BMJ

Postmarketing Surveillance Of Enalapril IAuthor(s): D. Millson, Tom Walley, D. Blowers, D. Chalmers, Alyn Morice, T. W. Higenbottamand Morris J. BrownSource: BMJ: British Medical Journal, Vol. 297, No. 6658 (Nov. 12, 1988), pp. 1269-1270Published by: BMJStable URL: http://www.jstor.org/stable/29701549 .

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Disciplining midwives

I read with interest the comments on my editorial

(1 October, p 806). A former member of the

United Kingdom Central Council (UKCC) for

Nursing, Midwifery and Health Visiting felt that I

was "impertinent" to suggest change (15 October,

p 981), whereas Ms Sheila Kitzinger believes I did

not go far enough,1 so I think the balance of the

article was about right.

May I respond, however, to Mr Reader's point (29 October, p 1125) that the UKCC already includes lay members? Though Mr Reader does

not belong to a nursing profession, he was ap?

pointed to the UKCC as an educationalist and

not as a lay person. Like the UKCC s financial

members, its educationalist members were ap?

pointed to speak for a particular non-nursing interest and not primarily to represent the view of

lay individuals. The distinction may seem trivial to

some people, but I am surprised that it escaped Mr

Reader and provoked him to such intemperate

language. Far from being written "out of ignorance," as

Mr Reader suggests, my article?like any BMJ editorial?was scrupulously checked during its

preparation. The final drafts were vetted by senior

midwives, doctors, and administrators, some of

whose experience of the UKCC is at least equal to

Mr Reader's. I am grateful to them for their

generous help. More importantly, drafts of the

article were discussed with many midwives work?

ing in hospital or in the community. From their

comments and from letters I have subsequently received I believe my article expresses the views of

a substantial number of practising midwives.

JAMES OWEN DRIFE

Department of Obstetrics and Gynaecology, Leicester Royal Infirmary, Leicester LE2 7LX

1 Kitzinger S. Midwives who are victims of a witchhunt. Independent 1988 Oct 19:15.

Postmarketing surveillance of

enalapril I

Professor William H W Inman and others

(1 October, p 826) studied prescription-event

monitoring of enalapril. Though we agree that

enalapril is an effective drug with a low incidence

of severe adverse reactions in the treatment of

hypertension and heart failure, we are concerned

that the safety profile of enalapril in comparison with other angiotensin converting enzyme in?

hibitors such as captopril has been overstated.

It is difficult to compare the results of their

study with previous studies of other angiotensin

converting enzyme inhibitors because the dose

of enalapril, duration of treatment, and rate of

withdrawal are not specified and the indication for

the use of enalapril is not specified. This is

important in view of the low mortalities recorded

Comparison of adverse effects ofenalapril and captopril in patients with hypertension

Enalapril study1 Captopril study6

No of patients 11710 13 295 Duration of treatment 6 weeks 3052 studied for one year;

mean duration not stated No of deaths 10 119 Mean fall in blood pressure (mm Hg) 24/15 27/17

Mean dose Not specified 72-66 mg/day

Adverse effects (%) Rash 0-5 0-81

Orthostatic symptoms 2 11 Cough 1 0-2 Taste disturbance 02 0-33 Blood dyscrasias 0 0 02 Renal impairment 0 013 Angio-oedema 003 0

in previous studies with enalapril for hypertension alone1 and the higher rate seen in studies of

enalapril in congestive heart failure.2 In addition, there is no comparable study of captopril. Previous

direct comparisons of enalapril and captopril in

congestive heart failure have favoured captopril,

probably because the prolonged hypotensive effects of enalapril compromised renal and cerebral

function.3

Early studies of captopril in hypertension

reported a high frequency of adverse drug reac?

tions that were related to dose.4 These are less

frequent with the lower dose regimens currently recommended. A recent review concluded that taste disturbance was the only adverse drug reaction that was more likely with captopril than

with enalapril and that there was no difference in

efficacy.5 Because the manner of reporting adverse drug

reactions in studies is not standardised it is difficult to make absolute comparisons between different

drugs in different studies. Nevertheless, we have

tried to compare the adverse effects of enalapril and captopril in similar populations of patients

with hypertension using published data from

postmarketing surveillance studies with a similar treatment end point (table).16 The frequency of adverse drug reactions are similar with both drugs.

The main differences are in the numbers of deaths and adverse renal effects reported, which may reflect the short duration of the enalapril study.

Comparison of published studies would be facilitated if there were a standardised framework of reporting adverse drug effects that included

incidence, withdrawal rate, treatment category, dose range, and patient demographic character?

istics and selection policy. Such a framework

should be mandatory and enforced by medical

journal editorial policy.

