european urology supplements 5 (2006) 1004–1012
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Safety and Tolerability of Treatment for BPH
Francesco Montorsi a,*, Ignacio Moncada b
a
b
Cattedra di Urologia, University Vita e Salute-San Raffaele, Milan, Italy
Department of Urology and Andrology, Hospital Gregorio Marañón, Madrid, Spain
Article info
Abstract
Keywords:
a1-Adrenergic antagonists
BPH
Dutasteride
5a-Reductase inhibitors
Tolerability
TURP
Treatment options for benign prostatic hyperplasia (BPH) include
watchful waiting, pharmacologic therapy, and surgery. For individual
patients, treatment choice depends on disease severity, comorbidity,
patient preferences, and the comparative efficacy and adverse effects
(AEs) of the available therapies. Disease-related symptoms and treatment-related factors influence health-related quality of life (HRQOL),
and treatment discontinuation occurs due to lack of efficacy or the
occurrence of AEs. This review explores the safety and tolerability of
current treatment options. Pharmacologic therapies include a1-adrenergic antagonists and 5a-reductase inhibitors (5ARIs). The a1-adrenergic
antagonists have comparable efficacy but tolerability profiles that differ
according to vasodilatory AEs and ejaculatory abnormalities. Alfuzosin
and tamsulosin are better tolerated than terazosin and doxazosin; tamsulosin causes fewer vasodilatory AEs than alfuzosin but causes more
ejaculatory abnormalities. AEs associated with 5ARIs are mainly sexual
(eg, erectile dysfunction, reduced libido, and gynaecomastia) and tend to
be confined to the first year of therapy. Surgery has the potential for
short- and long-term complications. Open surgery has been largely
replaced by less invasive approaches, particularly transurethral resection of the prostate (TURP). Short-term complications of TURP include
death, bleeding, clot retention, transurethral resection syndrome, urinary tract infection, and inability to void; long-term complications include
failure to void, retrograde ejaculation, erectile dysfunction, incontinence, and retreatment. More recent approaches (eg, transurethral
needle ablation, thermotherapy, and laser therapy) have promising
efficacy and safety. Patient expectations of therapy and AEs should be
considered to ensure that treatment is tailored to individual patient
needs and that HRQOL is maximised.
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# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Cattedra di Urologia, University Vita e Salute-San Raffaele, Via
Stamira D’Ancona 20, Milan 20129, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298.
E-mail address: [email protected] (F. Montorsi).
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.08.012
european urology supplements 5 (2006) 1004–1012
1.
Introduction
From the patient’s perspective, the focus of
attention of benign prostatic hyperplasia (BPH)
management today centres on patient choice and
health-related quality of life (HRQOL) [1]. The HRQOL
of patients treated for BPH depends both on diseaserelated and treatment-related factors. The degree to
which the same level of disease-related symptoms
and treatment-related side-effects of therapy bother
individual patients differs, and this is reflected in
appropriately measured HRQOL [1].
From the clinician’s perspective, the aims of
treatment for BPH are to: (1) reduce symptoms, (2)
improve HRQOL, and (3) prevent progression of the
disease and so avoid potentially serious complications such as acute urinary retention (AUR) and
the need for surgery. Treatment options include
watchful waiting, pharmacologic therapy with
a1-adrenergic antagonists or 5a-reductase inhibitors
(5ARIs), or surgery. Appropriate treatment choice
depends on disease severity, concurrent medical
conditions, patient preferences (eg, for or against
surgery), comparative efficacy, and adverse events
(AEs) [2]. In elderly patients, potential drug interactions also need to be considered. Discontinuation of
treatment can be due to lack of efficacy or the
occurrence of AEs. Within this context, the safety
and tolerability of the treatment options are
reviewed.
1005
patients receiving placebo, alfuzosin, or tamsulosin
withdrew from these studies. Among patients
receiving terazosin or doxazosin, however, an
additional 4–10% of patients discontinued therapy.
Withdrawal from these studies was mainly due to
expected side-effects, including dizziness, postural
hypotension, tiredness, stuffy nose, syncope, and
ejaculatory dysfunction.
