Tamsulosin and placebo vs tamsulosin and
tadalafil in male lower urinary tract symptoms: a
double-blinded, randomised controlled trial
Santhosh Nagasubramanian* , Nirmal Thampi John*, Belavendra Antonisamy†, Rajiv
Paul Mukha*, Chandra Singh Jeyachandra Berry*, Santosh Kumar*, Antony Devasia*
and Nitin Sudhakar Kekre*
†
* Departments of Urology, and Biostatistics, Christian Medical College, Vellore, India
Objective
To compare the efficacy and safety of tamsulosin vs the
combination of tamsulosin and tadalafil in male lower urinary
tract symptoms (LUTS).
Patients and Methods
This was a double-blinded, parallel-arm randomised controlled
trial. Men aged >45 years with moderate LUTS and a
maximum urinary flow rate (Qmax) of 5–15 mL/s were
included. One arm received 0.4 mg tamsulosin only (Group-A),
while the second received 5 mg tadalafil with tamsulosin
(Group-B). The primary outcome was the International
Prostate Symptom Score (IPSS). Secondary outcomes were IPSS
quality of life (QoL) score, five-item version of the International
Index of Erectile Function (IIEF-5) score, Qmax, and post-void
residual urine (PVR). Block randomisation was used. Placebo
was used for blinding and allocation concealment. Intention-to-
treat analysis was used for outcome measures.
Results
Of the 183 men screened, 140 were randomised (71 in
Group-A, 69 in Group-B); 116 (82.85%) (61 in Group-A, 55
Introduction
The prevalence of LUTS and erectile dysfunction (ED) rises
with increasing age [1,2] and both have a negative impact
on quality of life (QoL) [2,3]. The aetiology of LUTS is
multifactorial [4]. Phosphodiesterase type 5 inhibitors
(PDE5i) are beneficial in male LUTS as they act on
proposed pathways common to LUTS and ED [4,5]. PDE5i
monotherapy for LUTS has shown improvement in
symptom scores, QoL scores and erectile function; however,
the effect on urinary flow rate has not been significant [6].
PDE5i monotherapy (tadalafil 5 mg) is approved for use in
LUTS [7]. However, the role of the combination of a-
BJU Int 2020; 125: 718–724
wileyonlinelibrary.com
in Group-B) completed the study. Baseline characteristics
were comparable. The improvements in the IPSS, IPSS QoL
score, IIEF score and Qmax were 1.69 (95% confidence
interval [CI] 1.4 to 2.0), 0.70 (95% CI 0.60 to 0.80),
3.8 (95% CI 3.4–4.2) and 1.8 mL/s (95% CI 1.1–2.4)
respectively, in favour of the combination group. The
difference in PVR was not significant. There were no serious
adverse events (AEs). The dropout rate due to AEs was
2.85%. Myalgia (five patients) was the commonest AE in the
combination group.
Conclusion
The combination of tamsulosin and tadalafil produced
significantly better improvements in LUTS, QoL, erectile
function and Qmax compared to monotherapy with
tamsulosin, without an increase in AEs.
Keywords
tamsulosin, tadalafil, phosphodiesterase inhibitors, lower
urinary tract symptoms, erectile dysfunction, #UroBPH
blockers and PDE5i in LUTS is still emerging and there
are only a few studies comparing the combination of a-
blockers and PDE5i with a-blocker monotherapy (often
considered the first-line treatment in male LUTS) [7]. Even
among the existing studies, there is heterogeneity in both
the type of a-blocker used and the type and dosage of
PDE5i used [6]. This is despite the fact that tamsulosin is
the safest a-blocker for combination with PDE5i [8,9] and
tadalafil 5 mg is the only PDE5i approved for use in male
LUTS [7]. Also, to the best of our knowledge, none of the
existing studies have been double-blinded randomised
controlled trials (RCTs) with intention-to-treat (ITT)
analysis [6,10].
© 2020 The Authors
BJU International © 2020 BJU International | doi:10.1111/bju.15027
Published by John Wiley & Sons Ltd. www.bjui.org