Postmarketing surveillance of adverse drug reactions is now considered to be desirable by the

Committee on Safety of Medicines for all new

drugs. The study of Professor Inman and others

shows that prescription-event monitoring is

particularly valuable in detecting adverse effects of

drugs as they are used in practice rather than as

they are used in clinical trials. We look forward to further such studies which will allow better

comparisons between new and existing drugs in a

given class. D MILLSON

TOM WALLEY

Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool L69 3BX

1 Cooper WD, Sheldon D, Brown D, Kimber GR, Isitt VL, Currie WJC. Postmarketing surveillance of enalapril: experience in

11710 hypertensive patients in general practice. J R Coll Gen Pract 1987;37:346-9.

2 Consensus Trial Study Group. Effects of enalapril on mortality in severe chronic heart failure. N Engl J Med 1987;316:1429-34.

3 Packer M, Lee WH, Yushack M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986;315:847-53.

4 Fr?hlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med 1984;144:1441-4.

5 Breckenridge A. Angiotensin converting enzyme inhibitors. BrMedJ 1988;296:618-20.

6 Chalmers D, Dombey SL, Lawson DH. Post marketing surveillance of captopril (for hypertension): a preliminary report. BrJ Clin Pharmacol 1987;24:343-9.

The paper by Professor William H W Inman and others (1 October, p 826) included aspects

which need clarification and others which require challenge.

Prescription-event monitoring is a method of

detecting and measuring trends of events occurring in a population of patients receiving a specific drug

over a period of one year in general practice. It

depends entirely on meaningful data being recalled and recorded by doctors after at least a year in a

questionnaire sent from the Drug Safety Research Unit.

The unit identified over 120000 prescriptions for enalapril. These were "processed" to identify 22417 patients?15169 questionnaires were

returned and 12 543 (56%) were used as the basis for the paper. We are not told how this final figure

was derived but accept that in "real life" there will be large numbers of spoilt papers and non

respondents. From this information the authors

published a table of events of special interest and

compared some of these findings with those for

captopril.

Captopril was the first oral angiotensin convert?

ing enzyme inhibitor available to general practi? tioners. Unlike enalapril it was initially indicated for patients with severe hypertension resistant to other agents or with side effects from other treatments. Despite this restriction to difficult

patients the results from the postmarketing study by Chalmers et al showed a low incidence of events and side effects.

' These data allowed the Committee

on Safety of Medicines to broaden the indication for

captopril to mild to moderate hypertension, the indication initially granted to enalapril.

We believe that a more appropriate comparison of patients exists in a postmarketing study of

captopril, which comprised patients with data at one year together with patients withdrawn during this study (data on file, E R Squibb and Sons). The table lists the events reported by Professor Inman and others compared with the same events in the

Squibb study.

Events (percentages) reported in patients during pre? scription-event monitoring of enalapril (Inman et al) and

postmarketing study of captopril (Squibb)

Enalapril Captopril Event (n=12 543) (n=23035)

Hypotension 1-7 0-7 Syncope/dizziness 5-0 2 0 Cough 2-9 0-9 Taste disturbance 0-2 0-7 Angio-oedema 0-2 0-04* Other skin reactions 2-7 2-3 Renal 0-7 0-3

Deaths Total 3-5t 2-5 Renal 0-52 003

*Only one case of laryngeal swelling reported and eight of lip or facial swelling. fAdjusted from 975 deaths to 434 deaths recorded during treatment (see table II of Inman et at).

No case of neutropenia (white cells <lxl0Vl) was observed in the captopril study. The range of

reactions seem similar but the rates were generally lower for captopril than for enalapril.

A possible explanation of the difference seen in

renal events and deaths has been suggested by Packer et al and Cleland et al, who noted the long duration of activity of enalapril as a possible reason

for prolonged hypotension leading to myocardial

damage, renal failure, and cerebral ischaemia.2 *

In an article purporting to be a scientific approach to our knowledge of possible adverse drug re?

actions Professor Inman and others conclude "it

BMJ volume 297 12 November 1988 1269

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was plainly evident that enalapril had considerably

improved the quality of life and possibly prolonged it in many seriously ill patients" but give no data to support this observation.

Every method of assessing the benefit risk

profile of a new chemical entity has its drawbacks, but we believe that the yellow card reports,

prescription-event monitoring, and properly con?

ducted postmarketing studies each contribute to

our knowledge, albeit in different ways. In attempt?

ing to compare different methods care must be

exercised to ensure legitimacy of the conclusions.

