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EUROPEAN UROLOGY 64 (2013) 228–243
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Editorial by Herbert Lepor on pp. 244–246 of this issue
Systematic Review of Combination Drug Therapy for
Non-neurogenic Male Lower Urinary Tract Symptoms
Claudius Füllhase a, Christopher Chapple b, Jean-Nicolas Cornu c, Cosimo De Nunzio d,
Christian Gratzke a, Steven A. Kaplan e, Michael Marberger f, Francesco Montorsi g,
Giacomo Novara h, Matthias Oelke i, Hartmut Porst j, Claus Roehrborn k,
Christian Stief a, Kevin T. McVary l,*
a
Department of Urology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany; b Department of Urology, Royal Hallamshire Hospital,
Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; c Department of Urology, Tenon Hospital, Assistance publique-Hopitaux de Paris, University
Pierre et Marie Curie, Paris, France; d Department of Urology, Ospedale Sant’Andrea, University La Sapienza, Rome, Italy; e Iris Cantor Men’s Health Center,
New York Presbyterian Hospital, and Weill Cornell Medical College, New York, NY, USA; f Department of Urology, Medical University of Vienna, Vienna,
Austria; g Department of Urology, University Vita-Salute San Raffaele, Milan, Italy; h Department of Urology, University of Padua, Padua, Italy; i Department
of Urology, Hannover Medical School, Hannover, Germany; j Private Institute of Urology/Andrology, Hamburg, Germany; k Department of Urology, University
of Texas Southwestern Medical Center, Dallas, TX, USA; l Department of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA
Article info
Abstract
Article history:
Accepted January 15, 2013
Published online ahead of
print on January 25, 2013
Background: Several drugs are approved for the treatment of lower urinary tract symptoms
(LUTS) in men, but these are mostly used by clinicians as monotherapies. The combination of
different compounds, each of which targets a different aspect of LUTS, seems appealing.
However, only few clinical trials have evaluated the effects of combination therapies.
Objective: This systematic review analyzes the efficacy and adverse events of combination
therapies for male LUTS.
Evidence acquisition: PubMed and Cochrane databases were used to identify clinical trials and
meta-analyses on male LUTS combination therapy. The search was restricted to studies of level of
evidence 1b. A total of 49 papers published between January 1988 and March 2012 were identified.
Evidence synthesis: The a1-adrenoceptor antagonist (a1-blocker)/5a-reductase inhibitor (5-ARI)
combination provides the most data. This combination seems to be more efficacious in terms of
several outcome variables in patients whose prostate volume is between 30 ml and 40 ml when
treatment is maintained for >1 yr; when given for <1 yr, a1-blockers alone are just as effective.
The combination of a1-blocker/5-ARI shows a slightly increased rate of adverse events. It remains
unknown whether its safety and superiority over either drug as monotherapy are sustained after
>6 yr. The a1-blocker/muscarinic receptor antagonist (antimuscarinic) combination was most
frequently assessed as an add-on therapy to already existing a1-blocker therapy. Inconsistent
data derive from heterogeneous study populations and different study designs. Currently, the
a1-blocker/antimuscarinic combination appears to be a second-line add-on for patients with
insufficient symptom relief after monotherapy. The combination seems to be safe in men with
postvoid residual <200 ml. However, there are no trials >4 mo concerning safety and efficacy of
this combination. The a1-blocker/phosphodiesterase type 5 inhibitor combination is a new
treatment option with only preliminary reports. More studies are needed before definitive
conclusions can be drawn.
Conclusions: An a1-blocker/5-ARI combination is beneficial for patients whose prostate volume is
between 30 ml and 40 ml when medical treatment is intended for >1 yr. Based on short-term
follow-up studies, add-on of antimuscarinics to a1-blockers is an option when postvoid residual is
<200 ml.
# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords:
Lower urinary tract symptoms
Prostatic hyperplasia
Adrenergic a1-receptor
antagonists
5a-reductase inhibitors
Muscarinic antagonists
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* Corresponding author. 301 N. 8th Street, PO Box 19665, Springfield, IL 62794-9665, USA.
Tel. +217-545-8000; Fax: +217-545-7305.
E-mail address: [email protected] (K.T. McVary).
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.01.018
EUROPEAN UROLOGY 64 (2013) 228–243
1.
Introduction
Lower urinary tract symptoms (LUTS) can be divided into
storage, voiding, and postmicturition symptoms [1].
Depending on the severity threshold, the prevalence of
male LUTS ranges from 10.3% to 25.1% [2–4]. It was
estimated that in 2008, 917 million men worldwide were
affected by benign prostatic hyperplasia (BPH)/LUTS [5].
There is a clear increase of LUTS prevalence with age [6]. The
incidence of LUTS increases from 3 per 1000 per year among
men aged 45–49 yr to 38 per 1000 per year among men aged
75–79 yr [2]. Traditionally, LUTS in adult men were
attributed to benign prostatic enlargement, and terms such
as prostatism or BPH were used synonymously. However,
the bladder has also been recognized as a main contributor
to male LUTS [7], and consequently, drugs targeting the
bladder rather than the prostate could be added to the
armamentarium of LUTS treatment. This philosophy was
followed by most guidelines [8,9].
Several drugs for the treatment of male LUTS are
available [8,9]: a1-adrenoceptor antagonists (a1-blockers),
5a-reductase inhibitors (5-ARIs), muscarinic receptor
antagonists (antimuscarinics), and just recently approved
in the United States and Europe, phosphodiesterase type
5 inhibitors (PDE5-Is). The use of different modes of action
and targeting different symptom complexes by a drug
combination seems appealing. In response to previous
selective reviews on the topic, this systematic review
summarizes, in a methodical, evidence-based medicine
approach, the true evidence behind combination therapy
for men with LUTS.
2.
Evidence acquisition
A systematic literature search in the PubMed and Cochrane
databases was performed according to the Preferred
Reporting Items for Systematic Reviews and Meta-analysis
statement [10] to identify clinical trials, randomized
controlled trials (RCTs), meta-analyses, and guidelines on
male-LUTS combination therapy published from January
1988 to March 2012. In several search rounds, various
algorithms including the following MeSH terms were used:
lower urinary tract symptoms, prostatic hyperplasia, overactive urinary bladder, adrenergic alpha 1 receptor antagonists,
5 alpha reductase inhibitors, muscarinic antagonists, vasopressins, phosphodiesterase 5 inhibitors, adrenergic beta 3 receptor
agonists, phytotherapy, botulinum toxin, and combination drug
therapy. The limits used (ie, inclusion criteria) in all search
rounds were clinical trial, meta-analysis, randomized
controlled trial, guideline, male, humans, and English,
French, German, or Italian. Exclusion criteria were the
following: (1) articles reporting on neurogenic LUTS, (2)
articles reporting on LUTS in women or children, (3) articles
reporting on monotherapy and not on a combination of two
drugs (or, if the drug combination was not from two
different pharmacologic compound, eg, a combination of
two phytotherapeutics), (4) review articles, and (5) guidelines, which in their latest updated version were >3 yr old.
Each identified article was analyzed, classified, and labeled
229
according to the recommendations of the Centre for
Evidence Based Medicine [11]. Studies below the level of
evidence 1b (RCTs) were excluded; the agreement on such
exclusions was formulated via the Delphi approach [12].
3.
Evidence synthesis
A total of 49 papers published between January 1988 and
March 2012 were identified (Fig. 1).
3.1.
