Prescribing
The role of ACE inhibitors
in cardiovascular disease
Kate O’Donovan, Post Grad Course Coordinator, Cardiovascular Nursing, Acute Cardiology Unit, Mater Hospital, Dublin.
Email: kodonovan@mater.ie Twitter: @katyeggler
C
ardiovascular disease (CVD) is the leading cause of
death in the UK, accounting for approximately 26%
of all deaths and affecting an estimated 42 000
people aged under 75 years (British Heart Foundation
(BHF), 2018). It incorporates cerebrovascular disease,
coronary artery disease, heart failure (HF) and
hypertension, with the commonest types of CVD being
HF and ischaemic heart disease. Although the mortality
rate has declined since the 1960s because of advances in
percutaneous coronary intervention and pharmacological
therapy, there are approximately 7 million people living
with CVD in the UK. There is no difference in prevalence
between the sexes. The condition costs £9 billion in
healthcare expenditure nationally (BHF, 2018).
Activation of the renin–angiotensin–aldosterone sys-
tem increases the risk of experiencing a cardiovascular
event (Heart Outcomes Prevention Evaluation Study
Investigators (HOPEI) et al, 2000). Therefore, inhibition
of this system is central to the treatment of CVD and
contributes to a decline in cardiovascular mortality, espe-
Abstract
Cardiovascular disease is the leading cause of death in the UK, with
heart failure and ischaemic heart disease the commonest forms of the
condition. The renin–angiotensin–aldosterone system is recognised as
having an integral pathophysiological role by increasing afterload,
promoting sodium and water retention and contributing to ventricular
remodelling. Evidence from randomised controlled trials has
demonstrated that angiotensin-converting enzyme (ACE) inhibitors
reduce mortality, slow disease progression and reduce left ventricular
workload. This is achieved by inhibiting the conversion of angiotensin I
to angiotensin II. Preload and afterload are reduced, which preserves
left ventricular function. Common adverse effects include cough,
hypotension, hyperkalaemia and a decline in renal function. The
nurses’ role in caring for patients receiving ACE inhibitor therapy
includes clinical assessment, monitoring and detecting adverse effects
as well as patient education.
Key words
w Cardiovascular disease w Angiotensin-converting enzyme (ACE)
inhibitors w Vasoconstriction w Vasodilation w Renal function
w Hypotension
Submitted for peer review: 23 July 2018. Accepted for publication: 20 September
2018. Conflict of interest: None.
600
cially in the realm of secondary prevention. The mortality
benefit is because angiotensin II and aldosterone activity
is inhibited (Opie and Pfeffer, 2013). Long-term therapy
is associated with haemodynamic and symptomatic
improvement, especially in people with HF with reduced
ejection fraction (HFrEF) and ischaemic heart disease.
This translates into an improved functional capacity and
quality of life by slowing the progression of HFrEF and
atherosclerosis. Other beneficial effects include decreas-
ing risk of stoke by lowering blood pressure, and possibly
preventing diabetes-associated complications such as
nephropathy.
The focus of this paper is the role of angiotensin-con-
verting enzyme (ACE) inhibitors in the treatment of CVD.
It will provide an overview of the renin–angiotensin–
aldosterone system and its contribution to CVD develop-
ment and clinical presentation. The role of ACE inhibitors
will be discussed, drawing on evidence-based practice,
mode of action, potential for adverse effects and special
precautions. The practicalities in caring for patients receiv-
ing ACE inhibitor therapy will also be discussed through-
out the article.
Renin–angiotensin–aldosterone system
In response to a decrease in renal perfusion and stimula-
tion of the sympathetic nervous system, renin is released
from the juxtaglomerular cells in the nephron (McMurray,
2018). In the liver, this enzyme is responsible for the con-
version of angiotensinogen to angiotensin I, which is the
precursor to angiotensin  II. Subsequently, angiotensin-
converting enzyme (ACE) enables the conversion of
angiotensin I to angiotensin II.
The main function of angiotensin  II is to stimulate a
state of vasoconstriction and the release of aldosterone
from the adrenal gland. Angiotensin II activity is mediat-
ed by the AT  1 receptors, which are responsible for its
negative effect on ventricular function and vasoconstric-
tion. Although AT 2 receptors are thought to be beneficial
in that they oppose AT2 receptor activity, their role is less
well defined and is thought to be associated with inhibi-
© 2018 MA Healthcare Ltd
tion of growth in the late foetal stage and in adult life
(Scow et al, 2003).
Aside from vasoconstriction, Opie and Pfeffer (2013)
outline several characteristics associated with angioten-
sin II, such as stimulating the release of noradrenaline and
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increasing sympathetic activity, which results in further
vasoconstriction. The result is a rise in preload and after-
load, which increase left ventricular workload. Other
effects of angiotensin II include promotion of ventricular
hypertrophy and myocardial fibrosis, which decrease con-
tractility strength and lead to loss of ventricular function.
The final step in this cascade is the release of aldosterone
from the adrenal cortex. Aldosterone acts on the distal
tubule in the nephron. Aldosterone activity causes the
retention of sodium and water while potassium is excreted
because of inhibition of the sodium-potassium exchange.
The net effect is an increase in circulating volume and
preload. Opie and Pfeffer (2013) says that, in HFrEF,
