reply
TRANSCRIPT
Correspondence
5-Hydroxytryptamine-induced potentiation ofcholinergic responses to electrical ®eldstimulation in pig detrusor muscle
Sir,
We read with interest the paper by Sellers et al. [1], who
elegantly reported 5-hydroxytryptamine (5-HT) potentiation of
cholinergic responses to electrical ®eld stimulation in pig
bladder strips. These authors speculated that altered 5-HT
modulation of cholinergic responses might play a role in bladder
dysfunction. The authors based their hypothesis on previ-
ous studies, which have postulated that altered cholinergic
responses may be a possible cause of detrusor instability
associated with BOO. We also considered the possible role of
5-HT in bladder dysfunction associated with BOO. To this
effect we showed, in a rabbit model of partial BOO, that there
is a signi®cant time-dependent upregulation of neuronal 5-HT
binding sites in the detrusor [2]. We also showed that doxazosin,
an a-antagonist used in treating BPH, signi®cantly inhibits
5-HT-mediated contractions in the rabbit detrusor [3]. Auto-
radiography showed that doxazosin reduced 5-HT binding to
receptor sites in a concentration-dependent manner in this
tissue [3]. Hence, we speculated that the bene®cial effects of
doxazosin in BOO may be ascribable, at least in part, to 5-HT
antagonism. These ®ndings support the hypothesis that 5-HT
contributes to the pathogenesis of bladder dysfunction.
M.A. Khan, R.J. Morgan and D.P. Mikhailidis
Royal Free Hospital, London, UK
1 Sellers DJ, Chess-Williams R, Chapple CR. 5-Hydro-
xytryptamine- induced potentiation of cholinergic responses
to electrical ®eld stimulation in pig detrusor muscle. BJU Int
2000; 86: 714±8
2 Khan MA, Dashwood MR, Thompson CS, Mumtaz FH,
Morgan RJ, Mikhailidis DP. Time-dependent up-regulation of
neuronal 5-hydroxytryptamine binding sites in the detrusor
of a rabbit model of partial bladder outlet obstruction. World
J Urol 1999; 17: 255±60
3 Khan MA, Thompson CS, Dashwood MR, Mumtaz FH,
Mikhailidis DP, Morgan RJ. Doxazosin modi®es serotonin-
mediated rabbit urinary bladder contraction: potential
clinical relevance. Urol Res 2000; 28: 116±21
A prospective study of conservatively managedacute urinary retention: prostate size matters
Sir,
The authors of this paper [1] conclude that `a trial without
catheter is justi®ed in men presenting with AUR [acute urinary
retention] arising from BPH', a statement which I believe to be
true. It is also interesting to see a `real-life practice' study of a
condition commonly met by urologists, particularly given the
recent interest in AUR and its management, reviewed recently
[2]. However, this study [1] has several major ¯aws in its
methodology which call into question any conclusions that may
be drawn from the results. The authors report on the outcome of
a group of 40 men presenting with `primary AUR' de®ned as `an
episode of painful inability to void which was relieved by passing
a catheter'. They claim to have excluded those men with lower
urinary tract pathology which might have in¯uenced the
natural course of BPE. Included in the study were three men
who had had a previous episode of AUR; can they truly be
described as having primary AUR? At least one individual said
to have an acute retention had a residual volume of 2.8 L on
catheterization, and there is no comment within the paper as to
whether any patients had deranged renal function or not. Six
patients included in the study had undergone a previous TURP,
which of all the interventions offered by urologists must
in¯uence the natural course of BPE most dramatically! There
were also three men taking anticholinergic medication, and
several already taking a-blockers. Of the 40 men who were
included in the study, 16 were reported to have constipation on
admission, which was relieved before a trial without catheter
(TWOC). More men had a successful TWOC after clearance of
their constipation than failed to void (10 vs six). The de®nition
of an unsuccessful TWOC was stated to be failure to void
altogether, or voiding with a postvoid residual (PVR) of
>200 mL. This threshold of 200 mL appears to have been
chosen arbitrarily but is a good prognostic indicator of the
likely need for surgical intervention. Within a randomized trial
of the effect of alfuzosin on the outcome of a TWOC after AUR,
we followed up 34 men who voided successfully [3,4] and
found that the PVR was a good indicator of the likely need
for intervention. This observation echoes the ®ndings of
Klarskov et al. [5] that a PVR of <100 mL was a good
prognostic indicator for continued voiding after a TWOC.