Combination of a1-blocker with 5a-reductase inhibitor
The first clinical reports to combine the pharmacologic
principles of a-adrenergic blockade with androgen antagonism to treat male LUTS were published at the end of the last
century in Japan. At the time, the authors used compounds
that no longer have any clinical relevance due to their lack of
specificity and to their side effects [13,14]. Today, countless
review articles and guidelines suggest that the combination
of a1-blockers with 5-ARI is well established.
Six RCTs have been published on a1-blocker/5-ARI
combination therapy, five of which directly assessed the
impact of medication on LUTS: the Veterans Affairs
Cooperative Study (VA-COOP); the Alfuzosin, Finasteride,
and Combination in the Treatment of BPH study (ALFIN);
the Medical Therapy of Prostatic Symptoms study (MTOPS);
the Prospective European Doxazosin and Combination
Therapy study (PREDICT); and the Combination of Avodart
and Tamsulosin study (CombAT) [15–31] (Table 1). The
remaining study assessed whether the a1-blocker can be
omitted after initial successful combination therapy [32].
Only the MTOPS and the CombAT trials had study durations
>1 yr, a point that is important to remember given the longterm impact offered by the 5-ARI component of this
combination therapy.
3.1.1.
Subjective outcomes of a1-blocker/5a-reductase inhibitor
combination therapy
In the VA-COOP study, 1229 patients with LUTS were
treated with terazosin, finasteride, or placebo for 1 yr.
Patients receiving the combination treatment showed a
significant reduction from the baseline American Urological
Association symptom score (AUA-SS) of 6.2, which was
significantly higher than the reduction by the 5-ARI (AUASS: 3.2) or placebo (AUA-SS: 2.6) alone but not significantly
different from the a1-blocker alone (AUA-SS 6.1) [15]
(Table 1). The reduction of symptom scores was reached after
13 wk of treatment and did not change within the 39 wk
thereafter [15]. As such, the VA-COOP study does not report a
subjective advantage of combination therapy compared to
a1-blockers alone.
In the ALFIN trial, 1051 patients with LUTS received
either alfuzosin or finasteride or a combination of both over
6 mo. Starting at 1 mo after treatment, patients receiving
the combination had a significant reduction from baseline
International Prostate Symptoms Score (IPSS) of 6.1, which
was significantly higher than the reduction with finasteride
alone (IPSS: 5.2) but not different from alfuzosin alone
(IPSS: 6.3) [17]. Similar to the VA-COOP study, the ALFIN
230
EUROPEAN UROLOGY 64 (2013) 228–243
[(Fig._1)TD$IG]
Initial search (n = 1097)
After exclusion of duplicates (n = 462)
After exclusion of reviews, and of reports on
monotherapies, neurogenic LUTS, women
and children, and studies with level of
evidence <1b (n = 48)
Continuous
consultations among
the coauthors
(Delphi approach) to
obtain greatest
agreement upon
exclusion of papers
Inclusion of one paper via
manual search *1
n = 49 papers
α1-Blocker
+ 5-ARI
n = 29
papers
α1-Blocker
+
antimuscar
inic
18 papers
reporting on
6 studies
13 papers
reporting on
8 studies
6 studies, of
which 1
assessed
aspects other
than direct
clinical
outcomes
n=6
add-on
studies
and
n=2
studies
α1-Blocker
+ PDE5I
n = 1 (meta
analysis)
α1-Blocker
+
phytotherap
eutic
Guidelines
n=5
n = 1 paper
n=5
studies
Fig. 1 – Flow chart of study selection for inclusion in this review. *1 Five papers were included via manual search. Three of those do not report on
combination therapy, but were considered relevant by the authors (Andriole et al., Marberger et al., Bent et al.). One was published in Japanese, and only
available as a translated reprint (Saito et al.). And one was published in a journal (LUTS) that is not listed in PubMed yet (Nishizawa et al.).
Table 1 – a1-Adrenoceptor antagonists and 5a-reductase inhibitor combination trial characteristics and subjective outcome measures
Trial
Years
trial was
performed
Patients,
no.
Drug
(dose)
Trial
duration,
mo
Primary
end point
Age of patients
and size of
prostate at
baseline,
mean SD
1992–1995
1229
Terazosin
(10 mg)
finasteride
(5 mg)
12
AUA-SS
and Qmax
65 7 yr and
37 1 ml
ALFIN [17]
1994–1996
1051
Alfuzosin
(2 x 5 mg)
finasteride
(5 mg)
6
IPSS
and Qmax
63 6 yr and
41 24 ml
PREDICT [22]
2001–2007
1095
Doxazosin
(4–8 mg)
finasteride
(5 mg)
12
IPSS
and Qmax
63 7 yr and
36 14 ml
(assessed by DRE)
MTOPS [19]
1995–2001
3047
Doxazosin
(4–8 mg)
finasteride
(5 mg)
54–72
62 7 yr and
36 20 ml
CombAT [28]
2003–2009
3195–3822
Tamsulosin
(0.4 mg)
dutasteride
(0.5 mg)
24–48
Clinical
progression
(as defined
by, eg, an
AUA score
increase of
4 points)
Time to first
AUR or BPHrelated
surgery
66 7 yr and
55 23 ml
Change of symptom score from baseline (IPSS or AUA-SS)
a1-Blocker
Age 45–80 yr
AUA-SS >8 PSA
10 ng/ml Qmax
4–15 ml/s
No limits on prostate
size
Age 50–75 yr IPSS
>7 PSA 10 ng/ml
Qmax 5–15 ml/s
No limits on prostate
size
Age 50–80 yr IPSS
>12 PSA 10 ng/ml
Qmax 5–15 ml/s
Prostatic enlargement
assessed by DRE
Age >50 yr AUA-SS 8–30
PSA 10 ng/ml Qmax
4–14 ml/s
No limits on prostate size
Age >50 yr
IPSS >12
PSA 1.5–10 ng/ml
Qmax 5–15 ml/s
Prostate size >30 ml
5-ARI
Placebo
Combination
S6.1
Significant
vs baseline
vs 5-ARI
vs placebo
S3.2
Significant
vs baseline
S2.6
Significant
vs baseline
S6.2
Significant
vs baseline
vs 5-ARI
vs placebo
S6.3
Significant
vs baseline
vs 5-ARI
S5.2
Significant
vs baseline
n.a.
n.a.
S6.1
Significant
vs baseline
vs 5-ARI
S8.3
Significant
vs baseline
vs 5-ARI
vs placebo
S6.6
Significant
vs baseline
S5.7
Significant
vs baseline
S8.5
Significant
vs baseline
vs 5-ARI
vs placebo
S6.6
Significant
vs baseline
vs placebo
vs 5-ARI
S5.6
Significant
vs baseline
vs placebo
S4.9
Significant
vs baseline
S7.4
Significant
vs baseline
vs placebo
vs 5-ARI
vs a1-blocker
S3.8
Significant
vs baseline
S5.3
Significant
vs baseline
vs a1-blocker
n.a.
n.a.
S6.3
Significant
vs baseline
vs 5-ARI
vs a1-blocker
EUROPEAN UROLOGY 64 (2013) 228–243
VA-COOP [15]
Inclusion criteria
a1-blocker = a1-adrenoceptor antagonist; 5-ARI = 5a-reductase inhibitor; ALFIN = Alfuzosin, Finasteride, and Combination in the Treatment of Benign Prostatic Hyperplasia; AUA-SS = American Urological Association
symptom score; AUR = acute urinary retention; BPH = benign prostatic hyperplasia; CombAT = Combination of Avodart and Tamsulosin; DRE = digital rectal examination; IPSS = International Prostate Symptom Score;
MTOPS = Medical Therapy of Prostatic Symptoms; Qmax = maximum flow rate of urine; PSA = prostate-specific antigen; n.a. = not assessed; PREDICT = Prospective European Doxazosin and Combination Therapy;
SD = standard deviation; VA-COOP = Veteran Affairs Cooperative Study.