plasma aldosterone levels rise up to 20 times above normal
in response to angiotensin II activity.
Other functions associated with aldosterone include the
promotion of myocardial fibrosis and autonomic dysfunc-
tion which, together with the loss of potassium, increase
the risk of ventricular arrhythmias (McMurray, 2018).
Aside from water retention and the potential for electro-
lyte imbalance, aldosterone decreases nitric oxide release
which is responsible for vasodilation. This decrease in
nitric oxide release combined with angiotensin II activity
promotes a state of vasoconstriction.
To summarise, the renin–angiotensin–aldosterone sys-
tem causes angiotensin  II-mediated vasoconstriction,
which increases afterload. Sodium and water retention
raise preload. Other effects include myocardial hypertro-
phy and fibrosis. The net result is an increase in ventricular
workload with loss of contractility and function.
How ACE inhibitors work
ACE inhibitors prevent angiotensin-converting enzyme
from converting angiotensin  I to angiotensin  II. This
results in decreased aldosterone activity and the promo-
tion of vasodilation by inhibiting vasoconstriction (Opie
and Pfeffer, 2013). Other actions associated with ACE
inhibition include decreased degradation of bradykinin,
which also promotes vasodilation and reduced noradrena-
line secretion. The decrease in aldosterone production is
associated with an indirect natriuretic effect while potas-
sium is retained.
In people with hypertension, ACE inhibition lowers
blood pressure by multiple mechanisms, which result in
peripheral vasodilation, a decrease in systemic vascular
resistance and lowered noradrenaline activity (Opie and
Pfeffer, 2013). Lying and standing blood pressure is lowered
without causing an increase in heart rate (Accord Healthcare,
2016). Another benefit is the reversal of ventricular hyper-
trophy associated with hypertension. In a meta-analysis of
randomised controlled trials examining the reversal of left
ventricular hypertrophy in essential hypertension,
Schemieder et al (1996) demonstrated that ACE inhibitors
© 2018 MA Healthcare Ltd
were more potent than beta-blockers and calcium-channel
blockers in reversing ventricular hypertrophy.
HF affects more than half a million people in the UK
(BHF, 2018). The condition is classified as: HFrEF where
the ejection fraction is ≥40%; and HF with preserved ejec-
British Journal of Cardiac Nursing December 2018 Vol 13 No 12
Prescribing
tion fraction (HFpEF) where the ejection fraction is ≥50%
(Ponikowski et al, 2016). ACE inhibitors are recognised as
being firstline therapy along with beta-blockers in reduc-
ing HF symptoms, and improving exercise tolerance,
functional capacity and quality of life in patients with
HFrEF. These benefits are achieved by reducing ventricu-
lar filling pressures, preload and afterload. This, in turn,
reduces left ventricular workload which is translated into
an increase in cardiac output and cardiac index (Opie and
Pfeffer, 2013). In addition to vasodilation and the indirect
natriuretic effect, decreased bradykinin breakdown
increases nitric oxide activity, causing further vasodilation
thus lowering afterload and left ventricular workload
(McMurray, 2011). Other beneficial effects include a
reduction in aldosterone-induced ventricular hypertrophy
and fibrosis, and in ventricular dilation caused by an
increased preload (López-Sendón et al, 2004). For the
patient with HFrEF or an ST-elevation myocardial infarc-
tion (STEMI), these effects can help to preserve or
improve ventricular function.
In people with ischaemic heart disease, ACE inhibitors
slow the development of atherosclerosis by improving
endothelial function with the release of nitric oxide and
decreasing the influx of smooth muscle and inflammatory
cells that are associated with atherosclerotic development
(Pitt, 1995). This was evident in the Survival and
Ventricular Enlargement (SAVE) study (Pfeffer et al 1992),
where ACE inhibition with captopril reduced the risk of
unstable angina and myocardial infarction (MI) in people
with left ventricular dysfunction or HF.
Scientific evidence
Several randomised clinical trials have demonstrated
positive patient outcomes associated with ACE inhibition
(Table  1). Findings from these trials have included
increased survival and a reduction in mortality from sud-
den death or progressive deterioration across all New York
Heart Association (NYHA) classes of HF. Other benefits
include reduced hospital readmission rates, increased
functional capacity and improved quality of life. In the
patients with asymptomatic left ventricular dysfunction
following MI, the efficacy of ACE inhibitor therapy in
decreasing mortality, delaying progression to symptomat-
ic HF and morbidity has been demonstrated (Pfeffer et al
1992; HOPEI et al, 2000; Fox and EUROPA Trial
Investigators (ETI), 2003). In addition, the HOPE (HOPEI
et al, 2000) demonstrated that in those with established
vascular disease or who were at increased risk of cardio-
vascular events, ACE inhibition reduced the incidence of
MI, stroke and cardiovascular death.
These clinical outcomes were also demonstrated in
patients with established HFrEF receiving standard HF
therapy. Randomised controlled trials such as that by the
CONSENSUS Trial Study Group (1987) demonstrated
increased survival attributed to a decreased risk of sudden
death or death from progressive HF severity. These find-
ings were supported by later trials such as SOLVD (SOLVD
Trial Investigators, 1991); these researchers reported that
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 Table 1. Selection of clinical trials supporting the use of ACE inhibitors in cardiovascular disease

