclusion: Many of the available RCTs have good methodological quality. ER formulations should be preferred to the IR ones. With regard to IR formulations, dose escalation might yield some improvements in the efficacy with significant increase in the AE. More clinical studies are needed to indicate which of the drugs should be used as first-, second-, or third-line treatment. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Overactive bladder Urgency frequency syndrome Detrusor overactivity Muscarinic receptor antagonist Darifenacin Emepronium Fesoterodine Oxybutynin Propantheline Propiverine Solifenacin Tolterodine Trospium
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
* Corresponding author. Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV Floor, Via Giustiniani 2, 35128, Padua, Italy. Tel. +39 049 8212720; Fax: +39 049 8218757. E-mail address: [email protected] (W. Artibani).
0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.06.080
european urology 54 (2008) 740–764
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Fig. 1 – Flow-chart of meta-analysis. RCTs, randomized control trials, OAB, overactive bladder.
1.
Introduction
Overactive bladder (OAB) is a highly prevalent condition [1,2] with enormous related costs per year [3,4]. First-line treatments for OAB include lifestyle modifications, behavioral therapy, pelvic floor muscle training, and bladder training. Antimuscarinic drugs are the first-line drug therapy, while other therapeutic options, such as botulinum toxin injection, neuromodulation, or surgical interventions are used in a smaller percentage of patients who are non-responders to drug therapies [5,6]. Several antimuscarinic drugs are on the market, including oxybutynin, tolterodine, propiverine, trospium, the recently released solifenacin and darifenacin, and fesoterodine, which was the last one to receive the European Medicines Evaluation Agency (EMEA) marketing authorization in 2006. Moreover, some drugs such as oxybutynin, tolterodine, propiverine, or trospium are available both in immediate-release (IR) and extended-release (ER) formulations, while oxybutynin is also available in a sustained-delivery patch for transdermal administration [7]. Two meta-analyses evaluated the efficacy of the anticholinergic drugs in comparison to placebo, showing that the use of these drugs results in statistically significant improvements in symptoms and quality of life [8,9]. To date, however, the clinical data available on the active comparisons of different drugs, formulations, and routes of administration are more limited. Specifically, a Cochrane meta-analysis based on a systematic review performed in January 2002 demonstrated that tolter-
odine was as effective as, but better tolerated than, oxybutynin; moreover, ER formulations of oxybutynin and/or tolterodine were shown to cause a lower risk of dry mouth compared to the IR formulations. Comparing head-to-head the ER formulations, xerostomia was less common in those patients receiving tolterodine [10]. In a more recent meta-analysis which mainly focused on placebo-controlled trials, Chapple et al reported some data on the trials of drugs which provided active drug controls. Solifenacin was shown to be more effective than tolterodine IR in terms of reduction of both urgency episodes and number of micturitions, while oxybutynin ER was shown to be more effective than tolterodine ER, in terms of reduction of incontinence episodes. Finally, oxybutynin IR 15 mg once daily, solifenacin 5 mg once daily, and solifenacin 10 mg once daily were more effective than tolterodine IR in increasing the volume voided per micturitions [8]. The purpose of the present systematic review and meta-analysis was to evaluate all the clinical data derived from randomized controlled trials in order to assess the efficacy and safety of different doses, formulations, and routes of administration of the currently available anticholinergic drugs, as well as head-to-head comparisons of different drugs. 2.
Methods
The systematic review of the literature was performed in August 2007 using the Medical Literature Analysis and
Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in volume voided per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
742
Table 1 – Efficacy data from the randomized control trials (RCTs) comparing different doses and formulations of oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine Mean change in pads used per 24 h
Oxybutynin Nilsson et al 1997 [13]
Oxy IR 5 mg bid (17)
8 wk
1
NR
NR
Oxy ER 10 mg qd (16) Versi et al 2000 [14]
Oxy IR different doses (115)
2.8 (24%)
NR
NR
NR
NR
variable
3
NR
NR
NR
Oxy ER different doses (111) Barkin et al 2004 [15]
Oxy IR different doses (41)
6 wk
2.4 (22%)
+40 (18%)
1.3 (41%)
1.8 (16%)
+25 (14%)
1.0 (30%)
0.8 (7%)
+17.1 (8%)
1.8 (37%)
Oxy ER 10 mg qd (77)
1.1 (11%)
+20.5 (10%)
1.5 (34%)
Oxy ER 15 mg qd (83)
1.5 (14%)
+44.6 (21%)
2.0 (46%)
3
NR
NR
Oxy ER different doses (53) Corcos et al 2005 [16]
Oxy ER 5 mg qd (77)
NR
NR
NR
2.6 (23%)
4 wk
3
NR
NR
0.6 (76%)
0.7 (75%)
0.4 (83%)
0.5 (81%)
NR
2.41 (73%) 1.81 (54%)
NR
NR
NR 0.5 (21%) 0.6 (26%) NR
Junemann et al 2006 [17]
Propi IR 15 mg bid (395)
4 wk
1
NR
NR
Propi ER 30 mg qd (391)
3.69 (29%)
+46.5 ml (32.6%)
2.03 (33%)
3.63 (28%)
+40.1 ml (27.9%)
2.58 (40%)
1.4 (12%)
+20 ml*
1.7 (15%)
+20 ml*
NR
2.21 (67%)
NR
2.47 (73%)
Tolterodine Jonas et al 1997 [18]
Tolt IR 1 mg bid (99)
4 wk
3
NR
NR
Tolt IR 2 mg bid (99) Rentzhog et al 1998 [19]
Millard et al 1999 [20]
Tolt IR 0.5 mg bid (21)
+15%* +25%*
Tolt IR 2 mg bid (14)
2.5 (20%)
+30%*
0.8 (46%)
29%*
Tolt IR 4 mg bid (16)
2.0 (20%)
+30%*
1.6 (60%)
40%*
NR
NR
NR
Tolt IR 2 mg bid (129) Jacquetin et al 2001 [21]
Tolt IR 1 mg bid (97)
4 wk
1
NR
NR
Tolt IR 2 mg bid (103) Malone-Lee et al 2001 [22]
Tolt IR 1 mg bid (61)
4 wk
3
NR
NR
Tolt IR 2 mg bid (73) Van Kerrebroeck et al 2001 [23]
Tolt IR 2 mg bid (514)
12 wk
3
NR
NR
Tolt ER 4 mg qd (507) Swift et al 2003 [24]
NR
1.6*
1.0 (10%)
1
NR
1.1*
1.1 (10%)
12 wk
1
NR
Tolt IR 1 mg bid (16)
Tolt IR 1 mg bid (123)
2 wk
NR
Tolt IR 2 mg bid (408)
12 wk
3
NR
NR
Tolt ER 4 mg qd (417)
2.3 (20%)
+27 (18%)
2.3 (20%)
+36 (23%)
1.4 (13%)
+20 (13%)
1.4 (13%)
+19 (12%)
0.7 (6%)
+9 (6%)
0.7 (6%)
+16 (11%)
1.7 (15%)
+29 (21%)
1.8 (16%)
+34 (24%)
1.7 (15%)
+32 (24%)
1.9 (17%)
+37.9 (27%)
NR
NR
NR
1.7 (44%)
0.7 (35%)
10%*
0.6 (37%)
10%*
NR
NR
NR
NR
NR
NR
1.7 (47%) NR
1.1 (41%) 1.3 (41%)
NR
0.3 (13%) 0.7 (25%)
NR NR
NR NR
1.51 (46%)
0.5 (36%)
1.68 (53%)
0.5 (36%)
1.44 (44%)
0.5 (33%)
1.68 (53%)
0.6 (37%)
Solifenacin Cardozo et al 2004 [25]
Soli 5 mg qd (286)
12 wk
2
NR
Soli 10 mg qd (290) Chapple et al 2004 [26]
Soli 5 mg qd (264)
12 wk
2
NR
0.56 (25.3%)
2.37 (20%)
+30.75*
2.84 (25%)
1.3 (63%)
1.63 (61%)
0.71 (38.5%)
2.81 (22%)
+35.99*
2.90 (30%)
1.2 (57%)
1.57 (52%)
2.19 (17%)
+32.9 (25%)
2.85 (52%)
1.41 (65%)
1.42 (59%)
2.61 (20%)
+39.2 (29%)
3.07 (55%)
1.36 (63%)
1.45 (47%)
NR
Soli 10 mg qd (261) Chapple et al 2006** [27]
Soli 5 mg qd (552)
12 wk
NA
NR
Soli 10 mg qd (1158)
0.6*
2.3*
+32.3*
2.9*
0.6*
2.7*
+42.5*
3.4*
NR
1.5*
NR NR NR
1.8*
Darifenacin Chapple et al 2005** [28]
Dari 7.5 mg qd (337)
12 wk
NA
NR
NR
Dari 15 mg qd (334) Foote et al 2005** [29]
Dari 7.5 mg qd (97)
12 wk
NA
NR
NR
Dari 15 mg qd (110) Zinner et al 2005 [30]
Dari 15 mg qd (58)
2 wk
2
NR
NR
Dari 30 mg qd (58) Hill et al 2006 [31]
Dari 7.5 mg qd (108)
1.6 (17%)
+15 (10%)
2.0 (29%)
1.9 (17%)
+27 (17%)
2.3 (29%)
1.8 (18%)
+14 (10%)
2.1 (26%)
1.8 (17%)
+27 (18%)
2.4 (26%)
1.14 (12%)
NR
1.27 (16%)
1.62 (18%) 12 wk
NR
4.0 (77%)
NR
4.8 (79%) NR
1.6 (67%)
NR
1.5 (76%) NR
1.63 (21%)
1.44 (92%)
NR
1.74 (138%)
1.7 (17%)
+17 (10%)
1.8 (29%)
Dari 15 mg qd (107)
1.9 (18%)
+24 (16%)
2.3 (27%)
1.48 (76%)
Dari 30 mg qd (115)
2.2 (21%)
+44 (26%)
3.0 (33%)
1.62 (77%)
3
NR
NR
NR
1.15 (69%)
NR
european urology 54 (2008) 740–764
Propiverine
NR
NR
*Baseline values not provided in the published manuscript; **pooled analysis of RCTs; NR: not reported; NA, not applicable; qd, once daily; bid, twice daily.
1.65 (42%) 1.91 (15%)
2.3 (20%) +33.6 (21%)
+16.5 (11%) 1.61 (12%)
2.09 (17%) 0.55 (29%)
0.58 (26%) 1.04 (10%)
1.54 (15%)
3 Feso 8 mg (279)
Feso 4 mg (283) Nitti et al 2007 [34]
Feso 8 mg qd (288)
12 wk
12 wk Feso 4 mg qd (272)
2.28 (59%)
NR
NR 1.95 (80%)
2.22 (87%) 2.36 (19%) +33.62 (22%) 1.88 (19%) 0.39 (23%)
1.88 (18%) 1.37 (14%) 3
1.48 (17%)
+27.72 (17%)
+92.34* 1.784*
1.76 (17%) 0.39 (29%)
Feso 12 mg (39)
NR NR 2 8 wk Feso 4 mg qd (44) Nitti et al 2005 [32]
Fesoterodine
Chapple et al 2007 [33]
+27.94*
+58.69* 1.815*
0.996*
Mean change in micturitions per 24 h Mean change in nighttime micturitions per 24 h Mean change in daytime micturitions per 24 h Jadad score Treatment duration Dose (no. of cases)
Table 1 (Continued )
Reference
Feso 8 mg qd (47)
Mean change in volume voided per micturitions (ml)
NR
Mean change in urgency episodes per 24 h
NR
Mean change in UUI episodes per 24 h
NR
Mean change in incontinence episodes per 24 h
NR
Mean change in pads used per 24 h
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Retrieval System Online (U.S. National Library of Medicine’s life science database; MEDLINE), the Excerpta Medica database (EMBASE), and Thomson-Reuters’ Web of Science. The MEDLINE search employed a complex search strategy, including both ‘‘MeSH’’ (Medical Subject Heading) and ‘‘free text’’ protocols. Specifically, the MeSH search was conducted by combining the following terms retrieved from the MeSH browser provided by MEDLINE: ‘‘urinary bladder, overactive’’ and ‘‘cholinergic antagonists’’. Multiple free-text searches were performed applying singularly the following terms through all the fields of the records: overactive bladder, detrusor overactivity, bladder overactivity, urgency frequency syndrome, darifenacin, emepronium, fesoterodine, oxybutynin, propantheline, propiverine, solifenacin, tolterodine, and trospium. Subsequently, the searches were pooled and limited to randomized controlled trials (RCTs). No temporal limits were used. Searches on EMBASE and Web of Science used only the free-text protocol, with the same key words. Subsequently, the queries were pooled without applying any limits. In addition, other significant studies cited in the reference lists of the selected papers were considered. Three of the authors individually reviewed all the abstracts of the retrieved studies in order to select the papers that were relevant to the review topic. Specifically, all the full-test studies including data of efficacy (changes in daytime micturitions in 24 h, nighttime micturitions in 24 h, micturitions in 24 h, volume voided per micturitions, urgency, episodes in 24 h, urge urinary incontinence [UUI] episodes in 24 h, incontinence episodes in 24 h, pads used per 24 h, quality of life scores) and complications (overall rates of adverse events, withdrawals due to adverse events, dry mouth rate, moderate-to-severe or severe dry mouth rate, constipation, acute urinary retention, vision abnormality, headache, etc) of anticholinergic drugs comparing different drugs, formulations, doses, and routes of administration were considered. Data were extracted separately and independently by two of the authors and were cross-checked. Moreover, the web site of the Food and Drug Administration (http://www.fda.gov) was searched for RCTs concerning the same drugs. The quality of all the retrieved RCTs was assessed using the Jadad score [11]. All the identified RCTs were included in the meta-analysis, regardless of the quality score. Meta-analysis was conducted using the Review Manager software version 4.2 (The Cochrane Collaboration, Oxford, UK). Specifically, statistical heterogeneity was tested using the chi-square test. A p value <0.10 was used to indicate heterogeneity. In case of lack of heterogeneity, fixed-effects models were used for the meta-analyses. Random-effects models were used in case of heterogeneity. The results were expressed as weighted means and standard deviations for continuous outcomes and relative risk for dichotomous variables. Only the RCTs presenting data in this format were included in the meta-analysis. All the authors whose studies presented the data in a format not suitable for the metaanalysis were contacted and asked for the missing figures, but only three authors provided useful data. The presence of publication bias was evaluated using a funnel plot [12].
Reference
Oxybutynin Nilsson 1997 [13] Anderson 1999 [35] Birns et al 2000 [36] Versi et al 2000 [14]
Corcos et al 2005 [16]
Propiverine Abrams et al 2006 [37] Junemann et al 2006 [17]
Tolterodine Jonas 1997 [18] Rentzhog 1998 [19]
Millard 1999 [20] Jacquetin et al 2001 [21] Malone-Lee et al 2001 [22] Van Kerrebroeck et al 2001 [23] Swift et al 2003 [24]
Solifenacin Cardozo et al 2004 [25]
Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy
IR 5 mg bid (17) ER 10 mg qd (16) IR 5 mg different doses (52) ER different doses (53) IR 5 mg tid (67) ER 10 mg qd (63) IR different doses (115) ER different doses (111) IR different doses (60) ER different doses (65) ER 5 mg qd (77) ER 10 mg qd (77) ER 15 mg qd (83)
Propi Propi Propi Propi
Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt
IR 15 mg tid (42) ER 20 mg qd (38) IR 15 mg bid (395) ER 30 mg qd (391)
IR 1 mg bid (99) IR 2 mg bid (99) IR 0.5 mg bid (21) IR 1 mg bid (16) IR 2 mg bid (14) IR 4 mg bid (16) IR 1 mg bid (123) IR 2 mg bid (129) IR 1 mg bid (97) IR 2 mg bid (103) IR 1 mg bid (61) IR 2 mg bid (73) IR 2 mg bid (512) ER 4 mg qd (505) IR 2 mg bid (408) ER 4 mg qd (417)
Soli 5 mg qd (299) Soli 10 mg qd (307)
Treatment duration
8 wk
Jadad Adverse Withdrawals Dry Moderate to Constipation score events due to mouth severe or severe dry rate adverse events mouth 1
variable
3
4 wk
3
variable
3
100% 87% 94% 87% 67% 55% NR
0 0 NR
6 wk
3
NR
4 wk
3
NR
2 wk
3
NR
4 wk
1
81% 79% 38% 34%
4 wk
3
2 wk
1
12 wk
1
4 wk
1
4 wk
3
31% 32% 38% 37% 50% 75% 74% 73% 40% 53% NR
12 wk
3
NR
12 wk
3
NR
12 wk
3
NR
NR NR 13% 9% 4% 14% 14%
82% 69% 87% 68% 17% 23% 59% 48% 72% 68% 56% 68% 70%
AUR
NR
NR
NR
46% 25% NR
31% 30% NR
NR
45% 39% 45% 38% 3% 14% 5%
NR
NR
10% 8% 5% 4% 5%
NR
NR
4% 3%
52% 34% 23% 22%
4% 3% 5% 0 0 6% 2% 6% 3% 2% 7% 10% 5% 5% 5% 5%
8% 10% 9% 12% 36% 56% 24% 39% 21% 34% 49% 66% 30% 23% 31% 23%
NR
2% 4%
8% 23%
NR
3% 10% 7%
24% 16% 4% 3%
NR
2% 3% 5% 19% 7% 12% NR
NR
3% 2%
4% 2% 8% 0 7% 6% 7% 6%
2% 5%
4% 9%
NR
0 0 0 6% NR NR NR NR
Vision Headache abnormality
12% 25% 17% 28% 4% 6% NR
41% 44% NR
15% 3% 1% 1% 1%
22% 12% NR
4% 0 NR
33% 24% 3.8% 4.6%
7% 3% 2% 1%
3% 3% NR
NR
3% 5% 0 19% 7% 6% 2% 6% NR
0 0 NR
0 4% NR
NR
1% 1%
NR
4% 6%
NR
0 0 0 6% NR
NR 3% 3% 8% 10% 4% 6% 4% 7%
NR
european urology 54 (2008) 740–764
Barkin et al 2004 [15]
Dosage (no. of cases)
744
Table 2 – Safety data from the randomized control trials (RCTs) comparing different doses and formulations of emepropium, oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine
Table 2 (Continued ) Reference
Chapple et al 2004 [26] Chapple et al 2006* [27]
Darifenacin Chapple et al 2005* [28] Foote et al 2005* [29] Zinner et al 2005 [30]
Fesoterodine Nitti et al 2005 [32]
Chapple et al 2007 [33] Nitti et al 2008 [34]
Treatment duration
Jadad Adverse Withdrawals Dry Moderate to Constipation mouth severe or score events due to rate adverse severe dry mouth events
Soli Soli Soli Soli
5 mg qd (279) 10 mg qd (268) 5 mg qd (552) 10 mg qd (1158)
12 wk
3
NR
12 wk
3
91% 87%
Dari Dari Dari Dari Dari Dari Dari Dari Dari
7.5 mg qd (337) 15 mg qd (334) 7.5 mg qd (97) 15 mg qd (110) 15 mg qd (76) 30 mg qd (76) 7.5 mg qd (108) 15 mg qd (107) 30 mg qd (115)
12 wk
NA
12 wk
NA
2 wk
2
54% 66% 54% 69% NR
12 wk
3
57% 68% 80%
Feso Feso Feso Feso Feso Feso Feso
4 mg qd (43) 8 mg qd (47) 12 mg (38) 4 mg (272) 8 mg (282) 4 mg (283) 8 mg (279)
8 wk
2
NR
12 wk
3
12 wk
3
50% 58% 61% 69%
3% 3% 3% 7%
14% 21% 11% 28%
1% 5% 1% 9% 0 1% 0 2% 4%
20% 35% 21% 31% 13% 34% 23% 40% 59%
2% 4% 13% 3% 5% 6% 9
37% 43% 63% 22% 34% 16% 36%
* Pooled analysis of RCTs; NA, not applicable; qd, once daily; bid, twice daily; tid, three times daily; NR, not reported.