231
232
EUROPEAN UROLOGY 64 (2013) 228–243
trial did not support combination therapy over a1-blocker
monotherapy with regard to subjective outcome measures.
In the PREDICT trial, 1095 patients received either
doxazosin, finasteride, or a combination of both over 1 yr.
Patients receiving combination therapy or doxazosin alone
had a significantly higher IPSS reduction (IPSS: 8.5 and 8.3,
respectively) than patients receiving either finasteride
(IPSS: 6.6) or placebo (IPSS: 5.7) alone [22].
The VA-COOP, ALFIN, and PREDICT studies all failed to
show a subjective advantage of a1-blocker/5-ARI combination over a1-blocker monotherapy. However, none of the
three studies accounted for effects that might have occurred
after receiving therapy for >1 yr.
The MTOPS trial tested either doxazosin or finasteride,
alone or in combination, against placebo for 4–6 yr in 3047
symptomatic patients. Finasteride alone reduced the
AUA-SS by 5.6 points, doxazosin alone by 6.6 points, and
the combination by 7.4 points [19]. Thus, MTOPS was the
first trial with a long-term follow-up (mean: 4.5 yr) in
which an advantage of combination therapy over either
monotherapy was demonstrated, especially in subjective
outcome parameters. Similarly, the CombAT trial, another
trial with a duration of 4 yr, reported after 4 yr of treatment
a significantly larger IPSS reduction for combination
therapy (IPSS: 6.3) than for either tamsulosin (IPSS: 3.8)
or dutasteride (IPSS: 5.3) alone [28].
The different outcomes between the MTOPS and CombAT
studies can be explained by different study populations.
Whereas the MTOPS study recruited men suffering from
LUTS without any limitation in prostate size, the CombAT
study only included men with a prostate volume >30 ml. This
means that the results of the CombAT study cannot be
extrapolated to every man suffering from LUTS. At the
CombAT interim analysis 2 yr after onset of treatment, IPSS
values were reduced by 6.2 points in patients receiving
combination therapy, by 4.3 points for those receiving
tamsulosin, and by 4.9 points for dutasteride-alone group
[23]. During the first 9–12 mo of treatment, tamsulosin alone
also showed a larger IPSS reduction than dutasteride alone,
but this significant difference vanished after 12 mo of
treatment. After 18 mo of treatment, patients in the
dutasteride group had a significantly higher reduction of
voiding symptoms within the IPSS than patients in the
tamsulosin group [27]. The significantly higher IPSS reduction achieved with combination therapy was apparent after
3 mo versus dutasteride and 9 mo versus tamsulosin [23,30].
The apparent superiority of the 5-ARI arm over the a1-blocker
arm after the 18-mo period in the CombAT study was likely
related to the effect of patient enrolment: Patients were
selected for larger prostate volumes not previously tested in
any combination trial.
In addition to the longer treatment periods of the MTOPS
and CombAT studies, their informative value is more
sensitive because they used statistically better-defined,
primary, study end points than the VA-COOP, ALFIN, or
PREDICT studies (Table 1). Whereas the latter three used
IPSS and maximum flow rate of urine (Qmax) as primary end
points, the MTOPS study used a composite end point for BPH
progression, including as primary end points a somewhat
arbitrary 4-point IPSS worsening (confirmed at 2 wk), acute
urinary retention (AUR), urinary tract infection (UTI),
worsening of renal function attributed to obstruction, and
urinary incontinence that was socially unacceptable. The
MTOPS study was also unique in defining this composite
BPH progression as the end point rather than the classic
degree of symptom improvement used in all studies
previously. This slight variation in treatment perspective
transforms LUTS treatment from a process of symptom
treatment to one of disease management. Having had or not
having had BPH-related surgery was a secondary end point.
Similarly, the CombAT study used a well-defined scenario of
clinical progression as the primary end point after 4 yr.
Assessing quality of life (QoL) (eg, IPSS question 8, BPH
Impact Index, or the Patient Perception of Study Medication questionnaire) in the combination arm of the CombAT
trial showed a higher satisfaction rate than tamsulosin
alone starting from month 15 and dutasteride alone
starting at 3 mo [25]. Improved QoL with combination
therapy compared to each monotherapy was maintained
throughout the 4 yr of treatment [29]. After finishing the
trial, 64% of patients receiving combination therapy, 58% of
the dutasteride-only group, and 55% of the tamsulosin-only
group wished to continue the study medication [29].
However, these numbers also indicate that 36–45% of
patients were not satisfied with their medical treatment.
In summary, the results favor combination therapy when
subjective outcome measures (AUA-SS, IPSS) were assessed,
treatment lasted >1 yr (Table 1), and the patient selected for
treatment had some critical level of prostate enlargement.
When combination treatment was used for <1 yr or for LUTS
regardless of prostate volume, there were no significant
differences compared to a1-blocker monotherapy. Whether
the combination therapy is still more efficacious than 5-ARI
monotherapy after >6 yr or if the difference disappears
between the drug combination and 5-ARI has not yet been
thoroughly assessed and remains to be elucidated.
3.1.2.
Objective outcomes of a1-blocker and 5a-reductase inhibitor
combination therapy
Trials with a duration of <1 yr (ie, the VA-COOP, ALFIN, and
PREDICT studies) reported a Qmax increase of 2.3–3.8 ml/s
for combination therapy, 1.4 ml/s for placebo, 1.6–1.8 ml/s
for 5-ARI alone, and 1.8–3.6 ml/s for a1-blocker alone
[15,17,22]. The differences were significantly different
between combination and 5-ARI or placebo alone, but not
from a1-blocker alone [15,22]. However, long-term trials
(ie, MTOPS and CombAT) showed a significant Qmax increase
of 2.4–3.7 ml/s for combination therapy, 2.0–2.2 ml/s for
5-ARI alone, 0.7–2.5 ml/s for a1-blocker alone, and 1.4 ml/s
for placebo [19,28]; however, the different prostate sizes in
the trials have to be considered (Table 1).
Prostate size was reduced by 7 ml with combination
therapy and by 6.1 ml with finasteride but increased by
0.5 ml with terazosin or placebo in the VA-COOP study [15];
in the ALFIN study, prostate size decreased by 4.3 ml with
combination therapy, by 4.9 ml with finasteride, and by
0.2 ml with alfuzosin [17]. It should be kept in mind that the
effect on prostate size in the VA-COOP, ALFIN, and PREDICT
EUROPEAN UROLOGY 64 (2013) 228–243
233
studies is limited by their short study periods and the
methods used to measure volume, which vary greatly. Over
4 yr with combination therapy and 5-ARI monotherapy,
prostate sizes were equally reduced by 19–28%, whereas
prostate size increased by 4.6–24% with a1-blockers alone.
The increase in prostate size with a1-blocker therapy
represents the natural growth of the prostate as shown by
the same size increase in placebo groups [19,28] (Table 2).
