Angiotensin-II receptor antagonists: what is Volume 20

Volume 20
Number 2
Angiotensin-II receptor antagonists: what is
the evidence for their place in therapy?
SUMMARY
• ACE inhibitors are the first-line choice when a renin-angiotensin system drug
is indicated
– ACE inhibitors have a more robust evidence base than angiotensin-II receptor antagonists
(A2RAs) for all indications in terms of evidence for efficacy, safety and most patient
factors.
• A2RAs are an alternative to ACE inhibitors if a renin-angiotensin system drug
is indicated but an ACE inhibitor cannot be used because of an intolerable
ACE inhibitor-induced cough
– The major benefit of A2RAs over ACE inhibitors is their lower rate of cough. However,
cough may not be as common with ACE inhibitors as many health professionals perceive.
The percentage of people reporting cough with ACE inhibitors in randomised controlled
trials (RCTs) is about 10%, and as low as 2% in observational, real world studies.
Discontinuation rates due to cough are lower than this. In the ONTARGET study, only
4.2% of patients in the ACE inhibitor group stopped treatment due to cough compared with
1.1% in the A2RA group.
• Combination therapy with an A2RA plus an ACE inhibitor has a limited role and then
only in certain indications
• Based on this evidence, ACE inhibitors should comprise a higher proportion of reninangiotensin system drug prescribing than is currently the case
– Across primary care in England, only about 70% of renin-angiotensin system drug
prescribing is for ACE inhibitors at the current time, with 30% for A2RAs. However A2RAs
account for 70% of the total spend on renin-angiotensin system drugs.
– A review of prescribing in this area could improve quality of care and reduce prescribing
costs. However, implementing changes to prescribing in this area is not straightforward,
and a simple switch programme is not appropriate.
Introduction
Renin-angiotensin system drugs include ACE
inhibitors, A2RAs (also called angiotensinreceptor blockers [ARBs]) and the new direct
renin inhibitor, aliskiren▼ (which is licensed only
for use in hypertension).1 ACE inhibitors and
A2RAs are used in a wide range of indications
including hypertension, heart failure, treatment
post-myocardial infarction (MI), diabetes and
chronic kidney disease (CKD). Prescribing
can either be with an ACE inhibitor alone, an
A2RA alone or, in some limited circumstances,
combination therapy with an ACE inhibitor plus
an A2RA.
When choosing a renin-angiotensin system
drug, as in any other therapeutic area, the
decision should be guided by four factors:
efficacy, safety, patient factors and cost (see
Table 1 on page 2).2 The first priority is high
quality prescribing, i.e. prescribing drugs with
a robust evidence base. However, value for
money is also important, as the NHS must
make the most effective use it can of public
money to deliver high-quality healthcare.3
This Bulletin is part of a suite of materials available on the renin-angiotensin system drugs
floor of our e-learning website NPCi. If you want to test your understanding of the issues in
this therapeutic area you can complete the related quiz before and after reading this Bulletin
and compare your scores. For more details of the evidence in this area, see the reninangiotensin system drugs less than 60 minute workshop.
This publication was
correct at the time of
preparation:
March 2010
This MeReC Publication is produced by the NHS for the NHS
MeReC Bulletin Volume 20, Number 2
1
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
Table 1. Guiding choice in renin-angiotensin system drug prescribing based on
effectiveness, safety, patient factors and cost2
EFFECTIVE
SAFE
No evidence that A2RAs are more effective
than ACE inhibitors for any indication
No evidence that A2RAs are safer than ACE
inhibitors for any indication
Concern that A2RAs may be less effective
than ACE inhibitors in reducing some
cardiovascular outcomes
COST
ACE inhibitors
have a more robust
evidence base
than A2RAs for all
indications
PATIENT FACTORS
Generic ACE inhibitors are less expensive
than A2RAs
A2RAs cause cough in fewer patients
than ACE inhibitors (absolute difference
in discontinuation due to cough 3% in
ONTARGET)
No difference in dosing regimens or
monitoring requirements
NB. The references to support these statements can be found in the text.
