1. health and fitness
2. drugs

October 2001
Volume 10.4
Prescribing Points
A NEWSLETTER FOR GENERAL PRACTITIONERS AND PHARMACISTS IN OXFORDSHIRE PRODUCED BY THE PRESCRIBING
TEAM, DIRECTORATE OF PUBLIC HEALTH & HEALTH POLICY, OXFORDSHIRE HEALTH AUTHORITY, OLD ROAD
HEADINGTON, OXFORD OX3 7LG
This article was initially prepared for prescribers in
the Oxford Radcliffe Hospital NHS Trust. However
as many points are pertinent to prescribing in
primary care we though it would be of value to
publish it here.
Angiotensin Converting Enzyme (ACE)
Inhibitors
A
ngiotensin converting enzyme
inhibitors block the conversion of
angiotensin I to its acute metabolite
angiotensin II.
EDITORIAL BOARD
Editor
Julie Dandridge
Editorial Board
Tom Jones
Ian G. Simpson
Louise Cotton
Unless stated otherwise, the views expressed in this publication
are those of the authors, and do not necessarily represent the
policy of Oxfordshire Health Authority.
Desk Top Publishing
Louise Carlisle
The renin-angiotensin system is central to the
pathophysiology of hypertension and heart
failure. Although ACE inhibitors are effective
antihypertensive drugs, their benefits go
beyond simple blood pressure reduction or
vasodilatation and include vascular and cardiac
remodelling.
There are now eleven ACE inhibitors licensed
in the UK, of which four are in the Oxford
Radcliffe formulary (captopril, enalapril,
lisinopril, and ramipril). The choice has been
based on historical precedent, cost, and data
from published studies.
While there are important pharmacological
differences between ACE inhibitors, it is not
clearly established whether these result in
significant differences in the clinical benefits
produced.
The purpose of this article is to provide
clinicians with a summary of the trial /
evidence relating to the agents in the ORH
formulary, with guidance on doses and
frequency of administration.
Pharmacological Differences
Pharmacodynamics
It is not known whether full 24-hour ACE inhibition is required for the beneficial effects of ACE
inhibitors in hypertension or heart disease. It is essential to optimise treatment in terms of target
doses and dosing frequency (see Table 1).
For patient convenience, and hence compliance, captopril is not suitable for long-term treatment.
Elimination
All ACE inhibitors are renally excreted but lisinopril and ramipril have significant faecal excretion
(via the bile). Renal toxicity is well described; all patients should have their renal function checked
before starting/ or changing the dose of ACE inhibitor, and during treatment.
Licensed Indications
Table 1 summarises the licensed indications and dosages for the ACE inhibitors in the ORH
formulary. Captopril with its short half-life, is useful for initiation in unstable patients, but is not
ideal for longer-term use. Lisinopril is the only ACE inhibitor recommended for once-daily
dosing for all its indications.
1. Heart Failure
The use of ACE inhibitors in patients with heart failure characterised by left ventricular systolic
dysfunction is supported by good clinical evidence. [1, 2] Table 2 summarises the results of the
major clinical studies of ACE inhibitors in heart failure.
Table 1 – Licensed indications for ACE inhibitors with costs per 28 days in community
Indication
Dosage
Cost/28days
a
Hypertension
Indication
Dosage
Cost/28days
a
Diabetic
Nephropathy
Captoprilb
12.5 - 50mg twice daily
£2.21 - £3.75
Captoprilb
75mg - 100mg
daily, in 2 to 3
divided doses
£3.75 - £4.42
Lisinopril
2.5 - 40mg once daily
£6.26 - £21.94
Lisinopril
2.5 - 20mg once
daily
£6.26 - £10.97
Enalapril
10 - 20mg twice daily
£10.46 - £12.64
Ramipril
1.25 - 10mg once daily
£5.30 - £13.00
Heart Failure
Captoprilb
50mg three times daily
Lisinopril
30 - 35mg once daily
£20.67 - £28.53
£5.62
Enalapril
10 - 20mg twice daily
£10.46 - £12.64
Ramipril
5mg twice daily
£19.10
Acute MI
Captoprilb
50mg three time daily
£5.62
Lisinopril
10mg once daily
£9.70
Enalapril
10 - 20mg twice daily
£10.46 - £12.64
Ramipril
1.25mg - 5mg twice
daily
£10.30 - £19.10
HOPE studyc
Ramiprild
10mg once daily
£13.00
3
a.
b.
c.
d.
Prescribing Points
Based on Drug Tariff March 2001
For patient convenience and compliance, captopril is not suitable for longterm treatment
Reducing the risk of myocardial infarction, stroke or cardiovascular death
and/or the need for revascularisation procedures
It is not known whether this benefit is a class effect. It is however not
necessary to switch if a patient is already on an ACE inhibitor.