During the PREDICT study, AUR and need for surgery
occurred within 1 yr of treatment in 2.6% of patients treated
with placebo, in 1.9% of those treated with finasteride, and in
0.4% of those receiving doxazosin, but in no patient receiving
combination therapy [22]. Clinical progression, as defined by
an increase in 4 AUA-SS points, AUR, renal insufficiency,
recurrent UTIs, or self-reported, unacceptable incontinence
occurred in 4.5% of patients per year in placebo-treated
patients of the MTOPS study. Of all progression parameters,
symptom deterioration occurred most frequently (78%). The
number needed to treat (NNT) to prevent one instance of
overall clinical progression was 13.7 for doxazosin, 15.0 for
finasteride, and 8.4 for combination therapy (relative risk
[RR] reduction for disease progression was 39% for doxazosin,
34% for finasteride, and 66% for combination therapy). Within
4 yr, 17% of those treated with placebo, 10% with doxazosin,
10% with finasteride, and 5% with combination therapy
experienced clinical disease progression [19]. However, the
risk for AUR and/or invasive therapy was equally reduced by
finasteride monotherapy and combination therapy, whereas
doxazosin alone did not significantly affect AUR or the
need for invasive therapy [19]. As such, 5-ARIs reduce
disease progression (ie, prevent AUR or surgery), whereas
a1-blockers only delay but do not prevent BPH progression.
Similarly, the CombAT study showed a RR reduction for AUR
or surgery of 65.8% for combination therapy compared to
tamsulosin alone but was not significantly different from
dutasteride alone. The benefit of the prevention of AUR or
surgery in those receiving combination or dutasteride
became apparent at month 8 [28].
In analogy to subjective outcome parameters, a1blocker/5-ARI combination therapy is superior in increasing
Qmax and delaying disease progression to either monotherapy when given for >8 mo. Whether the combination
therapy is more efficacious than 5-ARI alone in the long
term (>6 yr) is not yet clear.
(>40 ml) have a higher risk of having invasive therapy later.
In the MTOPS study, the overall NNT to prevent one patient
from invasive therapy was 25.9 for combination therapy. In
patients with an initial PSA level >4 ng/ml or prostate size
>40 ml, the NNT was 23.1 and 15.9, respectively [19]. In the
CombAT study, the RR reduction of AUR or of BPH-related
surgery with combination therapy was only significant
(compared to tamsulosin alone) when prostate volume at
baseline was >42 ml [31]. RR reduction with combination
therapy (compared to tamsulosin) was 69.3% for patients
with an initial prostate size of 42.0–57.8 ml and 72.6% for
patients with initial prostate size >57.8 ml [31].
Combination therapy in the CombAT study was more
efficacious than any monotherapy with respect to IPSS
reduction. However, the onset at which these differences
became apparent was dependent on prostate size at baseline.
In patients whose prostate volume was <42 ml, combination
therapy compared to tamsulosin was more efficacious in IPSS
reduction starting at month 21. However, in patients with
prostate volume of 42–58 ml at baseline, the differences
occurred after only 6 mo, and after 3 mo in patients with
prostate volume >58 ml [24]. Dutasteride alone was only
significantly efficacious in reducing IPSS compared to
tamsulosin alone in patients with an initial prostate size
>49 ml [24].
Different degrees of outcomes in the MTOPS and
CombAT trials are most likely attributable to different
prostate sizes, PSA values, and age at baseline (Table 1). The
MTOPS study, which included patients with an average
prostate size of 36 20 ml, reported only a moderate
advantage of combination therapy compared to monotherapies. In contrast, the CombAT study, which only included
patients with a minimum prostate size of 30 ml and had an
average prostate size of 55 23 ml at baseline, reported a
more pronounced advantage of combination therapy over
monotherapies, indicating that patients with enlarged prostates (>40 ml) especially benefit from a1-blocker/5-ARI
combination therapy.
In summary, the subgroup analyses revealed that, in
particular, patients with enlarged prostates (>30–40 ml, or a
PSA value >4 ng/ml as proxy parameter for an enlarged
prostrate) benefit from a1-blocker/5-ARI combination when
treatment is given for a prolonged period. The impact of
combination treatment is linearly related to prostate volume.
3.1.3.
3.1.4.
Subgroup analyses of a1-blocker and 5a-reductase inhibitor
Adverse events of a1-blocker and 5a-reductase inhibitor
combination therapy
combination therapy
In the VA-COOP study, no significant change in Qmax was
shown for 5-ARI monotherapy. However, when patients
with a baseline prostate volume >50 ml were separately
analyzed, Qmax increase (2.7 ml/s) was significant and not
different from combination therapy or terazosin alone [16].
Similarly, in the ALFIN trial, Qmax increase in alfuzosin or
combination therapies became more pronounced when
patients with an initial Qmax <10 ml/s were analyzed [17].
It should be kept in mind that these subgroup findings were
post hoc analyses, limiting their scientific validity. Patients
with elevated, baseline, serum prostate-specific antigen
(PSA) concentrations (>4 ng/ml) and/or prostate volumes
A1-adrenoceptor-specific adverse events (AEs), such as
dizziness, hypotension, or rhinitis occurred significantly
more frequently in a1-blocker and combination therapy
than in 5-ARI therapy (Table 3). Antiandrogenic AEs, such as
erectile dysfunction (ED), decreased libido, or reduction of
semen volume, occurred significantly more often in 5-ARI
and combination treatments than in a1-blocker therapy
groups [15,19,22] (Table 3). Consequently, AEs were more
prevalent in patients with combination therapy than in any
monotherapy group. AEs seem to be additive and not
synergistic. Severe AEs were not observed in either
treatment group [15,19,22] and discontinuation rates were
234
Table 2 – a1-Adrenoceptor antagonists and 5a-reductase inhibitor combination objective outcome measures*
Change in Qmax from baseline (ml/s)
a1-Blocker
+2.7
ALFIN [17]
(alfuzosin/finasteride)
+1.8
PREDICT [22]
(doxazosin/finasteride)
+3.6
MTOPS [19]
(doxazosin/finasteride)
+2.5
CombAT [28]
(tamsulosin/dutasteride)
+0.7
Placebo
Combination
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
+1.6
Significant
vs baseline
+1.4
Significant
vs baseline
+3.2
+1.8
Significant
vs baseline
n.a.
n.a.
+2.3
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
vs placebo
+1.8
Significant
vs baseline
+1.4
Significant
vs baseline
+3.8
+2.2
Significant
vs baseline
vs placebo
+1.4
Significant
vs baseline
+3.7
+2.0
Significant
vs baseline
vs a1-blocker
n.a.
n.a.
+2.4
Significant
vs baseline
a1-Blocker
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
+0.5 ml
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
vs placebo
vs 5-ARI
vs a1-blocker
Significant
vs baseline
vs 5-ARI
vs a1-blocker
n.a.
n.a.
+24%
n.r.
+4.6%
Significant
vs baseline
0.2 ml
5-ARI
Significant
vs baseline
6.1 ml
n.s.
4.3 ml
Combination
+0.5 ml
Significant
vs baseline
7 ml
n.a.
n.a.
4.9 ml
n.a.
n.a.
n.r.
+24%
n.r.
19%
n.r.
Significant
vs baseline
vs a1-blocker
n.a.
n.a.
27.3%
Significant
vs baseline
vs 5-ARI
vs a1-blocker
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
vs a1-blocker
n.a.
19%
28%
n.a.
Placebo
n.a.
Significant
vs baseline
vs 5-ARI
vs placebo
Significant
vs baseline
vs a1-blocker
n.a.
Qmax = maximum flow rate of urine; 5-ARI = 5a-reductase inhibitor; a1-blocker = a1-adrenoceptor antagonist; ALFIN = Alfuzosin, Finasteride, and Combination in the Treatment of Benign Prostatic Hyperplasia;
AUR = acute urinary retention; CombAT = Combination of Avodart and Tamsulosin; MTOPS = Medical Therapy of Prostatic Symptoms; n.a. = not assessed; n.r. = not reported; PREDICT = Prospective European Doxazosin and
Combination Therapy; VA-COOP = Veteran Affairs Cooperative Study.
*
Prostate size was given only as percentage value in some trials.
