Reply

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 à 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 àn

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 à history of cardiovascular disease need no

longer be considered an absolute contraindication to the use of

sildena®l'. You also state that this is à 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 àbsolute'

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).

CORRESPONDENCE 905

# 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


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 ònly a small fraction of

CORRESPONDENCE 907


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


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

11 Ralph D, McNicholas T for the Erectile Dysfunction Alliance.

UK management guidelines for erectile dysfunction. Br Med

J 2000; 321: 499±503

12 Awan GM, Calderon E, Dagwood G, Alpert MA. Acute,

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CORRESPONDENCE 909


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