Consequently, the remaining 22 men selected for follow-up
in this study [1] fared very well.
The authors reported that those who failed a TWOC were
older than those who voided successfully (74.9 vs 72.4 years), a
®nding which although not statistically signi®cant in the study
also echoes our ®ndings [3]. It seems logical that if an enlarged
prostate is a risk factor for developing AUR [6] then the size of
the prostate may affect the outcome after AUR. The authors
used a DRE assessment of prostate size and concluded that those
patients with large prostates were less likely to fare well after a
TWOC. Assessing the prostate weight by a DRE is recognised as
being inaccurate when compared with a TRUS measurement
[7], but was used to show a statistically signi®cant difference
between the groups. The authors state in the methods section
that they used the chi-squared test for analysis, which is not an
appropriate test to compare ordinal data-sets. Whilst it might be
intuitively expected that those with large prostates fare less well,
I do not think conclusions can be drawn about how prostate size
may in¯uence the outcome after AUR until a study is conducted
using a reliable method for accurately assessing prostate size,
with an appropriate statistical analysis of the ®ndings. Whilst I
commend the authors for their efforts to carry out a study based
in `real-life practice', the potential for errors and bias in this
BJU International (2001), 87, 904±909
# 2001 BJU International904
study are so great that they must invalidate the ®ndings
reported.
A. McNeill
Ninewells Hospital and Medical School, Dundee, Scotland
1 Kumar V, Marr C, Bhuvangiri A, Irwin P. A prospective study
of conservatively managed acute retention: prostate size
matters. BJU Int 2000; 86: 816±9
2 Choong S, Emberton M. Acute urinary retention. BJU Int
2000; 85: 186±201
3 McNeill SA, Daruwala PD, Mitchell IDC, Shearer MG,
Hargreave TB. Sustained-release alfuzosin and trial without
catheter after acute urinary retention: a prospective placebo-
controlled trial. BJU Int 1999; 84: 622±7
4 McNeill SA, Gallagher HI, Daruwala PD, Mitchell IDC, Rizvi S,
Hargreave TB. Long-term follow-up after presentation with a
®rst episode of acute urinary retention. BJU Int 2000; 85
(Suppl 5): 30
5 Klarskov P, Andersen JT, Asmusses CF et al. Symptoms and
signs of the voiding pattern after acute urinary retention in
men. Scand J Urol Nephrol 1987; 21: 23±8
6 Jacobsen SJ, Jacobson DJ, Girman CJ et al. Natural history of
prostatism: risk factors for acute urinary retention. J Urol
1997; 158: 481±7
7 Roehrborn CG. Accurate determination of prostate size via
digital rectal examination and transrectal ultrasound.
Urology 1998; 51: 19±22
8 Taube M, Gajraj H. Trial without catheter following acute
retention of urine. Br J Urol 1989; 63: 180±2
Reply
I thank Mr McNeill for his observations and comments
on our paper, and I am pleased to address some of the
points. We de®ned AUR in subjective terms rather than
ascribing a speci®c residual volume drained by catheter-
ization; what volume would be chosen? I agree that it
would be unusual to include a patient with a catheterized
residual of 2.8 L, but this man presented with bladder
pain which was relieved by catheterization and, meeting
the inclusion de®nition, was included. On reviewing the
data I can con®rm that this patient had undergone a
previous TURP and is currently using CISC. Clearly he is
a case of `chronic retention' and perhaps it is regrettable
that, because of our de®nition, he was included. No other
patient, in either the successful- or failed-TWOC groups,
had a PVR of >1.8 L; none of the patients had deranged
renal function.