EUROPEAN UROLOGY 64 (2013) 228–243
VA-COOP [15]
(terazosin/finasteride)
5-ARI
Change in prostate size from baseline
Table 3 – a1-Adrenoceptor antagonists and 5a-reductase inhibitor combination selected side effects
3
7
1
5
n.r.
n.r.
1.9
n.r.
5
1.7
0.6
2.2
27
1.7
7.8
0.6
1.2
1.2
1.7
6.7
26
2.9
5.9
0.3
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
1.4
2.3
15.6
3.6
5.8
n.r.
n.r.
11.6
0.4
n.r.
8
3.4
4.9
n.r.
n.r.
13.6
1.9
n.r.
7.4
1.9
10.5
n.r.
n.r.
11.9
2.6
n.r.
13.6
2.3*
2.3*
4.5*
24
n.r.
n.r.
<1
n.r.
2.2*
1.4*
3.3*
n.r.
n.r.
n.r.
2
n.r.
3
7
21
<1
4
2.7
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.r.
n.r.
4.4*
1.5*
3.5*
27
n.r.
n.r.
1
n.r.
n.r.
2
2
5
19
<1
4
6.8
n.r.
<1
n.r.
n.r.
9.4
n.r.
2
7.4
26
2.3
8.1
0.3
2.1
3.3
n.r.
n.r.
12.6
0
5.3*
2.5*
5.1*
18
n.r.
n.r.
<1
2
4
9
28
<1
6
2.2
Impotence
9
21
Loss of libido
5
Dizziness and hypotension
AUR
n.r.
Discontinuation rate due to side effects
AUR
6.1
Severe side effects
Discontinuation rate due to side effects
n.r.
Side effects total
Severe side effects
n.r.
Headache
Side effects, total
9
Impotence
AUR
5
Loss of libido
Discontinuation rate due to side effects
8
Dizziness and hypotension
Severe side effects
6
Headache
Side effects, total
n.r.
Impotence
7.0
Loss of libido
n.r.
Dizziness and hypotension
n.r.
Headache
AUR
6
Impotence
3
26
Loss of libido
Discontinuation rate due to side effects
n.r.
Combination, %
Severe side effects
2
Placebo, %
Side effects, total
6
5ARI, %
EUROPEAN UROLOGY 64 (2013) 228–243
VA-COOP [15]
(terazosin/finasteride)
ALFIN [17]
(alfuzosin/finasteride)
PREDICT [22]
(doxazosin/finasteride)
MTOPS [19]
(doxazosin/finasteride)
CombAT [28]
(tamsulosin/dutasteride)
Dizziness and hypotension
Headache
a1-Blocker, %
a1-Blocker = a1-adrenoceptor antagonist; 5-ARI = 5a-reductase inhibitor; ALFIN = Alfuzosin, Finasteride, and Combination in the Treatment of Benign Prostatic Hyperplasia; AUR = acute urinary retention;
CombAT = Combination of Avodart and Tamsulosin; MTOPS = Medical Therapy of Prostatic Symptoms; n.a. = not assessed; n.r. = not reported; PREDICT = Prospective European Doxazosin and Combination Therapy;
VA-COOP = Veteran Affairs Cooperative Study.
*
Rate per 100 person-years of follow-up.
235
236
EUROPEAN UROLOGY 64 (2013) 228–243
similar between treatment groups (6–12.6%), depending on
study duration [22].
Within 2 yr of treatment, drug-related AEs occurred
more often in the combination therapy group (24%) than in
the tamsulosin (16%) or dutasteride (18%) groups. However,
the occurrence of a serious drug-related AE (<1% in each
treatment arm) or withdrawal rates from the CombAT trial
(<5% in each treatment arm) were similar among the
groups [23]. After 4 yr of treatment, 6% of patients receiving
combination therapy, 4% receiving tamsulosin, and 4%
receiving dutasteride discontinued the study due to drugrelated AEs [28]. In summary, AEs do not seem to be the key
criterion for or against combination therapy (Table 3).
It should also be mentioned that 60–80% of LUTS/BPH
patients are sexually active [33]. Both 5-ARI and a1-blockers
might cause sexually related side effects (eg, loss of libido
with 5-ARI therapy or ejaculation dysfunction [EjD] with
a1-blockers). When a1-blockers and 5-ARI are combined,
these potential side effects might be additive and affect
patients’ sexual life. The effect of a1-blockers on sexual
function in men with LUTS is variable during a short period,
with men reporting either no change or a modest improvement of unknown significance. However, the effect of
a1-blocker on EjD in men with LUTS is significantly affected
by tamsulosin and silodosin, whereas the other commonly
used a1-blockers have little or no impact on EjD. The effect of
5-ARI on sexual function in men with LUTS is modest but
global, with effects on penile erection, ejaculation, and sexual
desire. There seems to be no significant difference between
the two agents that are currently available. The veracity of
reports on persistence of the sexual side effects following
cessation of 5-ARIs when these drugs have been used to treat
male pattern baldness is unclear. The impact of drug therapies
for LUTS on sexual function should not be overlooked in
discussing potential side effects with individual patients.
3.1.5.
Additional aspects of a1-blocker and 5a-reductase inhibitor
combination therapy
Although they are outside of the scope of this review, the
authors would like to mention two additional aspects of
a1-blocker/5-ARI combination therapy that are still controversially debated. It should be noted that both of these
aspects are just mentioned here to raise awareness; they are
not discussed in detail. For further details please refer to the
cited studies.
The first concept is that of a1-blocker withdrawal after
initial successful combination therapy. The Symptom Management After Reducing Therapy (SMART) trial suggests that
after 6 mo the a1-blocker might be omitted without
symptom deterioration [32]. Similar results were reported
from a Canadian study in which the a1-blocker was omitted
after 9 mo [34]. However, current scientific data on this topic
are insufficient.
The second aspect is the possible effects of the a1-blocker/
5-ARI combination on prostate cancer (PCa) diagnosis and
PSA serum levels. It seems important to mention that
the Reduction by Dutasteride of Prostate Cancer Events
(REDUCE) trial, performed subsequently to CombAT, suggests that dutasteride over a 4-yr period might reduce the
risk of PCa [35]. Similarly, the Prostate Cancer Prevention
Trial (PCPT) reported that finasteride prevents or delays the
appearance of PCa [36]. However, it should also be noted that
although 5-ARI might reduce the likelihood of total PCa
diagnosis, it seems to concurrently increase the likelihood of
a high-grade PCa diagnosis. As a consequence, the US Food
and Drug Administration issued a warning in September
2011 and obliged pharmaceutical companies to change their
warning and precaution labels for 5-ARIs accordingly [37]. In
addition, the physician prescribing a 5-ARI should be aware
that these compounds affect PSA serum levels and, consequently, PCa screening. Several articles provide insight into
the interpretation and use of PSA serum levels under 5-ARI
therapy [38,39].
3.2.
Combination of a1-blockers and muscarinic receptor
antagonists
The first clinical study on combination therapy with a1blockers and muscarinic receptor antagonists (antimuscarinics) was published by Saito and coworkers in 1999 [40].
They administered tamsulosin and propiverine to patients
with enlarged prostates and increased frequency of any cause
(including neurogenic bladder). Following this study, clinical
studies with more homogeneous study populations were
performed on a1-blocker/antimuscarinic combinations
[41–53] (Table 4). The majority are add-on studies, in which
antimuscarinics have been added to baseline a1-blocker
therapy. Only one trial prospectively compared the antimuscarinic with placebo, a1-blocker, and a1-blocker/
antimuscarinic combination (the Tolterodine and Tamsulosin in Men With LUTS Including OAB: Evaluation of Efficacy
and Safety [TIMES] study) [42]. All studies defined an upper
limit of postvoid residual (PVR) and a lower limit of Qmax at
initiation; therefore, conclusions concerning efficacy and
safety are only valid for patients with PVR <200 ml and Qmax
>5 ml/s.
