A COMPARATIVE TRAIL TO COMPARE EFFICACY OF SOLIFENACIN,

DARIFENACIN AND MIRABEGRON ON OVER ACTIVE BLADDER.

Shabi Ahmad, Shashank Shekhar Tripathi, Nandan Rai
Department of SURGERY, MLN Medical college, Allahabad

nandanrai4@gmail.com
ABSTRACT

Aims and ObjectivesPage 1

 Introduction: Over active bladder is defined as Urgency with or
without Urge incontinence, usually with frequency and Nocturia. In
today scenario, Main treatment modality for Over active bladder is
Pharmacotherapy with life style modification. In pharmacotherapy,
A FDA approved β3-Adrenoceptor agonist drug Mirabegron is also
main stay of treatment with better and quick response and
improvements with lesser antimuscarinic side effects.

Aim: To compare efficacy as well as Side Effect of solifenacin,

Darifenacin and Mirabegron on over active bladder.

Material and method: All patients who were attending in

Urosurgery OPD during period from September 2017 to August
2018 were included in study. A Total of 94 pts was included in
which lost to follow up was 4. So, total 90 pts were divided into
three groups G1 solifenacin, G2 Darifenacin G3 Mirabegron in
which 30 pts allocated into each group. Initially, Drugs was given
then pts were called for follow up on 4wk and 12wk to access the
drug effect and side effect.

Result: The Result drawn from this study are as follows: -

 Mean age of the patients suffering from overactive bladder was

63.11 ± 12.11 years.
 Mirabegron has higher efficacy than Solifenacin and Solifenacin
has higher efficacy than Darifenacin to decrease number of
micturition episode per 24 hrs and in other symptoms of OAB,
mirabegron superior over solifenacin and Darifenacin which is
statically significant(p-value<0.05).
Conclusion: After 12 weeks of follow up, Mirabegron was superior
over Solifenacin and Darifenacin for over active bladder treatment
with lesser anti-muscarinic side-effects with better response and
quick control over symptoms.

Aims and ObjectivesPage 2

 PAPER:

INTRODUCTION:
Overactive Bladder (OAB) is defined as urgency with or without urge
incontinence, usually with frequency and nocturia.Urgency and urge
incontinence are the key symptoms of OAB.

All these complaints increase the morbidity of the patients and traditionally
four classes of treatment are used for overactive bladder and painful bladder
syndrome2,50,51. In treatment of intractable OAB, Conservative management
includes weight loss, cessation of smoking, & dietary factors like decreased
fluid intake, decreased alcohol intake, changes in food and drink. Lifestyle
interventions include pelvic floor muscle training and bladder retraining. The
goals of pharmacotherapy are to improve overactive bladder (OAB)
symptoms, reduce morbidity, and prevent complications. Anti-cholinergics
are the first-line agents used to treat OAB. Other treatments approved for use
in OAB include the beta3-receptor agonist Mirabegron and detrusor
injections of Onabotulinumtoxin-A. Antimuscarinic drugs like Solifenacin,
Darifenacin, Tolterodine, Trospium, and β3-Adrenoceptor agonist
Mirabegron are recommended drugs.

Out of all the drugs mentioned above, antimuscarinic drugs selectively

block muscarinic receptors and are used for treatment of overactive bladder
and detrusor over activity (DO). Non-antimuscarinic (MIRABEGRON- β3
adrenergic drug) is a newer drug class approved for OAB it claims better
control and less side-effects.

Aims and ObjectivesPage 3

 Antimuscarinic drugs used for the treatment of OAB/DO have different
efficiency and different grading of side effects like dry mouth, constipation,
upset stomach, dry eyes etc.Non-antimuscarinic (MIRABEGRON- β3 adrenergic
drug) now newer drug is used for better and quick treatment and control over
OAB symptoms and has less side-effects.

In Surgical therapy Neural stimulation/Modulation, Detrusor myectomy,

Cystoplasty are standards of treatment.Treatment of Intractable OAB includes
Catheters-Urethral/Suprapubic Appliances, Urethral Closure and Diversion.

Aims and Objectives

Aims of the study was to assess the effect of the three smooth muscle
relaxants, Mirabegron, Solifenacin and Darifenacin used for treatment of
overactive bladder, and Comparison of three drugs groups as monotherapy
(Solifenacin, Darifenacin and Mirabegron) regarding the efficacy as well as side
effects.