Why are ACE inhibitors the first-line choice?
effective than ACE inhibitors for any indication.
There is robust evidence that ACE inhibitors
reduce cardiovascular morbidity and mortality
over placebo in hypertension,14 heart failure15
and stable ischaemic heart disease.16 The
evidence that A2RAs reduce cardiovascular
outcomes and all-cause mortality over placebo
in these indications is less clear (see Table 3
on page 3). However, when A2RAs have been
compared with ACE inhibitors in heart failure20
and stable ischaemic heart disease,5 no
differences in cardiovascular outcomes have
been seen.
ACE inhibitors are the first-line renin-angiotensin
system drugs of choice for all indications (see
Table 2). They have a more robust evidence
base than A2RAs for all indications in terms of
evidence for efficacy, safety and most patient
factors (see Table 1). In all NICE guidance
where renin-angiotensin system drugs are
indicated, i.e. in hypertension,4 heart failure,7
post-MI,9 type 2 diabetes,10 type 1 diabetes11
and chronic kidney disease,12 ACE inhibitors
are the first-line renin-angiotensin system
drugs of choice.
There are two general points to consider
when comparing the evidence-base for ACE
There is no evidence that A2RAs are more
Table 2. Place in therapy of ACE inhibitors, A2RAs and combination therapy with an ACE inhibitor plus an A2RA
in various indications
ACE inhibitors
A2RAs
ACE inhibitor plus A2RA
Hypertension
First-line renin-angiotensin
system drug4
If ACE inhibitor discontinued
due to intolerable ACE
inhibitor-induced cough4 and
renin-angiotensin system
drug in particular indicated
No benefit, worse outcomes when
compared with ACE inhibitor alone
in ONTARGET5,6
Heart failure
First-line renin-angiotensin
system drug7
If ACE inhibitor discontinued
due to intolerable ACE
inhibitor-induced cough7
Possibly a specialist option after
ACE inhibitor and beta-blocker
optimised8
Requires careful monitoring of
renal function
Post-MI
First-line renin-angiotensin
system drug9
If ACE inhibitor discontinued
due to intolerable ACE
inhibitor-induced cough9
Not recommended in NICE postMI guidance9
Diabetes and CKD First-line renin-angiotensin
system drug10–12
If ACE inhibitor discontinued
due to intolerable ACE
inhibitor-induced cough10–12
No benefit, worse outcomes when
compared with ACE inhibitor alone
in ONTARGET5,6
Full NICE CKD guidance says no
evidence to suggest increased
effectiveness over ACE inhibitor
alone13
Requires careful monitoring of
renal function if specialists are
using in high-risk renal patients
2
MeReC Bulletin Volume 20, Number 2
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
Table 3. Summary of evidence for ACE inhibitors and A2RAs vs. placebo for cardiovascular morbidity and
mortality outcomes
Indication
ACE inhibitors vs. placebo
A2RAs vs. placebo
Hypertension
• Reduced coronary heart disease
(CHD) events, relative risk (RR)
0.83, 95% confidence interval (CI)
0.78 to 0.8914
• No statistically significant reduction in CHD events, RR 0.86,
95%CI 0.53 to 1.4014
• No studies of A2RAs vs. placebo in stroke14
• Reduced strokes, RR 0.78, 95%CI
0.66 to 0.9214
Heart failure
• Reduced all-cause mortality, odds
ratio (OR) 0.80, 95%CI 0.74 to
0.8715
• Reduction in all-cause mortality of borderline statistical
significance, OR 0.83, 95%CI 0.69 to 1.00 (P=0.048)17
• Reduced hospitalisations for heart failure, OR 0.64, 95%CI
0.53 to 0.7817
• Reduced hospitalisations for heart
failure, OR 0.67, 95%CI 0.61 to
0.7415
Stable
ischaemic
heart disease
• Reduced all-cause mortality, RR
0.87, 95%CI 0.81 to 0.9416
From one study TRANSCEND,18
• No statistically significant reduction in composite of CV death,
MI, stroke or hospitalisation for heart failure, hazard ratio