NR 0.2% 1%
NR NR NR NR
14% 21% 13% NR NR
AUR
7% 8% 5% 13%
NR
15% 21% 19% 24% 10% 21% 16% 25% 59%
Headache Vision abnormality
4% 6% 4% 5%
NR
NR
NR
NR
NR
NR NR
0 0 2% 0 3%
4% 5% 0 0 NR
NR
NR
NR
NR
3% 4% 5% 8%
0.3% 1% 1% 2%
2% 4% 0.7% 3%
4% 2% 4% 3%
NR
NR
6% 6% 6%
european urology 54 (2008) 740–764
Hill et al 2006 [31]
Dosage (no. of cases)
745
746
3.
european urology 54 (2008) 740–764
Results
984 records were retrieved by searching MEDLINE: 910 records were retrieved from EMBASE, and 669 records were retrieved from Web of Science. The studies evaluating lower urinary tract storage symptoms in patients with bladder-outlet obstructions, papers evaluating neurogenic OAB or OAB in children, phase I studies, post-hoc analyses of RCTs, and duplicate publications were excluded. We finally identified 50 RCTs and three pooled analyses of RCTs for inclusion in this review (Fig. 1). 3.1. Comparisons of different doses and formulations of the same drug
Tables 1 and 2 summarize the efficacy and safety data from the available RCTs comparing different
doses and formulations of oxybutynin, tolterodine, propiverine, trospium, darifenacin, solifenacin, and fesoterodine. 3.1.1.
Oxybutynin
A single study, published as congress abstract only and really outdated, evaluated the efficacy and safety of oxybutynin IR 2.5 mg, taken three times a day or as needed [38]. Five RCTs compared IR and ER formulations [13–15,35,36], while two further studies compared different doses of the ER formulation [16,39]. Meta-analysis of efficacy between oxybutynin IR and oxybutynin ER was not possible because the only two RCT reporting data in the proper format [15,16] were not suitable for cumulative evaluation of any clinical significance. With regard to adverse events, the occurrence of any adverse event (odds ratio [OR]: 1.9; 95% confidence interval [CI], 1.03–3.51;
Fig. 2 – Forest plots of adverse events after immediate release (IR) and extended release (ER) oxybutynin. (A) Occurrence of any adverse event; (B) dry mouth; (C) moderate-to-severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
747
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Table 3 – Meta-analysis of adverse events with oxybutynin immediate release (IR) and oxybutynin extended release (ER) Oxybutynin IR vs oxybutynin ER
Any adverse event Withdrawals due to adverse events Dry mouth Moderate-to-severe or severe dry mouth Headache Constipation Vision abnormality
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
3 2 5 3 3 2 4
268 158 619 456 288 230 393
1.9 1.51 1.45 1.49 1.77 1.11 0.92
1.03–3.51 0.49–4.65 1.02–2.05 1.02–2.16 0.84–3.72 0.56–2.22 0.50–1.69
0.04 0.47 0.04 0.04 0.13 0.76 0.79
Difference favors
Oxybutynin ER None Oxybutynin ER Oxybutynin ER None None None
RCT, randomized control trial; IR, immediate release; ER, extended release; OR, odds ratio; CI, confidence interval.
p = 0.04), dry mouth (OR: 1.45; 95% CI, 1.02–2.05; p = 0.04), and moderate-to-severe or severe dry mouth (OR: 1.49; 95 CI, 1.02–2.16; p = 0.04) were significantly more common with oxybutynin IR (Fig. 2). On the other hand, withdrawals due to adverse events, headache, constipation, and vision abnormality were similar for the two formulations of oxybutynin (Table 3). 3.1.2.
Tolterodine
Eight RCTs compared different doses and formulations of tolterodine. Specifically, four studies compared two different dosages of tolterodine IR 1 mg twice daily vs tolterodine IR 2 mg twice daily [18,20–22], while a further study evaluated four different dosages (0.5 mg twice daily vs 1 mg twice daily vs 2 mg twice daily vs 4 mg twice daily) [19]. Two RCTs compared tolterodine IR 2 mg twice daily and tolterodine ER 4 mg once daily [23,24], while a single study compared two dosages of tolterodine ER [39].
With regard to efficacy analysis, four papers presented the data in a format unsuitable for meta-analysis [18,19,22,39]. Comparing the tolterodine IR 1 mg and tolterodine IR 2 mg doses, micturitions per 24 h (weighted mean difference [WMD], 0.11; 95% CI, 0.45–0.66; p = 0.70), volume voided per micturition (WMD, 8.68; 95% CI, 18.62– 1.26; p = 0.09), and UUI episodes per 24 h (WMD, 0.06; 95% CI, 0.51–0.39; p = 0.81) were similar for both doses. With regard to adverse events, only dry mouth was significantly more frequent in those patients taking tolterodine IR 2 mg (OR: 0.52; 95% CI, 1.037–0.72; p < 0.0001). Regarding the comparison of tolterodine IR and tolterodine ER formulations, patients randomized to tolterodine ER formulation experienced a lower number of micturitions per 24 h (WMD, 0.34; 95% CI, 0.02–0.66; p = 0.03) and a higher volume voided per micturition (WMD, 9.12; 95% CI, 14.13– 4.12; p = 0.0004), but a similar number of incontinence episodes and pad use per day (Table 4). Evaluating
Table 4 – Meta-analysis of randomized control trials (RCTs) comparing tolterodine immediate release (IR) and tolterodine extended release (ER) Tolterodine IR vs tolterodine ER
RCT (no.)
Participants (no.)
2 2 2 2
1846 1846 1846 1846
Micturitions per 24 h Volume voided per micturition Incontinence episodes per 24 h Pad use per 24 h
Adverse events
Withdrawals due to adverse events Dry mouth Headache Constipation
WMD
0.34 9.12 0.09 0
95% CI, WMD
0.02–0.66 14.13–4.12 0.15–0.32 0.15–0.15
Test for overall effect ( p value) 0.03 0.0004 0.46 1
Difference favors
Tolterodine ER Tolterodine ER None None
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Difference favors
2
1846
0.98
0.65–1.48
0.92
None
2 2 2
1846 1846 1846
1.39 0.53 1.10
1.13–1.71 0.34–0.81 0.76–1.59
0.002 0.004 0.63
Tolterodine ER Tolterodine IR None
IR, immediate release; ER, extended release; UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.
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european urology 54 (2008) 740–764
Fig. 3 – Forest plots of efficacy and safety after tolterodine immediate release (IR) and tolterodine extended release (ER). (A) Micturitions per 24 h; (B) volume voided per micturition; (C) dry mouth; (D) headache. OAB, overactive bladder; N, number of patients in the study arm; SD, standard deviation; WMD, weighted-mean difference; CI, confidence interval.
the adverse events with the use of the two formulations of tolterodine, patients treated with tolterodine ER formulations had a significantly lower rate of dry mouth (OR: 1.39; 95% CI, 1.13– 1.71; p = 0.002) but a higher rate of headache (OR: 0.53; 95% CI, 0.34–0.81; p = 0.004). Withdrawals due to
adverse events and constipation were similarly prevalent in both cases (Table 4; Fig. 3). 3.1.3.
Propiverine
A single study evaluated the efficacy of 21-d treatment with different doses of propiverine IR
Fig. 4 – Forest plots of adverse events after different dosages of darifenacin (Dari). Darifenacin 7.5 mg versus darifenacin 15 mg: (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth; (D) constipation. Darifenacin 15 mg versus darifenacin 30 mg: (E) dry mouth; (F) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
european urology 54 (2008) 740–764
749
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european urology 54 (2008) 740–764
Table 5 – Meta-analysis of adverse events with immediate-release (IR) and extended-release (ER) formulations of propiverine Propiverine IR vs propiverine ER
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Any adverse event Dry mouth Headache Constipation Vision abnormality
2 2 2 2 2
866 866 866 866 866
1.20 1.16 1.54 1.29 1.95
0.90–1.58 0.84–1.58 0.59–4.02 0.69–2.41 0.89–4.02
0.21 0.36 0.38 0.42 0.10
Difference favors None None None None None
RCT, randomized control trial; OR, odds ratio; CI, confidence interval.
(15 mg twice daily vs 30 mg twice daily vs 45 mg three times daily vs 60 mg four times daily), showing that propiverine IR 15 mg twice daily and 30 mg twice daily were the doses with the most favorable ratio of efficacy in micturition frequency to tolerability [40]. Two studies compared propiverine hydrochloride IR and propiverine hydrochloride ER formulations [17,37]. Meta-analysis was possible only for complication rates, in spite of the different dosages of propiverine IR of in the two studies. The two formulations of propiverine showed similar rates of adverse events, dry mouth, constipation, headache, and vision abnormality (Table 5). 3.1.4.
Solifenacin
Four RCTs evaluated the efficacy of different doses of solifenacin [25,26,41,42]. The two studies by Gittelman et al [41,42] were not included in Tables 1 and 2 because it was not possible to obtain the data in an extended form. Three pooled analyses of these four RCTs sharing similar designs were published [27,43,44]. The largest analysis, which also included the patients without UUI, evaluated 2848 patients out of 3032 randomized patients: 552 patients received solifenacin 5 mg, 1158 patients received solifenacin 10 mg, and 1138 patients received placebo [27]. Both doses of solifenacin were significantly more efficacious than placebo. Indeed, comparing the two dosages, solifenacin 10 mg was significantly better only in terms of the percentage of patients having a 50% reduction in incontinence episodes ( p = 0.006). However, withdrawals due to adverse events ( p = 0.0005), dry mouth ( p < 0.0001), and constipation ( p < 0.0001) were significantly more common among the patients treated by solifenacin 10 mg [27].
which, however, failed to clearly report the included trials. The larger studies evaluated 337 patients randomized to receive darifenacin 7.5 mg and 334 patients who received darifenacin 15 mg. The analysis identified significant dose–response effects for change in weekly incontinence episodes [28]. The study from Foote et al [29] was a subgroup analysis of the patients aged 65 yr in Chapple et al [28] and was not evaluated in our analyses. Meta-analysis of efficacy between the different doses of darifenacin was not possible because all the studies reported the data in a format that was not suitable for the evaluation. With regard to adverse events, darifenacin 7.5 mg was followed by significantly lower rates of adverse events (OR: 0.62; 95% CI, 0.47–0.81; p = 0.0005), withdrawals due to adverse events (OR: 0.30; 95% CI, 0.11–0.80; p = 0.02), dry mouth (OR: 0.46; 95% CI, 0.34–0.62; p < 0.0001), and constipation (OR: 0.62; 95% CI, 0.44–0.87; p = 0.006), compared with darifenacin 15 mg. Similarly, comparing darifenacin 15 mg and darifenacin 30 mg, darifenacin 15 mg was followed by significantly lower rates of dry mouth (OR: 0.40; 95% CI, 0.26– 0.63; p < 0.0001) and constipation (OR: 0.27; 95% CI, 0.16–0.44; p < 0.0001; Table 6; Fig. 4). 3.1.6.
3.2. 3.1.5.
Fesoterodine
Three RCTs compared different doses of fesoterodine, the most recently released anticholinergic drug [32–34]. With regard to efficacy analysis, the three papers presented the data in a format unsuitable for meta-analysis. Regarding adverse events, adverse event rate (OR: 0.68; 95% CI, 0.53– 0.87; p = 0.002), dry mouth (OR: 0.46; 95% CI, 0.36– 0.60; p < 0.0001) and vision abnormality (OR: 0.38; 95% CI, 0.17–0.86; p = 0.02) were more common in those patients receiving fesoterodine 8 mg (Table 7). Comparisons of different drugs
Darifenacin
Our systematic search identified two RCTs evaluating the efficacy of darifenacin at different doses [30,31] and two pooled analyses of RCTs [28,29],
Tables 8 and 9 summarize the efficacy and safety data from the available RCTs comparing different drugs.
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european urology 54 (2008) 740–764
Table 6 – Meta-analysis of adverse events with different doses of darifenacin RCT (no.)
Darifenacin 7.5 mg vs darifenacin 15 mg Any adverse event Withdrawal due to adverse event Dry mouth Headache Constipation Darifenacin 15 mg vs darifenacin 30 mg Withdrawal due to adverse event Dry mouth Constipation
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Difference in favor
2 2 2 2 2
886 886 886 886 886
0.62 0.30 0.46 0.90 0.62
0.47–0.81 0.11–0.80 0.34–0.62 0.50–1.64 0.44–0.87
0.0005 0.02 <0.0001 0.74 0.006
Darifenacin Darifenacin Darifenacin None Darifenacin
2 2 2
374 374 374
0.40 0.40 0.27
0.09–1.74 0.26–0.63 0.16–0.44
0.22 <0.0001 <0.00001
None Darifenacin 15 mg Darifenacin 15 mg
7.5 mg 7.5 mg 7.5 mg 7.5 mg
RCT, randomized control trial; OR, odds ratio; CI, confidence interval; NR, not reported.
Table 7 – Meta-analysis of adverse events with different doses of fesoterodine Fesoterodine 4 mg vs fesoterodine 8 mg
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
2 3 3 2 2 2 2
1116 1211 1211 1116 1116 1116 1116
0.68 0.60 0.46 0.67 1.66 0.38 0.62
0.53–0.87 0.36–1 0.36–0.60 0.39–1.15 0.86–3.20 0.17–0.86 0.20–1.92
0.002 0.05 <0.0001 0.15 0.13 0.02 0.41
Any adverse event Withdrawal due to adverse event Dry mouth Constipation Headache Vision abnormality Acute urinary retention
Difference in favor of
Fersoterodine 4 mg None Fersoterodine 4 mg None None Fersoterodine 4 mg None
RCT, randomized control trial; OR, odds ratio; CI: confidence interval.
3.2.1.