The present study aimed to compare the efficacy and safety
of tamsulosin 0.4 mg vs the combination of tamsulosin
0.4 mg and tadalafil 5 mg in male LUTS.
Patients and Methods
Study Design and Participants
This was a double-blinded RCT with two parallel arms
conducted at a single institution from September 2015 to
August 2016. The study was performed in accordance with
the Declaration of Helsinki. Institution Review Board and
Ethics Committee approval was obtained. The internal Data
Safety Monitoring Board reviewed the study periodically.
Informed video-consent was taken from all patients enrolled.
The patients were recruited from the outpatient department
and LUTS clinic. Men aged >45 years with moderate LUTS
(IPSS 8–19), a maximum urinary flow rate (Qmax) of 5–15 mL/s,
and willing to consent were included. The recruited patients
were on no prior medications for LUTS. Those with prostate
carcinoma, urethral stricture, severe LUTS, absolute indications
for surgery, UTIs, prior transurethral surgery, a post-void
residual urine (PVR) >300 mL, nitrates medication intake,
5a-reductase medication treatment, neurological conditions,
poorly controlled diabetes or hypertension, drug allergy/
allergies, and those unwilling to consent were excluded.
A detailed history including co-morbidities, list of present
medications was noted in all patients screened. Physical
examination including blood pressure measurement, clinical
examination, and DRE was performed. Self-administered IPSS
and five-item version of the International Index of Erectile
Function (IIEF-5) questionnaires were used. Urine analysis,
serum creatinine, blood sugar levels and uroflowmetry (Qmax
with PVR) were performed in all patients assessed for
eligibility. Those that satisfied the inclusion and exclusion
criteria were enrolled for the study and randomised to one of
the two arms. One arm was treated with tamsulosin 0.4 mg
along with a placebo (Group-A), while the second arm
received a combination of tamsulosin 0.4 mg and tadalafil
5 mg (Group-B). At the 3-month follow-up, the IPSS and
IIEF-5 questionnaires were again administered and
uroflowmetry repeated. The patients were asked to bring back
the empty covers of the medications (one for each day) at the
end of 3 months to ensure compliance.
Outcome Measures
The primary outcome was the IPSS. The secondary outcomes
were IPSS QoL score; IIEF-5 score, Qmax, and PVR. The
primary and secondary outcomes were recorded at baseline
and 3 months after intervention.
The adverse events (AEs) were monitored by passive
surveillance of harms. Patient-reported AEs were recorded
Tamsulosin vs tamsulosin+tadalafil in LUTS
during the period of the study. The universal pain assessment
score was used for pain.
Sample Size
A sample size of 106 (53 in each arm) was calculated to
detect a 3-point improvement in IPSS with 80% power and
two-sided a of 0.05, and an expected standard deviation (SD)
of 5 and 6 respectively in the tamsulosin only and
combination of tamsulosin and tadalafil arms based on
existing literature [11]. Assuming a dropout rate of 30%, the
required sample size was 140.
Randomisation, Blinding and Allocation
Concealment
Computer-generated block randomisation was used in varied
permuted blocks of two, four and six. The principal
investigator, physician, nurses, and the patient were blinded.
Allocation concealment was maintained using a starch-based
placebo in the tamsulosin only arm (Group-A). The
medications (tamsulosin 0.4 mg, tadalafil 5 mg, and the
placebo) were repacked into sealed covers in containers
bearing the serial numbers of the randomisation sequence at
our institute’s main pharmacy.
Statistical Analysis
Baseline demographic data, primary and secondary outcomes
were described by treatment groups with the mean and SD or
median and range for continuous variables; and percentages
for categorical variables. We performed an ITT analysis. For
continuous primary and secondary outcome variables, the
Markov chain Monte Carlo multiple imputation method was
used to impute missing data using 10 iterations. The results
from the imputation were combined by using the MI Stata
regression estimation command. The 95% CI was estimated
for the difference in means in each of the outcome variables
adjusting for the baseline outcome variable and treatment
group. All analyses were performed by statistical software
STATA, version 13.1 (copyright StataCorp, College Station,
TX, USA).
Results
A total of 183 patients were assessed for eligibility; 43
patients were excluded as they did not meet the inclusion
criteria. Of the 140 patients enrolled and randomised, 71
were randomised to Group-A (tamsulosin and placebo) and
69 to Group-B (tamsulosin and tadalafil). Three patients in
Group-A and one in Group-B withdrew consent after
allocation. Of the 68 patients who received the intervention in
each of the groups, four patients in Group-A and seven
patients in Group-B were lost to follow-up, as they were not
contactable. Also, three patients in Group-A discontinued
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Nagasubramanian et al.