D BLOWERS

D CHALMERS

E R Squibb and Sons, Squibb House, Hounslow TW3 3JA

1 Chalmers D, Dombey SL, Lawson DH. Postmarketing surveil? lance of captopril (for hypertension): a preliminary report.

BrJ Clin Pharmacol 1987;24:343-9. 2 Packer M, Lee WH, Yushak M, Medina N. Comparison of

captopril and enalapril in patients with severe chronic heart failure. N EnglJ Med 1986;315:847-53.

3 Cleland JGF, Dargie HJ, McAlpine H, et al. Severe hypotension after first dose of enalapril in heart failure. Br Med J 1985;291:1309-12.

Professor William Inman and colleagues confirm

that cough is an increasingly recognised side effect

of drugs which inhibit angiotensin converting enzyme. The incidence of cough varies from 1 to

10% in other studies, but what has emerged, and is

not commented on by the authors, is a sex related

difference in the incidence of cough associated

with angiotensin converting enzyme inhibitors.1

We have recently examined preliminary data on the incidence of cough requiring withdrawal

from treatment in a large postmarketing study of

patients receiving captopril for hypertension (data on file, E R Squibb); 57% of the study population were women and 23% were current smokers. The

incidence of cough as a new symptom was high

(4-4%) and was slightly more common in smokers. In the United Kingdom there are 44 million

consultations a year where cough is the major

symptom and these data probably reflect the high incidence of cough in the general population. In

contrast, those patients who were withdrawn from

treatment because of cough were fewer (less than

1%) and showed a strong sex and smoking related

variation in incidence. Non-smokers were 2-25

times more likely to be withdrawn for cough than

smokers, and women were more likely to be

withdrawn than men (3-4 times for smokers and

2-3 for non-smokers).

Cough induced by angiotensin converting

enzyme inhibitors has previously been reported to

be commoner in women by a ratio of 2:1.' The reason for this sex related difference in the inci?

dence of cough is unknown, but it is unlikely that

hormonal influences are to blame as most reported cases are in postmenopausal women and when

cough does occur in younger women the menstrual

cycle seems to have no influence on the frequency of cough. The female preponderance in trouble? some cough induced by these drugs might reflect

the greater numbers of men who smoke and the

fact that smokers may be less likely to ascribe their

cough to a drug. In the captopril postmarketing

study, however, the sex related difference in

the incidence of cough was still present when

smoking history was taken into account.

The mechanism of the cough is unknown, but a

perineuronal increase in substrates of angiotensin

converting enzyme such as bradykinin or sub?

stance P has been suggested.2 We propose two

possible explanations for the sex and smoking related differences in the incidence of such cough. Individual susceptibility may be due to differences

in the activity of angiotensin converting enzyme. Thus lower tissue levels of enzyme in women and

non-smokers would predispose to cough. The

direct determination of intrapulmonary angio

tensin converting enzyme is difficult, but angio? tensin converting enzyme activity is increased by

cigarette smoke both in vitro' and in cells obtained at bronchial lavage from smokers.4 In normal

subjects serum angiotensin converting enzyme

may be used as an index of tissue angiotensin

converting enzyme, and Lieberman has shown

that serum angiotensin converting enzyme activity is significantly lower in women.'

An alternative hypothesis is that angiotensin

converting enzyme is the rate limiting step in the

perineuronal metabolism of peptides only in

certain individuals and that the lack of the enzyme such as encephalinase or neutral endopeptidase

normally responsible for the degradation of pep? tides may underlie the sex related difference in the

incidence of cough. Whatever the origin of the

cough induced by angiotensin converting enzyme

inhibitors, the detection of this novel side effect

has given a fascinating insight into the sensory innervation of the lung.

ALYN MORICE

T W HIGENBOTTAM

Department of Respiratory Physiology, Papworth Hospital, Cambridge CB3 8RE

MORRIS J BROWN

Department of Clinical Pharmacology, Addenbrooke's Hospital, Cambridge

1 Coulter DM, Edwards IR. Cough associated with captopril and enalapril. BrMedJ 1987;294:1521-3.

2 Morice AH, Lowry R, Brown MJ, Higgenbottam T. Angio? tensin converting enzyme and the cough reflex. Lancet 1987;n: 1116-8.

3 Bakkle YS, Yartiala J, Tovinson H, Volita I. Effect of cigarette smoke on the metabolism of vasoactive hormones in rat isolated lungs. BrJ Pharmacol 1979;65:495-9.

4 Sugiyama Y, Yotsumoto H, Okabe T, Takaku F. Measurement of angiotensin-converting enzyme activity in intact human

macrophages and effect of smoking. Respiration 1988;53: 153-7.