602
ACE Trial Overview Objective Outcome
inhibitor
Captopril Survival And Ventricular Double-blind trial To determine if long- Mortality was lower in the captopril group at 20%
Enlargement trial (SAVE) Pfeffer 2231 patients after myocardial infarction term administration vs 25% in the placebo group
et al (1992) (MI) with an ejection fraction (EF)≤40% but of captopril in those The reduction in risk from all-cause death was
no heart failure (HF) symptoms or evidence with left ventricular 19%
of myocardial ischaemia were randomised dysfunction after MI
reduced mortality The number of deaths caused by HF was 38 in
to receive placebo (n=1116 patients) or the captopril group and 58 in the placebo group
captopril (n=1115 patients ) and morbidity
Prescribing

Average follow-up at 42 months

Ramipril The Heart Outcomes Prevention 9292 high-risk patients with evidence of
Evaluation (HOPE) trial
The Heart Outcomes Prevention other cardiovascular risk factor but
Evaluation Study Investigators et preserved left ventricular function
al (2000)
Enalapril Cooperative North Scandinavian
ENalapril Survival Study
(CONSENSUS)
CONSENSUS Trial Study Group
(1987)
Enalapril Studies of Left Ventricular
Dysfunction (SOLVD)
SOLVD Investigators (1991)
Enalapril Studies of Left Ventricular
Dysfunction (SOLVD) Prevention
Trial (1992)
SOLVD Investigators (1991)
To evaluate the The primary outcome was reached by 17.8% in the
vascular disease or diabetes plus one effects of ramipril in placebo group vs 14% in the ramipril group
patients at high risk All-cause mortality was reduced from 12.2% to
in preventing the 10.4%
(EF>40%) were randomised to ramipril primary outcome
(n=4465) Or placebo ((n=4652) (composite of Incidence of MI was 9.9% in the ramipril group vs
cardiovascular-related 12.3% in the placebo group
Follow-up at 5 years
death, MI or stroke) Mortality from cardiovascular causes was 6.1% in
the ramipril group and 8.1% in the placebo group
Double blind study. To evaluate the The primary outcome of mortality at 6 months
253 patients with chronic HF (EF not influence of enalapril was significantly reduced in those treated with
specified) with NYHA class IV were on the prognosis of enalapril at 44% versus 26% in the placebo group
randomly assigned to receive placebo severe congestive Mortality at 1 year was reduced by 31%
(n=126) or enalapril (n=127) in addition to heart failure (NYHA There was a 27% relative risk reduction in
conventional HF therapy class IV)
mortality in those treated with enalapril
Average follow-up at 188 days
Double blind study To determine Cumulative mortality 39.7% in the placebo group
2569 patients in NYHA Class II–III heart whether treatment vs 35.2% in the enalapril group; this translates
failure with an ejection fraction ≤35% with enalapril in into 45 fewer deaths per 1000 patients treated
receiving conventional heart failure therapy patients with
were randomly assigned to placebo ejection fraction
(n= 1284) or enalapril ((n=1285) ≤35% reduced
mortality
Average follow-up at 3.45 years
Randomised double blind trial To determine whether Risk of death or hospitalisation for new or
4228 patients with asymptomatic left ACE inhibitors could worsening heart failure reduced from 24.5% to
ventricular dysfunction (ejection fraction reduce mortality, 20.6%
≤35%) and not receiving HF therapy incidence of HF and Risk of developing HF reduced from 38.6% to
randomly assigned to placebo (n=2117) or rate of hospitalisation 29.8%

British Journal of Cardiac Nursing

Perindopril The EURopean trial On reduction
of cardiac events with Perindopril
in stable coronary artery disease
enalapril (n=2111) in patients with
asymptomatic left
Average follow-up at 3.12 years ventricular dysfunction
Randomised, double-blind, placebo- To assess the ability Primary outcome composite of cardiovascular
controlled trial. 12,218 patients with of perindopril to death, non-fatal MI and successful resuscitation
stable coronary artery disease and without reduce for cardiac arrest