Oxybutynin versus tolterodine
Twelve RCTs compared efficacy and safety of oxybutynin and tolterodine [45–54,62,63]. Specifically, eight of these studies compared the IR formulations of the two drugs (oxybutynin 5 mg two or three times daily vs tolterodine 2 mg twice daily) [45–47,49,50,53,62,63]. With regard to the comparisons of the IR formulations, only four RCTs provided the data in a format suitable for meta-analysis of the efficacy data [47,49,50,53]. Micturitions per 24 h, volume voided per micturition, UUI episodes, and incontinence episodes per 24 h were overlapping for the IR formulations of the two drugs. Regarding adverse events, occurrence of any adverse event (OR: 2.30; 95% CI, 1.70–3.11; p 0.00001), withdrawal due to adverse events (OR: 1.82; 95% CI, 1.33–2.49; p = 0.0002), dry mouth of any grade (OR: 3.98; 95% CI, 3.16–5.02; p 0.00001), and moderate-to-severe or severe dry mouth (OR: 7.21; 95% CI, 4.50–11.52; p 0.00001) were significantly more common in those patients receiving oxybutynin IR (Table 10 and Fig. 5). A single trial compared oxybutynin ER to tolterodine IR [48]. After a 12-wk treatment, oxybutynin ER was shown to be more efficacious than tolterodine IR in terms of reduction in urgency incontinence
episodes ( p = 0.03), total incontinence episodes ( p = 0.02), and micturitions ( p < 0.0001), while all the evaluated adverse events (overall number, dry mouth, constipation, blurred vision, headache) were overlapping in the two arms [48]. Two further RCTs compared oxybutynin IR and tolterodine ER [52,54]. The larger study, which enrolled 608 patients with OAB, showed similar efficacy for both drugs in terms of reductions in the number of incontinence episodes per week and micturitions per day, but patients taking oxybutynin IR more frequently experienced dry mouth, severe dry mouth, and eye disorders [52]. Similar figures were provided in the RCT from Homma et al [54]. The format used in these two studies to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, dry mouth (OR: 2.44; 95% CI, 1.80– 3.30; p < 0.00001) and severe dry mouth (OR: 16.87; 95% CI, 3.23–87.95; p = 0.0008) were significantly more common with the IR formulation of oxybutynin. Finally, a single study compared the formulations of oxybutynin ER and tolterodine ER [51]. After a 12-wk treatment, the average number of weekly UUI episodes, which was the primary end point of the study, was overlapping between the two arms, as
752
Table 8 – Efficacy data from the randomized control trials (RCTs) comparing different drugs Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
Mean change in pads used per 24 h
Oxybutynin vs tolterodine Van Kerrebroeck 1997 [45]
Oxy IR 5 mg tid (120)
12 wk
1
NR
NR
Tolt IR 2 mg bid (120) Abrams et al 1998 [46]
Oxy IR 5 mg tid (118)
12 wk
3
NR
NR
Tolt IR 2 mg bid (118) Drutz et al 1999 [47]
Oxy IR 5 mg tid (112)
12 wk
3
NR
NR
Tolt IR 2 mg bid (109) Appell et al 2001 [48]
Oxy ER 10 mg qd(185)
12 wk
3
NR
NR
Tolt IR 2 mg bid(193) Malone–Lee et al 2001 [49]
Oxy IR 5 mg bid (188) Oxy IR 5 mg bid (116)
10 wk
3
NR
NR
8 wk
3
NR
NR
Oxy ER 10 mg qd (391) Oxy IR 3 mg tid (246)
12 wk
3
NR
NR
Oxy IR 5 mg tid (107)
+47 (31%) +38 (27%)
2.0 (17%)
+50 (33%)
2.0 (17%)
+ 34 (22%)
3.5 (27%)
NR
NR
NR
NR
1.7 (15%)
+34 (23%)
1.7 (15%)
+33 (22%)
1.8 (15%)
NR
3.75 (28%)
12 wk
3
NR
NR
6+6 wk
3
NR
NR
3
NR
NR
NR 1.7 (71%)
NR NR
1.3 (47%) NR
NR
1.7 (50%)
NR
1.7 (46%) NR NR
2.78 (76%)
3.07 (75%)
2.32 (68%)
2.52 (65%)
1.8 (62%)
NR
NR
0.9 (32%)
1.3 (54%) NR
NR
1.1 (35%) 1.4 (67%)
NR
2.2 (76%) NR
NR
3.42 (25%)
Tolt ER 4 mg qd (240) Giannitsas et al 2004 [53]
2.3 (19%) 2.7 (21%)
NR
2.6 (20%)
Tolt ER 4 mg qd (399) Homma et al 2003 [52]
+35 *
2.0 (18%)
+22.3 (18%)
2.1 (17%)
+17.2 (14%)
0.8 (9%)
+43.8 (22%)
3.82 (72%)
4.5 (73%)
3.42 (65%)
4.2 (69%)
NR
NR
NR
NR
0
NR
NR
NR
NR
NR
NR
87% *
NR
0
(crossover) Tolt IR 2 mg bid (107) Homma et al 2004 [54]
Oxy IR 3 mg tid (122)
0.9 (10%) 12 wk
Tolt ER 4 mg qd (114)
+40.6 (21%)
19.1%*
+22 *
17.9%*
+12.6 *
86% *
Oxybutynin vs propiverine Madersbacher et al 1999 [55]
Oxy IR 5 mg bid (121)
4 wk
2
NR
NR
Propi 15 mg tid (126)
1.6 (13%)
NR
1.9 (18%)
3 (24%)
NR
NR
NR
NR
NR
NR
3.1 (33%)
Oxybutynin vs trospium Halaska et al 2003 [56]
Oxy IR 5 mg bid (90)
52 wk
3
NR
NR
Trospium 20 mg bid (267)
4.2 (34%)
NR
3.5 (31%)
3.6 (33%) 3.5 (34%)
Oxybutynin vs darifenacin Zinner et al 2005 [30]
Oxy IR 5 mg tid (58)
2 wk
3
NR
NR
1.23 (13%)
NR
1.1 (13%)
NR
1.65 (122%)
Dari 15 mg qd (58)
1.14 (12%)
1.27 (16%)
1.44 (92%)
Dari 30 mg qd (58)
1.62 (18%)
1.63 (21%)
1.74 (138%)
NR
Tolterodine vs trospium Junemann et al 2000 [57]
Tolt IR 2 mg bid (60)
3 wk
1
NR
NR
Trospium IR 20 mg bid (57)
2.6*
NR
NR
NR
NR
NR
3.4*
Tolterodine vs propiverine Junemann et al 2005 [58]
Tolt IR 2 mg bid (101)
4 wk
2
NR
NR
Propi 15 mg bid (100)
3.07*
+28.43 *
3.04*
2.75*
+31.76 *
3.26*
NR
0.91*
0.43*
1.2*
0.65*
Tolterodine vs solifenacin Chapple et al 2004 [26]
Tolt IR 2 mg bid (250)
12 wk
3
NR
NR
Soli 5 mg qd (264) Soli 10 mg qd (261) Chapple et al 2005 [59]
Tolt ER 4 mg qd (599)
12 wk
3
NR
Soli 5/10 mg qd (578) Chapple et al 2007 [60]
Tolt ER 4 mg qd (599) Soli 5 mg qd (578)
Tolterodine vs fesoterodine
4 wk
3
NR
1.88 (15%)
+24.4 (20%)
2.05 (38%)
0.91 (58%)
1.14 (59%)
2.19 (17%)
+32.9 (25%)
2.85 52%)
1.41 (65%)
1.42 (59%)
NR
2.61 (20%)
+39.2 (29%)
3.07 (55%)
1.36 (63%)
1.45 (47%)
0.63 (33%)
2.24 (19%)
+31 (21%)
2.42 (41%)
0.83 (39%)
1.11 (43%)
1.19 (41%)
0.71 (35%)
2.45 (21%)
+38 (26%)
2.85 (47%)
1.42 (61%)
1.6 (58%)
1.72 (53%)
0.44 (23%)
1.47 (13%)
+24.3 (17%)
1.67 (29%)
0.91 (43%)
0.90 (42%)
0.80 (27%)
0.51 (23%)
1.71 (14%)
+28.5 (19%)
1.98 (33%)
1.22 (53%)
1.30 (53%)
1.21 (37%)
european urology 54 (2008) 740–764
Tolt IR 2 mg bid (112) Diokno et al 2003 [51]
+54 *
2.1 *
2.8 (22%)
Tolt IR 2mg bid (190) Lee et al 2002 [50]
2.7 *
NR 2.22 (87%)
3.2.2.
Oxybutynin versus propantheline
Two studies compared oxybutynin IR 5 mg three times daily and propantheline 15 mg three times daily [61,64]. The larger study evaluated 154 patients, 63 patiented receiving the oxybutynin dosage and 54 patients receiving the propantheline dosage. The propantheline arm showed a higher mean grade of improvements in visual analogue scale, counterbalanced by higher rate of adverse events in the oxybutynin arm [61]. The data from the two studies were unsuitable for meta-analysis.
2.36 (19%)
3.2.3. VV, voided volume; UUI, urge urinary incontinence; QD, once daily; BID, twice daily; TID, three times daily; NR, not reported.
+33.62 (22%) 1.88 (19%) 0.39 (23%) 1.48 (17%) Feso 8 mg (288)
753
well as the number of incontinence episodes of any type. Indeed, patients taking oxybutynin ER had a greater decrease in the mean weekly micturition frequency compared with tolterodine ER participants ( p = 0.003). Regarding adverse events, the occurrence of dry mouth was significantly less common in the patients randomized to tolterodine ER ( p = 0.02), although in most of the cases it was of mild degree [51].
NR 1.74 (70%)
1.95 (80%) 1.88 (18%) +27.72 (17%) 1.76 (17%) 0.39 (29%)
2.03 (16%) +23.64 (15%) 1.73 (14%) 0.4 (25%)
1.37 (14%)
1.35 (14%) 12 wk
3 Feso 4 mg qd (272)
Tolt ER 4 mg qd (290) Chapple et al 2007 [33]
Table 8 (Continued )
Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
Mean change in pads used per 24 h
european urology 54 (2008) 740–764
Oxybutynin versus propiverine
Two studies compared oxybutynin with propiverine [55,65]. In the larger study, the two drugs were similarly effective in terms of both bladder diary variables and urodynamic parameters, although dry mouth and severe dry mouth were less frequent in the propiverine arm [55]. 3.2.4.
Oxybutynin versus trospium
A single trial compared efficacy and safety of oxybutynin IR 5 mg twice daily and trospium IR 20 mg twice daily [56]. This study is of particular clinical relevance because the treatments were continued for 52 wk. This study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions and in the number of of urgency episodes per 24 h, and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. The occurrence of any adverse event ( p = 0.045) and dryness of the mouth ( p = 0.021) were significantly less common in those patients receiving trospium [56]. 3.2.5.
Oxybutynin versus darifenacin
Zinner et al evaluated the efficacy of oxybutynin IR and darifenacin in a four-way crossover study [30]. With regard to efficacy, darifenacin 15 mg once daily was comparable to oxybutynin in terms of the improvement in OAB symptoms, with both drugs similarly reducing the number of incontinence episodes per week and the number of micturitions and urgency episodes per day after a 2-wk treat-
754
Table 9 – Safety data from the randomized control trials (RCTs) comparing different drugs Reference
Dose (no. of cases)
Treatment duration
Jadad score
Adverse events rate
Withdrawal due to adverse events
Dry mouth
Moderate-to-severe or severe dry mouth
Headache
Constipation
AUR
NR
Vision abnormality
Oxybutynin vs propantheline Thuroff et al 1991 [61]
Oxy IR 5 mg tid (63)
4 wk
1
Propantheline 15 mg tid (54)
63%
3%
48%
27%
1%
3%
44%
5%
31%
18%
5%
0
3%
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR 2%
4%
Oxybutynin vs tolterodine Van Kerrebroeck et al 1997 [45]
Oxy IR 5 mg tid (120)
12 wk
1
Tolt IR 2 mg bid (120) Abrams et al 1998 [46]
Oxy IR 5 mg tid (118)
12 wk
3
Tolt IR 2 mg bid (118) Drutz et al 1999 [47]
Oxy IR 5 mg tid (112)
12 wk
3
Tolt IR 2 mg bid (109) Appell et al 2001 [48]
Oxy ER 10 mg qd (185)
12 wk
3
93%
21%
78%
23%
63%
11%
38%
3% NR
97%
17%
86%
89%
8%
50%
90%
21%
69%
44%
10%
78%
6%
30%
9%
15%
NR
8%
7%
3%
9%
6%
3%
1%
NR
5%
NR
28% 33%
Malone-Lee et al 2001 [49]
Oxy IR 5 mg bid (188)
10 wk
3
81%
15%
61%
15%
10%
6%
8 wk
3
Tolt IR 2mg bid (190) Lee et al 2002 [50]
Oxy IR 5 mg bid (116)
69%
12%
37%
4%
11%
8%
NR
16%
63%
28%
5%.
NR
NR
NR
10%
35%
9%
4%
49%
15%
NR
NR
NR
NR
NR
NR
60%
17% NR
NR
Tolt IR 2 mg bid (112) Leung et al 2002 [62]
Oxy IR5 mg bid (53)
10 wk
3
Tolt IR 2 mg bid (53) Diokno et al 2003 [51]
Oxy ER 10 mg qd (391)
12 wk
3
NR
Tolt ER 4 mg qd (399) Homma et al 2003 [52]
Oxy IR 3 mg tid (244)
12 wk
3
NR
Tolt ER 4 mg qd (239) Homma et al 2004 [54]
Oxy IR 3 mg tid (122)
12 wk
3
NR
5%
30%
7%
6%
6%
5%
22%
5%
6%
8%
17%
54%
8%
4%
6%
3%
3%
5%
33%
0.4%
4%
7%
0.4%
1%
NR
61%
3%
NR
NR
NR
NR
37%
0
83%
83%
NR
NR
NR
58%
50%
28%
NR
NR
NR
NR
NR
NR
18%
NR
83%
NR
15%
10%
NR
22%
Tolt ER 4 mg qd (114) Altan-Yacioglu et al 2005 [63]
Oxy IR 5 mg tid (24)
4 wk
2
NR
5%
NR
Tolt IR 2 mg bid (28)
43%
Oxybutynin vs propiverine Madersbacher et al 1999 [55]
Oxy IR 5 mg bid (145)
4 wk
2
Propi 15 mg tid (149) Abrams et al 2006 [37]
Oxy IR 5 mg tid (41)
72% 64%
2 wk
3
93%
27%
Propi 15 mg tid (42)
81%
52%
7%
24%
33%
Propi 20 mg qd (38)
79%
34%
0
16%
24%
9%
NR
Oxybutynin vs trospium Halaska et al 2003 [56]
Oxy IR 5 mg bid (90)
52 wk
3
Trospium 20 mg bid (267)
77%
7%
50%
68%
4%
33%
NR
NR
NR
4%
6% 3%
Oxybutynin vs darifenacin Zinner et al 2005 [30]
Oxy IR 5 mg tid (76)
5%
36%
Dari 15 mg qd (76)
2 wk
0
13%
10%
0
Dari 30 mg qd (76)
1%
34%
21%
0
NR
29%
3
NR
NR
8%
NR
3%
Tolterodine vs trospium Junemann et al 2000 [37]
Trospium IR 20 mg bid (76)
3 wk
1
Tolt IR 2 mg bid (77)
34% 32%
NR
NR
NR
NR
NR
NR
NR
NR
NR
7%
27%
Tolterodine vs propiverine Junemann et al 2005 [58]
Tolt IR 2 mg bid (101)
4 wk
2
Propi 15 mg bid (100)
43%
6%
19%
42%
6%
20%
9%
Tolterodine vs solifenacin Chapple et al 2004 [26]
2%
19%
Soli 5 mg qd (279)
Tolterodine IR 2 mg bid (263)
12 wk
3%
14%
7%
4%
Soli 10 mg qd (268)
3%
22%
8%
6%
3
NR
NR
NR
3%
NR
1%
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8% 8%
Tolt IR 2 mg bid (193)
2%
5% NR
4%
NR NR
NR 1%
2%
Headache
34% 5% 58%
17%
22%
3%
3%
NR, not reported; qd, once daily; bid, twice daily; tid, three times daily.
Feso 8 mg qd (282)
12 wk
3.2.8.
Feso 4 mg qd (272)
Tolt ER 4 mg qd (290) Chapple et al 2007 [33]
Soli 5 mg qd (593) Tolterodine vs fesoterodine
Tolterodine versus propiverine
A single study compared tolterodine IR 2 mg bid and propiverine 15 mg bid [58]. The study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions, number of UUI episodes per 24 h, and number of incontinence episodes per 24 h and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. Similarly, the number of adverse events was comparable in both treatment groups [58].
3
50%
3% 3%
4 wk Tolt ER 4 mg qd (607) Chapple et al 2007 [60]
Soli 5/10 mg qd (578)
50%
3% 3% 3
18%
30% 3%
15%
24% 3% NR 3 Chapple et al 2005 [59]
Tolt ER 4 mg qd (599)
12 wk
Withdrawal due to adverse events Jadad score Treatment duration Dose (no. of cases)
Table 9 (Continued )
Tolterodine versus trospium
A single RCT, published as congressional abstract, compared tolterodine IR 2 mg twice daily and trospium IR 20 mg twice daily. The study showed similar efficacy and similar adverse event rates for the two drugs [57]. The lack of a publication in a peer-reviewed journal does not permit the evaluation of the power of the statistical analysis for the comparisons between tolterodine and trospium. 3.2.7.
Adverse events rate
Dry mouth
Moderate-to-severe or severe dry mouth
3.2.6.
Reference
755
ment. Concerning adverse events, dry mouth was significantly more common in the oxybutynin arm than in the darifenacin 15 mg arm ( p < 0.05), while overlapping rates occurred between the oxybutynin 30 mg and darifenacin 30 mg arms. On the other hand, constipation was significantly more frequent in those patients treated by darifenacin 30 mg, but it occurred in similar percentages in the oxybutynin 15 mg arm and the darifenacin 15 mg arm [30].
4% 1% 4%
2.2% 0.3%
0.3% 0
3%
3%
3%
1%
NR NR 1%
2% NR 2%
6%
AUR Constipation
Vision abnormality
european urology 54 (2008) 740–764
Tolterodine versus solifenacin
Two studies reported data on the comparisons between solifenacin and tolterodine [26,59,60]. The first study, designed for the registration of solifenacin, compared solifenacin 5-mg and solifenacin 10-mg to tolterodine IR 2 mg twice daily or placebo [26]. However, the most interesting data came from the STAR study, whose primary end point tested the non-inferiority of solifenacin compared to tolterodine ER [59]. Solifenacin 5 mg and solifenacin10 mg were not inferior to tolterodine ER with regard to change from baseline in the following ways: mean number of micturitions per 24 h ( p = 0.004 for noninferiority), reduction in number of urgency episodes per day ( p < 0.05), urge incontinence episodes per day ( p < 0.01), incontinence episodes per day ( p < 0.01), and pad usage ( p < 0.002). Dry mouth ( p = 0.02) and constipation ( p = 0.002) were significantly more common in the solifenacin arm, although they were mainly of mild or moderate severity [59]. A secondary analysis of the same trial was recently published, limiting all the evaluation
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european urology 54 (2008) 740–764
Table 10 – Meta-analysis of randomized control trials (RCTs) comparing immediate-release (IR) formulations of oxybutynin and tolterodine Oxybutynin IR vs tolterodine IR
RCT (no.)
Participants (no.)
4 3 1
1041 813 378
0.02 1.89 0.50
0.33–0.36 7.73–11.51 0.11–1.11
0.92 0.70 0.11
None None None
2
449
0.11
0.54–0.32
0.61
None
Micturitions per 24 h Volume voided per micturition Urgency urinary incontinence episodes per 24 h Incontinence episodes per 24 h
Adverse events
Adverse events Withdrawals due to adverse events Dry mouth Moderate to severe or severe dry mouth Headache Constipation Vision abnormality
WMD
95% CI, WMD
Test for overall effect ( p value)
Difference in favor
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
5 6
1181 1409
2.30 1.82
1.70–3.11 1.33–2.49
<0.00001 0.0002
Tolterodine IR Tolterodine IR
6 4
1355 894
3.98 7.21
3.16–5.02 4.50–11.52
<0.00001 <0.00001
Tolterodine IR Tolterodine IR
3 1 2
826 378 430
0.83 0.68 1.39
0.52–1.34 0.30–1.50 0.69–2.82
0.45 0.33 0.36
None None None
UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.
during the first 4 wk of active treatment before solifenacin dose escalation, showed similar efficacy for solifenacin 5 mg and tolterodine ER with regard to reduction in number of micturitions per 24 h and most of the secondary end points [60]. In the two RCTS comparing solifenacin and tolterodine [26,59] the format used to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, the meta-analysis, although impaired by the use of different doses of solifenacin and different formulations of tolterodine, suggests that only constipation (OR: 2.78; 95% CI, 1.70–4.54; p < 0.0001) was more common in the solifenacin arm (Table 11). 3.2.9.
Tolterodine versus fesoterodine
A single RCT compared fesoterodine to tolterodine [33]. The trial was designed to compare the fesoterodine 4 mg and fesoterodine 8 mg to placebo and included an active control arm in which the
patients were treated with tolterodine ER 4 mg. Fesoterodine 8 mg outperformed tolterodine 4 mg with regard to the median change from baseline in number of UUI episodes ( p < 0.05) and volume voided per micturition ( p < 0.05), while similar efficacy was shown for fesoterodine 4 mg and tolterodine 4 mg. Fesoterodine 4 mg and tolterodine ER 4 mg had overlapping statistics with regard to complications and adverse events, while fesoterodine 8 mg was followed by significantly higher rates of dry mouth ( p < 0.0001) and dry eye ( p = 0.02), compared with tolterodine 4 mg [33]. 3.3.
Comparison of different routes of administration
Tables 12 and 13 summarize the efficacy and safety data from the available RCTs comparing different routes of administration of anticholinergic drugs. Two RCTs compared the oral and transdermal routes of administration of oxybutynin [64,65].