This prospective study was done in the `real world' of a
busy NHS acute urology ward, and the patients included
were those usually encountered in normal practice. The
starting point of the study was the admission with AUR
(by de®nition), regardless of previous history. If a man
with AUR had undergone previous bladder neck surgery
or previous episodes of retention, or was constipated, or
was on anticholinergic medication, then so be it; this was
accepted. The subsequent management and outcome
were important in this study; previous events were
unimportant in terms of this episode of AUR. Hence,
patients already on a-blockers or anticholinergics were
included and were continued on their drugs. Likewise,
previous episodes of retention or of bladder neck surgery
were not considered to be relevant to the conduct of
the study but were felt to be important in assessing the
end results.
As to prostate size, the aim was simply to distinguish
large from small prostates as objectively yet practically
as possible. Prostate size was therefore estimated (as
opposed to measured) with the relatively experienced
right index ®nger of the senior author. To Mr. McNeill's
assertion that prostate size should have been measured
by TRUS, may I suggest that the `real-life' situation to
which he refers is clearly not one with which he
is familiar.
P.P. Irwin, MCh, FRCSI(Urol)
Editor's comment on: `Press release: Furtherresearch supports Viagra@ safety pro®le'
Sir,
We take issue with your recent editorial comment and the
commentary by Gordon Williams about the cardiovascular
safety pro®le of ViagraTM (sildena®l citrate) [1]. In your
comment you misquote P®zer by suggesting that the press
release claims that `a history of cardiovascular disease need no
longer be considered an absolute contraindication to the use of
sildena®l'. You also state that this is `a very signi®cant departure
from previously accepted clinical practice with implications for
patients with erectile dysfunction (ED).' The prescribing
information for the product (e.g. UK/EU summary of product
characteristics) has never speci®ed that a history of cardiovas-
cular disease is a contraindication. Nor has P®zer ever claimed
that cardiovascular disease per se should be an absolute
contraindication to the use of Viagra; indeed, the only `absolute'
cardiovascular contraindication is co-administration with
nitrates. The pre-registration clinical trials (P®zer, data on
®le) included many men with a history of cardiovascular disease
such as hypertension, angina, myocardial infarction and pre-
vious by-pass surgery. These data and subsequent studies [2]
have shown that Viagra had a good ef®cacy and safety pro®le
when used to treat ED in men with these cardiovascular diseases
and risk factors.
Caution is recommended when prescribing Viagra to certain
cardiovascular patients i.e. those whose cardiac condition
makes it unsafe for them to engage in sexual activity (a cau-
tion applicable to all treatments for ED) and those who may be
more susceptible to the action of drugs with vasodilatory
properties (e.g. patients with left ventricular out¯ow obstruc-
tion, or with multiple system atrophy and severe autonomic
neuropathy).
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# 2001 BJU International 87, 904±909
Your commentary and accompanying editorial discuss the
safety of Viagra. The concerns arise mostly from two main
sources; preclinical studies using predominantly suprathera-
peutic concentrations/doses of sildena®l and anecdotal case
reports of adverse reactions in patients who may have taken
sildena®l. Gordon Williams cites two such preclinical studies
[3,4], and the post-marketing adverse-event reports [5,6], to
draw conclusions without acknowledging the important
information from many clinical studies which are more directly
relevant to the safety of sildena®l.
Both preclinical studies [3,4] were conducted at concentra-
tions of sildena®l many times higher than the maximum free
plasma concentrations of sildena®l (< 40 nmol/L) achieved in
man after therapeutic doses. Thus we consider that these
studies are not relevant to the normal use of sildena®l in man.
Moreover, there have been no reports of torsade de pointes
(the dysrhythmia that would be associated with prolonged
cardiac action potential) after administering sildena®l to man.
In contrast, many clinical and epidemiological studies of Viagra
have been carried out in man and all have shown a favourable
safety pro®le [2,7±10].
Worldwide, up to 1 July 2000, over 25 million prescriptions
for Viagra have been written for more than 10 million men. As
men with ED (which is predominantly a vascular condition)
have a high prevalence of cardiac disease and are at increased
risk of cardiac events, it is not surprising that some cases of
myocardial infarction and death have occurred in men treated
with Viagra. The key question is whether these events are
occurring more frequently than would be expected by chance.