5 Lieberman J. Elevation of serum angiotensin-converting-enzyme (ACE) levels in sarcoidosis. Am J Med 1975;59:365-72.

Preoperative biochemical

screening

I had hoped that I had nailed1 the erroneous idea

that serum creatinine concentration alone is a

sufficient measure of renal function, but Drs Iain T

Cam bell and Peter Gosling, writing with the

authority of the Association of Clinical Biochemists

(1 October, p 803), indicate otherwise. If clinicians

accept this suggestion they will not recognise about

half the patients with renal impairment above

50 ml/min because, although serum creatinine

concentration is only just above the (broad) normal range, the patient has functionally lost one

kidney.1 Such imprecision in assessing renal function is

acceptable in the context of an unexpected pre?

operative proteinuria provided that no one deludes

himself or herself that serum creatinine concentra?

tion is a direct measure of glomerular filtration

rate.

ROGER GABRIEL

Renal Unit, St Mary's Hospital, London W2 IN Y

1 Gabriel R. Time to scrap creatinine clearance? Br Med J 1986;293:119-20.

Drs Iain T Campbell and Peter Gosling (1 October,

p 803) in their editorial on preoperative biochemical

screening conclude that in patients under 50

routine urine screening is adequate. There is much

evidence, however, that clinicians often ignore abnormal results of unsolicited tests.1 In one study of analyses of urine over half of the positive results

for blood and protein and one third of the cases of

glycosuria did not seem to have been recognised by the clinician.2

In a prospective study (Hoffbrand and Watts,

unpublished data) eight patients presented to us

with major renal disease (five with the nephrotic

syndrome, three with chronic renal failure) having had heavy proteinuria detected on routine analysis of urine and recorded in hospital notes on a total of 11 occasions up to three years before. In six

instances the records were nursing admission notes

and checklists before surgery. The five other

occasions were outpatient attendances. In all cases

the complaints and surgery were unrelated to the

coincidental renal disease and the proteinuria seemed to have been ignored. On an appreciable number of occasions, also, we have been called to

see patients with postoperative renal failure whose

"routine" preoperative biochemistry showed a

raised plasma urea concentration about which no

action had been taken.

The formal prospective studies to which Camp? bell and Gosling refer are likely to overestimate the

value of preoperative biochemical screening in

everyday clinical practice owing to poor com?

munication between nursing and medical staff and

the latter's tendency to ignore abnormal test results.

B I HOFFBRAND

Department of Medicine, Whittington Hospital, London N19 5NF

1 Schneiderman LJ, DeSalvo L, Bayler S. The "abnormal" screening laboratory result. Arch Intern Med 1971;129:88.

2 Fraser CG, Smith BC, Peake MJ. Effectiveness of an outpatient screening program. Clin Chem 1977;23:2216-8.

Psychosis from alcohol or

drug abuse

In recent years the number of patients admitted in

this district with psychosis resulting from the

abuse of alcohol or drugs, or both, commonly

presenting with morbid suspicions, delusions,

hallucinations, or passivity phenomena seems to

have risen substantially, particularly in those

under 30. To measure this impression the case

summaries of all patients admitted to one of

our acute wards for the first time in 1975 and

in 1985 were examined and patients with the

above symptoms, delirium tremens, or Wernicke's

encephalopathy were identified. Diagnosis

depended mainly on the history of substance

abuse obtained at the time of admission or retro?

spectively when the patient was well and also on

the fact that the symptoms subsided within a short

time of admission, often a matter of days in the

absence of any other treatment. In several cases,

however, there was a relapse either after discharge or after a weekend at home followed by a remission

on readmission. Although in many cases there was

laboratory evidence of substance abuse, it was

often difficult to obtain specimens for testing. The total number of admissions during 1975 and

1985 was similar (133, 136). The mean age and sex

distribution of patients admitted was also similar.

The number of admissions related to alcohol abuse

rose, however, from seven to 20 (p=0018) while

those attributable to drug abuse with or without

the use of alcohol rose from five to 16 (p=0*026). The total number of psychoses not related to

substance abuse was hardly changed (14, 17), but

psychoses resulting from abuse of alcohol or drugs, or both, increased from two to 14. Of these, those

resulting from alcohol increased from one to four

and those from drugs from one to 10. To put this in

another way, whereas psychoses resulting from

substance abuse amounted to one eighth (2/16) of

all psychoses in 1975 they accounted for almost

half (14/31) in 1985. The commonest drugs of

abuse in 1975 were barbiturates, accounting for

40% of the total, and in 1985 cannabis (38%). The

mean age of the 10 patients with drug psychosis in

1985 was 25 years. Three of the four patients with

alcohol psychosis and six of the 10 with drug

1270 BMJ volume 297 12 November 1988

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