Materials and Methods

It was a Comparative Clinical Trial, the study was carried out in Swaroop Rani
Nehru Hospital of MLN Medical College, Allahabad, during period of study
(study period Oct 2017 to Sept 2018).All the patients who were attending OPD
of general surgery/urosurgery in Swaroop Rani Nehru Hospital of MLN Medical
College, Allahabad, during study period with complaints of frequent urination,
urgent need to urinate and inability to control urination, increased episodes of
urination in night were included in the study. All old patients who were already
taking drugs (solifenacin /darifenacin) were also included.

Aims and ObjectivesPage 4

 All new patients were divided into three groups G1, G2, and G3. Patient were
consecutively enumerated for each group. Patient1 for G1, patient 2 for G2 and
patient 3 for G3, patient 4 for G1 and so on.

Thus, a total of 100 new patients were enumerated during study period to be
included in study in which 34 in G1, 33 in G2 and 33 in G3. Group offered -

G1-Solifenacin for treatment (doses-5mg, 10mg)

G2-Darifenacin for treatment (doses- 7.5mg, 15mg)

G3-Mirabegron for treatment (doses- 25mg, 50mg)

A total of 100 patients were fulfilling the inclusion criteria and thus were
included in study. New patient was divided into three groups G1, G2 and G3,
34patients were allocated to G1, 33 to G2 and 33 to G3 respectively. The
patient was examined and evaluated. A semi-structured questionnaire was used
for collection of data from patients. The patients were followed up at 4weeks
and 12weeks and improvement and side-effects, if any were assessed in each
visit. During the follow-up, 4 patients from G1; 3 from G2; and 3 from G3
were lost as they missed either one or more of the follow-up visits. So finally,
data was analysed for these 90 new patients, 30 remaining in each group after
excluding the patients lost to follow-up. The data was entered in statistical
software SPSS 21.0. Appropriate statistical tests including Chi-square,
ANOVA and REPEAT MEASURES ANALYSIS were used in this study. In
this study, comparison of improvements and side-effects were calculated as in
terms of GOOD, BAD OR NO-RESPONSE in term of-
FOR NEW PTS:
GOOD- in term of improvement in numbers of nocturia episode, decrease in
no. of frequency, decreased incontinence, improvements in life style, decrease
in urge incontinence.

Aims and ObjectivesPage 5

BAD: in term of NO improvement in numbers of nocturia episode, NO decrease
or increase in frequency, NO decreases or increase in incontinence, NO
improvements in life style, NO decrease or increase in urge incontinence.
NO-RESPONSE: in term of response in between GOOD and BAD or no response
or improvement in symptoms after continues long treatment.

Observations

Aims and ObjectivesPage 6

Table-1: Patient's Characteristics

Aims and ObjectivesPage 7

 Demographics

S D M

No. of patient 30 30 30

Gender

Male 29(96.6%) 27(90%) 25(83.33%)

Female 1(3.33%) 3(10%) 5(16.66%)

Age(Avg) 68.13 59.3 59.33

Aims and ObjectivesPage 8

 Table-2: Baseline characteristics of symptoms of patients –

Group S D M

No. of
30 30 30
Patient

MEAN±SD

M 5.36±0.668 5.4±O.723 5.24±0.623

U 1.4±0.563 1.6±0.553 1.806±0.654

IN 1.23±0.568 1.73±0.784 1.870±0.670

UI 1.46±0.507 1.76±0.626 1.870±0.718

N 2.13±0.628 2.73±0.639 1.870±0.718

Aims and ObjectivesPage 9

 6

0
M
U
IN
UI
N

S D M

Graph 2: Baseline characteristics of symptoms of patients

Efficacy regarding Decrease in Micturition Episodes per 24 hrs

Table-3 : Mean±SD of Micturition Episodes per 24 hrs

Baseline 4wk 12wk P-Value F-Value

S 5.36±.668 5.20±.633 4.9±.602 0.021 4.058

D 5.4±.723 5.1±.682 5.02±.662 0.085 2.533

M 5.54±.623 5.21±.592 5.01±.549 0.003 6.199

Aims and ObjectivesPage 10

 5.6

5.4

5.2

4.8

4.6

4.4
S
D
M

Baseline 4wk 12wk

Graph 3: Mean base line to end point changes in

micturition episodes/24 hrs.

A. MONOTHERAPY GROUPS: -

Outcome from above table and graph show that Mirabegron treatment was
superior than Solifenacin, whereas Solifenacin treatment was superior to
Darifenacin with respect to change from baseline in mean number of
micturition for 24 hrs. Solifenacin treatment resulted in a mean baseline to end
point reduction of 0.46 micturition per 24 hours compared with reduction of
0.38 episodes for patients of Darifenacin group and reduction of 0.53 episodes
per 24 hrs for Mirabegron taking patients. The changes in frequency of
micturition over the duration of 12wks was found to be statistically significant
in case of Solifenacin (p-value=0.021) and in case Mirabegron (p-value =0.003).