Information to address this question comes from three main
sources; (i) haemodynamic and mechanistic studies; (ii) large-
scale clinical trials permitting an analysis of the incidence of
cardiac adverse events in men randomized to sildena®l
compared with placebo; and (iii) large-scale epidemiological
studies. All these sources of information show a favourable
safety pro®le of sildena®l, with no evidence that the product
could provoke serious cardiac problems, and this is further
detailed below.
As to haemodynamic and mechanistic studies, a variety of
studies in animal models of coronary artery disease [11,12] and
in patients with angina [13±15], congestive heart failure
[16,17] and pulmonary hypertension [18] has shown no
detrimental effect of Viagra on a range of variables of cardiac
function.
Data from randomized clinical trials provide objective
evidence for determining the ef®cacy and safety of a medical
treatment, drug, device or procedure. A retrospective analysis of
the Viagra clinical trials database (containing 30 double-blind
placebo-controlled and 23 open-label studies, with almost 7000
person-years of observation of patients on Viagra and almost
600 person-years of observation on placebo) showed no
difference in the incidence of myocardial infarction or all-
cause mortality between Viagra and placebo [6].
For epidemiological studies, the Drug Safety Research Unit (at
Southampton) reported on Phase I data from their indepen-
dently conducted Prescription Event Monitoring study of 5391
men prescribed sildena®l in a general practice setting in the UK
[19]. This study is very important as it is the ®rst to provide
quantitative data on the incidence of cardiovascular and other
adverse events in patients who have been prescribed sildena®l in
clinical practice. The authors found no evidence of an increased
risk of cardiac morbidity or mortality after the ®rst 5 months of
the study in men treated with Viagra. The rates for these
conditions in these men were comparable with rates for the
general population of men of the same age. Moreover, there
were no myocardial infarctions, strokes or deaths reported
during the ®rst month after prescribing sildena®l, indicating
that resumption of sexual activity assisted by Viagra is not
associated with an undue risk of these types of cardiovascular
events.
Finally, as the editorial and commentary indicate, there is
some confusion about which kind of patients can safely resume
sexual activity and can receive Viagra or other treatments; we
refer you to the clear, concise guidelines on prescribing for ED in
patients with cardiovascular disease [20]. These guidelines
emphasize the need to assess the patient's ®tness for sexual
activity before prescribing any treatment for ED, recognizing the
importance of the activity rather than the treatment as the
potential risk factor in these patients. Similar guidelines have
also recently been published in the USA [21].
I. Osterloh MBBS, MSc, MRCP, Director/Team Leader,
Viagra Medical Strategies
R. Hargreaves, MD, MRCP, MRCGP, MRCPath,
Category Medical Manager, Viagra, P®zer Inc.
1 Editor's Comment. Press release: Further research supports
Viagra@ safety pro®le. BJU Int 2000; 86
2 Conti CR, Pepine CJ, Sweeney M. Ef®cacy and safety of
sildena®l citrate in the treatment of erectile dysfunction in
patients with ischemic heart disease. Am J Cardiol 1999; 83:
29C±34C
3 Stief CG, Uckert S, Becker AJ et al. Effects of sildena®l on
cAMP and cGMP levels in isolated human cavernous and
cardiac tissue. Urology 2000; 55: 146±50
4 Geelen P, Drolet B, Rail J et al. Sildena®l (VIAGRA) prolongs
cardiac repolarisation by blocking the rapid component of
the delayed recti®er potassium current. Circulation 2000;
102: 275±7
5 Mitka M. Some men who take Viagra die ± why? JAMA
2000; 283: 590±1
6 Azarbal B, Mirocha J, Shah PK et al. Adverse cardiovascular
events associated with the use of VIAGRA. J Am Coll Cardiol
2000; 35 (Suppl. A): 553A(1147±13)
7 Mittleman MA, Glasser DB, Orazem J et al. Incidence of
myocardial infarction and death in 53 clinical trials of
VIAGRA1 (sildena®l citrate). J Am Coll Cardiol 2000; 35