(HR) 0.92, 95%CI 0.81 to 1.0518
• Reduced non-fatal MI, RR 0.83,
95%CI 0.73 to 0.9416
• No significant reduction in all-cause mortality, HR 1.05,
95%CI 0.91 to 1.2218
• Reduced strokes, RR 0.78, 95%CI
0.63 to 0.9716
• No statistically significant reduction in MI, HR 0.79, 95%CI
0.62 to 1.0118
• No statistically significant reduction in stroke, HR 0.83, 95%CI
0.64 to 1.0618
Various
indications
• No statistically significant reduction in MI, OR 0.94, 95%CI
0.84 to 1.0619
—
inhibitors and A2RAs. Firstly, A2RAs came to
the market later than ACE inhibitors, therefore,
many trials are versus active comparators
not placebo. Secondly, as A2RA studies
were generally conducted more recently
than ACE inhibitor studies, greater use of
other preventative drugs, such as statins,
antiplatelets and beta-blockers, is a possibility.
The “law of diminishing benefits” means that
statistical benefit can become increasingly
difficult to demonstrate with the addition of
each preventative drug.
The major benefit of A2RAs over ACE inhibitors
is their lower rate of cough (but see below).
There is no advantage with A2RAs over most
ACE inhibitors in terms of dosing regimens or
monitoring requirements.21
ACE inhibitors are considerably less expensive
than A2RAs, as they are widely available
generically. This could change in the future as
patents begin to expire on A2RAs and generic
forms become available (the first of which
is likely to be losartan▼ in March 2010).22
However, it will probably be some years before
several A2RAs become available at costs
similar to the current costs of generic ACE
inhibitors.
What about cough?
In all NICE guidance where renin-angiotensin
system drugs are indicated, A2RAs are
reserved for patients where a renin-angiotensin
system drug is indicated, but an ACE inhibitor
MeReC Bulletin Volume 20, Number 2
has to be discontinued because of an
intolerable ACE inhibitor-induced cough.4,7,9–12
The current NICE heart failure guidance
states that ACE inhibitor-induced cough rarely
requires treatment discontinuation.7 A cough
may occur in a patient taking an ACE inhibitor
for reasons other than as a side effect to this
drug. Therefore, other possible causes should
be considered before switching to an A2RA.
In patients with heart failure, it might be a
symptom of pulmonary oedema.7
How common is cough?
Evidence from clinical studies suggests that
cough may not be as common with ACE
inhibitors as many health professionals
perceive. The true rate of cough is difficult
to quantify, but a systematic review of reninangiotensin system drugs in hypertension
suggested the rate of cough with ACE inhibitors
was about 10% from RCT data and 2% from
observational data.23 The latter is probably
closer to ‘real life’ with regard to the reporting
of side effects. However, not all coughs (even
if they are thought to be caused by the ACE
inhibitor) require the drug to be stopped. In
the ONTARGET study, a large RCT which
included more than 25,000 patients at high
cardiovascular risk but without heart failure,
just 4.2% of patients stopped treatment due
to cough with the ACE inhibitor, ramipril.5
ONTARGET had a run-in period, whereby
included patients had already demonstrated
tolerability to both telmisartan▼ and ramipril
over a short period of time. This may have
skewed the results in favour of tolerance to
Cough may not be as
common with ACE
inhibitors as many
health professionals
perceive
3
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
Figure 1. Effect of A2RA treatment rather than ACE inhibitor treatment on risk of cough
over 4.5 years for people at high cardiovascular risk (without heart failure)5
Imagine 100 people at high cardiovascular risk (without heart failure) taking an ACE inhibitor.