2.1.1.
Vasodilatory AEs
It is because the effects of the nonselective
a1-blockers (terazosin, doxazosin, and alfuzosin)
are not limited to the lower urinary tract but also
affect other tissues such as the vasculature, that
these agents can cause vasodilatory AEs such as
2.
Safety and tolerability of pharmacologic
therapy
2.1.
a1-Blockers
The a1-blockers reduce smooth muscle tone in the
prostate and result in rapid improvements in
urinary symptoms and flow. Currently available
a1-blockers include the nonselective a1-blockers,
terazosin, doxazosin, and alfuzosin, and the highly
selective a1A-blocker, tamsulosin. These agents
have comparable efficacy; the main difference
among these agents relates to their tolerability
profiles.
An extensive review of data from trials of
a1-blockers, including data from 6333 patients in
placebo-controlled trials and 507 patients in direct
comparative studies, revealed that alfuzosin (sustained-release formulation) and tamsulosin (0.4 mg
modified-release formulation) are better tolerated
than terazosin and doxazosin [3]. The discontinuation rate observed with alfuzosin and tamsulosin
was similar to that observed with placebo; 4–10% of
Fig. 1 – Percentage of patients with (A) dizziness, (B)
postural hypotension, (C) who discontinued therapy due
to adverse events (AEs) in placebo-controlled studies.
ALF = alfuzosin; IR = immediate release; SR = sustained
release; TER = terazosin; DOX = doxazosin;
TAM = tamsulosin. Reproduced with permission from
Djavan B et al. Urology 2004;64:1081–8.
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european urology supplements 5 (2006) 1004–1012
dizziness and postural hypotension. These AEs are a
concern because they have the potential to lead to
serious complications such as falls and fractures [4].
Due to its selectivity as an a1A-blocker, tamsulosin
tends to interfere less with blood pressure regulation
and causes fewer vasodilatory AEs [4,5].
In the updated meta-analysis of data from trials
of the a1-blockers conducted by Djavan et al, data
from placebo-controlled trials indicated that vasodilatory AEs occurred at rates comparable to or only
slightly higher than placebo with alfuzosin and
tamsulosin, but occurred at a higher rate than
placebo with terazosin and doxazosin (Fig. 1A and B)
[6]. Discontinuation due to AEs was lower with
alfuzosin XL and tamsulosin compared with terazosin and doxazosin (Fig. 1C) [6].
Data from direct-comparison studies indicated
that, overall, tamsulosin is associated with a slightly
lower incidence of vasodilatory AEs than other
a1-blockers. A comparison of tamsulosin and
alfuzosin, for example, revealed that compared with
baseline, tamsulosin had no effect on blood pressure,
whereas alfuzosin caused a significant reduction in
both standing and supine blood pressure ( p < 0.05)
[7]. Dizziness was also more common with alfuzosin
and terazosin than with tamsulosin, whereas the
incidences of syncope and hypotension were similar
for tamsulosin and alfuzosin [6]. Discontinuation due
to vasodilatory AEs was comparable for tamsulosin
and alfuzosin and higher with terazosin; discontinuation due to dizziness was 0.6% with tamsulosin
and 2.0% with terazosin [6]. Data from the use
of alfuzosin in the clinical setting rather than in
trials demonstrate that treatment discontinuation
remains at about 4%, and vasodilatory AEs continue
to be the main cause of treatment discontinuation [8].
In a post-marketing surveillance survey involving
13,389 patients with BPH who received alfuzosin,
499 patients (3.7%) discontinued therapy due to
intolerance and 722 reported AEs [8]. The AEs
resulting in discontinuation were mainly vasodilatory (Table 1) [8].
2.1.2. Interaction with cardiovascular disease or
cardiovascular medications
Among patients taking a1-blockers, vasodilatory AEs
are more common and severe in patients with
cardiovascular disease or receiving cardiovascular
medications and in those who are elderly [4,8]. Data
from direct-comparison studies show that the slightly higher incidence of vasodilatory AEs observed
with alfuzosin and terazosin compared with tamsulosin is particularly pronounced in patients aged 75 yr
or older and those with cardiovascular comorbidity
or comedications [6,7,9].