December 2018
(EUROPA) trial
The EURopean trial on reduction
of cardiac events with Perindopril
in stable coronary artery disease
trial investigators (2003)
heart failure or hypertension were
randomly assigned to perindopril (n=6110)
or placebo (n=6108)
Mean follow-up at 4.2 years
cardiovascular 8% of patients in the perindopril group reached
death, MI and the primary endpoint compared to 10% in the
cardiac arrest placebo group; absolute risk reduction in the
primary endpoint of 1.9% and a relative risk
reduction of 20% in those treated with perindopril

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© 2018 MA Healthcare Ltd

their results translated to 45 fewer deaths per 1000 patients
treated with an ACE inhibitor.
In patients with hypertension, ACE inhibitors are
known to lower blood pressure. However, many patients
require a combination of blood pressure-lowering agents
to maintain blood pressure control. Williams et al (2018),
in the most recent European Society of Cardiology (ESC)
guidelines on hypertension, outline that despite a number
of trials with long-term follow-up examining the efficacy
of different blood pressure-lowering agents, no one agent
has been found to be better than another. They note that
ACE inhibitors are among the most commonly used class
of antihypertensive agent (Williams et al, 2018). This
could be because evidence from trials examining the role
of ACE inhibitors in other cardiovascular disorders has
found they are superior in patients with HFrEF or diabe-
tes, who are at high risk of cardiovascular disease.
Indications
Based on the evidence from several randomised con-
trolled trials (Table 1), ACE inhibitors are indicated in the
treatment of hypertension, cardiovascular protection in
those with atherosclerotic disease who have not experi-
enced a primary cardiovascular event, secondary preven-
tion after MI and treatment of HFrEF (National Institute
for Health and Care Excellence (NICE), 2013; Ponikowski
et al 2016; Roffi et al, 2016; Ibanez et al, 2018).
ACE inhibition is considered an integral component of
acute coronary syndrome treatment. In the European
Society of Cardiology guidelines on the management of
STEMI (Ibanez et al, 2017), ACE Inhibitors are recom-
mended in patients with an ejection fraction of ≤40% or in
those who experienced HF in the early phase of a MI. For
patients experiencing unstable angina or non-ST segment
elevation MI, Roffi et al (2015) recommends starting ACE
inhibitors in patients with left ventricular dysfunction,
heart failure or hypertension. Other indications in the
acute coronary syndrome population include asympto-
matic left ventricular systolic dysfunction to reduce the
risk of HF development, hospitalisation for HF and death
(Roffi et al, 2015; Ibanez et al, 2018).
ACE inhibitors are the most commonly used blood
pressure-lowering agent in people with hypertension.
NICE (2013) advocates ACE inhibitors as a firstline treat-
ment in patients who are less than 55  years of age. For
those older than 55  years, the initial treatment is with a
calcium-channel blocker. For patients who are at risk of
angioedema, such as those of African or Caribbean origin,
a calcium-channel blocker is considered as an alternative
to ACE inhibitors (NICE, 2013).
ACE inhibitors can be used as a monotherapy or as part
of combined therapy with other antihypertensive agents,
and have potential benefits in those with diabetes, HFrEF
© 2018 MA Healthcare Ltd
or previous acute coronary syndrome (Mancia et al, 2013).
There are more than 500 000 people with HF in the UK
(BHF, 2018). ACE inhibitors are considered an essential
firstline therapy in those with HFrEF (NICE, 2010;
Ponikowski et al, 2016) and are a class 1A recommenda-
British Journal of Cardiac Nursing December 2018 Vol 13 No 12
Prescribing
tion unless contraindicated or intolerance is experienced.
As a firstline therapy, ACE inhibitors are combined with
beta-blocker therapy to decrease mortality and further
deterioration in left ventricular function.
The addition of beta-blockers to ACE inhibitor therapy
is perceived as complementary and should be started as
soon as is clinically feasible. The rationale for this drug
combination is that ACE inhibition exerts a modest effect
on left ventricular remodelling whereas beta-blockers lead
to an improvement in ejection fraction as well as reduc-
tion in mortality and the risk of sudden death through
attenuation of the sympathetic nervous system (McMurray
et al, 2012).
Starting ACE inhibitor therapy
When ACE inhibition is being considered as a therapy,
contraindications, current medication regime and the risk
of adverse effects must be assessed. In the community,
ACE inhibitors should be started at a low dose and titrated
as per clinical tolerability at intervals of not less than
2 weeks until the target dose or optimally tolerated dose is
achieved (Ponikowski et al, 2016). For the inpatient, more
rapid uptitration can be carried out, depending on toler-
ance and haemodynamic stability. If the target dose cannot
be achieved, patients receiving lower doses still benefit and
continuation of therapy should be encouraged despite the
optimal dose not being achieved (McMurray et al, 2005).
Before therapy is started, baseline renal function and
estimated glomerular filtration rate (eGFR) are measured,
and repeat measurement is recommended after each dose
uptitration. If the patient is on established diuretic thera-
py, to protect against hypotension and deterioration in
renal function, diuretic therapy may be reduced or tempo-
rarily discontinued if feasible for approximately 2  days
before starting ACE inhibitor therapy (Opie and Pfeffer,
2013; Accord Healthcare, 2017). If it is not feasible to
change diuretic therapy, ACE inhibitors should be started
at the lowest possible dose (Opie and Pfeffer, 2013).
Hypotension is a potential adverse effect associated with
the vasodilatory action of ACE inhibitors. Patients at risk
include those with hyponatraemia who have a sodium
level of <130 mmol/litre and/or a raised creatinine level of
>135  µmol/litre (Opie and Pfeffer, 2013). To reduce the
risk of hypotension, the summaries of product character-
istics reviewed here (Aurobindopharma-Millpharm, 2015;
Accord Healthcare, 2016; 2017; ER Squibb & Sons, 2017)
recommend correcting dehydration, hypovolaemia and
salt depletion before starting therapy, while being aware of
the risk of volume overload in patients with HFReF. If
hypotension is avoided, uptitration may be started.