In the next 4.5 years about 4 of them will stop treatment due to a cough, 96 of them will not
stop treatment due to a cough (100 – 4 = 96).
However, if those same 100 people each take an A2RA rather than an ACE inhibitor for 4.5
years:
• About 3 people will be ‘saved’ from stopping treatment due to a cough (the yellow
faces).
• About 96 people will not stop treatment due to a cough — but would not have done so
even if they had taken an ACE inhibitor (the green faces).
• About 1 person will still stop treatment due to a cough even though they take an A2RA
(the red faces).
But remember
• It is impossible to know for sure what will happen to each individual person.
• All 100 people will have to take the A2RA rather than the ACE inhibitor for 4.5 years.
These 96 people will not
stop treatment due to a
cough within 4.5 years
whether they take an ACE
inhibitor or an A2RA.
These 3 people will be
‘saved’ from stopping
treatment due to a cough
within 4.5 years because
they take an A2RA instead
of an ACE inhibitor.
This 1 person will stop
treatment due to a cough
within 4.5 years whether
they take an ACE inhibitor
or an A2RA.
The image has been produced using Dr Chris Cates’ software VisualRx 3.0. More information
can be obtained from the website www.nntonline.net
some extent, but other studies have found
similar rates, and this large trial in a wide
ranging population of patients still provides
valuable evidence for the rate of cough with
ACE inhibitors compared with A2RAs.
4
Cough is common in patients with heart failure,
many of whom have smoking-related lung
disease.7 However, the proportions of patients
who stopped treatment because of cough in
the main heart failure trials which compared
ACE inhibitors with A2RAs are similar to those
in ONTARGET. Discontinuation due to cough
in the ACE inhibitor groups in other studies
ranged from 2.5% to 4.1%.24–26
due to cough compared with 1.1% in the
A2RA (telmisartan) group.5 This is an absolute
difference of just 3.1% and indicates a number
needed to harm (NNH) with ramipril of 32 over
56 months. This means 32 people need to be
treated with telmisartan rather than ramipril for
four and a half years to prevent one person
having to stop treatment because of cough.
Put another way, if 100 people like those in
ONTARGET all took telmisartan rather than
ramipril for four and a half years, only three of
them would avoid discontinuation due to cough,
and one person would still have to discontinue
treatment because of cough. Figure 1 gives a
pictorial representation of these figures.
How much less common is cough with
A2RAs?
In ONTARGET, 4.2% of patients in the ACE
inhibitor (ramipril) group stopped treatment
Although, like the ACE inhibitor, the A2RA was
well tolerated in ONTARGET, it was not without
side effects. A significantly greater number
of patients discontinued telmisartan than
MeReC Bulletin Volume 20, Number 2
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
ramipril because of hypotension (telmisartan
2.7% vs. ramipril 1.7%, NNH with telmisartan
100). In contrast, significantly fewer patients
discontinued treatment because of angioedema
(telmisartan 0.1% vs. ramipril 0.3%, NNH with
ramipril 500).5
Why does combination therapy with an
A2RA plus an ACE inhibitor have a limited
role?
Combination therapy is based on the theory
that an A2RA plus an ACE inhibitor blocks the
renin-angiotensin system more completely than
either drug alone, possibly benefiting patients
with hypertension, kidney disease and heart
failure. However, it is important to consider
what type of evidence there is for combination
therapy. Is prescribing based on surrogate,
disease-oriented outcomes (DOOs), such as
blood pressure or albuminuria reduction or,
more appropriately, on clinical patient-oriented
outcomes (POOs), such as cardiovascular
morbidity and mortality and the development of
end-stage renal disease? The clinical outcome
data from the ONTARGET study has started to
change views on whether combination therapy
has benefits for patients in terms of them living
longer or better.