All studies on a1-blocker/antimuscarinic combination
therapy have only a short follow-up (usually 12 wk), and no
study assessed the outcomes of this combination for >4 mo.
Therefore, it is currently unknown if long-term a1-blocker/
antimuscarinic combination is useful, safe, and/or effective.
3.2.1.
Subjective outcomes of a1-blocker/antimuscarinic
combination therapy
Add-on studies reported significant IPSS reductions when
patients were treated with a1-blocker/antimuscarinic combination instead of an a1-blocker only, especially reductions
of the IPSS storage subscore (questions 2, 4, and 7) [49,50,53].
A reduction in IPSS of 3 points was observed in 74.4% of
patients when oxybutinin was given as an add-on but only in
65% of patients receiving placebo add-ons [45]. Reports on
antimuscarinics as add-on therapy regarding the patients’
QoL are controversial, but most studies concluded that addon therapy does not significantly improve QoL compared to
placebo [49,50,53]. However, different inclusion criteria in
the studies and different time periods regarding duration of
previous a1-blocker use make outcome parameters difficult
to compare (Table 4). Another flaw of several studies
Table 4 – a1-Adrenoceptor antagonist and antimuscarinic combination: International Prostate Symptom Score outcome and trial characteristics
Trial
Level of Patients,
evidence
no.
Drug (dose)
Duration, mo
Inclusion criteria
Time during which an
a1-blocker was given prior to
add-on antimuscarinic, wk
Total IPSS reduction from baseline
(IPSS storage symptom reduction, where assessed separately)
a1-Blocker
7.8
(3.4)
Significant
vs baseline
vs placebo
Placebo
6.8
(3.4)
Significant
vs baseline
6.2
(2.8)
Significant
vs baseline
7.4
(3.8)
Significant
vs baseline
7.3
(2.9)
Significant
vs baseline
4
6.9
(3.7)
Significant
vs baseline
vs placebo
5.2
(2.4)
Significant
vs baseline
4
5.4
(2.8)
Significant
vs baseline
4.9
(2.3)
Significant
vs baseline
4
4.8
(2.7)
Significant
vs baseline
vs placebo
4.3
(2.2)
Significant
vs baseline
6
3.5
(2.4)
Significant
vs baseline
vs placebo
3.1
(1.8)
Significant
vs baseline
8
(2.2)
Significant
vs baseline
(1.1)
Significant
vs baseline
Significant
vs baseline
Significant
vs baseline
4.6
Significant
vs baseline
Significant
vs baselin
Unknown
15 ml/s
5.1
Unknown
<15 ml/s
5.3
3.7
Combination
8.0
(4.2)
Significant
vs baseline
vs placebo
237
a1-Blocker = a1-adrenoceptor antagonist; ADAM = Add-on study of Detrol LA to Alpha-blockers in men; ASSIST = Add-on therapy of Solifenacin Succinate in men for BPH with OAB symptoms treated by Tamsulosin;
BPH = benign prostatic hyperplasia; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; OAB = overactive bladder; PVR = postvoid residual; PSA = prostate-specific antigen;
Qmax = maximum flow rate of urine; TAABO = Trial of combination treatment of an Alpha-blocker plus an Anticholinergic for BPH with OAB; TIMES = Tolterodine and Tamsulosin in men with LUTS; VICTOR = Vesicare
in combination with Tamsulosin in OAB residual symptoms.
EUROPEAN UROLOGY 64 (2013) 228–243
Studies in which a1-blocker, antimuscarinic, or a combination of both was tested from the start
TIMES [42]
1b
879
Tamsulosin
3
Age >40 yr
(0.4 mg)
Qmax >5 ml/s
tolterodine
PVR <200 ml
(4 mg)
IPSS >12
>8 voids/24 h
PSA 10 ng/ml
Studies in which a1-blocker/antimuscarinic or a1-blocker/placebo was tested from the start
Lee et al. [41]
1b
228
Doxazosin
2
Age 50–80 yr
(4 mg) propiverine
>8 voids/24 h
(20 mg)
urodynamically obstructed
(Abrams-Griffith >20)
PVR <30% bladder capacity
Studies in which antimuscarinic or placebo was tested as add-on to an a1-blocker
MacDiarmid
1b
409
Tamsulosin
3
Age >45 yr
et al. [45]
(0.4 mg)
Qmax >8 ml/s
oxybutinin
PVR <150 ml
(10 mg)
IPSS >13
IPSS storage subset >8
PSA 4 ng/ml
VICTOR [48]
1b
397
Tamsulosin
4
Age >45 yr
(0.4 mg)
Qmax >5 ml/s
solifenacin (5 mg)
PVR <100 ml
IPSS >13
>8 voids/24 h
PSA 10 ng/ml
ADAM [49]
1b
652
Any a1-blocker
3
Age >45 yr
tolterodine (4 mg)
no limit on Qmax
PVR <200 ml
>8 voids/24 h
>1 urgency episode/24 h
PSA 10 ng/ml
3
Age >50 yr
ASSIST [50]
1b
638
Tamsulosin
Qmax >5 ml/s
(0.2 mg)
solifenacin
PVR <50 ml
(2.5–5 mg)
>8 voids/24 h
>2 urgency episodes/24 h
3
Age >50 yr
TAABO [53]
1b
214
Tamsulosin
Qmax 5–15 ml/s
(0.2 mg)
propiverine
PVR <100 ml
(10–20 mg)
IPSS >8
>8 voids/24 h
>1 urgency episodes/24 h
3
Age >40 yr
Oelke et al. [52]
1b
1849
Propiverine
Qmax >10 ml/s
(30 mg) with or
without a1-blocker
PVR <100 ml
(any)
IPSS <20
>8 voids/24 h
prostate size<40 ml
Antimuscarinic
238
EUROPEAN UROLOGY 64 (2013) 228–243
assessing a1-blocker/antimuscarinic combinations by using
IPSS questionnaires only is that antimuscarinics target
mainly those OAB symptoms that are not adequately
assessed by the IPSS questionnaires.
Regardless of initial PSA values, the effects of add-on
tolterodine were dependant on prostate size [51]. Another
study reported that IPSS reduction with propiverine was
more pronounced in patients with Qmax <15 ml/s at baseline
[52]. However, data on specific patient groups that might
profit from add-on treatment are scarce. Particularly, low
case numbers and high patient heterogeneity in existing
trials make it difficult to determine which LUTS patient
benefits most from an add-on antimuscarinic therapy.
The TIMES study was the only one that included an
antimuscarinic alone and showed that patients treated with
combination therapy, but not with tamsulosin, tolterodine,
or placebo alone, had a significant treatment benefit as
defined by the patient perception questionnaire (80% vs
71%, 65%, and 62%, respectively) [42]. Similarly, following
the 12 wk of treatment, only combination therapy
significantly improved total IPSS and QoL; tolterodine alone
did not differ from the placebo. Interestingly, after the same
treatment period, tamsulosin alone did improve total IPSS
but without significant effects on the IPSS QoL item [42].
Furthermore, the IPSS storage subscore was only significantly reduced in the combination group [46]. However, in
men with a PSA value <1.3 ng/ml or prostate size <29 ml,
tolterodine alone was also able to significantly reduce
storage symptoms [44,47]. As such, the TIMES study
indicated that in the short term, especially men with
enlarged prostates benefit from a1-blocker/antimuscarinic
combination therapy. In men with small prostates, antimuscarinics alone appear to be just as efficacious [37].