In the open-label, non-controlled post-marketing
surveillance study of alfuzosin, cardiovascular AEs
occurred more often in patients aged 75 yr or older
than in younger patients. Vertigo/dizziness leading
to study discontinuation, for example, occurred in
0.9% of patients aged <65 yr, 1.5% of patients
aged 65–74 yr, and 2.3% of patients aged 75 yr
[8]. The risk of withdrawal of a patient aged 75 yr was
1.5-fold higher than for a patient aged 60 yr, and the
risk increased with cardiovascular comorbidity or
use of cardiovascular medications [10]. Tamsulosin,
on the other hand, causes fewer vasodilatory AEs
than alfuzosin (particularly in the elderly) and is
well tolerated in patients with cardiovascular
comorbidity or comedication [4].
2.1.3.
Ejaculatory abnormalities
In the meta-analysis of data from a1-blockers,
ejaculatory abnormalities were reported to occur
Table 1 – The nature of adverse events resulting in discontinuation of therapy in the 722 patients who withdrew and
incidence in the overall population [8]
Adverse event
Vasodilatory
Vertigo/dizziness
Syncope/malaise
Postural hypotension
Headache
Miscellaneous
Gastrointestinal
Urinary tract infections
Skin and muscle disorders
Other cardiovascular disorders
Central nervous system disorders
General status
Data from Lukacs et al. Eur Urol 1996;29:29–35.
Adverse event leading to
withdrawal, % (n = 722)
Incidence in overall population,
% (n = 13,389)
59.0
25.1
10.2
7.9
7.2
8.6
21.0
3.5
3.5
3.2
2.6
6.7
3.20
1.35
0.55
0.42
0.39
0.46
1.16
0.19
0.19
0.17
0.14
0.35
european urology supplements 5 (2006) 1004–1012
in about 1% of patients receiving alfuzosin, doxazosin, or terazosin in placebo-controlled trials, which is
roughly comparable with the rate of ejaculatory
abnormalities observed with placebo [6]. The incidence of abnormal ejaculation with alfuzosin, for
example, was reported to be 0.6% in pooled data from
three randomised, placebo-controlled studies involving 955 patients [11]. Tamsulosin causes a higher
incidence of ejaculatory abnormalities, with rates of
5–11% reported from European and US studies [6].
However, abnormal ejaculation tends to be better
tolerated than vasodilatory AEs [12], and abnormal
ejaculation with tamsulosin resulted in discontinuation of treatment in <1% of cases in placebocontrolled studies [13]. Despite the existence of a
higher incidence of abnormal ejaculation with
tamsulosin, in the study by Höfner et al. this was
not considered by patients to be a major problem, and
there was no overall negative impact on sexual
function compared with placebo or alfuzosin [13].
2.1.4.
Interaction with phosphodiesterase type-5 inhibitors
Erectile dysfunction increases with age, so it is
probable that many men with BPH will also have
erectile dysfunction and may use medications for
this condition [4]. The phosphodiesterase type-5
inhibitors (PDE5-Is; eg, sildenafil, tadalafil, and
vardenafil) are widely used for management of
erectile dysfunction, but, like a1-blockers, these
agents can cause vasodilatation. Although data on
comedication with these two classes are currently
limited, the use of PDE5-Is in patients receiving
a1-blockers can lead to symptomatic hypotension.
The use of sildenafil in conjunction with an
a1-blocker is permitted as long as the initial dose
of the PDE5-I is low and the patient is stable on the
a1-blocker [14]. The precautions for use of vardenafil
with an a1-blocker are similar [14].