(Suppl. A): 302A(807±6)
8 Kloner RA. Cardiovascular risk and sildena®l. Am J Cardiol
2000; 86 (Suppl): 57F±61F
9 Morales A, Gingell C, Collins M et al. Clinical safety of oral
sildena®l citrate (VIAGRA@) in the treatment of erectile
dysfunction. Int J Impot Res 1998; 10: 69±74
10 Olsson AM, Persson CA. Ef®cacy and safety of VIAGRA1
(sildena®l citrate) in men with cardiovascular disease and
906 CORRESPONDENCE
# 2001 BJU International 87, 904±909
erectile dysfunction. For the Swedish sildena®l investigators
group. J Am Coll Cardiol 2000; 35: A1202±54
11 Traverse JH, Du R, Chen YJ et al. Sildena®l (VIAGRA)
improves coronary blood ¯ow distal to a coronary stenosis
during exercise. Circulation 1999; 100 (Suppl. I): I±
489(2580)
12 Przyklenk K, Kloner RA. VIAGRA does not exacerbate
ischemia, but renders platelets refractory to the inhibitory
effects of adenosine. Circulation 2000; 102 (Suppl. II): II±
254(1244)
13 Herrmann HC, Chang G, Klugherz BD et al. Hemodynamic
effects of sildena®l in men with severe coronary artery
disease. NEJM 2000; 342: 1622±6
14 Pelliccia F, Leonardo F, Pagnotta P et al. Effects of
phosphodiesterase-5 inhibition on myocardial ischaemia
in patients with chronic stable angina in therapy with beta-
blockers. J Am Coll Cardiol 2000; 35 (Suppl. A):
339A(1016±108)
15 Vardi Y, Bulus M, Reisner S, Nassar S et al. Ergometric
studies for evaluating sildenadil effect in cardiac patients.
J Urol 2000; 163 (Suppl. 4): 200(886)
16 Katz SD, Balidemaj K, Homma S et al. Acute type 5
phosphodiesterase inhibition with sildena®l enhances ¯ow-
mediated vasodilation in patients with chronic heart failure.
J Am Coll Cardiol 2000; 36: 845±51
17 Hebert KA, Arcement LM, Ferguson TG. Is sildena®l
(VIAGRA) safe and effective for the treatment of erectile
dysfunction in patients with heart failure? Circulation 2000;
102 (Suppl. II): II±413, 2009
18 Lepore JJ, Pereira N, Maroo A et al. Sildena®l is a pulmonary
vasodilator which augments and prolongs vasodilation by
inhaled nitric oxide in patients with pulmonary hyperten-
sion. Circulation 1999; 100 (Suppl. I): I±240(1247)
19 Shakir S, Freemantle S, Pearce G. IHD morbidity and
mortality in a community based cohort of sildena®l users in
England: phase 1 results. Presented at the European Society
of Pharmacovigilance (ESOP) 8th Annual meeting.
September 21±23. 2000 Verona, Italy
20 Jackson G, Betteridge J, Dean J et al. A systematic approach
to erectile dysfunction in the cardiovascular patient: a
consensus statement. Int J Clin Pract 1999; 53: 445±51
21 DeBusk R, Drory Y, Goldstein I et al. Management of sexual
dysfunction in patients with cardiovascular disease: recom-
mendations of the Princeton Consensus Panel. Am J Cardiol
2000; 86: 175±81
Sir,
Of course, urologists can comment on cardiovascular issues,
but they must be fully informed and armed with the facts.
Unfortunately, Gordon Williams' comment fails on both counts.
Indeed, the Editor's comment is also strange because it fails
to invite a balanced view, one of the essentials of an editor's
responsibilities. Recognising that ED is predominantly a cardio-
vascular problem, two consensus panels have published their
recommendations and guidelines [1,2]; neither are referenced
by Gordon Williams, which is a serious omission. Selective
referencing (a potential subject for an editorial) undermines the
scienti®c argument. Both the British and American consensus
panels showed broad agreement and their publications should
be read by all urologists, because of the signi®cant incidence of
coronary disease in men with ED. There is no evidence that any
of the currently licensed treatments for ED add to the overall
cardiovascular risk in patients with or without (silent)
documented coronary disease providing they are properly
assessed according to the clear guidelines developed by both
panels. When quoting experimental electrophysiological data in
isolated heart models it is essential to recognise that the drug
levels used far exceed (in one paper by >1000-fold) those
obtained in clinical practice and may only be relevant if
sildena®l was used as a bizarre form of suicidal overdose.