intervention (one due to myalgia) and six patients in Group-
B discontinued intervention (two due to myalgia and one due
to giddiness and dyspepsia). Thus, 61 patients in Group-A
and 55 in Group-B completed the study (116/140, 82.85%).
Among the patients that completed the study, the compliance
was 98.20% in Group-A and 97.30% in Group-B.
ITT analysis was used, with 71 patients in Group-A and 69
in Group-B included in the ITT analysis. The above has been
summarised in the Consolidated Standards of Reporting
Trials (CONSORT) flow chart in Fig. 1.
The baseline demographic and clinical characteristics (including
mean IPSS, IPSS QoL score, IIEF-5 score, Qmax, and PVR) were
comparable between the two groups as shown in Table 1.
improvement was seen in both the voiding and storage
domains. These have been summarised in Table 2.
In all, 52.50% of patients in Group-A and 80% in Group-B
improved greater than the minimally important difference of
3 points of our primary outcome IPSS (P = 0.002).
Secondary Outcomes
There was significant improvement in the IPSS QoL score
( 0.70), IIEF-5 score (3.8) and Qmax (1.8 mL/s) in favour of
Group-B. There was no difference in PVR between the two
groups. The secondary outcomes have been summarised in
Table 2.
AEs

Primary Outcome There were no serious AEs in either of the groups. The
dropout rate due to AEs was four of 140 patients (2.85%; one
At the 3-month follow-up, there was a significant in Group-A and three in Group-B). Six patients (5.2%; one in
improvement in the IPSS ( 1.69) in Group-B. The Group-A and five in Group-B) had myalgia. Three patients

Fig. 1 CONSORT diagram of the study.

Screen failures = N =43

Assessed for eligibility = N= 183 Declined Rx = 11
Enrolment Cannot follow up = 12
On nitrates = 8
Enrolled and randomised = N= 140 Flow normal = 6
Stricture = 1
Allocation Parkinson’s = 1

Group A (Tamsulosin + Placebo) Group B (Tamsulosin + Tadalafil)

N = 71 N = 69

Allocation to intervention = 71 Allocation to intervention = 69

Received intervention = 68 Received intervention = 68

Did not receive intervention =3 Follow up Did not receive intervention =1

(Withdrew consent = 3) (Withdrew consent = 1)

Lost to follow up = Not contactable = 4 Lost to follow up = Not contactable = 7

Discontinued intervention = 3 Discontinued intervention = 6
(Myalgia = 1, Following lap cholecystectomy=1 (Myalgia = 2, Giddiness and dyspepsia = 1
Increased sugars = 1) Personal reasons = 2, Heat stroke = 1)

Completed study = N = 61 Completed study = N = 55

Analysis

Number analysed by intention-to-treat analysis Number analysed by intention-to-treat analysis

N = 71 N = 69

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720 BJU International © 2020 BJU International
 Tamsulosin vs tamsulosin+tadalafil in LUTS

Table 1 Baseline characteristics. Table 3 AEs.