2.1.5.
dual inhibitor of 5a reductase types I and II. The
5ARIs inhibit the steroid 5a reductase isoenzymes,
which are responsible for the conversion of testosterone to dihydrotestosterone (DHT), the main
androgen stimulating prostate growth. Removal of
DHT results in relative androgen withdrawal in the
prostate, causing shrinking of the gland and subsequent improvements in urinary symptoms and
flow, and a reduction in the risk of acute urinary
retention [15,16]. Because DHT potentiates the effect
of testosterone on erectile function, the sexual sideeffects seen with these agents are not unexpected
[17]. Treatment-related AEs reported during trials of
these agents are mainly sexual events; other AEs
occur at an incidence <1%. The 5ARIs are also
known to affect testosterone and prostate-specific
antigen (PSA) levels.
2.2.1.
Sexual AEs and gynaecomastia
In trials of dutasteride and finasteride, the only AEs
that occurred more often with these agents than
with placebo were sexual AEs and gynaecomastia
[16,18,19]. In the phase 3, long-term, double-blind,
placebo-controlled studies of dutasteride, for example, the drug-related AEs observed were mainly
impotence, reduced libido, ejaculation disorders,
and gynaecomastia (Fig. 2) [16,20]. These studies
included 4325 patients with BPH who were randomised to receive placebo (n = 2158) or dutasteride
(n = 2167), followed for 2 yr in the double-blind phase
and then in a 2-yr, open-label extension. Sexual AEs
tended to occur during the first 6 mo of therapy but
decreased with study duration. The incidence of
drug-related gynaecomastia was low and remained
constant throughout the study; gynaecomastia
occurred in 1.3% of patients in years 1 and 2, 1.8%
in year 3, and 0.7% in year 4. Fewer than 1% of
Conclusions
The a1-blockers are generally well tolerated. The
main AEs are vasodilatory effects and ejaculatory
dysfunction. Alfuzosin and tamsulosin are better
tolerated than terazosin and doxazosin. Tamsulosin
causes fewer vasodilatory AEs than alfuzosin, but
causes more ejaculatory abnormalities. The use of
PDE5-Is for management of erectile dysfunction in
patients receiving a1-blockers should be done with
care due to the risk of a synergistic lowering of blood
pressure.
2.2.
5a-Reductase inhibitors
The 5a-reductase inhibitors (5ARIs) are finasteride,
an inhibitor of 5a reductase type I, and dutasteride, a
1007
Fig. 2 – Sexual adverse events and gynaecomastia
associated with dutasteride use. *Includes breast
enlargement and breast/nipple tenderness [16].
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european urology supplements 5 (2006) 1004–1012
patients withdrew due to drug-related sexual AEs in
the open-label phase [16].
Data on the sexual AEs associated with finasteride are available from the Proscar Long-Term
Efficacy and Safety Study (PLESS), in which 3040
patients with BPH were randomised to receive
placebo (n = 1516) or finasteride (n = 1524) and were
followed for 4 yr [18]. On entry to the study, a large
proportion of patients already had sexual dysfunction; 46% of patients in both groups had a history of
sexual dysfunction. During the first year of the
study, significantly more patients in the finasteride
group (15%) compared with the placebo group (7%)
experienced drug-related sexual AEs ( p < 0.001).
These sexual AEs included reduced libido, erectile
dysfunction, decreased ejaculate volume, and
other ejaculation disorders (Fig. 3) [18]; most of
these AEs were mild to moderate in intensity.
During the remaining 3 yr of the study, there was
no difference between the groups in the incidence
of new sexual AEs (7% in both groups). Sexual AEs
resolved with continued therapy in 12% of patients
in the finasteride group and 19% of patients in the
placebo group, and only 4% of finasteride and 2% of
placebo patients discontinued therapy due to
sexual AEs.
In a comparator study of dutasteride and finasteride involving 1630 men with BPH, the incidence of
drug-related AEs was slightly lower with dutasteride, with a 17% incidence in dutasteride-treated
patients and a 20% incidence in finasteride-treated
men, primarily of a sexual nature (not significant)
[20]. It is interesting to note that although dutasteride is able to reduce DHT levels to a greater extent
than finasteride [21], the incidence of AEs is
comparable with the two 5ARIs.
2.2.2.
PSA levels
In the studies of dutasteride reported by Debruyne
and coworkers, PSA levels fell by a mean of 53% from
baseline at 2 yr and 57% from baseline at 4 yr [16].