Authors should also carefully scrutinise any text to which they
add their names, particularly when reading journals such as
Circulation (surely not regular reading for urologists). Viagra has
proved to be a successful and well-tolerated therapy for ED,
providing a convenient oral option for the ®rst time. It is
therefore a signi®cant addition to the range of therapeutic
options available. ED is far too important to become a
battleground for those advocating one therapy above another.
Urologists, cardiologists and family doctors need to work
together using their individual expertise to optimise the
treatment of ED.
G. Jackson
Consultant Cardiologist, Cardiothoracic Centre, St Thomas'
Hospital, London
Replies
In response to Drs. Osterloh and Hargreaves from P®zer,
an expert panel from the American College of Cardiology
(ACC) and the American Heart Association (AHA)
provided the most authoritative and unbiased assessment
of the cardiac risk of sildena®l [1]. It is surprising that this
critical 1999 consensus document was not cited in their
letter. The ACC/AHA consensus document stated the
following: `Given the increasing reports of deaths in
which the use of Viagra may be implicated, clinicians
need to exercise caution when advising their patients
with heart disease about taking this medication.' The
ACC/AHA consensus panel noted that the use of Viagra
was contraindicated in patients using nitrates (for at least
24 h after nitrate ingestion). Similarly, the use of nitrates,
a common medicine for cardiac patients, is contra-
indicated in any patient who used Viagra within 24 h.
Viagra was also judged to be `potentially hazardous' in
patients with active coronary ischaemia; in patients with
congestive heart failure, borderline low blood pressure, or
low-volume status; in patients on a complicated multi-
drug, antihypertensive programme; and in patients using
drugs that can prolong the half-life of Viagra (including
nearly 50 approved medications).
Objective, peer-reviewed epidemiological data asses-
sing the safety of Viagra are remarkably scant. Patients
with heart disease represented `only a small fraction of
CORRESPONDENCE 907
# 2001 BJU International 87, 904±909
studied patients' in the P®zer-sponsored clinical trials, as
indicated by the ACC/AHA consensus panel [1]. This
occurred in part because the following common cardiac
patients were excluded from the Viagra clinical trials:
patients with heart failure; patients with myocardial
infarction or stroke within 6 months; patients with low-
normal blood pressure; and patients with uncontrolled
hypertension. Thus, the epidemiological data based on
the P®zer clinical trials, despite the impressive total of
patient-years, is somewhat arti®cial and provides no
strong reassurance about Viagra's safety in the typical
cardiac patient.
Adding to this uncertainty about the safety of Viagra
in the cardiac patient are the more than 500 deaths
reported to the USA FDA during Viagra's ®rst 15 months
of marketing [2,3] and a reported rate of death per
million prescriptions that is much higher for Viagra than
for other prescription therapies for ED [2]. In addition to
the laboratory reports from Stief et al. [4] and Geelen et al.
[5] suggesting a potential effect of Viagra on cardiac
energy metabolism and conduction, clinical reports in
patients have appeared that suggest a cause-and-effect
relationship of Viagra use with the development of:
ventricular arrhythmias [6]; myocardial infarction in the
absence of sexual activity or known coronary risk factors
[7]; and atrial ®brillation, ventricular tachycardia, and
haemodynamic instability in patients with obstructive
cardiomyopathy [8,9]. The risk of using Viagra in the
cardiac patient is therefore not insigni®cant. Viagra is
`contraindicated' in patients receiving nitrates and
`potentially hazardous', as noted by the ACC/AHA
expert panel, in many other cardiac patients. In
summary, it is clear that: (i) Viagra has a life-threatening
interaction with an important medication class (nitrates)
used commonly by the cardiac patient; and (ii) there are
many cardiac patients for whom Viagra use poses a
serious health risk.
The continuing efforts by the Drug Safety Research
Unit in Southampton are very useful and will help to
complete our knowledge once the data are critically
examined. However, until those and other objective
studies are completed and analysed adequately, it is
sensible to heed the ample warning signals suggesting
that caution and vigilance are appropriate when
considering whether or not it is safe to prescribe Viagra
to a cardiac patient.