Variable Tamsulosin and Tamsulosin and AE Tamsulosin and Tamsulosin %

placebo (n = 71) tadalafil (n = 69) placebo, n and tadalafil, n

Mean (SD) Myalgia 1 5 5.2

Age, years 61.28 (8.23) 58.87 (8.16) Dyspepsia 1 2 2.6
BMI, kg/m2 24.39 (3.38) 24.17 (3.50) Retrograde ejaculation 2 0 1.7
Waist circumference, cm 94.85 (8.50) 95.17 (7.75)
IPSS 15.10 (3.96) 16.26 (3.32)
IPSS QoL 4.23 (0.90) 4.55 (0.85)
IIEF-5 score 9.93 (4.08) 10.06 (3.48)
the treatment of LUTS [7]. Monotherapy with a PDE5i has
Qmax, mL/s 9.89 (3.11) 9.75 (2.17) shown improvement in symptom scores and erectile function,
PVR, mL, median (IQR) 41 (26–64) 48 (28–86) with a variable effect on Qmax (most studies did not show an
Co-morbidities, n (%)
Diabetes mellitus 12 (16.9) 14 (20.3)
improvement in Qmax) [6,14,15].
Hypertension 18 (25.4) 10 (14.5)
Diabetes and hypertension 9 (12.7) 6 (8.7)
The aetiology of LUTS is multifactorial and the effect of
Others 6 (8.4) 3 (4.3) PDE5i in LUTS is through proposed pathways common to
None 26 (36.6) 36 (52.2) LUTS and ED [4,5]. Studies using a combination of
IQR, interquartile range. a-blockers and PDE5i in LUTS were also heterogeneous in
the type of a-blockers and PDE5is used [6,10]. Tamsulosin
(2.6%; one in Group-A and two in Group-B) had dyspepsia, 0.4 mg is the safest a-blocker in combination with PDE5i
while two (1.7%) in Group-A reported retrograde ejaculation. [8,9]. There have been only a few studies comparing
The AEs have been summarised in Table 3. tamsulosin monotherapy with the combination of tamsulosin
and tadalafil 5 mg (the approved dose in LUTS) [6,10,16].
All the patients who had myalgia developed the same within None of the studies to the best of our knowledge were
2–3 days from intervention. The myalgia resolved with double-blinded RCTs with ITT analysis.
analgesics (paracetamol) within the first week from
intervention. In our present study, the improvement in the IPSS and
IIEF-5 score in the combination group was 1.69 (95% CI
2.0 to 1.4) and 3.8 (95% CI 3.4–4.2), respectively. This
Discussion was comparable to the meta-analysis by Gacci et al. [6],
The use of PDE5is in LUTS have been studied for over a where the improvement in the IPSS and IIEF score in the
decade. Earlier studies used different drugs in varying doses combination group was 1.85 (95% CI 3.73 to 0.00) and
including sildenafil, vardenafil, and 10 and 20 mg tadalafil 3.60 (95% CI 3.07–4.12), respectively; and the meta-analysis
[6]. Lower doses of tadalafil showed improvement in LUTS by Yan et al. [10], which showed improvement in the IPSS
with decreased AEs [12,13]. Only 5 mg tadalafil has been and IIEF score of 4.21 (95% CI 7.09 to 1.32) and 2.25
licensed for use in LUTS and is also a part of guidelines for (95% CI 0.07–4.43), respectively, in the combination group.

Table 2 Comparison of primary and secondary outcomes by treatments (ITT).

Tamsulosin and Tamsulosin and Difference between P†

placebo (n = 71) tadalafil (n = 69) means (95% CI)
Mean (SD) Mean (SD)