However, there is a risk of hypotensive episodes associated
with uptitration (Opie and Pfeffer, 2013).
Another consideration is selection of an ACE inhibitor.
The consensus is that there is little advantage in using any
one agent over another but, when a specific agent has been
proven efficacious in clinical trials, it provides confidence
of that agent for that indication (Opie and Pfeffer, 2013).
Table 2 outlines a selection of ACE inhibitors with target
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Prescribing
doses indicated in cardiovascular disease. For specific
information on different agents, practitioners should refer
to the British National Formulary (BNF) (Joint Formulary
Committee, 2018).
Although target doses are set out, the majority of patients
receive suboptimal doses in clinical practice despite demon-
strated evidence from randomised controlled trials and
subsequent class  I recommendations in national and
European guidelines (McMurray et al, 2005). This could be
attributed to a wish to minimise the risk of adverse effects
such as hypotension and renal impairment.
Contraindications
Before therapy is started, several contraindications must
be addressed so that patient safety is maintained (Table 3).
Angioedema is a rare but potentially life-threatening com-
plication, especially if it involves the upper airway. Patients
who could potentially have ACE inhibitor therapy are
assessed for a history of this condition. Patients at high
risk are those of African-Caribbean origin, with a history
or taking glucose-lowering agents such as sitagliptin (Opie
and Pfeffer, 2013).
Bilateral renal artery stenosis or renal artery stenosis in a
single kidney is considered a contraindication because of
the potential of deteriorating renal function with ACE
inhibitor therapy (López-Sendón et al, 2004), where loss of
renal function may occur with only mild alteration in
serum creatinine. This is attributed to vasodilation reducing
the glomerular filtration rate.
ACE inhibitors are not contraindicated in women of
childbearing age but advice regarding family planning and
what to do if pregnancy occurs is essential. In pregnancy,
therapy is contraindicated as potential foetal effects
including renal dysfunction, oligohydramnios and skull
ossification retardation may occur, with the highest risk
being in the second and third trimester (Accord Healthcare,
2017). If exposure to ACE inhibitors occurs during preg-
nancy, a foetal ultrasound with urgent obstetrician review
is mandated. For women considering pregnancy, an alter-
native agent with an established safety profile during preg-
nancy should be offered if clinically indicated. Although
limited data demonstrate low concentrations in breast-
milk, breastfeeding is not advised because of potential
risks of infant cardiovascular and renal adverse effects.
Adverse effects and precautions for use
In the majority of patients, ACE inhibition is well tolerat-
ed but there is potential for adverse effects. Common
adverse effects include cough, hypotension, hyperkalae-
mia and deterioration in renal function.
Cough
Cough affects 5–10% of patients receiving ACE inhibitor
therapy. In the HOPE trial (HOPEI et al, 2000), cough was
given as the reason for discontinuing therapy in 7.3% of
patients in the ramipril study arm. It is described as a dry,
irritating cough that is non-productive in nature, and that
develops between 1 week and a few months of therapy. The
604
cough is attributed to increased sensitivity of the cough
reflex because of elevated bradykinin levels. Clinically, the
challenge is in differentiating the cough from that associ-
ated with pulmonary congestion or respiratory disease. If
tolerated by the patient, cough does not require discon-
tinuation of ACE inhibitor therapy. However, if it is trou-
blesome, the therapy may be substituted with an angioten-
sin-receptor blocker (ARB).
Hypotension
Hypotension (systolic blood pressure <90 mmHg) caused
by the vasodilatory action of ACE inhibitor therapy is
recognised as a potential adverse effect. In the EUROPA
study (Fox and ETI, 2003), withdrawal from treatment
occurred in 1.0% of patients treated with perindopril.
Dizziness and light-headedness are common symptoms
associated with hypotension (Ponikowski et al, 2016).
Patients at high risk of hypotension include those who
are volume- or salt-depleted because of diuretic therapy
and those on dialysis, as well as patients with HF and con-
comitant aldosterone inhibitor therapy. If symptomatic
hypotension is experienced, the patient should be placed
in the supine position and some may require intravenous
volume replacement (Aurobindo Pharma-Milpharm,
2015). A transient hypotensive episode that is asympto-
matic does not mean therapy should be discontinued but
a dose reduction may be indicated with close monitoring
of blood pressure. Other actions include reviewing the
patient’s medication regimen with the possibility of dis-
continuing or reducing concomitant nitrates, vasodilators
and/or diuretics (Ponikowski et al, 2016). For patients
who experience asymptomatic hypotension that does not
negatively affect quality of life, no dose adjustment is nec-
essary (Opie and Pfeffer, 2013).
Hyperkalaemia and renal impairment
Hyperkalaemia and renal impairment are acknowledged
adverse effects but rarely occur in those with normal renal
function. The mechanism underpinning hyperkalaemia is
decreased aldosterone production associated with ACE
inhibition and a reduction in diuretic-induced potassium
loss. The incidence of hyperkalaemia ranges from 6% in
the ATLAS study (Packer et al, 1999) to 10.7% in the
SOLVD trial (SOLVD Trial Investigators, 1992). Patients
at high risk include older people and those with HF, pre-
existing renal impairment and diabetes mellitus (Ahuja et
al, 2000). Concomitant pharmacological therapy, with
potassium-sparing diuretics or supplements, heparins and
non-steroid anti-inflammatory drugs (NSAIDs), also
increases the risk of hyperkalaemia.
Monitoring of serum potassium is an essential compo-
nent of care when starting or uptitrating ACE inhibitors.
McMurray et al (2005) considers an increase of <5.5 mmol/
© 2018 MA Healthcare Ltd
litre acceptable. If serum potassium level is above this
level, the ACE inhibitor should be discontinued and
serum potassium levels monitored until baseline values
have returned (McMurray et al, 2005). Reintroduction of
therapy at a lower dose may then be reconsidered.
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 Prescribing