With placebo, PSA levels increased by 15% from
baseline at 2 yr, but when dutasteride therapy was
started at this point, PSA levels fell to 48% below
baseline at 4 yr. A similar effect is seen with
finasteride, where a 50% decrease in PSA level has
been reported [17]. Thus, although PSA levels fall
with 5ARIs, this parameter still maintains its role as
a marker of prostatic cancer, and in individuals
taking these agents who are also undergoing PSA
screening, PSA levels can be doubled and then
compared with age-related norms [22]. Recent data
from the Prostate Cancer Prevention Trial (PCPT)
suggest that PSA performance is improved in
patients receiving finasteride, in terms of overall
detection of cancer, and for high-grade cancers [23].
2.2.3.
Serum testosterone levels
Serum testosterone levels remained within the
physiologic range during therapy with dutasteride
[16], increasing by 20% from baseline at 2 yr and
maintained at 4 yr. With placebo, serum testosterone levels increased by 2% from baseline at 2 yr and
increased to 20% above baseline at 4 yr. Finasteride
treatment led to a modest (but statistically significant) increase in serum testosterone levels compared with placebo ( p < 0.001) [24].
2.2.4.
Fig. 3 – Incidence of selected drug-related sexual AEs (mild,
moderate and severe) in patients; (A) with a history of
sexual dysfunction at baseline; (B) without a history of
sexual dysfunction at baseline [18].
Interaction with cardiovascular drugs and PDE5-Is
The 5ARIs have few, if any, effects on the cardiovascular system, so do not tend to cause vasodilatory AEs such as dizziness or postural hypotension
[25]. The 5ARIs do not interact negatively with
cardiovascular drugs and use of PDE5-Is is unrestricted with these agents [14].
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european urology supplements 5 (2006) 1004–1012
2.2.5.
Conclusions
3.
Safety and tolerability of surgical
approaches
The overall conclusion from these studies is that
5ARIs are well tolerated. Sexual AEs are the most
common drug-related AEs, although they occur
infrequently and do have a significant impact on
treatment continuation. With both agents, these
AEs occur during the first year of treatment, and
there is no evidence of increased AEs compared with
placebo after the first year of therapy.
2.3.
3.1.
Open prostatectomy versus less invasive approaches
When considering the safety and tolerability of
treatments for BPH, surgery of any form involves
hospitalisation and presents a significant rate of
short-term and long-term complications. Open
prostatectomy, though an effective approach to
BPH treatment, is seldom used today except for
patients with specific indications (eg, very large
prostate gland or renal insufficiency). Interestingly,
a recent study by Vela-Navarrete et al. has reported
an increased incidence of open procedures conducted between 1992 and 2002 due to larger sized
glands [28]. They speculate that this might be due to
the longer use of a1-blockers during this period,
which allowed the prostate to grow to a greater
extent before the need for surgery.
The open procedure has largely been replaced by
less invasive techniques [28] and, of these, transurethral resection of the prostate (TURP) is the most
widely used. Although promising in terms of
efficacy and safety, none of the more recently
developed approaches (eg, transurethral needle
ablation [TUNA]; transurethral microwave thermotherapy [TUMT]; water-induced thermotherapy
[WIT]; and a variety of laser-based approaches),
has yet demonstrated clear superiority to TURP in
terms of a superior cost–benefit ratio [29]. Of the
minimally invasive therapies, European Association
of Urology guidelines suggest that holmium laser
enucleation of the prostate (HoLEP) can be used
safely in patients receiving anticoagulant medication or who are in urinary retention [30]. Good
outcomes have been reported immediately after
surgery [31] and were comparable to TURP [32].