Table 11 – Meta-analysis of randomized control trials (RCTs) comparing solifenacin and tolterodine Solifenacin 5 mg and solifenacin 10 mg vs tolterodine ER Withdrawals due to adverse events Dry mouth Constipation Vision abnormality CI, confidence interval; OR, odds ratio.
RCT
Participants
OR
95% CI, OR
Test for overall effect ( p value)
2 2 2 2
1987 1987 1987 1987
1.27 1.21 2.78 1.34
0.74–2.18 0.97–1.50 1.70–4.54 0.68–2.64
0.39 0.08 <0.0001 0.40
Difference in favor
None None Tolterodine ER None
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Table 12 – Efficacy data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference
Dosage (no. of cases)
Treatment duration
Davila et al 2001 [64]
Oxy IR 2.5 mg bid or tid (38) Oxy TDS twice a week (38)
Dmochowski et al 2003 [65]
Tolt ER 4 mg qd (123) Oxy TDS 3.9 mg qd (121)
Jadad score
4 wk
3
12 wk
3
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
NR
2.2 (18%) 1.9 (15%)
Mean change in incontinence episodes per 24 h
NR
0.8 (23%) 0.4 (17%)
+29 (19%) +32 (19%)
3.2 (64%) 2.9 (62%)
VV, voided volume; NR, not reported; qd: once daily; bid: twice daily; tid: three times daily. Placebo transdermal system was used in those patients taking oral anticholinergic drugs.
Table 13 – Safety data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference
Dosage (no. of cases)
Davila et al 2001 [64]
Oxy IR 2.5 mg bid or tid (38) Oxy TDS twice a week (38)
Dmochowski et al 2003 [65]
Tolt ER 4 mg qd (123) Oxy TDS 3.9 mg qd (121)
Treatment Jadad Systemic Localized Withdrawal Dry Constipation duration score adverse application due to mouth event site adverse (%) rate reaction* events
AUR
Vision abnormality
4 wk
3
NR
23% 38%
NR
82% 39%
50% 21%
34% 24%
24% 18%
12 wk
3
24% 19%
5.7% 26%
2% 11%
7% 4%
6% 3%
NR
NR
AUR, acute urinary retention; NR, not reported; qd, once daily; bid, twice daily; tid, three timse daily. *
Placebo transdermal system was used in those patients taking oral anticholinergic drugs.
Specifically, Davila et al compared the efficacy and safety of oxybutynin IR at different doses administered orally or transdermally [65], while Dmochowski et al evaluated transdermal oxybutynin 3.9 mg once daily and tolterodine ER 4 mg once daily [65]. Meta-analysis of efficacy showed similar reduction in the number of incontinence episodes per 24 h (WMD: 0.05; 95% CI, 0.58–0.67; p = 0.88). Dry mouth (OR: 3.67; 95% CI, 1.73–7.81; p = 0.0007) and constipation (OR: 2.78; 95% CI, 1.27–6.08; p = 0.01) were significantly more common in those patients taking the drug orally, while localized application side effects (OR: 0.26; 95% CI, 0.14– 0.49; p < 0.0001) and withdrawal due to adverse events (OR: 0.14; 95% CI, 0.03–0.62; p = 0.01) were significantly more frequent in those patients receiving active transdermal formulations (Table 14; Fig. 6).
3.4.
Publication bias
‘‘Funnel plots’’ of the studies used in this metaanalysis were generated for all of the evaluated comparisons. Only four studies [15,21,45,62] lay outside the 95% CI with an even distribution around the vertical, suggesting little evidence of publication bias (plots not shown).
4.
Discussion
Due to the large number of drugs available on the market, the selection of the most appropriate one for every single patient might be quite a complex task. The choice of the first drug to be used, the selection of the most appropriate dosage, formulation, and route of administration, the criteria for selection of a
Table 14 – Meta-analysis of adverse events with oral and transdermal formulations of anticholinergic drugs Oral oxybutynin vs transdermal oxybutynin
RCT (no.)
Participants (no.)
OR
95% CI, OR
Systemic adverse event Localized application site reactions Withdrawals due to adverse events Dry mouth Constipation Vision abnormality
1 2 1 2 2 1
244 320 244 320 320 76
1.31 0.26 0.14 3.67 2.78 1.37
0.71–2.43 0.14–0.49 0.03–0.62 1.73–7.81 1.27–6.08 0.45–4.17
RCT, randomized control trials; OR, odds ratio; CI, confidence interval.
Test for overall effect ( p value) 0.38 <0.0001 0.01 0.0007 0.01 0.57
Difference favors
None Oral Oral Transdermal Transdermal None
758
european urology 54 (2008) 740–764
Fig. 5 – Forest plots of adverse events after oxybutynin immediate release (IR) or tolterodine IR. (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth of any severity; (D) moderate to severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
european urology 54 (2008) 740–764
759
Fig. 6 – Forest plots of adverse events after oral and transdermal formulations of anticholinergic drugs. (A) Localized application site reactions; (B) withdrawal due to adverse events; (C) dry mouth of any severity; (D) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
second anticholinergic drug in case of insufficient efficacy or intolerable adverse events, and, finally, costs are some of the most important issues that should be evaluated. The data from our systematic review and metaanalyses showed that tolterodine IR had a more favorable profile of adverse events than oxybutynin IR, while the ER formulations of the two drugs had
similar efficacy and safety profiles. In all the comparisons among IR and ER formulations, the latter showed some advantages, either in terms of efficacy (tolterodine IR vs oxybutynin ER; tolterodine IR vs tolterodine ER) or safety (oxybutynin IR vs oxybutynin ER; oxybutynin IR vs tolterodine ER; oxybutynin IR vs darifenacin). With regard to solifenacin, a single RCT demonstrated the non-
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inferiority of solifenacin compared to tolterodine ER [59], while our meta-analysis showed similar rates of adverse events, with the exception of constipation, which was more common in the solifenacin arm. A single trial is currently available on fesoterodine, suggesting that the new drug might be more efficacious than tolterodine ER. With regard to the routes of administration, the transdermal route does not seem to provide any significant advantage compared to the oral intake, considering the higher rate of side effects from localized application and withdrawal due to adverse events. Providing clear indications for the clinical practice, however, is quite difficult. With regard to the selection of the first drug to use in naı¨ve patients, the RCTs comparing different drugs often enrolled a large number of patients who had previously been treated with other drugs. Considering this issue as a mandatory starting point, according to our data, the first drug which might be used in naı¨ve patients is oxybutynin ER, tolterodine ER 4 mg, solifenacin 5 mg, or solifenacin 10 mg. Similarly, darifenacin 15 mg and fesoterodine 4 mg might be considered as valuable options, but further evaluation is needed, and further RCTs are ongoing. In case of insufficient clinical efficacy, the choice of the second drug cannot really be based on evidence because, to our knowledge, no randomized trials were aimed at identifying the most efficient drug in the case of lack of success with some of the other first-line choices. Making assumptions from the available data, in case of lack of efficacy of the first-line ER drug, fesoterodine 8 mg and solifenacin 10 mg might be a possible option, due to the results of the two available trials comparing fesoterodine or solifenacin to tolterodine ER [26,33,59], although an increased rate of adverse events must be taken into account. In case of failure of the first-line ER drug due to intolerable adverse events, the availability of clear evidence-based recommendations is limited. In case of dry mouth, a transdermal formulation might provide some advantages compared to the oral one, and some authors suggested that it might be used as first-line therapy [66], but the metaanalysis suggested that localized application site reactions are very common and might significantly impact the patients’ compliance with this formulation. On the other hand, if constipation is the most bothersome adverse event, it can be managed by shifting from solifenacin to tolterodine ER. However, despite the lack of evidence, it might be wise to suggest that the patients take one of the other oral drugs before starting more invasive treatments, but controlled studied are needed to provide evidence-
based answers to these clinical questions. Conversely, those patients taking IR formulations of anticholinergic drugs without successful results might be offered dose titration in case the patients did not experienced significantly adverse events, but ER formulations might be the preferred choice. The overall quality of the randomized controlled trials available in the field of OAB was good, with most of the RCTs having a Jadad score 3. However, almost all the trials evaluated short-term therapy (mostly 12 wk), with only a single study continuing the drug therapy for 52 wk [56], and some adverse events, such as the impact on cognitive function, should be better evaluated. Moreover, almost all of the studies provided efficacy data derived from bladder diaries [67]; a more suitable evaluation should also include subjective outcomes, such as the so-called patient-reported outcomes [7], which are lacking in most of the studies. However, virtually all the evidence has been derived from pharmaceutical company–sponsored trials, which, to date, have been the only way to realize those very expensive, good-quality, large-scale trials. However, the studies’ designs reflect the needs of the companies for registrational studies, rather than addressing the questions that are more relevant for clinical practice. According to the criteria of the Overview Quality Assessment Questionnaire (OQAQ) [68], our systematic review can be considered to be a goodquality review. However, due to the limitations of the Review Manager software, which allows the evaluation of continuous variables only if they are expressed as means and standard deviations, it was not possible to perform meta-analysis for some clinically relevant efficacy outcomes due to the lack of data in the published reports. Although all the authors of the RCTs were contacted with the aim of obtaining the needed data in the appropriate format, the attempt was not successful in most cases.
5.
Conclusions
Many of the available RCTs in the field of muscarinic receptor antagonists for overactive bladder are of good methodological quality. ER formulations should be preferred to the IR formulations due to the more favorable profile of efficacy and adverse events. With regard to IR formulations, dose escalation might yield some improvements in the efficacy, but at the cost of a significant increase in the rate of adverse events. More clinical studies are needed to determine which of the available drugs should be used as first-, second-, and third-line treatments.
european urology 54 (2008) 740–764
Author contributions: Walter Artibani had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Novara, Ficarra, Artibani. Acquisition of data: Galfano, Secco, D’Elia. Analysis and interpretation of data: Novara, Galfano, Ficarra, Artibani. Drafting of the manuscript: Novara. Critical revision of the manuscript for important intellectual content: Galfano, Secco, D’Elia, Cavalleri, Ficarra, Artibani. Statistical analysis: Novara. Obtaining funding: None. Administrative, technical, or material support: Cavalleri. Supervision: Ficarra, Artibani. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr Novara has been a consultant, investigator, or speaker for Bioxell, GlaxoSmithKleine, Pfizer Inc., and Pierre Fabre. Dr Galfano has been a consultant or investigator for Astellas, Bayer, Bioxell, Novartis, and Pfizer Inc. Prof Ficarra has been a consultant, investigator or speaker for Bioxell, Novartis, and Pfizer Inc. Prof Artibani has been a consultant, investigator, or speaker for Astellas, Bayer, Bioxell, Novartis, Pfizer Inc., Pierre Fabre, and UCB. Drs Secco, D’Elia, and Cavalleri have nothing to disclose. Funding/Support and role of the sponsor: None.
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[24] Swift S, Garely A, Dimpfl T, Payne C, The Tolterodine Study Group. A new once-daily formulation of tolterodine provides superior efficacy and is well tolerated in women with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:50–4. [25] Cardozo L, Lisec M, Millard R, et al. Randomized, doubleblind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172:1919–24. [26] Chapple CR, Rechberger T, Al-Shukri S, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004;93:303–10. [27] Chapple CR, Cardozo L, Steers WD, Govier FE. Solifenacin significantly improves all symptoms of overactive bladder syndrome. Int J Clin Pract 2006;60:959–66. [28] Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int 2005;95:993–1001. [29] Foote J, Glavind K, Kralidis G, Wyndaele J-J. Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist. Eur Urol 2005;48:471–7. [30] Zinner N, Tuttle J, Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J Urol 2005;23:248–52. [31] Hill S, Khullar V, Wyndaele JJ, Lheritier K, The Darifenacin Study Group. Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose study. Int Urogynecol J Pelvic Floor Dysfunct 2006;17:239–47. [32] Nitti V, Wiatrak M, Kreitman L, Lipsitz D. Fesoterodine is an effective antimuscarinic for patients with overactive bladder (OAB): results of a phase 2 trial. ICS annual meeting; 2005. Abstract 306. Available at https://www. icsoffice.org/publications/2005/PDF/0306.PDF. [33] Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007; 52:1204–12, Corrigendum. Eur Urol 2008;53:1319. [34] Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety, and tolerability of fesoterodine for overactive bladder syndrome. J Urol 2007;178:2488–94. [35] Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS, OROS Oxybutynin Study Group. Once-daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. Urology 1999;161: 1809–12. [36] Birns J, Lukkari E, Malone-Lee JG. A randomized controlled trial comparing the efficacy of controlled-release oxybutynin tablets (10 mg once daily) with conventional oxybutynin tablets (5 mg twice daily) in patients whose symptoms were stabilized on 5 mg twice daily of oxybutynin. BJU Int 2000;85:793–8.
[37] Abrams P, Cardozo L, Chapple C, Serdarevic D, Hargreaves K, Khullar V, The 1032 Study Group. Comparison of the efficacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome. Int J Urol 2006;13:692–8. [38] Burton G. A randomized crossover trial comparing oxybutynin taken three times a day or taken ‘‘when needed’’. Neurourol Urod 1994;13:351–2, abstract. [39] Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Curr Med Res Opin 2002;18:177–84. [40] Mazur D, Wehnert J, Dorschner W, Schubert G, Herfurth G, Alken RG. Clinical and urodynamic effects of propiverine in patients suffering from urgency and urge incontinence. A multicentre dose-optimizing study. Scand J Urol Nephrol 1995;29:289–94. [41] Gittelman MC, Kaufman J. Solifenacin succinate 10 mg once daily significantly improves symptoms of overactive bladder. Presented at the 17th International Federation of Gynecology and Obstetrics World Congress, Abstract 111. November 2–7, 2003; Santiago, Chile. [42] Gittelman M. The efficacy and safety of solifenacin in adults with overactive bladder: a multicenter, placebocontrolled study. Int J Gynaecol Obstetr 2003;83(Suppl 3):94. [43] Staskin DR, Te AE. Short- and long-term efficacy of solifenacin treatment in patients with symptoms of mixed urinary incontinence. BJU Int 2006;97:1256–61. [44] Cardozo L, Castro-Diaz D, Gittelman M, Ridder A, Huang M. Reductions in overactive bladder-related incontinence from pooled analysis of phase III trials evaluating treatment with solifenacin. Int Urogynecol J Pelvic Floor Dysfunct 2006;17:512–9. [45] Van Kerrebroeck EV, Serment G, Dreher E. Clinical efficacy and safety of tolterodine compared to oxybutynin in patients with overactive bladder. Neurourol Urod 1997;16:478–9, abstract #91. [46] Abrams P, Freeman R, Anderstro¨m C, Mattiasson A. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81:801–10. [47] Drutz HP, Appell RA, Gleason D, Klimberg I, Radomski S. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:283–9. [48] Appell RA, Sand P, Dmochowski R, et al. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc 2001;76:358–63. [49] Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001;165:1452–6. [50] Lee JG, Hong JY, Choo MS, et al. Tolterodina: as effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder. Int J Urol 2002;90:247–52.
european urology 54 (2008) 740–764
[51] Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003;78:687–95. [52] Homma Y, Paick JS, Lee JG, Kawabe K, Japanese, Korean Tolterodine Study Group. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU Int 2003;92:741–7. [53] Giannitsas K, Perimenis P, Athanasopoulos A, Gyftopoulos K, Nikiforidis G, Barbalias G. Comparison of the efficacy of tolterodine and oxybutynin in different urodynamic severity grades of idiopathic detrusor overactivity. Eur Urol 2004;46:776–83. [54] Homma Y, Kawabe K. Health-related quality of life of Japanese patients with overactive bladder treated with extended-release tolterodine or immediate-release oxybutynin: a randomized, placebo-controlled trial. World J Urol 2004;22:251–6. [55] Madersbacher H, Halaska M, Voigt R, Alloussi S, Ho¨fner K. A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84:646–51. [56] Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol 2003;20:392–9. [57] Junemann KP, Al-Shukri S. Efficacy and tolerability of trospium chloride and tolterodine in 234 patients with urgesyndrome: a double blind, placebo-controlled, multicentre clinical trial. Neurourol Urodynam 2000;488–90, abstract. [58] Ju¨nemann K-P, Halaska M, Rittstein T, et al. Propiverine versus tolterodine: efficacy and tolerability in patients with overactive bladder. Eur Urol 2005;48:478–82. [59] Chapple CR, Martinez-Garcia R, Selvaggi L, et al. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating
Editorial Comment on: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder Rufus Cartwright Department of Urogynaecology, King’s College Hospital, London, UK [email protected] Previous meta-analyses and evidence-based guidelines concerning antimuscarinic medications for overactive bladder (OAB) have conflicting
[60]
[61]
[62]
[63]
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[68]
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overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48:464–70. Chapple CR, Fianu-Jonsson A, Indig M, et al. Treatment outcomes in the STAR study: a subanalysis of solifenacin 5 mg and tolterodine ER 4 mg. Eur Urol 2007;52:1195– 1203. Thu¨roff JW, Bunke B, Ebner A, et al. Randomized, doubleblind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 1991;145:813–6. Leung HY, Yip SK, Cheon C, et al. A randomized controlled trial of tolterodine and oxybutynin on tolerability and clinical efficacy for treating Chinese women with an overactive bladder. BJU Int 2002;90:375–80. Altan-Yaycioglu R, Yaycioglu O, Aydin Akova Y, Guvel S, Ozkardes H. Ocular side-effects of tolterodine and oxybutynin, a single-blind prospective randomized trial. Br J Clin Pharmacol 2005;59:588–92. Davila GW, Daugherty CA, Sanders SW, Transdermal Oxybutynin Study Group. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 2001;166:140–5. Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders SW, Transdermal Oxybutynin Study Group. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 2003;62:237–42. Cartwright R, Cardozo L. Transdermal oxybutynin: sticking to the facts. Eur Urol 2007;51:907–14. Colli E, Parazzini F, Olivieri L, et al. Number of daytime micturitions and volume voided per micturition in the evaluation of efficacy of drugs for overactive bladder: findings from randomized clinical trials. Eur Urol 2007;52:525–30. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991;44:1271–8.
recommendations with no consensus about appropriate first-line or second-line therapy [1–3]. With an increasing number of available agents and formulations licensed, the choice of antimuscarinic for patients with OAB has become complicated. The authors of this paper [4] have taken on the Herculean task of reviewing and analysing existing randomised controlled trials (RCTs) that might potentially help clinicians to make an evidencebased choice. So, is it a case of cleaning the Augean stables? The good news is clearly that existing RCTs are generally of high methodological quality.