Table 2. Common ACE inhibitors prescribed in cardiovascular disease

Drug Hypertension Heart failure/ Cardiovascular Secondary prevention
asymptomatic left prevention after acute myocardial
ventricular dysfunction infarction
Enalapril Initial dose 5 mg Initial dose 2.5 mg
Target dose 20 mg once Target dose 40 mg in two
daily divided doses
Ramipril Initial dose 2.5 mg Initial dose 2.5 mg or Initial dose 2.5 mg Initial dose 2.5 mg twice
Target dose 10 mg daily 125 mg Target dose 10 mg daily daily
Target dose 10 mg daily Target dose 10 mg daily
Captopril Initial dose 25 mg–50 mg Initial dose Initial dose 6.25 mg
daily in divided doses 6.25 mg–12.5 mg two or three times a day
Target 100 mg–150 mg three times a day Target dose
daily in divided doses Target dose 75 mg–150 mg daily in
75 mg–150 mg daily in divided doses
divided doses
Perindopril Initial dose 4 mg Initial dose 2 mg Initial dose 4 mg
Target dose 8 mg daily Target dose 4 mg daily Target dose 8 mg daily

Sources: Aurobindo Pharma-Milpharm (2015); Accord Healthcare (2016; 2017); ER Squibb & Sons (2017)

Table 3. Contraindications, precautions and common adverse effects

Contraindications
History of angioneurotic oedema;
hereditary/idiopathic angioneurotic
oedema; known bilateral renal artery
stenosis; renal artery stenosis in a
single kidney; hypersensitivity;
symptomatic hypotension (systolic blood
pressure <90 mmHg); clinically
haemodynamic unstable status;
concomitant use with aliskiren products
in those with diabetes mellitus or renal
impairment (GFR <60 ml/min/1.73m²);
pregnancy; breastfeeding
Sources: Opie and Pfeffer 2013; Aurobindo Pharma-Milpharm, 2015; Accord Healthcare, 2017; ER Squibb & Sons, 2017
Special precautions
Pre-existing renal failure; concomitant
medication increasing the risk of
hyperkalaemia or decrease in renal
function; risk of hypotension
Common adverse effects
Headache; depression; blurred vision;
dizziness; hypotension; syncope; chest
pain; rhythm disturbances; angina
pectoris; tachycardia; cough; dyspnoea;
nausea; gastrointestinal disturbance;
taste alteration; rash; asthenia; fatigue;
hyperkalaemia; increase in creatinine;
sleep disturbance; dry mouth