3.2.2.
Objective outcomes of a1-blocker/antimuscarinic combination
therapy
Studies in which antimuscarinics were assessed as add-ons
to a1-blockers showed no significant differences in Qmax
between treatment groups [41,49,53]. Add-on combination
therapy, when compared to a1-blockers alone, showed a
significantly higher reduction in 24-h voiding frequency
[41,49,50,52,53] (eg, 23.5% vs 14.3% [41]) and urgency
episodes per day [48–50,52] (eg, 2.9 vs 1.8 [49]).
The TIMES study reported that in patients with prostate
size >29 ml, only combination therapy significantly reduced 24-h voiding frequency (2.8 vs 1.7 with tamsulosin
alone, 1.4 with tolterodine alone, or 1.6 with placebo). In
patients with prostate size <29 ml, tolterodine alone also
reduced 24-h voiding frequency (tamsulosin/tolterodine
combination: 2.2 voids, tolterodine: 1.9, placebo: 1.1, and
tamsulosin: 1.6) [47]. The significant frequency reduction
began 1 wk after the start of treatment [42].
The a1-blocker/antimuscarinic combination does not
seem to influence Qmax but improves other objective
outcome parameters such as 24-h frequency and urgency
episodes. Similar to other subjective outcome parameters,
combination therapy appears to be as efficacious as
antimuscarinics alone in men with small prostate volume
(<30 ml).
3.2.3.
Adverse events of a1-blocker/antimuscarinic combination
therapy
Although some studies found a statistically significant
increase in PVR with antimuscarinics (alone or in combination), most studies did not find a significant increase in AUR
with antimuscarinics [41,42,45,49,52,53] (Table 3). For
example, when oxybutinin was given to patients who had
already received tamsulosin, mean PVR increased by 18.2 ml,
whereas placebo increased PVR by 7.8 ml. No AUR occurred
either in the oxybutinin/tamsulosin or in the placebo/
tamsulosin group [45]. Only a few studies reported a higher
frequency of AUR in patients treated with antimuscarinic
add-on compared to placebo add-on, ranging from 1.9% to 3%
versus 0% after a treatment period of 3 mo [48,50].
Nevertheless, other studies including placebo groups
reported an AUR incidence of approximately 1.8% (Table 5).
When considering the natural incidence of AUR in
untreated LUTS patients, the AUR rate with antimuscarinics
appears to be similar or only slightly increased. However, it
should be kept in mind that a selected group of patients was
investigated who had an upper PVR limit of 200 ml and Qmax
>5 ml/s at the time of inclusion and men with increased risk
for AUR were excluded from the trials (a man with a PVR
>200 ml is already at considerable risk for developing AUR)
(Table 5). Results from these trials and subsequent
recommendations can only be applied to patients with a
similar risk profile. In general, caution (ie, regular evaluation of PVR) is recommended when prescribing antimuscarinics to patients with increased risk of developing AUR
[8,9]. Interestingly, prostate size and serum PSA concentration at study initiation had no influence on AUR development during antimuscarinic treatment [47,51].
Study discontinuation occurred more frequently in
patients with add-on combination therapy than in patients
with placebo add-on (4.7–7% and 1.5–4%, respectively
[41,48,50]). Other studies found no difference in discontinuation rates due to drug-related AEs [42,45] (Table 5).
Antimuscarinic AEs, such as dry mouth or constipation,
occurred in the combination therapy group more often than
in patients receiving a1-blocker monotherapy [41,42,48–50].
For example, dry mouth occurred in 15.3% of patients taking
oxybutinin or combination but in only 4.8% of patients taking
tamsulosin or placebo [45]. In most studies, side effects were
mild and disappeared upon drug discontinuation [41,48].
Similar to a1-blocker/5-ARI combination therapy, AEs do
not seem to be a decisive criterion, since the type of AEs are
identical with either monotherapy and do not potentiate.
3.3.
Combination of a1-blockers with phosphodiesterase type 5
inhibitors
Only small, clinical, pilot studies were conducted to assess
a1-blocker/PDE5-I for the treatment of LUTS/BPH. These
data were pooled in a meta-analysis [54].
Preliminary clinical studies testing a1-blocker therapy
with intermittent PDE5-I (as a treatment for ED) focused
primarily on safety (particularly on hemodynamic side
effects), but they did not report any urologic outcome with
regard to LUTS [55–59]. In conclusion, the combination of
Table 5 – a1-Adrenoceptor antagonist and antimuscarinic combination side effects, postvoid residual volume increase, and acute urinary retention
Acute urinary retention
Study discontinuation due to side effects
Side effects (dry mouth)
2.3
16.8 (2.2)
0 ( 3.6)
1.8
3.1
47.1 (20.8)
42.7 (18.3)
42.6 (15.3)
0 (6.4)
1.4 (20.7)
2.9 (18)
0.8
0
0
8.8
4.9
10.3
18.9 (5.8)
42.6 (4.8)
0 (n.r.)
0.5 (7)
0
0
1.4
9.7
<200 ml and >5 ml/s
<30% bladder capacity
<150 ml and >8 ml/s
45 (7)
34.7 (9.7)
55.9 (11.3)
13.1 (3.2)
n.r. ( 13.5)
0 (13.6)
6.1 (22.6)
2.4 (n.r.)
3
0.9
1.9
0.8
7
4
4.7
7.4
39 (3)
27.6 (5.6)
42.1 (2.8)
0 (0)
n.r. (0)
0 (1)
0.9 (5.9)
0 (n.r.)
0
0.6
0
0
4
2.5
2.8
0
<100 ml and >5 ml/s
<200 ml and no Qmax limit
<50 ml and >5 ml/s
<100 ml and 5–15 ml/s
Side effects (dry mouth)
Study discontinuation due to side effects
ClinicalIy significant* increase in PVR (mean increase, ml)
1.8
Acute urinary retention
Side effects (dry mouth)
0 (5.2)
ClinicalIy significant* increase in PVR (mean increase, ml)
Study discontinuation due to side effects
19.9 (7.4)
PVR and Qmax limitations of
study patients
Study discontinuation due to side effects
Acute urinary retention
3.2
a1-Blocker/placebo, %
Acute urinary retention
ClinicalIy significant* increase in PVR (mean increase, ml)
0
ClinicalIy significant* increase of PVR (mean increase, ml)
Side effects (dry mouth)
a1-Blocker/antimuscarinic, %
Acute urinary retention
0 (0.1)
Placebo alone, %
Study discontinuation due to side effects
Clinically significant* increase in PVR (mean increase, ml)
27.9 (6.9)
Antimuscarinic alone, %
EUROPEAN UROLOGY 64 (2013) 228–243
TIMES [42]
Lee et al. [45]
MacDiarmid
et al. [45]
VICTOR [48]
ADAM [49]
ASSIST [50]
TAABO [53]
a1-Blocker alone, %
Side effects (dry mouth)
Trial
a1-Blocker = a1-adrenoceptor antagonist; ADAM = Add-on study of Detrol LA to Alpha-blockers in men; ASSIST = Add-on therapy of Solifenacin Succinate in men for BPH with OAB symptoms treated by Tamsulosin;
BPH = benign prostatic hyperplasia; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; n.r. = not reported; OAB = overactive bladder; PVR = postvoid residual; PSA = prostate-specific
antigen; Qmax = maximum flow rate of urine; TAABO = Trial of combination treatment of an Alpha-blocker plus an Anticholinergic for BPH with OAB; TIMES = Tolterodine and Tamsulosin in men with LUTS;
VICTOR = Vesicare in combination with Tamsulosin in OAB residual symptoms.