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It is lamentable, however, that even within the limited scope of the objective outcomes considered in this review, many trials are still reporting data in a format that is not amenable to meta-analysis. This difficulty in comparing and assimilating data from different trials is compounded by the wide variety of outcome measures employed, some of which are of limited relevance to patients. The increased regulation in the European Union puts large, multicentre drug trials out of the reach of all but the most organised and determined bodies. As the authors note, most available antimuscarinic data are, therefore, from industry-led trials. There may be a conflict between so-called ‘‘experimercials’’ [5], aiming to increase market share, and the needs of clinicians in providing targeted interventions. The key question, which remains largely unanswered for this class of medication, regards long-term subjective efficacy for different subgroups of OAB patients. As efficacious pharmaceutical agents from different classes are developed and as different modalities of treatment become established, it is to be hoped that long-term, head-to-head studies will help define the roles of different antimuscarinic medications and formulations more clearly.
References [1] Hay-Smith J, Herbison P, Ellis G, Morris A. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database of Systematic Reviews;2005. Abstract CD005429. [2] Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005; 48:5–26. [3] National Institute for Health and Clinical Excellence. Urinary incontinence: the management of urinary incontinence in women [clinical guideline]. Available at: http:// guidance.nice.org.uk/CG40. Accessed June 2008. [4] Novara G, Galfano A, Secco S, et al. A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol 2008;54:740–64. [5] Brownlee S. Medicine. In: Blum D, Knudson M, Henig RM, editors. A Field Guide for Science Writers: The Official Guide of the National Association of Science Writers. 2nd ed. New York, NY: Oxford University Press; 2006. p. 155–61.
DOI: 10.1016/j.eururo.2008.06.081 DOI of original article: 10.1016/j.eururo.2008.06.080
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Review – Neuro-urology
A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder Giacomo Novara a, Antonio Galfano b, Silvia Secco b, Carolina D’Elia b, Stefano Cavalleri b, Vincenzo Ficarra b, Walter Artibani b,* a b
I.R.C.C.S. Istituto Oncologico Veneto (I.O.V.), Padova, Italy Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Italy
Article info
Abstract
Article history: Accepted June 25, 2008 Published online ahead of print on July 9, 2008
Context: Anticholinergic drugs are commonly used in patients with overactive bladder (OAB) who do not achieve symptom relief and quality of life improvement with conservative management. Several drugs, with different doses, formulations, and routes of administration are currently available, making the choice quite difficult. Objective: To evaluate efficacy and safety of different doses, formulations, and route of administration of the available anticholinergic drugs. Evidence acquisition: A systematic review of the literature was performed in August 2007 using Medline, Embase, and Web of Science. Efficacy (micturitions per 24 h, volume voided per micturition, urgency urinary incontinence episodes per 24 h, incontinence episodes per 24 h) and safety (mainly, adverse events and withdrawal rates) end points were evaluated in the randomized control trials (RCTs) assessing the role of anticholinergic drugs in non-neurogenic OAB. Meta-analysis of RCTs was conducted using the Review Manager software 4.2 (Cochrane Collaboration). Evidence synthesis: Our systematic search identified 50 RCTs and three pooled analyses. Tolterodine immediate release (IR) had a more favorable profile of adverse events than oxybutynin IR. Regarding different dosages of IR formulations, dose escalation might yield some limited improvements in the efficacy but at the cost of significant increase in the rate of adverse events. In the comparisons between IR and extended-release (ER) formulations, the latter showed some advantages, both in terms of efficacy and safety. With regard to the route of administration, use if a transdermal route of administration does not provide significant advantage over an oral one. Conclusion: Many of the available RCTs have good methodological quality. ER formulations should be preferred to the IR ones. With regard to IR formulations, dose escalation might yield some improvements in the efficacy with significant increase in the AE. More clinical studies are needed to indicate which of the drugs should be used as first-, second-, or third-line treatment. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Overactive bladder Urgency frequency syndrome Detrusor overactivity Muscarinic receptor antagonist Darifenacin Emepronium Fesoterodine Oxybutynin Propantheline Propiverine Solifenacin Tolterodine Trospium
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
* Corresponding author. Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV Floor, Via Giustiniani 2, 35128, Padua, Italy. Tel. +39 049 8212720; Fax: +39 049 8218757. E-mail address: [email protected] (W. Artibani).
0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.06.080
european urology 54 (2008) 740–764
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Fig. 1 – Flow-chart of meta-analysis. RCTs, randomized control trials, OAB, overactive bladder.
1.
Introduction
Overactive bladder (OAB) is a highly prevalent condition [1,2] with enormous related costs per year [3,4]. First-line treatments for OAB include lifestyle modifications, behavioral therapy, pelvic floor muscle training, and bladder training. Antimuscarinic drugs are the first-line drug therapy, while other therapeutic options, such as botulinum toxin injection, neuromodulation, or surgical interventions are used in a smaller percentage of patients who are non-responders to drug therapies [5,6]. Several antimuscarinic drugs are on the market, including oxybutynin, tolterodine, propiverine, trospium, the recently released solifenacin and darifenacin, and fesoterodine, which was the last one to receive the European Medicines Evaluation Agency (EMEA) marketing authorization in 2006. Moreover, some drugs such as oxybutynin, tolterodine, propiverine, or trospium are available both in immediate-release (IR) and extended-release (ER) formulations, while oxybutynin is also available in a sustained-delivery patch for transdermal administration [7]. Two meta-analyses evaluated the efficacy of the anticholinergic drugs in comparison to placebo, showing that the use of these drugs results in statistically significant improvements in symptoms and quality of life [8,9]. To date, however, the clinical data available on the active comparisons of different drugs, formulations, and routes of administration are more limited. Specifically, a Cochrane meta-analysis based on a systematic review performed in January 2002 demonstrated that tolter-
odine was as effective as, but better tolerated than, oxybutynin; moreover, ER formulations of oxybutynin and/or tolterodine were shown to cause a lower risk of dry mouth compared to the IR formulations. Comparing head-to-head the ER formulations, xerostomia was less common in those patients receiving tolterodine [10]. In a more recent meta-analysis which mainly focused on placebo-controlled trials, Chapple et al reported some data on the trials of drugs which provided active drug controls. Solifenacin was shown to be more effective than tolterodine IR in terms of reduction of both urgency episodes and number of micturitions, while oxybutynin ER was shown to be more effective than tolterodine ER, in terms of reduction of incontinence episodes. Finally, oxybutynin IR 15 mg once daily, solifenacin 5 mg once daily, and solifenacin 10 mg once daily were more effective than tolterodine IR in increasing the volume voided per micturitions [8]. The purpose of the present systematic review and meta-analysis was to evaluate all the clinical data derived from randomized controlled trials in order to assess the efficacy and safety of different doses, formulations, and routes of administration of the currently available anticholinergic drugs, as well as head-to-head comparisons of different drugs. 2.
Methods
The systematic review of the literature was performed in August 2007 using the Medical Literature Analysis and
Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in volume voided per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
742
Table 1 – Efficacy data from the randomized control trials (RCTs) comparing different doses and formulations of oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine Mean change in pads used per 24 h
Oxybutynin Nilsson et al 1997 [13]
Oxy IR 5 mg bid (17)
8 wk
1
NR
NR
Oxy ER 10 mg qd (16) Versi et al 2000 [14]
Oxy IR different doses (115)
2.8 (24%)
NR
NR
NR
NR
variable
3
NR
NR
NR
Oxy ER different doses (111) Barkin et al 2004 [15]
Oxy IR different doses (41)
6 wk
2.4 (22%)
+40 (18%)
1.3 (41%)
1.8 (16%)
+25 (14%)
1.0 (30%)
0.8 (7%)
+17.1 (8%)
1.8 (37%)
Oxy ER 10 mg qd (77)
1.1 (11%)
+20.5 (10%)
1.5 (34%)
Oxy ER 15 mg qd (83)
1.5 (14%)
+44.6 (21%)
2.0 (46%)
3
NR
NR
Oxy ER different doses (53) Corcos et al 2005 [16]
Oxy ER 5 mg qd (77)
NR
NR
NR
2.6 (23%)
4 wk
3
NR
NR
0.6 (76%)
0.7 (75%)
0.4 (83%)
0.5 (81%)
NR
2.41 (73%) 1.81 (54%)
NR
NR
NR 0.5 (21%) 0.6 (26%) NR
Junemann et al 2006 [17]
Propi IR 15 mg bid (395)
4 wk
1
NR
NR
Propi ER 30 mg qd (391)
3.69 (29%)
+46.5 ml (32.6%)
2.03 (33%)
3.63 (28%)
+40.1 ml (27.9%)
2.58 (40%)
1.4 (12%)
+20 ml*
1.7 (15%)
+20 ml*
NR
2.21 (67%)
NR
2.47 (73%)
Tolterodine Jonas et al 1997 [18]
Tolt IR 1 mg bid (99)
4 wk
3
NR
NR
Tolt IR 2 mg bid (99) Rentzhog et al 1998 [19]
Millard et al 1999 [20]
Tolt IR 0.5 mg bid (21)
+15%* +25%*
Tolt IR 2 mg bid (14)
2.5 (20%)
+30%*
0.8 (46%)
29%*
Tolt IR 4 mg bid (16)
2.0 (20%)
+30%*
1.6 (60%)
40%*
NR
NR
NR
Tolt IR 2 mg bid (129) Jacquetin et al 2001 [21]
Tolt IR 1 mg bid (97)
4 wk
1
NR
NR
Tolt IR 2 mg bid (103) Malone-Lee et al 2001 [22]
Tolt IR 1 mg bid (61)
4 wk
3
NR
NR
Tolt IR 2 mg bid (73) Van Kerrebroeck et al 2001 [23]
Tolt IR 2 mg bid (514)
12 wk
3
NR
NR
Tolt ER 4 mg qd (507) Swift et al 2003 [24]
NR
1.6*
1.0 (10%)
1
NR
1.1*
1.1 (10%)
12 wk
1
NR
Tolt IR 1 mg bid (16)
Tolt IR 1 mg bid (123)
2 wk
NR
Tolt IR 2 mg bid (408)
12 wk
3
NR
NR
Tolt ER 4 mg qd (417)
2.3 (20%)
+27 (18%)
2.3 (20%)
+36 (23%)
1.4 (13%)
+20 (13%)
1.4 (13%)
+19 (12%)
0.7 (6%)
+9 (6%)
0.7 (6%)
+16 (11%)
1.7 (15%)
+29 (21%)
1.8 (16%)
+34 (24%)
1.7 (15%)
+32 (24%)
1.9 (17%)
+37.9 (27%)
NR
NR
NR
1.7 (44%)
0.7 (35%)
10%*
0.6 (37%)
10%*
NR
NR
NR
NR
NR
NR
1.7 (47%) NR
1.1 (41%) 1.3 (41%)
NR
0.3 (13%) 0.7 (25%)
NR NR
NR NR
1.51 (46%)
0.5 (36%)
1.68 (53%)
0.5 (36%)
1.44 (44%)
0.5 (33%)
1.68 (53%)
0.6 (37%)
Solifenacin Cardozo et al 2004 [25]
Soli 5 mg qd (286)
12 wk
2
NR
Soli 10 mg qd (290) Chapple et al 2004 [26]
Soli 5 mg qd (264)
12 wk
2
NR
0.56 (25.3%)
2.37 (20%)
+30.75*
2.84 (25%)
1.3 (63%)
1.63 (61%)
0.71 (38.5%)
2.81 (22%)
+35.99*
2.90 (30%)
1.2 (57%)
1.57 (52%)
2.19 (17%)
+32.9 (25%)
2.85 (52%)
1.41 (65%)
1.42 (59%)
2.61 (20%)
+39.2 (29%)
3.07 (55%)
1.36 (63%)
1.45 (47%)
NR
Soli 10 mg qd (261) Chapple et al 2006** [27]
Soli 5 mg qd (552)
12 wk
NA
NR
Soli 10 mg qd (1158)
0.6*
2.3*
+32.3*
2.9*
0.6*
2.7*
+42.5*
3.4*
NR
1.5*
NR NR NR
1.8*
Darifenacin Chapple et al 2005** [28]
Dari 7.5 mg qd (337)
12 wk
NA
NR
NR
Dari 15 mg qd (334) Foote et al 2005** [29]
Dari 7.5 mg qd (97)
12 wk
NA
NR
NR
Dari 15 mg qd (110) Zinner et al 2005 [30]
Dari 15 mg qd (58)
2 wk
2
NR
NR
Dari 30 mg qd (58) Hill et al 2006 [31]
Dari 7.5 mg qd (108)
1.6 (17%)
+15 (10%)
2.0 (29%)
1.9 (17%)
+27 (17%)
2.3 (29%)
1.8 (18%)
+14 (10%)
2.1 (26%)
1.8 (17%)
+27 (18%)
2.4 (26%)
1.14 (12%)
NR
1.27 (16%)
1.62 (18%) 12 wk
NR
4.0 (77%)
NR
4.8 (79%) NR
1.6 (67%)
NR
1.5 (76%) NR
1.63 (21%)
1.44 (92%)
NR
1.74 (138%)
1.7 (17%)
+17 (10%)
1.8 (29%)
Dari 15 mg qd (107)
1.9 (18%)
+24 (16%)
2.3 (27%)
1.48 (76%)
Dari 30 mg qd (115)
2.2 (21%)
+44 (26%)
3.0 (33%)
1.62 (77%)
3
NR
NR
NR
1.15 (69%)
NR
european urology 54 (2008) 740–764
Propiverine
NR
NR
*Baseline values not provided in the published manuscript; **pooled analysis of RCTs; NR: not reported; NA, not applicable; qd, once daily; bid, twice daily.
1.65 (42%) 1.91 (15%)
2.3 (20%) +33.6 (21%)
+16.5 (11%) 1.61 (12%)
2.09 (17%) 0.55 (29%)
0.58 (26%) 1.04 (10%)
1.54 (15%)
3 Feso 8 mg (279)
Feso 4 mg (283) Nitti et al 2007 [34]
Feso 8 mg qd (288)
12 wk
12 wk Feso 4 mg qd (272)
2.28 (59%)
NR
NR 1.95 (80%)
2.22 (87%) 2.36 (19%) +33.62 (22%) 1.88 (19%) 0.39 (23%)
1.88 (18%) 1.37 (14%) 3
1.48 (17%)
+27.72 (17%)
+92.34* 1.784*
1.76 (17%) 0.39 (29%)
Feso 12 mg (39)
NR NR 2 8 wk Feso 4 mg qd (44) Nitti et al 2005 [32]
Fesoterodine
Chapple et al 2007 [33]
+27.94*
+58.69* 1.815*
0.996*
Mean change in micturitions per 24 h Mean change in nighttime micturitions per 24 h Mean change in daytime micturitions per 24 h Jadad score Treatment duration Dose (no. of cases)
Table 1 (Continued )
Reference
Feso 8 mg qd (47)
Mean change in volume voided per micturitions (ml)
NR
Mean change in urgency episodes per 24 h
NR
Mean change in UUI episodes per 24 h
NR
Mean change in incontinence episodes per 24 h
NR
Mean change in pads used per 24 h
european urology 54 (2008) 740–764
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Retrieval System Online (U.S. National Library of Medicine’s life science database; MEDLINE), the Excerpta Medica database (EMBASE), and Thomson-Reuters’ Web of Science. The MEDLINE search employed a complex search strategy, including both ‘‘MeSH’’ (Medical Subject Heading) and ‘‘free text’’ protocols. Specifically, the MeSH search was conducted by combining the following terms retrieved from the MeSH browser provided by MEDLINE: ‘‘urinary bladder, overactive’’ and ‘‘cholinergic antagonists’’. Multiple free-text searches were performed applying singularly the following terms through all the fields of the records: overactive bladder, detrusor overactivity, bladder overactivity, urgency frequency syndrome, darifenacin, emepronium, fesoterodine, oxybutynin, propantheline, propiverine, solifenacin, tolterodine, and trospium. Subsequently, the searches were pooled and limited to randomized controlled trials (RCTs). No temporal limits were used. Searches on EMBASE and Web of Science used only the free-text protocol, with the same key words. Subsequently, the queries were pooled without applying any limits. In addition, other significant studies cited in the reference lists of the selected papers were considered. Three of the authors individually reviewed all the abstracts of the retrieved studies in order to select the papers that were relevant to the review topic. Specifically, all the full-test studies including data of efficacy (changes in daytime micturitions in 24 h, nighttime micturitions in 24 h, micturitions in 24 h, volume voided per micturitions, urgency, episodes in 24 h, urge urinary incontinence [UUI] episodes in 24 h, incontinence episodes in 24 h, pads used per 24 h, quality of life scores) and complications (overall rates of adverse events, withdrawals due to adverse events, dry mouth rate, moderate-to-severe or severe dry mouth rate, constipation, acute urinary retention, vision abnormality, headache, etc) of anticholinergic drugs comparing different drugs, formulations, doses, and routes of administration were considered. Data were extracted separately and independently by two of the authors and were cross-checked. Moreover, the web site of the Food and Drug Administration (http://www.fda.gov) was searched for RCTs concerning the same drugs. The quality of all the retrieved RCTs was assessed using the Jadad score [11]. All the identified RCTs were included in the meta-analysis, regardless of the quality score. Meta-analysis was conducted using the Review Manager software version 4.2 (The Cochrane Collaboration, Oxford, UK). Specifically, statistical heterogeneity was tested using the chi-square test. A p value <0.10 was used to indicate heterogeneity. In case of lack of heterogeneity, fixed-effects models were used for the meta-analyses. Random-effects models were used in case of heterogeneity. The results were expressed as weighted means and standard deviations for continuous outcomes and relative risk for dichotomous variables. Only the RCTs presenting data in this format were included in the meta-analysis. All the authors whose studies presented the data in a format not suitable for the metaanalysis were contacted and asked for the missing figures, but only three authors provided useful data. The presence of publication bias was evaluated using a funnel plot [12].