ACE inhibition primarily affects renal function by renal
artery vasodilation and decreased aldosterone production.
Renal impairment and acute renal failure are potential
adverse effects. Before therapy is started, baseline renal
function should be monitored. Opie and Pfeffer (2013) say
significant renal failure is identified when serum creati-
nine is >221  µmol/litre and should be considered as a
contraindication to therapy.
In people who have a pre-existing renal impairment,
specialist renal opinion should be sought before ruling out
ACE inhibitors as a therapeutic option. For some ACE
inhibitors, treatment feasibility and choice of agent are
© 2018 MA Healthcare Ltd
renal artery stenosis of a single kidney, or who have had a
kidney transplant, are at high risk of acute renal failure
(López-Sendón et al, 2004). In these patients, renin stimu-
lation is raised, which leads to higher angiotensin II pro-
duction and renal vasoconstriction. This maintains glo-
merular filtration rate. ACE inhibitors in these clinical
scenarios reduce angiotensin II levels, resulting in renal
arteriolar vasodilation and a reduction in glomerular fil-
tration rate leading to a rise in serum creatinine.
When therapy is started, some increase in urea and cre-
atinine is expected, and an increase of 50% above baseline
or creatinine of up to 266  µmol/litre, whichever is the

based on creatinine clearance and referring to the specific
summary of product characteristics is advisable. For the
majority of patients, renal function will be unaffected.
Patients with volume depletion because of high-dose
diuretics, hyponatraemia, bilateral renal artery stenosis or
smaller, is acceptable (McMurray et al, 2005). If the rise is
small and the patient is asymptomatic, continued moni-
toring of renal function with no downward adjustment of
the ACE inhibitor is recommended (McMurray et al,
2005). If there is a rise above acceptable levels, concomi-