Primary outcomes
Total IPSS
3 months follow-up 11.53 (0.9) 9.84 (0.8) 1.69 ( 2.0 to 1.4) 0.01
Voiding
3 months follow-up 6.35 (1.0) 5.7 (0.8) 0.65 ( 1.0 to 0.4) 0.01
Storage
3 months follow-up 5.18 (0.8) 4.18 (0.8) 1.0 ( 1.3 to 0.7) 0.01
Secondary outcomes
IPSS QoL
3 months follow-up 3.10 (0.2) 2.40 (0.2) 0.70 ( 0.8 to 0.6) 0.001
IIEF-5
3 months follow-up 10.6 (1.3) 14.4 (1.2) 3.8 (3.4 to 4.2) <0.001
Qmax, mL/s
3 months follow-up 11.13 (2.1) 12.88 (1.5) 1.8 (1.2 to 2.4) 0.003
PVR, mL
3 months follow-up* 47.88 (41.5–57.7) 49.06 (40.5–65.3) 1.2 ( 5.5 to 7.8) 0.81
†
*Median and interquartile range, with 95% CI for difference between medians. P-value is based on the difference in the means between the treatment groups adjusting for baseline
outcome variable (pre-treatment outcome) using ITT analysis. P-value is based on difference in means using log-transformed values.

© 2020 The Authors

BJU International © 2020 BJU International 721
Nagasubramanian et al.
In the present study, the IPSS improvement was seen in both
the voiding and storage domains. In an integrated analysis,
Chapple et al. [17] concluded that the improvement in LUTS
due to tadalafil was seen in both the voiding and storage
domains, and was independent of the baseline storage
dysfunction.
The IPSS QoL score improved by 0.70 (95% CI 0.80 to
0.60) compared to a change of 0.01 in a study by Singh
et al. [11,16] and 0.1 in study by Takeda et al. [11,16]. The
95% CI for IPSS QoL score was not available in these studies.
Synergistic effects of tadalafil and tamsulosin through
common pathways may lead to improvement in LUTS and
erectile function in the combination group. Angulo et al. [18]
reported that tadalafil enhanced the inhibitory effects of
tamsulosin on the bladder neck and prostate. Further, Oger
et al. [19] showed that a combination of a-blocker and
tadalafil had an additional relaxant effect on human corpus
cavernosum in their in vitro study. These may explain the
favourable effect of the combination in LUTS and ED.
The mean (SD) baseline IIEF-5 score in the present study was
9.93 (4.08) and 10.06 (3.48) in the tamsulosin and
combination groups, respectively. Studies by Brock et al. [20],
Broderick et al. [21], and an integrated analysis by Brock
et al. [22], showed that the improvement in LUTS with
tadalafil was independent of pre-treatment erectile function
status.
The improvement in Qmax in our present study was 1.8 mL/s
(95% CI 1.2–2.4). This was comparable to improvements of
1.53 mL/s (95% CI 0.91–2.16) and 1.43 mL/s (95% CI 0.38–
2.47) noted in two meta-analyses by Gacci et al. [6] and Yan
et al. [10], respectively. One of the five studies included in the
meta-analysis by Gacci et al. [6] had a more significant
increase in the flow rate of 3.7 mL/s [6,23]. In that study, the
baseline flow rate was also significantly higher, which lead the
author to suggest that the baseline flow rate may be a
determinant of improvement in flow rate. Also, tadalafil had
no negative effect on the detrusor function on urodynamic
studies [24]. In another study, tadalafil produced objective
improvements in storage and voiding functions by
significantly reducing detrusor overactivity and decreasing the
BOO Index with an increase in Qmax [25]. These effects were
maintained at 1 year [26]. One study on urodynamic effects
of the combination of tadalafil and tamsulosin showed a
significant decrease in detrusor pressure at Qmax with the
improvement in the flow rate [27]. More such studies on the
urodynamic effects of the combination are needed.
Studies on PDE5i monotherapy did not show improvement
in flow; however, those studying the combination of PDE5i
and a-blockers showed improvement in flow [6,10]. It has
been argued that the relaxant effect of PDE5i on the bladder
detrusor muscle may counter the relaxant effect on the
© 2020 The Authors
722 BJU International © 2020 BJU International
bladder neck and prostate; hence, leading to no improvement
in flow with PDE5i monotherapy [15]. However, the
combination of a-blockers and PDE5i may act in synergy
producing a positive effect on the bladder neck, prostate and
detrusor leading to an improvement in flow. Translational
studies to elucidate the exact mechanism of action of the
combination on the bladder neck, prostate and detrusor are
needed.
Further, the optimisation of voided volumes due to the
relaxant effect of PDE5i on the bladder detrusor may lead to
an improvement in flow. As shown by Drach et al. [28] and
Schafer et al. [29], voided volumes determine optimal flow
readings. Also, in a study by Roehrborn et al. [30], the
difference in Qmax in the tadalafil arm was more pronounced,
with an increase in baseline voided volumes. Similarly, the
optimisation of voided volumes in the combination arm may
contribute to the improvement in Qmax. In our present study,
the voided volumes at baseline and follow-up between the
two groups did not show any significant difference. As voided
volumes are variable, further studies designed to study this
aspect are needed. Also, future studies powered for detecting
changes in flow rate in the combination arm may throw more
light on the effect of the combination on flow.
There were no serious AEs in either group in the present
study. The dropout rate due to AEs was 2.85%, which was
similar to 3.7% in a prior study [11]. Also, as in the study by
Liguori et al. [31], myalgia was the commonest AE leading to
discontinuation of therapy. Studies have shown the
combination of a-blockers and PDE5i to be
haemodynamically safe [32–34]. Further, PDE5i is safe in the
treatment of LUTS irrespective of age and pre-existing co-
morbidities [35,36].
The present study had a follow-up period of 3 months.
Studies with larger numbers, longer follow-up and cost
analysis may throw light on the long-term effects, safety and
costing of the combination therapy. However, a study by
Donatucci et al. [12] showed in a long-term follow-up of
1 year that the safety and efficacy of tadalafil were
maintained. Also, Oelke et al. [37] showed that in 70% of
patients a clinically meaningful improvement in LUTS on
tadalafil was seen in 4 weeks.
Although the improvement in the IPSS in the present study
was significant, for a perceptible improvement a 3-point
change is required as shown by Barry et al. [38]. Future
studies including other questionnaires may aid in the careful
selection of patients who may benefit from the combination.
Although blinding is an important quality criterion in clinical
studies, experience with prior studies has shown that due to
clinical effects, the patient may know which group he was in
thereby partly invalidating blinding. This is inherent to some
clinical trials involving drugs.