Reference
Oxybutynin Nilsson 1997 [13] Anderson 1999 [35] Birns et al 2000 [36] Versi et al 2000 [14]
Corcos et al 2005 [16]
Propiverine Abrams et al 2006 [37] Junemann et al 2006 [17]
Tolterodine Jonas 1997 [18] Rentzhog 1998 [19]
Millard 1999 [20] Jacquetin et al 2001 [21] Malone-Lee et al 2001 [22] Van Kerrebroeck et al 2001 [23] Swift et al 2003 [24]
Solifenacin Cardozo et al 2004 [25]
Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy Oxy
IR 5 mg bid (17) ER 10 mg qd (16) IR 5 mg different doses (52) ER different doses (53) IR 5 mg tid (67) ER 10 mg qd (63) IR different doses (115) ER different doses (111) IR different doses (60) ER different doses (65) ER 5 mg qd (77) ER 10 mg qd (77) ER 15 mg qd (83)
Propi Propi Propi Propi
Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt Tolt
IR 15 mg tid (42) ER 20 mg qd (38) IR 15 mg bid (395) ER 30 mg qd (391)
IR 1 mg bid (99) IR 2 mg bid (99) IR 0.5 mg bid (21) IR 1 mg bid (16) IR 2 mg bid (14) IR 4 mg bid (16) IR 1 mg bid (123) IR 2 mg bid (129) IR 1 mg bid (97) IR 2 mg bid (103) IR 1 mg bid (61) IR 2 mg bid (73) IR 2 mg bid (512) ER 4 mg qd (505) IR 2 mg bid (408) ER 4 mg qd (417)
Soli 5 mg qd (299) Soli 10 mg qd (307)
Treatment duration
8 wk
Jadad Adverse Withdrawals Dry Moderate to Constipation score events due to mouth severe or severe dry rate adverse events mouth 1
variable
3
4 wk
3
variable
3
100% 87% 94% 87% 67% 55% NR
0 0 NR
6 wk
3
NR
4 wk
3
NR
2 wk
3
NR
4 wk
1
81% 79% 38% 34%
4 wk
3
2 wk
1
12 wk
1
4 wk
1
4 wk
3
31% 32% 38% 37% 50% 75% 74% 73% 40% 53% NR
12 wk
3
NR
12 wk
3
NR
12 wk
3
NR
NR NR 13% 9% 4% 14% 14%
82% 69% 87% 68% 17% 23% 59% 48% 72% 68% 56% 68% 70%
AUR
NR
NR
NR
46% 25% NR
31% 30% NR
NR
45% 39% 45% 38% 3% 14% 5%
NR
NR
10% 8% 5% 4% 5%
NR
NR
4% 3%
52% 34% 23% 22%
4% 3% 5% 0 0 6% 2% 6% 3% 2% 7% 10% 5% 5% 5% 5%
8% 10% 9% 12% 36% 56% 24% 39% 21% 34% 49% 66% 30% 23% 31% 23%
NR
2% 4%
8% 23%
NR
3% 10% 7%
24% 16% 4% 3%
NR
2% 3% 5% 19% 7% 12% NR
NR
3% 2%
4% 2% 8% 0 7% 6% 7% 6%
2% 5%
4% 9%
NR
0 0 0 6% NR NR NR NR
Vision Headache abnormality
12% 25% 17% 28% 4% 6% NR
41% 44% NR
15% 3% 1% 1% 1%
22% 12% NR
4% 0 NR
33% 24% 3.8% 4.6%
7% 3% 2% 1%
3% 3% NR
NR
3% 5% 0 19% 7% 6% 2% 6% NR
0 0 NR
0 4% NR
NR
1% 1%
NR
4% 6%
NR
0 0 0 6% NR
NR 3% 3% 8% 10% 4% 6% 4% 7%
NR
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Barkin et al 2004 [15]
Dosage (no. of cases)
744
Table 2 – Safety data from the randomized control trials (RCTs) comparing different doses and formulations of emepropium, oxybutynin, tolterodine, propiverine, trospium, solifenacin, darifenacin, and fesoterodine
Table 2 (Continued ) Reference
Chapple et al 2004 [26] Chapple et al 2006* [27]
Darifenacin Chapple et al 2005* [28] Foote et al 2005* [29] Zinner et al 2005 [30]
Fesoterodine Nitti et al 2005 [32]
Chapple et al 2007 [33] Nitti et al 2008 [34]
Treatment duration
Jadad Adverse Withdrawals Dry Moderate to Constipation mouth severe or score events due to rate adverse severe dry mouth events
Soli Soli Soli Soli
5 mg qd (279) 10 mg qd (268) 5 mg qd (552) 10 mg qd (1158)
12 wk
3
NR
12 wk
3
91% 87%
Dari Dari Dari Dari Dari Dari Dari Dari Dari
7.5 mg qd (337) 15 mg qd (334) 7.5 mg qd (97) 15 mg qd (110) 15 mg qd (76) 30 mg qd (76) 7.5 mg qd (108) 15 mg qd (107) 30 mg qd (115)
12 wk
NA
12 wk
NA
2 wk
2
54% 66% 54% 69% NR
12 wk
3
57% 68% 80%
Feso Feso Feso Feso Feso Feso Feso
4 mg qd (43) 8 mg qd (47) 12 mg (38) 4 mg (272) 8 mg (282) 4 mg (283) 8 mg (279)
8 wk
2
NR
12 wk
3
12 wk
3
50% 58% 61% 69%
3% 3% 3% 7%
14% 21% 11% 28%
1% 5% 1% 9% 0 1% 0 2% 4%
20% 35% 21% 31% 13% 34% 23% 40% 59%
2% 4% 13% 3% 5% 6% 9
37% 43% 63% 22% 34% 16% 36%
* Pooled analysis of RCTs; NA, not applicable; qd, once daily; bid, twice daily; tid, three times daily; NR, not reported.
NR 0.2% 1%
NR NR NR NR
14% 21% 13% NR NR
AUR
7% 8% 5% 13%
NR
15% 21% 19% 24% 10% 21% 16% 25% 59%
Headache Vision abnormality
4% 6% 4% 5%
NR
NR
NR
NR
NR
NR NR
0 0 2% 0 3%
4% 5% 0 0 NR
NR
NR
NR
NR
3% 4% 5% 8%
0.3% 1% 1% 2%
2% 4% 0.7% 3%
4% 2% 4% 3%
NR
NR
6% 6% 6%
european urology 54 (2008) 740–764
Hill et al 2006 [31]
Dosage (no. of cases)
745
746
3.
european urology 54 (2008) 740–764
Results
984 records were retrieved by searching MEDLINE: 910 records were retrieved from EMBASE, and 669 records were retrieved from Web of Science. The studies evaluating lower urinary tract storage symptoms in patients with bladder-outlet obstructions, papers evaluating neurogenic OAB or OAB in children, phase I studies, post-hoc analyses of RCTs, and duplicate publications were excluded. We finally identified 50 RCTs and three pooled analyses of RCTs for inclusion in this review (Fig. 1). 3.1. Comparisons of different doses and formulations of the same drug
Tables 1 and 2 summarize the efficacy and safety data from the available RCTs comparing different
doses and formulations of oxybutynin, tolterodine, propiverine, trospium, darifenacin, solifenacin, and fesoterodine. 3.1.1.
Oxybutynin
A single study, published as congress abstract only and really outdated, evaluated the efficacy and safety of oxybutynin IR 2.5 mg, taken three times a day or as needed [38]. Five RCTs compared IR and ER formulations [13–15,35,36], while two further studies compared different doses of the ER formulation [16,39]. Meta-analysis of efficacy between oxybutynin IR and oxybutynin ER was not possible because the only two RCT reporting data in the proper format [15,16] were not suitable for cumulative evaluation of any clinical significance. With regard to adverse events, the occurrence of any adverse event (odds ratio [OR]: 1.9; 95% confidence interval [CI], 1.03–3.51;
Fig. 2 – Forest plots of adverse events after immediate release (IR) and extended release (ER) oxybutynin. (A) Occurrence of any adverse event; (B) dry mouth; (C) moderate-to-severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
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Table 3 – Meta-analysis of adverse events with oxybutynin immediate release (IR) and oxybutynin extended release (ER) Oxybutynin IR vs oxybutynin ER
Any adverse event Withdrawals due to adverse events Dry mouth Moderate-to-severe or severe dry mouth Headache Constipation Vision abnormality
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
3 2 5 3 3 2 4
268 158 619 456 288 230 393
1.9 1.51 1.45 1.49 1.77 1.11 0.92
1.03–3.51 0.49–4.65 1.02–2.05 1.02–2.16 0.84–3.72 0.56–2.22 0.50–1.69
0.04 0.47 0.04 0.04 0.13 0.76 0.79
Difference favors
Oxybutynin ER None Oxybutynin ER Oxybutynin ER None None None
RCT, randomized control trial; IR, immediate release; ER, extended release; OR, odds ratio; CI, confidence interval.
p = 0.04), dry mouth (OR: 1.45; 95% CI, 1.02–2.05; p = 0.04), and moderate-to-severe or severe dry mouth (OR: 1.49; 95 CI, 1.02–2.16; p = 0.04) were significantly more common with oxybutynin IR (Fig. 2). On the other hand, withdrawals due to adverse events, headache, constipation, and vision abnormality were similar for the two formulations of oxybutynin (Table 3). 3.1.2.
Tolterodine
Eight RCTs compared different doses and formulations of tolterodine. Specifically, four studies compared two different dosages of tolterodine IR 1 mg twice daily vs tolterodine IR 2 mg twice daily [18,20–22], while a further study evaluated four different dosages (0.5 mg twice daily vs 1 mg twice daily vs 2 mg twice daily vs 4 mg twice daily) [19]. Two RCTs compared tolterodine IR 2 mg twice daily and tolterodine ER 4 mg once daily [23,24], while a single study compared two dosages of tolterodine ER [39].
With regard to efficacy analysis, four papers presented the data in a format unsuitable for meta-analysis [18,19,22,39]. Comparing the tolterodine IR 1 mg and tolterodine IR 2 mg doses, micturitions per 24 h (weighted mean difference [WMD], 0.11; 95% CI, 0.45–0.66; p = 0.70), volume voided per micturition (WMD, 8.68; 95% CI, 18.62– 1.26; p = 0.09), and UUI episodes per 24 h (WMD, 0.06; 95% CI, 0.51–0.39; p = 0.81) were similar for both doses. With regard to adverse events, only dry mouth was significantly more frequent in those patients taking tolterodine IR 2 mg (OR: 0.52; 95% CI, 1.037–0.72; p < 0.0001). Regarding the comparison of tolterodine IR and tolterodine ER formulations, patients randomized to tolterodine ER formulation experienced a lower number of micturitions per 24 h (WMD, 0.34; 95% CI, 0.02–0.66; p = 0.03) and a higher volume voided per micturition (WMD, 9.12; 95% CI, 14.13– 4.12; p = 0.0004), but a similar number of incontinence episodes and pad use per day (Table 4). Evaluating
Table 4 – Meta-analysis of randomized control trials (RCTs) comparing tolterodine immediate release (IR) and tolterodine extended release (ER) Tolterodine IR vs tolterodine ER
RCT (no.)
Participants (no.)
2 2 2 2
1846 1846 1846 1846
Micturitions per 24 h Volume voided per micturition Incontinence episodes per 24 h Pad use per 24 h
Adverse events
Withdrawals due to adverse events Dry mouth Headache Constipation
WMD
0.34 9.12 0.09 0
95% CI, WMD
0.02–0.66 14.13–4.12 0.15–0.32 0.15–0.15
Test for overall effect ( p value) 0.03 0.0004 0.46 1
Difference favors
Tolterodine ER Tolterodine ER None None
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Difference favors
2
1846
0.98
0.65–1.48
0.92
None
2 2 2
1846 1846 1846
1.39 0.53 1.10
1.13–1.71 0.34–0.81 0.76–1.59
0.002 0.004 0.63
Tolterodine ER Tolterodine IR None
IR, immediate release; ER, extended release; UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.
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european urology 54 (2008) 740–764
Fig. 3 – Forest plots of efficacy and safety after tolterodine immediate release (IR) and tolterodine extended release (ER). (A) Micturitions per 24 h; (B) volume voided per micturition; (C) dry mouth; (D) headache. OAB, overactive bladder; N, number of patients in the study arm; SD, standard deviation; WMD, weighted-mean difference; CI, confidence interval.
the adverse events with the use of the two formulations of tolterodine, patients treated with tolterodine ER formulations had a significantly lower rate of dry mouth (OR: 1.39; 95% CI, 1.13– 1.71; p = 0.002) but a higher rate of headache (OR: 0.53; 95% CI, 0.34–0.81; p = 0.004). Withdrawals due to
adverse events and constipation were similarly prevalent in both cases (Table 4; Fig. 3). 3.1.3.
Propiverine
A single study evaluated the efficacy of 21-d treatment with different doses of propiverine IR
Fig. 4 – Forest plots of adverse events after different dosages of darifenacin (Dari). Darifenacin 7.5 mg versus darifenacin 15 mg: (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth; (D) constipation. Darifenacin 15 mg versus darifenacin 30 mg: (E) dry mouth; (F) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
european urology 54 (2008) 740–764
749
750
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Table 5 – Meta-analysis of adverse events with immediate-release (IR) and extended-release (ER) formulations of propiverine Propiverine IR vs propiverine ER
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Any adverse event Dry mouth Headache Constipation Vision abnormality
2 2 2 2 2
866 866 866 866 866
1.20 1.16 1.54 1.29 1.95
0.90–1.58 0.84–1.58 0.59–4.02 0.69–2.41 0.89–4.02
0.21 0.36 0.38 0.42 0.10
Difference favors None None None None None
RCT, randomized control trial; OR, odds ratio; CI, confidence interval.
(15 mg twice daily vs 30 mg twice daily vs 45 mg three times daily vs 60 mg four times daily), showing that propiverine IR 15 mg twice daily and 30 mg twice daily were the doses with the most favorable ratio of efficacy in micturition frequency to tolerability [40]. Two studies compared propiverine hydrochloride IR and propiverine hydrochloride ER formulations [17,37]. Meta-analysis was possible only for complication rates, in spite of the different dosages of propiverine IR of in the two studies. The two formulations of propiverine showed similar rates of adverse events, dry mouth, constipation, headache, and vision abnormality (Table 5). 3.1.4.
Solifenacin
Four RCTs evaluated the efficacy of different doses of solifenacin [25,26,41,42]. The two studies by Gittelman et al [41,42] were not included in Tables 1 and 2 because it was not possible to obtain the data in an extended form. Three pooled analyses of these four RCTs sharing similar designs were published [27,43,44]. The largest analysis, which also included the patients without UUI, evaluated 2848 patients out of 3032 randomized patients: 552 patients received solifenacin 5 mg, 1158 patients received solifenacin 10 mg, and 1138 patients received placebo [27]. Both doses of solifenacin were significantly more efficacious than placebo. Indeed, comparing the two dosages, solifenacin 10 mg was significantly better only in terms of the percentage of patients having a 50% reduction in incontinence episodes ( p = 0.006). However, withdrawals due to adverse events ( p = 0.0005), dry mouth ( p < 0.0001), and constipation ( p < 0.0001) were significantly more common among the patients treated by solifenacin 10 mg [27].
which, however, failed to clearly report the included trials. The larger studies evaluated 337 patients randomized to receive darifenacin 7.5 mg and 334 patients who received darifenacin 15 mg. The analysis identified significant dose–response effects for change in weekly incontinence episodes [28]. The study from Foote et al [29] was a subgroup analysis of the patients aged 65 yr in Chapple et al [28] and was not evaluated in our analyses. Meta-analysis of efficacy between the different doses of darifenacin was not possible because all the studies reported the data in a format that was not suitable for the evaluation. With regard to adverse events, darifenacin 7.5 mg was followed by significantly lower rates of adverse events (OR: 0.62; 95% CI, 0.47–0.81; p = 0.0005), withdrawals due to adverse events (OR: 0.30; 95% CI, 0.11–0.80; p = 0.02), dry mouth (OR: 0.46; 95% CI, 0.34–0.62; p < 0.0001), and constipation (OR: 0.62; 95% CI, 0.44–0.87; p = 0.006), compared with darifenacin 15 mg. Similarly, comparing darifenacin 15 mg and darifenacin 30 mg, darifenacin 15 mg was followed by significantly lower rates of dry mouth (OR: 0.40; 95% CI, 0.26– 0.63; p < 0.0001) and constipation (OR: 0.27; 95% CI, 0.16–0.44; p < 0.0001; Table 6; Fig. 4). 3.1.6.
3.2. 3.1.5.
Fesoterodine
Three RCTs compared different doses of fesoterodine, the most recently released anticholinergic drug [32–34]. With regard to efficacy analysis, the three papers presented the data in a format unsuitable for meta-analysis. Regarding adverse events, adverse event rate (OR: 0.68; 95% CI, 0.53– 0.87; p = 0.002), dry mouth (OR: 0.46; 95% CI, 0.36– 0.60; p < 0.0001) and vision abnormality (OR: 0.38; 95% CI, 0.17–0.86; p = 0.02) were more common in those patients receiving fesoterodine 8 mg (Table 7). Comparisons of different drugs
Darifenacin
Our systematic search identified two RCTs evaluating the efficacy of darifenacin at different doses [30,31] and two pooled analyses of RCTs [28,29],
Tables 8 and 9 summarize the efficacy and safety data from the available RCTs comparing different drugs.
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Table 6 – Meta-analysis of adverse events with different doses of darifenacin RCT (no.)
Darifenacin 7.5 mg vs darifenacin 15 mg Any adverse event Withdrawal due to adverse event Dry mouth Headache Constipation Darifenacin 15 mg vs darifenacin 30 mg Withdrawal due to adverse event Dry mouth Constipation
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
Difference in favor
2 2 2 2 2
886 886 886 886 886
0.62 0.30 0.46 0.90 0.62
0.47–0.81 0.11–0.80 0.34–0.62 0.50–1.64 0.44–0.87
0.0005 0.02 <0.0001 0.74 0.006
Darifenacin Darifenacin Darifenacin None Darifenacin
2 2 2
374 374 374
0.40 0.40 0.27
0.09–1.74 0.26–0.63 0.16–0.44
0.22 <0.0001 <0.00001
None Darifenacin 15 mg Darifenacin 15 mg
7.5 mg 7.5 mg 7.5 mg 7.5 mg
RCT, randomized control trial; OR, odds ratio; CI, confidence interval; NR, not reported.
Table 7 – Meta-analysis of adverse events with different doses of fesoterodine Fesoterodine 4 mg vs fesoterodine 8 mg
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
2 3 3 2 2 2 2
1116 1211 1211 1116 1116 1116 1116
0.68 0.60 0.46 0.67 1.66 0.38 0.62
0.53–0.87 0.36–1 0.36–0.60 0.39–1.15 0.86–3.20 0.17–0.86 0.20–1.92
0.002 0.05 <0.0001 0.15 0.13 0.02 0.41
Any adverse event Withdrawal due to adverse event Dry mouth Constipation Headache Vision abnormality Acute urinary retention
Difference in favor of
Fersoterodine 4 mg None Fersoterodine 4 mg None None Fersoterodine 4 mg None
RCT, randomized control trial; OR, odds ratio; CI: confidence interval.