Aims and ObjectivesPage 11

At the same time, it was observed that at the end of 4wk week treatment with
Mirabegron 25mg OD, Solifenacin 5 mg OD and Darifenacin 7.5 mg OD, the
efficacy of Mirabegron was more than Solifenacin, and Solifenacin was more
than that of Darifenacin, because at 4 weeks, reduction of micturition episode
per 24 hours for Mirabegron was 0.33 micturition/24 hrs, with Solifenacin
reduction was 0.16 micturition/24 hrs and for Darifenacin it was 0.30
micturition/24 hrs. And at 12 weeks, reduction of micturition episodes per 24
hours for Mirabegron was 0.53 micturition/24 hrs, while with Solifenacin 0.46
micturition/24 hrs and for Darifenacin it was 0.38 micturition/24 hrs.
Efficacy of Improvement in Urgency Episodes per 24 Hrs.

Table-4: Mean±SD of Urgency Episodes/24 hrs.

Aims and ObjectivesPage 12

 Baseline 4wk 12wk P-Value F-Value

S 1.4±0.563 1.2±0.532 1.03±0.512 0.032 3.581

D 1.6±.553 1.4±.533 1.3±.512 0.091 2.465

M 1.89±0.634 1.683±0.412 1.581±0.362 0.046 3.192

2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
S
D
M

Baseline 4wk 12wk

Graph 4: Mean base line to end point changes

in urgency episodes \ 24 hrs.

A. MONOTHERAPY GROUPS: -Outcome from above table and graph

show that Mirabegron treatment was superior to solifenacin where as
Solifenacin treatment was superior to Darifenacin with respect to change
from baseline in mean number of micturition for 24 hrs. Solifenacin
treatment resulted in a mean baseline to end point reduction of 0.27
micturitions per 24 hours compared with reduction of 0.30 episodes for
patients of Darifenacin group and reduction of 0.31 episodes per 24 hrs
for Mirabegron taking patients. The changes in frequency of urgency over
the period of 12wks was found to be statistically significant in case of
Solifenacin (P-value=0.032) and Mirabegron (p-value=0.046).

Aims and ObjectivesPage 13

At the same time, it was observed that at the end of 4 weeks treatment with
Mirabegron 25mg, Solifenacin 5 mg OD and Darifenacin 7.5 mg OD, the efficacy
of Mirabegron was more than Solifenacin and Solifenacin was more than that
of Darifenacin, because at 4 week , reduction of micturition episode per 24
hours for Mirabegron (0.21 micturition/24 hrs.), Solifenacin (0.20
micturition/24 hrs.) and for Darifenacin it was (0.20 micturition/24 hrs.) and at
12 week , reduction of micturition episode per 24 hours for Mirabegron (0.31
micturition/24 hrs.), Solifenacin (0.37 micturition/24 hrs.) and for Darifenacin it
was (0.30 micturition/24 hrs).

Aims and ObjectivesPage 14

Efficacy Regarding Improvement in Incontinence Episodes / 24 hrs.

Table-5 : Mean±SD of Incontinence Episodes/24 hrs.

Aims and ObjectivesPage 15

 Baseline 4wk 12wk P-Value F-Value

S 1.23±0.568 1.02±0.512 0.96±0.490 0.118 2.193

D 1.73±0.784 1.52±0.722 1.50±0.708 0.892 0.413

M 1.87±0.601 1.631±0.49 1.562±0.381 0.048 3.15

2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
S
D
M

Baseline 4wk 12wk

Graph 5: Mean base line to end point changes in incontinence episodes \24
hrs

A. MONOTHERAPY GROUPS: -Outcome from above table and graph

show that Mirabegron treatment was superior than solifenacin with
respect to change from baseline in mean number of micturition for 24 hrs.
Solifenacin treatment resulted in a mean baseline to end point reduction
of 0.27 micturition per 24 hours compared with reduction of 0.23 episode
for patients of Darifenacin group and reduction of 0.31 episodes per 24
hrs for Mirabegron taking patients over the duration of 12wks.The
changes in frequency of incontinence over the period of duration of
12wks was found to be statistically significant in case of Mirabegron (P-
value=0.048).