Table 2 - Studies of ACE inhibitors in Heart Failure (includes only ACE inhibitors on ORH formulary)
Drug
Trial
Captopril
Enalapril
Enalapril
Average daily dose
ξ
Patient Selection
Follow up period
SAVE[1]
LVEF <40%
42 months
150mg
24
SOLVD[2]
SOLVD[2]
LVEF<35% Symptomatic
LVEF <35% (Asymptomatic)
41 months
37 months
11.2 mg
16.7 mg
22
105
NNT
Table 3 - Studies of ACE inhibitors Post MI (includes only ACE inhibitors on ORH formulary)
Drug
Trial
Patient Selection
Captopril
Captopril
Enalapril
Lisinopril
Ramipril
SAVE[1]
ISIS-4[3]
CONSENSUS-II[4]
GISSI 3[5]
AIRE[6]
LVEF<40% (Asymptomatic)
All patients
All patients
All patients
Heart failure (clinical
evidence)
Days drug started
3-16 days (Average 11dy)
<24hrs
<24hrs
<24hrs
3-10 days
Average daily
dose
NNT
90% on 150mg
18.4mg
8.8mg
8.2 mg
ξ
24
200
125
17
ξ
NNT = Number needed to treat to prevent one death. The NNT is greatly affected by the event rate. Thus the NNT is much more
favourable in trials where overall mortality was higher i.e. in those with clinically apparent heart failure.
2. Acute Myocardial Infarction
ACE inhibitors significantly reduce mortality following acute myocardial infarction.[1, 3-6] The size
of the benefit appears greater in patients with left ventricular impairment or clinical evidence of
heart failure (Table 3).
3. Hypertension
All ACE inhibitors are effective antihypertensives, but the effect of a single dose of enalapril is less
marked in the second 12 hours of the day. Twice- daily dosing is recommended for enalapril.
4. Diabetic Nephropathy
The ACE inhibitors slow the progression of diabetic nephropathy. The mechanism appears to
involve not only blood pressure.
5. HOPE Study
HOPE was a 5-year study of 9000 patients with vascular disease or diabetes plus one other
cardiovascular risk factor, i.e. they were at high risk of cardiovascular events but were not known
to have left ventricular impairment.[7] Outcome was a composite of myocardial infarction, stroke,
and cardiovascular death. The absolute risk reduction for this outcome was 3.7% (NNT= 27). The
dose used was 10mg of ramipril once a day. Whilst it is likely that this benefit is a class effect, at
present ramipril is the only ACE inhibitor licensed in this group of patients.
Adverse Drug Reactions
•
ACE inhibitors cause first-dose hypotension, especially in patients taking diuretics, on a lowsodium diet, on dialysis, dehydrated, or with heart failure.
•
Cough is the most troublesome common adverse effect. Reporting of this in trials is very
variable, and there are no sound systematic data on the relative incidences for the different
agents.
ACE may cause angioedema (onset may be delayed), and should be used with care (or
avoided
•
4
•
Prescribing Points
ACE inhibitors should be avoided in patients who are volume depleted. This is a particular
problem in patients with decompensated liver cirrhosis.
Contraindications/Cautions
•
•
•
•
•
ACE inhibitors are contraindicated in patients with severe bilateral renal artery stenosis.
ACE inhibitors are best avoided in patients with known or suspected renovascular disease.
Use of prodrugs such as enalapril and ramipril, requires close monitoring in patients with
impaired liver function.
Renal function and electrolytes (particularly potassium) should be checked before starting
ACE inhibitors and monitored during treatment.
Concomitant treatment with NSAIDs increases the risk of renal damage, and potassiumsparing diuretics (or potassium-containing salt substitutes) increase the risk of hyperkalaemia
References
1.
2.
3.
4.
5.
6.
7.
Pfeffer, M.A., et al., Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular
enlargement trial. The SAVE Investigators. N Engl J Med, 1992. 327(10): p. 669-77.
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med, 1991. 325(5): p. 293-302.
ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet, 1995. 345(8951): p. 669-85.
Edner, M., et al., Effect of enalapril initiated early after acute myocardial infarction on heart failure parameters, with reference to clinical class and echocardiographic determinants.
CONSENSUS II Multi-Echo Study Group. Clin Cardiol, 1996. 19(7): p. 543-8.
GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo
Studio della Sopravvivenza nell'infarto Miocardico. Lancet, 1994. 343(8906): p. 1115-22.
Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study
Investigators. Lancet, 1993. 342(8875): p. 821-8.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention
Evaluation Study Investigators. Lancet, 2000. 355(9200): p. 253-9.
Contributors:
Dr Duncan Richards (Clinical Pharmacology, RI);
Dr DJ Reynolds (Consultant Physician, JR)
'Bunmi Fajemisin (Clinical Effectiveness Pharmacist)
With advice from:
Dr. K Channon (Honorary Consultant Cardiologist, JR)
The follow ing gra ph give s de ta ils of pre scribing costs in Ox fordshire
10000
9000
8000
7000
5000
4000
3000
2000
1000
captopril
lis inopril
ram ipril
Apr-01
Mar-01
Feb-01
Jan-01
Dec-00
Oct-00
Nov-00
Sep-00
Aug-00
Jul-00
Jun-00
Apr-00
May-00
Mar-00
Jan-00
Feb-00
Dec-99
Oct-99
Nov-99
Sep-99
Jul-99
Aug-99
Jun-99
0
May-99
total items
6000
enalapril
perindopril