Retrograde ejaculation occurs in 75–80% of patients,
Combination therapy: a1-blocker plus 5ARI
A combination of an a1-blocker and a 5ARI has been
assessed in the Medical Therapy of Prostate Symptoms (MTOPS) study. Finasteride and doxazosin in
combination provided superior benefits in terms of
symptom relief and improvement in maximum flow
rate (Qmax) than either agent alone [26]. But it has to
be considered whether combining the two types of
therapy actually increases the likelihood of AEs. The
MTOPS study revealed that patients on combination
therapy experienced AEs similar to those for each
drug alone and that these were typical for patients
receiving these classes of drugs, that is, dizziness,
erectile dysfunction, postural hypotension, and
asthenia. There was a higher incidence of AEs in
the combination arm compared with either monotherapy. Nevertheless, the discontinuation rates
were lower with combination therapy (18%) compared with finasteride (24%) and doxazosin (27%)
monotherapies. The overall safety of long-term
combination medical therapy was shown by the
fact that none of the side-effects had a frequency
greater than six events per 100 patient-years of
follow-up. In the Symptom Management After
Reducing Therapy (SMART) trial involving a combination of tamsulosin and dutasteride for a fixed
period followed by withdrawal of the a1-blocker, the
AEs were as expected for either medication [27].
Table 2 – Example perioperative (intraoperative, early and late postoperative) complication rates for transurethral
resection of the prostate
Study
No. of patients
Complication
Overall
Bleeding requiring transfusions
Clot retention
Transurethral resection syndrome
Myocardial arrhythmia
Myocardial infarction
Failure to void
Urinary tract infection
Death
Mebust et al.
1989 [34]
3885
24.9
6.4
3.3
2.0
1.1
0.05
6.5
2.3
0.2
Borboroglu et al.
1999 [35]
520
13.3
0.4
1.3
0.8
1.3
0.2
–
2.1
0.0
Uchida et al.
1999 [36] (1971–1985)
1930
Uchida et al. 1999 [36]
(1985–1996)
1931
17.2
20.2
–
0.5
9.5
6.1
–
0.3
–
–
–
0.2
–
–
–
0.5
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european urology supplements 5 (2006) 1004–1012
but no postoperative erectile dysfunction has been
reported [33].
3.2.
TURP
In the case of TURP, short-term (mainly perioperative) complications include death, bleeding, clot
retention, transurethral resection (TUR) syndrome
(hyponatraemia resulting in mental confusion,
nausea, vomiting, and raised blood pressure),
urinary tract infection, and inability to void, among
which, bleeding is the most common. Some of these
complications (eg, bleeding and TUR syndrome) may
be serious and life-threatening. In the largest TURP
series reported so far (a retrospective evaluation of
3885 patients), perioperative mortality was 0.2% and
perioperative morbidity was 24.9% [34]. More recent
reports give better results, although morbidity
remains significant (Table 2) [34–36].
Long-term complications of TURP include failure
to void, retrograde ejaculation, impotence, partial or
complete incontinence, and retreatment. Example
rates for these complications are about 13% for
failure to void [37,38], 58% for retrograde ejaculation
[39], about 15% for impotence [40,41], about 2% for
partial incontinence, and 1% for complete incontinence [42]. Up to 10% of patients require retreatment for urethral stricture or bladder-neck
contracture [42]. The current American Urological
Association guidelines on BPH estimate the incidence of erectile dysfunction following TURP to be of
the order of 10% [43]. A review of 29 randomised
controlled trials revealed an incidence of 6.5%
following TURP [44].
3.3.
Conclusions
Surgery of any form involves hospitalisation and
presents a significant rate of short-term and longterm complications. Among the less invasive techniques, TURP is the most widely used. Short-term
complications of TURP include death, bleeding, clot
retention, TUR, urinary tract infection, and inability
to void. Long-term complications of TURP include
failure to void, retrograde ejaculation, impotence,
partial or complete incontinence, and retreatment.
4.
Conclusions
The medical and surgical treatments for BPH are
associated with an acceptable level of morbidity. For
individual patients, treatment choice depends on
disease severity, comorbidity, patient preferences,
and the comparative efficacy and AEs of the
available therapies. Disease-related symptoms and
treatment-related factors also influence HRQOL.
Patient expectations of therapy should be considered, particularly with regard to AEs, so that
treatment can be tailored to individual patient
needs and HRQOL can be maximised.
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