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Prescribing
tant pharmacological therapy should be reviewed, with a
view to decreasing or stopping nephrotoxic drugs such as
NSAIDs or potassium-retaining agents (McMurray et al,
2005). If the patient is on a diuretic and has no clinical
evidence of fluid overload, a reduced dose may be consid-
ered (McMurray et al, 2005).
If renal impairment or acute renal failure persists
despite adjustment of the medication regimen, it is recom-
mended to reduce the ACE inhibitor dose by half and
monitor renal function within 1–2 weeks, or more fre-
quently in inpatients (McMurray et al, 2005). Obtaining
specialist renal opinion is also suggested.
For patients who experience a rise in serum creatinine
greater than 100% or above 310  µmol/litre, the ACE
inhibitor should be discontinued and renal function
monitored until baseline creatinine returns. Reintroduction
of a lower-dose ACE inhibitor therapy may be considered
at that stage (McMurray et al, 2005).
Although rare, angioedema is a potentially life-threat-
ening side effect. It is more frequent in the first month of
therapy. Clinical presentation varies from mild to life-
threatening and requires discontinuation of therapy.
Antihistamines and/or corticosteroids may be required to
relieve symptoms but, if angioedema involves the upper
airways, treatment is directed at maintaining a patent air-
way with effective respirations. Symptoms tend to resolve
within hours of discontinuing therapy.
Drug combinations and adverse effects
Several drug combinations or interactions between drug
may cause adverse effects such as hypotension, acute renal
failure or hyperkalaemia. Dual-blockade of the renin–
angiotensin–aldosterone system with concurrent therapy
of ACE inhibitors and angiotensin II receptor blockers or
aliskiren is associated with an increased occurrence of
hypotension, acute renal impairment and hyperkalaemia
(Accord Healthcare, 2016; 2017) and is therefore not rec-
ommended.
Hyperkalaemia and deterioration in renal function are
recognised adverse effects associated with ACE inhibitor
therapy but the risk of these adverse effects is increased
when used with other drugs such as diuretics and other
inhibitors of the renin–angiotensin–aldosterone system.
In patients with HFrEF, concurrent therapy with aldoster-
one antagonists is recognised as beneficial in reducing
symptoms of fluid overload and slowing disease progres-
sion. However, there is a risk of hyperkalaemia and renal
impairment with this drug combination and close moni-
toring of serum potassium and renal function is recom-
mended (Ponikowski et al, 2016).
Opie and Pfeffer (2013) recommend reducing ACE
inhibitor dose if a renal function deteriorates and/or if
serum potassium levels rise. The potential for a rise in
serum potassium is also increased with concomitant
therapy involving potassium-sparing diuretics, NSAIDs,
heparin-based products, potassium supplements and
immunosuppressant agents such as ciclosporin or tacroli-
mus (Aurobindo Pharma-Milpharm, 2015; Accord
606
Healthcare, 2016). NSAIDs and ACE inhibitor therapy
increase the risk of hyperkalaemia and renal impairment.
The risk is greatest in those who are dehydrated or have
pre-existing renal dysfunction. If this combination is con-
sidered essential, monitoring renal function and serum
potassium is recommended (Opie and Pfeffer, 2013). For
patients with hypertension, the anti-hypertensive effects
of ACE inhibitor therapy is reduced as NSAIDs reduce
vasodilating effects.
Hypotension and hypovolaemia are potential risks when
ACE inhibitors are combined with diuretic therapy. Opie
and Pfeffer (2013) state that these risks may be reduced by
decreasing the diuretic dose where clinically feasible. The
risk of hypotension may be increased in some patients
who are prescribed long-term diuretic therapy and may
therefore be sensitive to the vasodilating effects of the
ACE inhibitor. In addition, hypotension may occur with
combination therapy of other blood pressure-lowering
agents such as nitrates or other vasodilators (Opie and
Pfeffer, 2013).
In mental health care, concomitant therapy with lithi-
um, tricyclic antidepressants and antipsychotic medica-
tions increase the potential for adverse effects when pre-
scribed alongside ACE inhibitors. In those receiving lithi-
um therapy who are prescribed an ACE inhibitor, there is
an increased potential for lithium toxicity and increased
lithium concentrations. This is attributed to decreased
excretion of lithium. According to the summary of prod-
uct characteristics reviewed (Accord Healthcare, 2016;
2017; Aurobindo Pharma-Milpharm, 2015; ER Squibb &
Sons, 2017). The addition of a thiazide diuretic to this
drug combination also increases the risk of lithium toxic-
ity. If the drug combination is considered essential, the
patient will require monitoring of serum lithium levels. In
relation to concurrent ACE inhibitor therapy with tricy-
clic antidepressants and antipsychotics, there is an
increased risk of hypotension
For patients with diabetes who are prescribed glucose
-lowering agents or insulin, there is a risk that blood glu-
cose-lowering effects are potentiated when concurrent
ACE inhibitor therapy is prescribed; this increases the risk
of hypoglycaemic episodes (Aurobindo Pharma-
Milpharm, 2015). Close monitoring of blood glucose lev-
els and education on the signs of impending hypoglycae-
mia are essential, especially in the first month of therapy.
Risk is more prevalent during the first weeks of combined
therapy, particularly in patients with renal impairment or
as patients gradually build up a tolerance.
Nursing implications and follow-up
Cardiovascular nurses, specialist nurses in heart failure
and community nurses have a pivotal role in monitoring
and educating patients who are being started on ACE
© 2018 MA Healthcare Ltd
inhibitor therapy. Nurses, especially HF nurses, are in an
ideal position to facilitate follow-up via clinic visits or
telephone consultations (McMurray et al, 2005).
In relation to monitoring, nurses assess response to ACE
inhibitor therapy by considering improvements in symp-
British Journal of Cardiac Nursing December 2018 Vol 13 No 12
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toms and functional capacity, impact on renal function
and serum potassium as well as haemodynamic response,
especially blood pressure and volume status. In addition to
monitoring, nursing assessment aims to identify adverse
effects and potential for interactions between drugs by
reviewing the patient’s prescription.
Many nurses in nurse-led clinics are nurse prescribers,
so ACE inhibitor therapy can be uptitrated in such clinics.
Nurse prescribing allows adjustment of therapeutic regime
to decrease the risk of interactions between drugs and
adverse effects. Once a target dose or tolerated dose is
optimised, renal function and serum potassium may be
monitored at 4-monthly intervals in those who tolerate
the therapy.
Nurses have a central role in educating patients and
enhancing patient empowerment. From an educational
perspective, key points include the reason why the drug is
prescribed, the importance of adherence and the potential
for interactions between drugs, especially with diuretics,
NSAIDs, potassium-containing drugs and other vasodila-
tors (McMurray et al, 2005). Patients are educated on
potential adverse effects and are advised to report dry
irritating persistent cough, dizziness and symptomatic
hypotension (Ponikowski et al 2016). Nurses also empha-
sise the importance of attending follow-up appointments
for evaluation of therapy and monitoring of blood pres-
sure, renal function and serum potassium.
Conclusion
ACE inhibitor therapy is beneficial in alleviating symptoms
of fluid overload, preventing negative ventricular remodel-
ling and lowering blood pressure. Data from several ran-
domised controlled trials have demonstrated that these
effects have reduced mortality, lowered hospital readmis-
sion rates and improved functional capacity and quality of
life in patients with cardiovascular disease.  BJCN
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Prescribing
Key Points
The renin–angiotensin–aldosterone system has an active role in
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the pathophysiology of cardiovascular disease
Increased preload and afterload are the main effects of this
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system when active, which increases left ventricular workload
Angiotensin-converting enzyme (ACE) inhibitors prevent conversion
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of angiotensin I to angiotensin II, lowering afterload and preload
Patient outcomes include reduced mortality, decreased hospital
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readmission rates and improved quality of life
Hypotension, renal impairment and hyperkalaemia are common
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adverse effects
Nurses are integral to monitoring of patient haemodynamics, renal
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function and promoting awareness of the potential for adverse
effects and drug interactions
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CPD Reflection Questions
Consider the impact of the renin–angiotensin–aldosterone system on cardiovascular disease pathophysiology
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Critically reflect on how ACE inhibition impacts patient mortality risk, functional capacity and quality of life
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Discuss the role of the cardiovascular nurse or nurse specialist in caring for the cardiovascular patient commencing ACE Inhibition
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