EURURO Vol. 71 No. 4

577 692

combined with doxazosin 2 mg versus doxazosin alone,
but dosing frequency was not reported An 8-wk trial
evaluated sildenafil 25 mg taken 4 d/wk combined with
tamsulosin 0.4 mg daily compared with tamsulosin
monotherapy . Three trials enrolled men with a
history of ED . All trials were open label or
otherwise inadequately blinded and enrolled patients
after they failed to respond to AB monotherapy. Overall
RoB was mostly high.
Mean reductions in I-PSS scores were 5.4 with combina-
tion and 3.9 with monotherapy, with both treatments
exceeding MDD. However, the SOE to assess the compara-
tive effectiveness was insufficient due to the study
limitations and imprecision in measurement
. In the 8-wk trial without data sufficient for
pooling, improvement in mean I-PSS scores was similar
with combination or monotherapy (–6.4 vs –5.4) . Evi-
dence was insufficient for overall withdrawals and with-
drawals due to AEs.
3.15. Vardenafil AB combination versus AB monotherapy
One double-blinded trial (n = 60) compared vardenafil
10 mg daily combined with tamsulosin 0.4 mg to tamsu-
losin monotherapy over 12 wk The overall RoB was
moderate. Mean reductions in I-PSS scores were 5.8 with
combination treatment and 3.7 with monotherapy, both
achieving MDD (insufficient SOE).
One withdrawal was reported with tamsulosin. No
participant withdrew due to AEs. Persistent AEs were
reported in three participants with combination therapy
(headache with flushing, headache with stomach pain, and
stomach pain) and two with tamsulosin (headache and
flushing). No serious AEs were reported.
3.16. Tadalafil plus 5-ARI combination versus 5-ARI
monotherapy and tadalafil versus 5-ARI/AB combination
The evidence from a single trial of tadalafil 5-ARI
combination versus 5-ARI monotherapy as well as
that from a single trial comparing tadalafil versus 5-ARI/AB
combination was insufficient for both comparative
effectiveness and safety.
3.17. Longer-term harms from observational studies
We identified two observational studies reporting longer-
term AEs related to silodosin treatment . In a 40-wk
open label extension (cumulative treatment duration of
52 wk) of a previous RCT, 435 patients completed the
extension in which a total of 431 experienced 924 AEs
. Twenty-nine patients (4.4%) experienced serious AEs
including two deaths; none of the serious AEs were
considered drug related, although no criteria were reported.
The second study reviewed FDA data for AEs associated with
ABs and found the evidence of silodosin insuffient to
compare with other ABs .
We identified one study examining long-term AEs
associated with solifenacin/AB combination therapy,
reporting an open extension from a previous RCT for a
subset of patients with inclusion criteria that included a
postvoid residual 150 ml Forty-seven percent of
participants who continued solifenacin/AB combination
treatment reported treatment-emergent AEs, most com-
monly dry mouth, constipation, and dyspepsia. In addition,
86 serious AEs occurred in 64 patients and included three
deaths, six cases of AUR (0.7%), and three cases of
intervertebral disc protrusion.
We found two longer-term observational studies on
tadalafil . In a 42-wk open label extension of a
previous trial, 59% of 394 participants reported at least one
AE and 9% withdrew due to an AE. Serious AEs were
reported in 3% (11 participants) . In another open
extension study in a subset of 229 of 886 original
participants, nearly 5% experienced serious AEs .
4. Discussion
In this systematic review and meta-analysis we evaluated
whether newer drugs for the treatment of BPH associated
LUTS offered advantages over established treatments,
primarily older ABs (ie, tamsulosin, alfuzosin, doxazosin).
Our principal finding was that none of the drugs or drug
combinations newly used to treat LUTS attributed to BPH
were more effective compared with older AB monotherapy.
Further, AEs with newer treatments or combinations were
similar or greater than those for older AB monotherapy
when evidence was sufficient to assess.
Strengths of this review include its rigorous methodol-
ogy that followed a written, a priori protocol that was
developed according to AHRQ standards. We focused on the
analysis of comparative effectiveness with prespecified
outcomes addressing treatment effectiveness and poten-
tial harms, which are equally important to patients
considering these treatments. Lastly, we used a well-
established and comprehensive approach to determine the
SOE beyond study limitations alone that included domains
such as inconsistency and imprecision. Although our focus
on English language publications is a potential limitation,
we were reassured by the finding that supplemental
searching of , which requires regis-
tration of drug trials subject to FDA administration did not
identify any additional publications for trials within 2 yr of
completion. We therefore do not believe that the results of
this study were affected by language bias. Weaknesses of
this study largely relate to the limitation of the body of
evidence that we critically reviewed. Few comparisons
were assessed as high SOE in our review as the result of
study limitations (for example lack of blinding), impreci-
sion, and heterogeneity. Important outcomes relating to
potential treatment-related harms such as disease pro-
gression leading to AUR and/or surgical intervention could
not be evaluated due to the short duration of all eligible
RCTs and a paucity of observational studies and their
limited quality. Given that LUTS attributed to BPH is a
chronic and progressive condition, available evidence
provided little insight about the relative long-term
effects of treatments including prevention of symptom
E U R O P E A N U R O L O G Y 7 1 ( 2 0 1 7 ) 5 7 0 – 5 8 1 577