In reply to Dr Jackson; of course cardiologists can
comment on urological issues, but they must be fully
informed and armed with the facts. My comment was
intended to provide the balanced view Dr. Jackson invites
to a `press release' from P®zer, in which the company
implied that the cardiac safety of Viagra had been
con®rmed in a study involving only 14 men. My attempt
at editorial balance was further supported by the USA
FDA of®cers who also voiced their concerns about
extrapolating too much from this very small study
conducted in a highly controlled setting [10].
The cardiovascular safety of Viagra continues to be
under great scrutiny, as it should be. More than 500
deaths were associated with the use of Viagra in its ®rst
15 months of marketing [2,3]. In my opinion these
deaths have not been adequately explained,. How many
more Viagra-associated deaths have now occurred? How
many of these deaths have been sudden? Are these deaths
expected or unexpected? How many deaths have been
associated with sexual intercourse and how many have
occurred before sexual intercourse was attempted? These
are some of the questions that need to be answered
objectively by unbiased parties before we (the urologists
who treat this urological condition) understand how to
prescribe this drug responsibly.
Perhaps the best advice on how to prescribe Viagra can
be found in the UK management guidelines published
recently by the Erectile Dysfunction Alliance. The
alliance has stated that Viagra is `contraindicated in
patients taking nitrates and those with severe hepatic
impairment, hypertension, hereditary degeneration, ret-
inal disorders, and recent stroke or myocardial infarc-
tion' [11]. In addition, patients with hypertrophic
obstructive cardiomyopathy who use Viagra may be at
risk of arrhythmia [12]. The full risk of Viagra in more
ordinary cardiac patients is not yet known. As mentioned
in the editorial, several biochemical studies in heart tissue
suggest a pro-arrhythmic potential for sildena®l, and time
will tell whether or not these results have clinical
relevance. Meanwhile, caution and vigilance in prescrib-
ing Viagra in the cardiac patient seems to be a prudent
philosophy. Urologists should not be dissuaded from
attempting to understand the side-effects of a drug,
especially one with potential cardiac toxicity, that is used
by their patients.
Gordon Williams
1 Cheitlin MD, Hutter AM, Brindis RG et al. Use of sildena®l
(Viagra) in patients with cardiovascular disease. Circulation
1999; 99: 168±77
2 Mitka M. Some men who take Viagra die ± why? JAMA
2000; 283: 590±1
3 Azarbal B, Mirocha J, Shah PK et al. Adverse cardiovascular
events associated with the use of VIAGRA. J Am Coll Cardiol
2000; 35 (Suppl. A): 553A(1147±13)
4 Stief CG, Uckert S, Becker AJ et al. Effects of sildena®l on
cAMP and cGMP levels in isolated human cavernous and
cardiac tissue. Urology 2000; 55: 146±50
5 Geelen P, Drolet B, Rail J et al. Sildena®l (VIAGRA) prolongs
cardiac repolarisation by blocking the rapid component of
the delayed recti®er potassium current. Circulation 2000;
102: 275±7
908 CORRESPONDENCE
# 2001 BJU International 87, 904±909
6 Shah PK. Sildena®l in the treatment of erectile dysfunction.
N Engl J Med 1998; 339: 699
7 Feenstra J, van Drie-Pierik RJ, Lacle CF, Stricker BH. Acute
myocardial infarction associated with sildena®l. Lancet
1998; 352: 957±8
8 Stauffer JC, Ruiz V, Morard JD. Subaortic obstruction after
sildena®l in a patient with hypertrophic cardiomyopathy.
N Engl J Med 1999; 341: 700±1
9 Awan GM, Calderon E, Dagwood G, Alpert MA. Acute,
symptomatic atrial ®brillation after sildena®l citrate
therapy in a patient with hypertrophic obstructive cardio-
myopathy. Am J Med Sci 2000; 320: 69±71
10 Malozowski S, Sahlroot JT. Hemodynamic effects of
sildena®l. N Engl J Med 2000; 343: 967±8
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CORRESPONDENCE 909
# 2001 BJU International 87, 904±909