In the future, the addition of PDE5i may also play a role in
men with a-blocker resistant LUTS [39,40]. A meta-
regression analysis by Gacci et al. [6] showed a younger age
and lower body mass index (BMI) predictive of a better
response to tadalafil. In another study, age <75 years was a
favourable predictor of response to tadalafil [41]. Future
studies to explore better predictors of response, elucidate
mechanism of action more clearly, and study the effect on the
progression of disease are needed.
In conclusion, the combination of tamsulosin and tadalafil
produced significantly better improvements in LUTS, QoL,
erectile function and Qmax compared to tamsulosin
momotherapy, without an increase in AEs.
Registration
Central Trial Registry of India (CTRI): CTRI No. 2015/09/
006226.
Conflict of Interests
Sponsor: The medications for the study were provided by Sun
Urology (Sun Pharma India Private Ltd, Mumbai, India).
However, the design, data collection, outcome assessment,
and analyses were done by the Department of Urology,
Christian Medical College Vellore with support from the
Department of Biostatistics and Department of Pharmacy.
The authors report no other conflict of interest in this work.
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Correspondence: Professor Nirmal Thampi John, Department
of Urology, Christian Medical College, Vellore 632004, India.
e-mail: nirmaltj@gmail.com
Abbreviations: BMI, body mass index; CONSORT,
Consolidated Standards of Reporting Trials; ED, erectile
dysfunction; IIEF-5, five-item version of the International
Index of Erectile Function; ITT, intention to treat; PDE5i,
phosphodiesterase type 5 inhibitors; PVR, post-void residual
urine; Qmax, maximum urinary flow rate; QoL, quality of life;
RCT, randomised controlled trial.