3.2.1.
Oxybutynin versus tolterodine
Twelve RCTs compared efficacy and safety of oxybutynin and tolterodine [45–54,62,63]. Specifically, eight of these studies compared the IR formulations of the two drugs (oxybutynin 5 mg two or three times daily vs tolterodine 2 mg twice daily) [45–47,49,50,53,62,63]. With regard to the comparisons of the IR formulations, only four RCTs provided the data in a format suitable for meta-analysis of the efficacy data [47,49,50,53]. Micturitions per 24 h, volume voided per micturition, UUI episodes, and incontinence episodes per 24 h were overlapping for the IR formulations of the two drugs. Regarding adverse events, occurrence of any adverse event (OR: 2.30; 95% CI, 1.70–3.11; p 0.00001), withdrawal due to adverse events (OR: 1.82; 95% CI, 1.33–2.49; p = 0.0002), dry mouth of any grade (OR: 3.98; 95% CI, 3.16–5.02; p 0.00001), and moderate-to-severe or severe dry mouth (OR: 7.21; 95% CI, 4.50–11.52; p 0.00001) were significantly more common in those patients receiving oxybutynin IR (Table 10 and Fig. 5). A single trial compared oxybutynin ER to tolterodine IR [48]. After a 12-wk treatment, oxybutynin ER was shown to be more efficacious than tolterodine IR in terms of reduction in urgency incontinence
episodes ( p = 0.03), total incontinence episodes ( p = 0.02), and micturitions ( p < 0.0001), while all the evaluated adverse events (overall number, dry mouth, constipation, blurred vision, headache) were overlapping in the two arms [48]. Two further RCTs compared oxybutynin IR and tolterodine ER [52,54]. The larger study, which enrolled 608 patients with OAB, showed similar efficacy for both drugs in terms of reductions in the number of incontinence episodes per week and micturitions per day, but patients taking oxybutynin IR more frequently experienced dry mouth, severe dry mouth, and eye disorders [52]. Similar figures were provided in the RCT from Homma et al [54]. The format used in these two studies to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, dry mouth (OR: 2.44; 95% CI, 1.80– 3.30; p < 0.00001) and severe dry mouth (OR: 16.87; 95% CI, 3.23–87.95; p = 0.0008) were significantly more common with the IR formulation of oxybutynin. Finally, a single study compared the formulations of oxybutynin ER and tolterodine ER [51]. After a 12-wk treatment, the average number of weekly UUI episodes, which was the primary end point of the study, was overlapping between the two arms, as
752
Table 8 – Efficacy data from the randomized control trials (RCTs) comparing different drugs Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
Mean change in pads used per 24 h
Oxybutynin vs tolterodine Van Kerrebroeck 1997 [45]
Oxy IR 5 mg tid (120)
12 wk
1
NR
NR
Tolt IR 2 mg bid (120) Abrams et al 1998 [46]
Oxy IR 5 mg tid (118)
12 wk
3
NR
NR
Tolt IR 2 mg bid (118) Drutz et al 1999 [47]
Oxy IR 5 mg tid (112)
12 wk
3
NR
NR
Tolt IR 2 mg bid (109) Appell et al 2001 [48]
Oxy ER 10 mg qd(185)
12 wk
3
NR
NR
Tolt IR 2 mg bid(193) Malone–Lee et al 2001 [49]
Oxy IR 5 mg bid (188) Oxy IR 5 mg bid (116)
10 wk
3
NR
NR
8 wk
3
NR
NR
Oxy ER 10 mg qd (391) Oxy IR 3 mg tid (246)
12 wk
3
NR
NR
Oxy IR 5 mg tid (107)
+47 (31%) +38 (27%)
2.0 (17%)
+50 (33%)
2.0 (17%)
+ 34 (22%)
3.5 (27%)
NR
NR
NR
NR
1.7 (15%)
+34 (23%)
1.7 (15%)
+33 (22%)
1.8 (15%)
NR
3.75 (28%)
12 wk
3
NR
NR
6+6 wk
3
NR
NR
3
NR
NR
NR 1.7 (71%)
NR NR
1.3 (47%) NR
NR
1.7 (50%)
NR
1.7 (46%) NR NR
2.78 (76%)
3.07 (75%)
2.32 (68%)
2.52 (65%)
1.8 (62%)
NR
NR
0.9 (32%)
1.3 (54%) NR
NR
1.1 (35%) 1.4 (67%)
NR
2.2 (76%) NR
NR
3.42 (25%)
Tolt ER 4 mg qd (240) Giannitsas et al 2004 [53]
2.3 (19%) 2.7 (21%)
NR
2.6 (20%)
Tolt ER 4 mg qd (399) Homma et al 2003 [52]
+35 *
2.0 (18%)
+22.3 (18%)
2.1 (17%)
+17.2 (14%)
0.8 (9%)
+43.8 (22%)
3.82 (72%)
4.5 (73%)
3.42 (65%)
4.2 (69%)
NR
NR
NR
NR
0
NR
NR
NR
NR
NR
NR
87% *
NR
0
(crossover) Tolt IR 2 mg bid (107) Homma et al 2004 [54]
Oxy IR 3 mg tid (122)
0.9 (10%) 12 wk
Tolt ER 4 mg qd (114)
+40.6 (21%)
19.1%*
+22 *
17.9%*
+12.6 *
86% *
Oxybutynin vs propiverine Madersbacher et al 1999 [55]
Oxy IR 5 mg bid (121)
4 wk
2
NR
NR
Propi 15 mg tid (126)
1.6 (13%)
NR
1.9 (18%)
3 (24%)
NR
NR
NR
NR
NR
NR
3.1 (33%)
Oxybutynin vs trospium Halaska et al 2003 [56]
Oxy IR 5 mg bid (90)
52 wk
3
NR
NR
Trospium 20 mg bid (267)
4.2 (34%)
NR
3.5 (31%)
3.6 (33%) 3.5 (34%)
Oxybutynin vs darifenacin Zinner et al 2005 [30]
Oxy IR 5 mg tid (58)
2 wk
3
NR
NR
1.23 (13%)
NR
1.1 (13%)
NR
1.65 (122%)
Dari 15 mg qd (58)
1.14 (12%)
1.27 (16%)
1.44 (92%)
Dari 30 mg qd (58)
1.62 (18%)
1.63 (21%)
1.74 (138%)
NR
Tolterodine vs trospium Junemann et al 2000 [57]
Tolt IR 2 mg bid (60)
3 wk
1
NR
NR
Trospium IR 20 mg bid (57)
2.6*
NR
NR
NR
NR
NR
3.4*
Tolterodine vs propiverine Junemann et al 2005 [58]
Tolt IR 2 mg bid (101)
4 wk
2
NR
NR
Propi 15 mg bid (100)
3.07*
+28.43 *
3.04*
2.75*
+31.76 *
3.26*
NR
0.91*
0.43*
1.2*
0.65*
Tolterodine vs solifenacin Chapple et al 2004 [26]
Tolt IR 2 mg bid (250)
12 wk
3
NR
NR
Soli 5 mg qd (264) Soli 10 mg qd (261) Chapple et al 2005 [59]
Tolt ER 4 mg qd (599)
12 wk
3
NR
Soli 5/10 mg qd (578) Chapple et al 2007 [60]
Tolt ER 4 mg qd (599) Soli 5 mg qd (578)
Tolterodine vs fesoterodine
4 wk
3
NR
1.88 (15%)
+24.4 (20%)
2.05 (38%)
0.91 (58%)
1.14 (59%)
2.19 (17%)
+32.9 (25%)
2.85 52%)
1.41 (65%)
1.42 (59%)
NR
2.61 (20%)
+39.2 (29%)
3.07 (55%)
1.36 (63%)
1.45 (47%)
0.63 (33%)
2.24 (19%)
+31 (21%)
2.42 (41%)
0.83 (39%)
1.11 (43%)
1.19 (41%)
0.71 (35%)
2.45 (21%)
+38 (26%)
2.85 (47%)
1.42 (61%)
1.6 (58%)
1.72 (53%)
0.44 (23%)
1.47 (13%)
+24.3 (17%)
1.67 (29%)
0.91 (43%)
0.90 (42%)
0.80 (27%)
0.51 (23%)
1.71 (14%)
+28.5 (19%)
1.98 (33%)
1.22 (53%)
1.30 (53%)
1.21 (37%)
european urology 54 (2008) 740–764
Tolt IR 2 mg bid (112) Diokno et al 2003 [51]
+54 *
2.1 *
2.8 (22%)
Tolt IR 2mg bid (190) Lee et al 2002 [50]
2.7 *
NR 2.22 (87%)
3.2.2.
Oxybutynin versus propantheline
Two studies compared oxybutynin IR 5 mg three times daily and propantheline 15 mg three times daily [61,64]. The larger study evaluated 154 patients, 63 patiented receiving the oxybutynin dosage and 54 patients receiving the propantheline dosage. The propantheline arm showed a higher mean grade of improvements in visual analogue scale, counterbalanced by higher rate of adverse events in the oxybutynin arm [61]. The data from the two studies were unsuitable for meta-analysis.
2.36 (19%)
3.2.3. VV, voided volume; UUI, urge urinary incontinence; QD, once daily; BID, twice daily; TID, three times daily; NR, not reported.
+33.62 (22%) 1.88 (19%) 0.39 (23%) 1.48 (17%) Feso 8 mg (288)
753
well as the number of incontinence episodes of any type. Indeed, patients taking oxybutynin ER had a greater decrease in the mean weekly micturition frequency compared with tolterodine ER participants ( p = 0.003). Regarding adverse events, the occurrence of dry mouth was significantly less common in the patients randomized to tolterodine ER ( p = 0.02), although in most of the cases it was of mild degree [51].
NR 1.74 (70%)
1.95 (80%) 1.88 (18%) +27.72 (17%) 1.76 (17%) 0.39 (29%)
2.03 (16%) +23.64 (15%) 1.73 (14%) 0.4 (25%)
1.37 (14%)
1.35 (14%) 12 wk
3 Feso 4 mg qd (272)
Tolt ER 4 mg qd (290) Chapple et al 2007 [33]
Table 8 (Continued )
Reference
Dose (no. of cases)
Treatment duration
Jadad score
Mean change in daytime micturitions per 24 h
Mean change in nighttime micturitions per 24 h
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
Mean change in urgency episodes per 24 h
Mean change in UUI episodes per 24 h
Mean change in incontinence episodes per 24 h
Mean change in pads used per 24 h
european urology 54 (2008) 740–764
Oxybutynin versus propiverine
Two studies compared oxybutynin with propiverine [55,65]. In the larger study, the two drugs were similarly effective in terms of both bladder diary variables and urodynamic parameters, although dry mouth and severe dry mouth were less frequent in the propiverine arm [55]. 3.2.4.
Oxybutynin versus trospium
A single trial compared efficacy and safety of oxybutynin IR 5 mg twice daily and trospium IR 20 mg twice daily [56]. This study is of particular clinical relevance because the treatments were continued for 52 wk. This study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions and in the number of of urgency episodes per 24 h, and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. The occurrence of any adverse event ( p = 0.045) and dryness of the mouth ( p = 0.021) were significantly less common in those patients receiving trospium [56]. 3.2.5.
Oxybutynin versus darifenacin
Zinner et al evaluated the efficacy of oxybutynin IR and darifenacin in a four-way crossover study [30]. With regard to efficacy, darifenacin 15 mg once daily was comparable to oxybutynin in terms of the improvement in OAB symptoms, with both drugs similarly reducing the number of incontinence episodes per week and the number of micturitions and urgency episodes per day after a 2-wk treat-
754
Table 9 – Safety data from the randomized control trials (RCTs) comparing different drugs Reference
Dose (no. of cases)
Treatment duration
Jadad score
Adverse events rate
Withdrawal due to adverse events
Dry mouth
Moderate-to-severe or severe dry mouth
Headache
Constipation
AUR
NR
Vision abnormality
Oxybutynin vs propantheline Thuroff et al 1991 [61]
Oxy IR 5 mg tid (63)
4 wk
1
Propantheline 15 mg tid (54)
63%
3%
48%
27%
1%
3%
44%
5%
31%
18%
5%
0
3%
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR 2%
4%
Oxybutynin vs tolterodine Van Kerrebroeck et al 1997 [45]
Oxy IR 5 mg tid (120)
12 wk
1
Tolt IR 2 mg bid (120) Abrams et al 1998 [46]
Oxy IR 5 mg tid (118)
12 wk
3
Tolt IR 2 mg bid (118) Drutz et al 1999 [47]
Oxy IR 5 mg tid (112)
12 wk
3
Tolt IR 2 mg bid (109) Appell et al 2001 [48]
Oxy ER 10 mg qd (185)
12 wk
3
93%
21%
78%
23%
63%
11%
38%
3% NR
97%
17%
86%
89%
8%
50%
90%
21%
69%
44%
10%
78%
6%
30%
9%
15%
NR
8%
7%
3%
9%
6%
3%
1%
NR
5%
NR
28% 33%
Malone-Lee et al 2001 [49]
Oxy IR 5 mg bid (188)
10 wk
3
81%
15%
61%
15%
10%
6%
8 wk
3
Tolt IR 2mg bid (190) Lee et al 2002 [50]
Oxy IR 5 mg bid (116)
69%
12%
37%
4%
11%
8%
NR
16%
63%
28%
5%.
NR
NR
NR
10%
35%
9%
4%
49%
15%
NR
NR
NR
NR
NR
NR
60%
17% NR
NR
Tolt IR 2 mg bid (112) Leung et al 2002 [62]
Oxy IR5 mg bid (53)
10 wk
3
Tolt IR 2 mg bid (53) Diokno et al 2003 [51]
Oxy ER 10 mg qd (391)
12 wk
3
NR
Tolt ER 4 mg qd (399) Homma et al 2003 [52]
Oxy IR 3 mg tid (244)
12 wk
3
NR
Tolt ER 4 mg qd (239) Homma et al 2004 [54]
Oxy IR 3 mg tid (122)
12 wk
3
NR
5%
30%
7%
6%
6%
5%
22%
5%
6%
8%
17%
54%
8%
4%
6%
3%
3%
5%
33%
0.4%
4%
7%
0.4%
1%
NR
61%
3%
NR
NR
NR
NR
37%
0
83%
83%
NR
NR
NR
58%
50%
28%
NR
NR
NR
NR
NR
NR
18%
NR
83%
NR
15%
10%
NR
22%
Tolt ER 4 mg qd (114) Altan-Yacioglu et al 2005 [63]
Oxy IR 5 mg tid (24)
4 wk
2
NR
5%
NR
Tolt IR 2 mg bid (28)
43%
Oxybutynin vs propiverine Madersbacher et al 1999 [55]
Oxy IR 5 mg bid (145)
4 wk
2
Propi 15 mg tid (149) Abrams et al 2006 [37]
Oxy IR 5 mg tid (41)
72% 64%
2 wk
3
93%
27%
Propi 15 mg tid (42)
81%
52%
7%
24%
33%
Propi 20 mg qd (38)
79%
34%
0
16%
24%
9%
NR
Oxybutynin vs trospium Halaska et al 2003 [56]
Oxy IR 5 mg bid (90)
52 wk
3
Trospium 20 mg bid (267)
77%
7%
50%
68%
4%
33%
NR
NR
NR
4%
6% 3%
Oxybutynin vs darifenacin Zinner et al 2005 [30]
Oxy IR 5 mg tid (76)
5%
36%
Dari 15 mg qd (76)
2 wk
0
13%
10%
0
Dari 30 mg qd (76)
1%
34%
21%
0
NR
29%
3
NR
NR
8%
NR
3%
Tolterodine vs trospium Junemann et al 2000 [37]
Trospium IR 20 mg bid (76)
3 wk
1
Tolt IR 2 mg bid (77)
34% 32%
NR
NR
NR
NR
NR
NR
NR
NR
NR
7%
27%
Tolterodine vs propiverine Junemann et al 2005 [58]
Tolt IR 2 mg bid (101)
4 wk
2
Propi 15 mg bid (100)
43%
6%
19%
42%
6%
20%
9%
Tolterodine vs solifenacin Chapple et al 2004 [26]
2%
19%
Soli 5 mg qd (279)
Tolterodine IR 2 mg bid (263)
12 wk
3%
14%
7%
4%
Soli 10 mg qd (268)
3%
22%
8%
6%
3
NR
NR
NR
3%
NR
1%
european urology 54 (2008) 740–764
8% 8%
Tolt IR 2 mg bid (193)
2%
5% NR
4%
NR NR
NR 1%
2%
Headache
34% 5% 58%
17%
22%
3%
3%
NR, not reported; qd, once daily; bid, twice daily; tid, three times daily.
Feso 8 mg qd (282)
12 wk
3.2.8.
Feso 4 mg qd (272)
Tolt ER 4 mg qd (290) Chapple et al 2007 [33]
Soli 5 mg qd (593) Tolterodine vs fesoterodine
Tolterodine versus propiverine
A single study compared tolterodine IR 2 mg bid and propiverine 15 mg bid [58]. The study showed similar efficacy for the two drugs in terms of both bladder diary variables such as mean change in micturitions, number of UUI episodes per 24 h, and number of incontinence episodes per 24 h and in terms of urodynamic parameters, such as change in maximum cystometric capacity and change in volume at first contraction. Similarly, the number of adverse events was comparable in both treatment groups [58].
3
50%
3% 3%
4 wk Tolt ER 4 mg qd (607) Chapple et al 2007 [60]
Soli 5/10 mg qd (578)
50%
3% 3% 3
18%
30% 3%
15%
24% 3% NR 3 Chapple et al 2005 [59]
Tolt ER 4 mg qd (599)
12 wk
Withdrawal due to adverse events Jadad score Treatment duration Dose (no. of cases)
Table 9 (Continued )
Tolterodine versus trospium
A single RCT, published as congressional abstract, compared tolterodine IR 2 mg twice daily and trospium IR 20 mg twice daily. The study showed similar efficacy and similar adverse event rates for the two drugs [57]. The lack of a publication in a peer-reviewed journal does not permit the evaluation of the power of the statistical analysis for the comparisons between tolterodine and trospium. 3.2.7.
Adverse events rate
Dry mouth
Moderate-to-severe or severe dry mouth
3.2.6.
Reference
755
ment. Concerning adverse events, dry mouth was significantly more common in the oxybutynin arm than in the darifenacin 15 mg arm ( p < 0.05), while overlapping rates occurred between the oxybutynin 30 mg and darifenacin 30 mg arms. On the other hand, constipation was significantly more frequent in those patients treated by darifenacin 30 mg, but it occurred in similar percentages in the oxybutynin 15 mg arm and the darifenacin 15 mg arm [30].