Aims and ObjectivesPage 16

At the same time, it was observed that at the end of 4wk week treatment with
Mirabegron 25mg, Solifenacin 5 mg OD and Darifenacin 7.5 mg OD,
Mirabegron was superior than Solifenacin because at 4wk week, reduction of
micturition episode per 24 hours for Mirabegron(0.24 micturition/24 hrs.),
Solifenacin (0.21 micturition/24 hrs.) and for Darifenacin it was (0.21
micturition/24 hrs.) and at 12 week, reduction of micturition episode per 24
hours for Mirabegron (0.31 micturition/ 24 hrs.), Solifenacin (0.37 micturition/
24 hrs.) and for Darifenacin it was (0.23 micturition/ 24 hrs).

Efficacy of Improvement in Urge Incontinence Episodes/24 hrs.

Table-6: Mean±SD of Urge Incontinence Episodes/24 hrs.

Baseline 4wk 12wk P-Value F-Value

S 1.46±.507 1.42±.49 1.40±.37 P=0.729 F=0.317

D 1.76±.626 1.38±0.492 1.06±0.41 P=0.000 F=13.81

M 1.87±0.618 1.692±0.403 1.562±0.294 P=0.037 F=3.44

Aims and ObjectivesPage 17

 2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
S
D
M

Baseline 4wk 12wk

Graph 6: Mean base line to end point changes in

urge incontinence episodes\24hrs

A. MONOTHERAPY GROUPS: -Outcome from above table and graph

show that Mirabegron treatment was superior than solifenacin where as
Darifenacin treatment was superior to Solifenacin with respect to change
from baseline in mean number of micturition for 24 hrs. Solifenacin
treatment resulted in a mean baseline to end point reduction of 0.06
micturition per 24 hours compared with reduction of 0.70 episode for
patients of Darifenacin group and reduction of 0.31 episodes per 24 hrs
for Mirabegron taking patients over the duration of 12wks.The changes in
urge incontinence episodes over the duration of 12wks was found to be
statistically significant in case of Mirabegron (P=value=0.037) and
Darifenacin (P-value=0.00000001)

Aims and ObjectivesPage 18

At the same time, it was observed that at the end of 4wk week treatment with
Mirabegron 25mg,Solifenacin 5 mg OD and Darifenacin 7.5 mg OD, the efficacy
of Mirabegron was more than Solifenacin and Darifenacin was more than that
of Solifenacin, because at 4 week, reduction of micturition episode per 24
hours for Mirabegron (0.18 micturition/24 hrs.), Solifenacin (0.04
micturition/24 hrs.) and for Darifenacin it was (0.38 micturition/24 hrs.) and at
12 week, reduction of micturition episode per 24 hours for Mirabegron (0.31
micturition/24 hrs.), Solifenacin (0.06 micturition/24 hrs.) and for Darifenacin it
was (0.70 micturition/24 hrs).

Efficacy regarding improvement in Nocturia Episodes per 24 hours

Table-7: Mean±SD of Nocturia Episodes/24 hrs.

Baseline 4wk 12wk P-Value F-Value

S 2.13±0.678 2.07±0.47 1.82±0.302 0.046 3.197

D 2.73±.63 2.52±.603 2.24±.592 0.01 4.89

M 1.87±0.638 1.668±0.483 1.502±0.334 0.02 4.065

Aims and ObjectivesPage 19

 3

2.5

1.5

0.5

0
S
D
M

Baseline 4wk 12wk

Graph 7: Mean base line to end point changes

in Nocturia episodes\24hrs

A. MONOTHERAPY GROUPS: -Outcome from above table and graph

show that Mirabegron treatment was superior than Solifenacin where as
Darifenacin treatment was superior to Solifenacin with respect to change
from baseline in mean number of micturition for 24 hrs. Solifenacin
treatment resulted in a mean baseline to end point reduction of 0.31
micturition per 24 hours compared with reduction of 0.49 episode for
patients of Darifenacin group and reduction of 0.37 episodes per 24 hrs
for Mirabegron taking patients over the duration of 12wks.The changes in
frequency of nocturia over the duration of 12wks was found to be
statistically significant in case of Solifenacin (P-value=0.046),
Darifenacin (P-value=0.010) and Mirabegron (P-value=0.020)

Aims and ObjectivesPage 20

At the same time, it was observed that at the end of 4 week treatment with
Mirabegron 25mg, Solifenacin 5 mg OD and Darifenacin 7.5 mg OD, the efficacy
of Mirabegron was more than Solifenacin and Darifenacin was more than that
of Solifenacin, because at 4wk week, reduction of nocturia episode per 24
hours for Mirabegron (0.21 micturition/24 hrs.), Solifenacin (0.06
micturition/24 hrs.) and for Darifenacin it was (0.21 micturition/24 hrs.) and at
12 week, reduction of micturition episode per 24 hours for Mirabegron (0.37
micturition/24 hrs.), Solifenacin (0.31 micturition/24 hrs.) and for Darifenacin it
was (0.49 micturition/24 hrs).