*
Clinically significant increase in PVR depending on the study, defined as increase requiring catheterization or increase >300 ml or increase >50% of initial PVR or over the initially defined PVR threshold for exclusion.
239
240
EUROPEAN UROLOGY 64 (2013) 228–243
PDE5-I and a1-blocker is safe, and slight hemodynamic
changes seem to be of no clinical relevance [55–59].
Kaplan et al. compared the daily use of alfuzosin,
sildenafil, or the combination of the two in 62 patients
with LUTS and ED. Alfuzosin reduced IPSS by 15.6%,
sildenafil reduced IPSS by 11.8%, and the combination
reduced IPSS by 24.1%. These differences were only
significant when compared to baseline; they were not
significant between groups. Alfuzosin and the combination
with sildenafil increased Qmax by 11.7% and 21.1%,
respectively, whereas sildenafil alone increased Qmax by
only 6.2%, a difference without statistical significance. There
appeared to be no differences between groups regarding
AEs [60]. In 66 patients with LUTS/BPH and ED treated for
12 wk with either alfuzosin, tadalafil, or the combination,
the latter showed significantly greater increase in IPSS
(41.6%), Qmax (29.6%), and QoL (49.5%) than either monotherapy (alfuzosin alone: 27.2%, 21.7%, and 27.2%, respectively; tadalafil alone: 8.4%, 9.5%, and 28.8%, respectively),
but again, these differences lacked statistical significance
between groups [61]. In a crossover pilot study, 30 patients
with LUTS/BPH (but not necessarily with concomitant ED)
experienced higher IPSS reductions with tamsulosin/tadalafil
(9.2 points) than with tamsulosin/placebo (6.7 points); this
difference was significant compared to the baseline and
between the groups [62].
The meta-analysis of these studies, which also included
some additional pilot studies [63,64], evaluated a total of
278 patients with PDE5-I/a1-blocker combination therapy
[54] and demonstrated increases of IPSS (1.8 points),
International Index of Erectile Function (3.6 points), and
Qmax (1.5 ml/s) when compared to a1-blockers alone.
AEs with combination therapy occurred in 6.8% of patients
and in 5.1% of patients receiving a1-blockers. Overall, there
were no serious AEs, and combination treatment was well
tolerated [54].
Treating LUTS and ED concurrently is already possible by
tadalafil monotherapy (it was recently approved for that
specific indication). This aspect seems particularly interesting because, according to the Multinational Survey of the
Aging Male-7, 60–80% of patients suffering from BPH/LUTS
are simultaneously affected by ED [65]. Improvement in
symptoms of LUTS has been shown with PDE5-I, either alone
or in combination with a1-blockers. However, whether the
a1-blocker/PDE5-I combination is more efficacious in the
treatment of LUTS ED is still to be elucidated.
3.4.
Currently, none of these combination therapies have been
recommended for the treatment of patients in clinical
routine.
4.
Conclusions
The number of adequate and high-level clinical trials
assessing combination therapy in male LUTS is surprisingly
low.
The a1-blocker/5-ARI combination has been examined the
most thoroughly and provides sufficient scientific evidence
for the treatment of particular patient groups. This combination appears to supersede either monotherapy where longterm treatment is intended (>1 yr). Patients with an enlarged
prostate (volume >30–40 ml) and who are high risk for
disease progression benefit most from this combination
therapy. It remains unknown if the favorable effects of
combination therapy are maintained when treatment is
continued for >6 yr. Effects of 5-ARI on PCa screening and
diagnosis should be considered. The present review did not
include cost-effectiveness analyses of a1-blocker/5-ARI
combinations, which might be of relevance in some countries
[72,73].
The a1-blocker/antimuscarinic combination was mostly
assessed as add-on therapy to a1-blocker therapy. This is
in line with the target group, which comprises men with
persistent symptoms after a1-blocker therapy. The combination therapy is a second-line, add-on treatment rather than
a first-line treatment. Exclusion of patients with an increased
risk of AEs (eg, high PVR) in existing studies weakens the
informative value on AUR occurrence. In patients with
increased PVR, an a1-blocker/antimuscarinic combination
should be used with caution and regular measurements
of PVR is advised. Currently, there is no scientific evidence
that a1-blocker/antimuscarinic combination therapy is
efficacious or safe when used for >4 mo.
Only preliminary reports exist on the a1-blocker/PDE5-I
combination therapy. Further research should explore if a
5-ARI is just as effective as an a1-blocker/5-ARI combination
on a long-term basis (>6 yr), and at what time point the
a1-blocker should be omitted. Studies on a1-blocker/
antimuscarinic combinations should verify the long-term
safety and efficacy of this combination. Larger and longer
studies are needed to assess the value of PDE5-I combinations. Combinations of 5-ARI/antimuscarinics, 5-ARI/PDE5I, antimuscarinics/PDE5-I, or even triple therapy might be of
value for certain patients.
Other combinations
Author contributions: Kevin T. McVary had full access to all the data in
Only one RCT was identified that assessed the combination of
saw palmetto, a plant extract, with tamsulosin (the
Tamsulosin With or Without Serenoa repens in Benign
Prostatic Hyperplasia [OCOS] trial) [66]. Although the value
of saw palmetto in the treatment of LUTS remains ambiguous
[67], the study did not report a significant advantage
for combination therapy. Other combinations, with antiinflammatory drugs, antihypertensive drugs, and statins or
5-ARIs/antimuscarinics, for example, are still experimental
and have included only small study populations [68–71].
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Roehrborn, Marberger, McVary, Stief, Oelke,
Füllhase, Novara, Chapple.
Acquisition of data: Oelke, Füllhase, De Nunzio.
Analysis and interpretation of data: Porst, Roehrborn, Marberger, McVary,
Oelke, Füllhase, Chapple, Gratzke, Kaplan.
Drafting of the manuscript: McVary, Stief, Oelke, Füllhase, Chapple.
Critical revision of the manuscript for important intellectual content: Porst,
Roehrborn, Marberger, McVary, Stief, Oelke, Novara, Cornu, De Nunzio,
Chapple, Gratzke, Kaplan.
241
EUROPEAN UROLOGY 64 (2013) 228–243
Statistical analysis: None.
[11] Howick J, Chalmers I, Glasziou P., OCEBM Levels of Evidence Working
Obtaining funding: None.
Group. 2011 levels of evidence system. Centre for Evidence Based
Administrative, technical, or material support: Oelke, Gratzke, Kaplan.
Medicine
Supervision: Roehrborn, McVary, Oelke, Chapple.
Accessed May 1, 2012.
Other (specify): None.
Web
site.
http://www.cebm.net/index.aspx?o=5513.
[12] Jones J, Hunter D. Consensus methods for medical and health
services research. BMJ 1995;311:376–80.
Financial disclosures: Kevin T. McVary certifies 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: Kevin McVary
has been a consultant, investigator, and speaker for Eli Lilly and
Company and Bayer Healthcare. Matthias Oelke has received lecturer
and/or consultant honoraria in the field of male LUTS from Astellas,
GlaxoSmithKline, Lilly, Pfizer, Recordati, and Sophiris. Giacomo Novara
has served as an advisory board member, consultant, researcher, and
speaker for Astellas, GlaxoSmithKline, Lilly, Pierre Fabre, Recordati, and
Takeda. Jean-Nicolas Cornu has been a consultant for Pfizer and Takeda.
Christopher Chapple has been a consultant for AMS and Lilly, a
consultant and researcher for ONO, and a consultant, researcher, and
speaker for Allergan, Astellas, Pfizer, and Recordati.
Support and role of the sponsor: None.
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