4% 1% 4%
2.2% 0.3%
0.3% 0
3%
3%
3%
1%
NR NR 1%
2% NR 2%
6%
AUR Constipation
Vision abnormality
european urology 54 (2008) 740–764
Tolterodine versus solifenacin
Two studies reported data on the comparisons between solifenacin and tolterodine [26,59,60]. The first study, designed for the registration of solifenacin, compared solifenacin 5-mg and solifenacin 10-mg to tolterodine IR 2 mg twice daily or placebo [26]. However, the most interesting data came from the STAR study, whose primary end point tested the non-inferiority of solifenacin compared to tolterodine ER [59]. Solifenacin 5 mg and solifenacin10 mg were not inferior to tolterodine ER with regard to change from baseline in the following ways: mean number of micturitions per 24 h ( p = 0.004 for noninferiority), reduction in number of urgency episodes per day ( p < 0.05), urge incontinence episodes per day ( p < 0.01), incontinence episodes per day ( p < 0.01), and pad usage ( p < 0.002). Dry mouth ( p = 0.02) and constipation ( p = 0.002) were significantly more common in the solifenacin arm, although they were mainly of mild or moderate severity [59]. A secondary analysis of the same trial was recently published, limiting all the evaluation
756
european urology 54 (2008) 740–764
Table 10 – Meta-analysis of randomized control trials (RCTs) comparing immediate-release (IR) formulations of oxybutynin and tolterodine Oxybutynin IR vs tolterodine IR
RCT (no.)
Participants (no.)
4 3 1
1041 813 378
0.02 1.89 0.50
0.33–0.36 7.73–11.51 0.11–1.11
0.92 0.70 0.11
None None None
2
449
0.11
0.54–0.32
0.61
None
Micturitions per 24 h Volume voided per micturition Urgency urinary incontinence episodes per 24 h Incontinence episodes per 24 h
Adverse events
Adverse events Withdrawals due to adverse events Dry mouth Moderate to severe or severe dry mouth Headache Constipation Vision abnormality
WMD
95% CI, WMD
Test for overall effect ( p value)
Difference in favor
RCT (no.)
Participants (no.)
OR
95% CI, OR
Test for overall effect ( p value)
5 6
1181 1409
2.30 1.82
1.70–3.11 1.33–2.49
<0.00001 0.0002
Tolterodine IR Tolterodine IR
6 4
1355 894
3.98 7.21
3.16–5.02 4.50–11.52
<0.00001 <0.00001
Tolterodine IR Tolterodine IR
3 1 2
826 378 430
0.83 0.68 1.39
0.52–1.34 0.30–1.50 0.69–2.82
0.45 0.33 0.36
None None None
UUI, urgency urinary incontinence; WMD, weighted mean difference; CI, confidence interval; OR, odds ratio.
during the first 4 wk of active treatment before solifenacin dose escalation, showed similar efficacy for solifenacin 5 mg and tolterodine ER with regard to reduction in number of micturitions per 24 h and most of the secondary end points [60]. In the two RCTS comparing solifenacin and tolterodine [26,59] the format used to report efficacy data was unsuitable for meta-analysis. With regard to adverse events, the meta-analysis, although impaired by the use of different doses of solifenacin and different formulations of tolterodine, suggests that only constipation (OR: 2.78; 95% CI, 1.70–4.54; p < 0.0001) was more common in the solifenacin arm (Table 11). 3.2.9.
Tolterodine versus fesoterodine
A single RCT compared fesoterodine to tolterodine [33]. The trial was designed to compare the fesoterodine 4 mg and fesoterodine 8 mg to placebo and included an active control arm in which the
patients were treated with tolterodine ER 4 mg. Fesoterodine 8 mg outperformed tolterodine 4 mg with regard to the median change from baseline in number of UUI episodes ( p < 0.05) and volume voided per micturition ( p < 0.05), while similar efficacy was shown for fesoterodine 4 mg and tolterodine 4 mg. Fesoterodine 4 mg and tolterodine ER 4 mg had overlapping statistics with regard to complications and adverse events, while fesoterodine 8 mg was followed by significantly higher rates of dry mouth ( p < 0.0001) and dry eye ( p = 0.02), compared with tolterodine 4 mg [33]. 3.3.
Comparison of different routes of administration
Tables 12 and 13 summarize the efficacy and safety data from the available RCTs comparing different routes of administration of anticholinergic drugs. Two RCTs compared the oral and transdermal routes of administration of oxybutynin [64,65].
Table 11 – Meta-analysis of randomized control trials (RCTs) comparing solifenacin and tolterodine Solifenacin 5 mg and solifenacin 10 mg vs tolterodine ER Withdrawals due to adverse events Dry mouth Constipation Vision abnormality CI, confidence interval; OR, odds ratio.
RCT
Participants
OR
95% CI, OR
Test for overall effect ( p value)
2 2 2 2
1987 1987 1987 1987
1.27 1.21 2.78 1.34
0.74–2.18 0.97–1.50 1.70–4.54 0.68–2.64
0.39 0.08 <0.0001 0.40
Difference in favor
None None Tolterodine ER None
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european urology 54 (2008) 740–764
Table 12 – Efficacy data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference
Dosage (no. of cases)
Treatment duration
Davila et al 2001 [64]
Oxy IR 2.5 mg bid or tid (38) Oxy TDS twice a week (38)
Dmochowski et al 2003 [65]
Tolt ER 4 mg qd (123) Oxy TDS 3.9 mg qd (121)
Jadad score
4 wk
3
12 wk
3
Mean change in micturitions per 24 h
Mean change in VV per micturitions (ml)
NR
2.2 (18%) 1.9 (15%)
Mean change in incontinence episodes per 24 h
NR
0.8 (23%) 0.4 (17%)
+29 (19%) +32 (19%)
3.2 (64%) 2.9 (62%)
VV, voided volume; NR, not reported; qd: once daily; bid: twice daily; tid: three times daily. Placebo transdermal system was used in those patients taking oral anticholinergic drugs.
Table 13 – Safety data from the randomized control trials (RCTs) comparing oral and transdermal formulations of anticholinergic drugs Reference
Dosage (no. of cases)
Davila et al 2001 [64]
Oxy IR 2.5 mg bid or tid (38) Oxy TDS twice a week (38)
Dmochowski et al 2003 [65]
Tolt ER 4 mg qd (123) Oxy TDS 3.9 mg qd (121)
Treatment Jadad Systemic Localized Withdrawal Dry Constipation duration score adverse application due to mouth event site adverse (%) rate reaction* events
AUR
Vision abnormality
4 wk
3
NR
23% 38%
NR
82% 39%
50% 21%
34% 24%
24% 18%
12 wk
3
24% 19%
5.7% 26%
2% 11%
7% 4%
6% 3%
NR
NR
AUR, acute urinary retention; NR, not reported; qd, once daily; bid, twice daily; tid, three timse daily. *
Placebo transdermal system was used in those patients taking oral anticholinergic drugs.
Specifically, Davila et al compared the efficacy and safety of oxybutynin IR at different doses administered orally or transdermally [65], while Dmochowski et al evaluated transdermal oxybutynin 3.9 mg once daily and tolterodine ER 4 mg once daily [65]. Meta-analysis of efficacy showed similar reduction in the number of incontinence episodes per 24 h (WMD: 0.05; 95% CI, 0.58–0.67; p = 0.88). Dry mouth (OR: 3.67; 95% CI, 1.73–7.81; p = 0.0007) and constipation (OR: 2.78; 95% CI, 1.27–6.08; p = 0.01) were significantly more common in those patients taking the drug orally, while localized application side effects (OR: 0.26; 95% CI, 0.14– 0.49; p < 0.0001) and withdrawal due to adverse events (OR: 0.14; 95% CI, 0.03–0.62; p = 0.01) were significantly more frequent in those patients receiving active transdermal formulations (Table 14; Fig. 6).
3.4.
Publication bias
‘‘Funnel plots’’ of the studies used in this metaanalysis were generated for all of the evaluated comparisons. Only four studies [15,21,45,62] lay outside the 95% CI with an even distribution around the vertical, suggesting little evidence of publication bias (plots not shown).
4.
Discussion
Due to the large number of drugs available on the market, the selection of the most appropriate one for every single patient might be quite a complex task. The choice of the first drug to be used, the selection of the most appropriate dosage, formulation, and route of administration, the criteria for selection of a
Table 14 – Meta-analysis of adverse events with oral and transdermal formulations of anticholinergic drugs Oral oxybutynin vs transdermal oxybutynin
RCT (no.)
Participants (no.)
OR
95% CI, OR
Systemic adverse event Localized application site reactions Withdrawals due to adverse events Dry mouth Constipation Vision abnormality
1 2 1 2 2 1
244 320 244 320 320 76
1.31 0.26 0.14 3.67 2.78 1.37
0.71–2.43 0.14–0.49 0.03–0.62 1.73–7.81 1.27–6.08 0.45–4.17
RCT, randomized control trials; OR, odds ratio; CI, confidence interval.
Test for overall effect ( p value) 0.38 <0.0001 0.01 0.0007 0.01 0.57
Difference favors
None Oral Oral Transdermal Transdermal None
758
european urology 54 (2008) 740–764
Fig. 5 – Forest plots of adverse events after oxybutynin immediate release (IR) or tolterodine IR. (A) Occurrence of any adverse event; (B) withdrawals due to adverse events; (C) dry mouth of any severity; (D) moderate to severe or severe dry mouth. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
european urology 54 (2008) 740–764
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Fig. 6 – Forest plots of adverse events after oral and transdermal formulations of anticholinergic drugs. (A) Localized application site reactions; (B) withdrawal due to adverse events; (C) dry mouth of any severity; (D) constipation. OAB, overactive bladder; n, number of patients with the observed event; N, number of patients in the study arm; OR, odds ratio; CI, confidence interval.
second anticholinergic drug in case of insufficient efficacy or intolerable adverse events, and, finally, costs are some of the most important issues that should be evaluated. The data from our systematic review and metaanalyses showed that tolterodine IR had a more favorable profile of adverse events than oxybutynin IR, while the ER formulations of the two drugs had
similar efficacy and safety profiles. In all the comparisons among IR and ER formulations, the latter showed some advantages, either in terms of efficacy (tolterodine IR vs oxybutynin ER; tolterodine IR vs tolterodine ER) or safety (oxybutynin IR vs oxybutynin ER; oxybutynin IR vs tolterodine ER; oxybutynin IR vs darifenacin). With regard to solifenacin, a single RCT demonstrated the non-
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inferiority of solifenacin compared to tolterodine ER [59], while our meta-analysis showed similar rates of adverse events, with the exception of constipation, which was more common in the solifenacin arm. A single trial is currently available on fesoterodine, suggesting that the new drug might be more efficacious than tolterodine ER. With regard to the routes of administration, the transdermal route does not seem to provide any significant advantage compared to the oral intake, considering the higher rate of side effects from localized application and withdrawal due to adverse events. Providing clear indications for the clinical practice, however, is quite difficult. With regard to the selection of the first drug to use in naı¨ve patients, the RCTs comparing different drugs often enrolled a large number of patients who had previously been treated with other drugs. Considering this issue as a mandatory starting point, according to our data, the first drug which might be used in naı¨ve patients is oxybutynin ER, tolterodine ER 4 mg, solifenacin 5 mg, or solifenacin 10 mg. Similarly, darifenacin 15 mg and fesoterodine 4 mg might be considered as valuable options, but further evaluation is needed, and further RCTs are ongoing. In case of insufficient clinical efficacy, the choice of the second drug cannot really be based on evidence because, to our knowledge, no randomized trials were aimed at identifying the most efficient drug in the case of lack of success with some of the other first-line choices. Making assumptions from the available data, in case of lack of efficacy of the first-line ER drug, fesoterodine 8 mg and solifenacin 10 mg might be a possible option, due to the results of the two available trials comparing fesoterodine or solifenacin to tolterodine ER [26,33,59], although an increased rate of adverse events must be taken into account. In case of failure of the first-line ER drug due to intolerable adverse events, the availability of clear evidence-based recommendations is limited. In case of dry mouth, a transdermal formulation might provide some advantages compared to the oral one, and some authors suggested that it might be used as first-line therapy [66], but the metaanalysis suggested that localized application site reactions are very common and might significantly impact the patients’ compliance with this formulation. On the other hand, if constipation is the most bothersome adverse event, it can be managed by shifting from solifenacin to tolterodine ER. However, despite the lack of evidence, it might be wise to suggest that the patients take one of the other oral drugs before starting more invasive treatments, but controlled studied are needed to provide evidence-
based answers to these clinical questions. Conversely, those patients taking IR formulations of anticholinergic drugs without successful results might be offered dose titration in case the patients did not experienced significantly adverse events, but ER formulations might be the preferred choice. The overall quality of the randomized controlled trials available in the field of OAB was good, with most of the RCTs having a Jadad score 3. However, almost all the trials evaluated short-term therapy (mostly 12 wk), with only a single study continuing the drug therapy for 52 wk [56], and some adverse events, such as the impact on cognitive function, should be better evaluated. Moreover, almost all of the studies provided efficacy data derived from bladder diaries [67]; a more suitable evaluation should also include subjective outcomes, such as the so-called patient-reported outcomes [7], which are lacking in most of the studies. However, virtually all the evidence has been derived from pharmaceutical company–sponsored trials, which, to date, have been the only way to realize those very expensive, good-quality, large-scale trials. However, the studies’ designs reflect the needs of the companies for registrational studies, rather than addressing the questions that are more relevant for clinical practice. According to the criteria of the Overview Quality Assessment Questionnaire (OQAQ) [68], our systematic review can be considered to be a goodquality review. However, due to the limitations of the Review Manager software, which allows the evaluation of continuous variables only if they are expressed as means and standard deviations, it was not possible to perform meta-analysis for some clinically relevant efficacy outcomes due to the lack of data in the published reports. Although all the authors of the RCTs were contacted with the aim of obtaining the needed data in the appropriate format, the attempt was not successful in most cases.
5.
Conclusions
Many of the available RCTs in the field of muscarinic receptor antagonists for overactive bladder are of good methodological quality. ER formulations should be preferred to the IR formulations due to the more favorable profile of efficacy and adverse events. With regard to IR formulations, dose escalation might yield some improvements in the efficacy, but at the cost of a significant increase in the rate of adverse events. More clinical studies are needed to determine which of the available drugs should be used as first-, second-, and third-line treatments.
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Author contributions: Walter Artibani had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Novara, Ficarra, Artibani. Acquisition of data: Galfano, Secco, D’Elia. Analysis and interpretation of data: Novara, Galfano, Ficarra, Artibani. Drafting of the manuscript: Novara. Critical revision of the manuscript for important intellectual content: Galfano, Secco, D’Elia, Cavalleri, Ficarra, Artibani. Statistical analysis: Novara. Obtaining funding: None. Administrative, technical, or material support: Cavalleri. Supervision: Ficarra, Artibani. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr Novara has been a consultant, investigator, or speaker for Bioxell, GlaxoSmithKleine, Pfizer Inc., and Pierre Fabre. Dr Galfano has been a consultant or investigator for Astellas, Bayer, Bioxell, Novartis, and Pfizer Inc. Prof Ficarra has been a consultant, investigator or speaker for Bioxell, Novartis, and Pfizer Inc. Prof Artibani has been a consultant, investigator, or speaker for Astellas, Bayer, Bioxell, Novartis, Pfizer Inc., Pierre Fabre, and UCB. Drs Secco, D’Elia, and Cavalleri have nothing to disclose. Funding/Support and role of the sponsor: None.
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[51] Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003;78:687–95. [52] Homma Y, Paick JS, Lee JG, Kawabe K, Japanese, Korean Tolterodine Study Group. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU Int 2003;92:741–7. [53] Giannitsas K, Perimenis P, Athanasopoulos A, Gyftopoulos K, Nikiforidis G, Barbalias G. Comparison of the efficacy of tolterodine and oxybutynin in different urodynamic severity grades of idiopathic detrusor overactivity. Eur Urol 2004;46:776–83. [54] Homma Y, Kawabe K. Health-related quality of life of Japanese patients with overactive bladder treated with extended-release tolterodine or immediate-release oxybutynin: a randomized, placebo-controlled trial. World J Urol 2004;22:251–6. [55] Madersbacher H, Halaska M, Voigt R, Alloussi S, Ho¨fner K. A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84:646–51. [56] Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol 2003;20:392–9. [57] Junemann KP, Al-Shukri S. Efficacy and tolerability of trospium chloride and tolterodine in 234 patients with urgesyndrome: a double blind, placebo-controlled, multicentre clinical trial. Neurourol Urodynam 2000;488–90, abstract. [58] Ju¨nemann K-P, Halaska M, Rittstein T, et al. Propiverine versus tolterodine: efficacy and tolerability in patients with overactive bladder. Eur Urol 2005;48:478–82. [59] Chapple CR, Martinez-Garcia R, Selvaggi L, et al. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating
Editorial Comment on: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder Rufus Cartwright Department of Urogynaecology, King’s College Hospital, London, UK [email protected] Previous meta-analyses and evidence-based guidelines concerning antimuscarinic medications for overactive bladder (OAB) have conflicting
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recommendations with no consensus about appropriate first-line or second-line therapy [1–3]. With an increasing number of available agents and formulations licensed, the choice of antimuscarinic for patients with OAB has become complicated. The authors of this paper [4] have taken on the Herculean task of reviewing and analysing existing randomised controlled trials (RCTs) that might potentially help clinicians to make an evidencebased choice. So, is it a case of cleaning the Augean stables? The good news is clearly that existing RCTs are generally of high methodological quality.
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It is lamentable, however, that even within the limited scope of the objective outcomes considered in this review, many trials are still reporting data in a format that is not amenable to meta-analysis. This difficulty in comparing and assimilating data from different trials is compounded by the wide variety of outcome measures employed, some of which are of limited relevance to patients. The increased regulation in the European Union puts large, multicentre drug trials out of the reach of all but the most organised and determined bodies. As the authors note, most available antimuscarinic data are, therefore, from industry-led trials. There may be a conflict between so-called ‘‘experimercials’’ [5], aiming to increase market share, and the needs of clinicians in providing targeted interventions. The key question, which remains largely unanswered for this class of medication, regards long-term subjective efficacy for different subgroups of OAB patients. As efficacious pharmaceutical agents from different classes are developed and as different modalities of treatment become established, it is to be hoped that long-term, head-to-head studies will help define the roles of different antimuscarinic medications and formulations more clearly.
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DOI: 10.1016/j.eururo.2008.06.081 DOI of original article: 10.1016/j.eururo.2008.06.080