Aims and ObjectivesPage 21

COMPARISON OF RESPONSE OF DRUGS-

Table-8: Comparison of response of drugs .

Bad No Response Good
S 7 23.33% 8 26.33% 15 50.00%
D 7 23.33% 11 36.66% 12 40%%
M 3 10% 4 13.33% 23 76.66%

Aims and ObjectivesPage 22

 25

20

15

10

0
S
D
M

Bad No Response Good

Graph 8: Comparison of response of drugs

Comparison of response was done using chi-square test (2*2) and following
results was evaluated-

A. MONOTHERAPY COMPARISION-

1. Solifenacin v/s Mirabegron-

Good No-Response/Bad

Group-1(S) 15 15

Group-2(M) 23 7

p-Value=0.032 (<0.05)

Chi-Square = 4.59

Aims and ObjectivesPage 23

 25

20

15

10

0
Good
No-Response/Bad

Group-1(S) Group-2(M)

 Above chart and graph showing, Mirabegron was superior in terms of

Response than Solifenacin.

 Mirabegron having lesser side effects than solifenacin was statistically

significant.

2.Darifenacin v/s Mirabegron-

Good No-Response/Bad

Group-1(D) 12 18

Group-2(M) 23 7

p-Value= 0.003 (<0.05)

Chi-Square = 8.297

Aims and ObjectivesPage 24

 25

20

15

GROUP-1(D)
10 GROUP-2(M)

GOOD
NO-RESPONSE/BAD

 Above chart and graph showing, Mirabegron was Superior in terms of

Response than Darifenacin.

 Mirabegron having less side effects than Darifenacin which was

statistically significant.

3. Darifenacin v/s Solifenacin-

Good No-Response/Bad

Group-1(D) 12 18

Group-2(M) 15 15

p-Value=0.436 (>0.05)

Chi-Square = 0.606

Aims and ObjectivesPage 25

 18

16

14

12

10

GROUP-1(D)
8
GROUP-2(M)

GOOD
NO-RESPONSE/BAD

 Above chart and graph showing, Solifenacin and Darifenacin was in

terms of response was non- significant.

 Solifenacin having less side effects than darifenacin which was

statistically non- significant.

Table-9 : Comparison of Side Effects

Acute retention Acute exacerbation of Anti-
Side effect Headache
of urine hypertension Cholinergic
S 2 6.66% 3 10% 2 6.66% 5 16.66%
D 3 10% 4 13.33% 3 10% 6 20%
M 3 10% 3 10% 3 10% 2 6.66%

Aims and ObjectivesPage 26

 6

0
Acute retention of
urine Headache
Acute exacerbation of
hypertension Anti-Cholinergic

S D M

Graph 9: Comparing side-effects of drugs

Above table shows that most common side effects of Darifenacin and
Solifenacin were Anti-cholinergic (eg.-dry mouth, constipation, blurring of
vision).

 Mirabegron had lesser side effects than Solifenacin was statistically significant.

 Mirabegron had lesser side effects than Darifenacin which was statistically
significant.

 Solifenacin had lesser side effects than Darifenacin which was statistically non-
significant.

Conclusions
The conclusions drawn from this study are, Mean age of the patients suffering
from overactive bladder was 63.11 ± 12.11 years.
IN MONOTHERAPY: -

Aims and ObjectivesPage 27

  Mirabegron has higher efficacy than Solifenacin and Solifenacin has
higher efficacy than Darifenacin to decrease number of micturition
episode per 24 hrs.

 Solifenacin and Mirabegron both are almost equally efficacy but more
than Darifenacin to decrease urgency episode per 24 hrs.

 Darifenacin and Mirabegron were superior to Solifenacin for treatment of

urge incontinence but Mirabegron and Darifenacin have equal efficacies.

 Regarding nocturia, Mirabegron, Solifenacin and Darifenacin all three

were of equal efficacy in controlling nocturia episodes per 24 hours
however darifenacin controls better.

 Therefore, regarding treatment of overactive bladder, Mirabegron can be

suggested as first choice of drug in monotherapy.

Aims and ObjectivesPage 28