ONTARGET
One of the key findings from ONTARGET was
that combination therapy with ramipril plus
telmisartan was no more effective than ramipril
alone, but was associated with significantly
more discontinuations due to hypotension,
syncope, diarrhoea and renal impairment.5
After a median of 56 months, there was no
difference in the rates of the primary outcome
(a composite of death from cardiovascular
causes, MI, stroke or hospitalisation for heart
failure) between any of the groups (16.5% with
ramipril, 16.7% with telmisartan, and 16.3%
with combination).5
The effects of combination therapy on renal
outcomes are of particular concern as, rather
than being beneficial, combination therapy
actually worsened major renal outcomes.5,6
ONTARGET was not a study specifically in
renal patients – patients with significant renal
disease were excluded and most patients did
not have nephropathy at baseline. However,
it did have prespecified renal endpoints,
most of which were adversely affected by
combination therapy.6 Compared with ramipril
alone, telmisartan plus ramipril significantly
increased the primary renal outcome (a
composite of any dialysis, doubling of serum
creatinine and death) with a NNH of 91 over
56 months (HR 1.09, 95%CI 1.01 to 1.18);
the secondary renal outcome (any dialysis
or doubling of serum creatinine) with a NNH
of 215, and the component renal endpoint of
acute dialysis with a NNH of 562.6 Even in the
subgroup of patients with microalbuminuria
or macroalbuminuria at baseline, there was
MeReC Bulletin Volume 20, Number 2
no benefit from combination therapy on the
primary renal outcome.6
What is the place, if any, of combination
therapy for various indications?
Table 2 on page 2, summarises the place of
combination renin-angiotensin system drug
therapy in various indications. In hypertension,
the best evidence comes from ONTARGET,
where 69% of patients had hypertension.5 As
discussed above, there was no benefit with
combination therapy in this trial in terms of
cardiovascular morbidity or mortality, and there
were more harms, with worse renal outcomes
and more discontinuations compared with
ramipril alone.5
In its post-MI guidance, NICE states that
combining an ACE inhibitor with an A2RA is
not recommended for routine use post-MI.9
The VALIANT study with captopril, valsartan▼
or both these drugs in patients with heart
failure post-MI found combination therapy was
no more effective than captopril alone and was
associated with more adverse effects.26
The full CKD guidance from NICE states that
there is no evidence to suggest increased
effectiveness of combining an ACE inhibitor
with an A2RA over and above the maximum
recommended dose of each individual drug.13
A meta-analysis of 49 RCTs in patients with
nephropathy found that combination therapy
reduced proteinuria (a DOO) more than either
drug alone, but whether this actually benefits
patients is unclear.27 The trials in this metaanalysis were mainly small and short-term, and
there were no data on clinical endpoints, or on
long-term safety. In ONTARGET, combination
therapy showed contrasting effects on
renal DOOs.6 It had beneficial effects on
proteinuria, but worsened glomerular filtration
rate. Most importantly, however, ONTARGET
found combination therapy led to worse not
better major renal outcomes.5,6 Therefore,
if specialists are using combination therapy
in high-risk renal patients, this requires very
careful patient monitoring.
ONTARGET found
combination therapy
with an ACE inhibitor
plus an A2RA was no
more effective than
an ACE inhibitor
alone
Combination therapy
in ONTARGET
worsened major
renal outcomes
Finally, in heart failure, combination therapy
could be an option for a minority of patients.8
In 2003, when NICE heart failure guidance 7
was published, no firm recommendation on
combination therapy with an ACE inhibitor plus
an A2RA could be made, but this pre-dated
the publication of the CHARM studies with
candesartan.28 NICE heart failure guidance
is due to be updated in August 2010 and the
NICE website should be consulted for updates.
Based mainly on CHARM-Added,29 heart
failure guidance from SIGN recommends that
patients with heart failure due to left ventricular
systolic dysfunction who are still symptomatic
despite optimised ACE inhibitor and betablocker therapy may benefit from the addition
of candesartan following specialist advice.8
5
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
Figure 2. Variation in renin-angiotensin system drug prescribing at practice level (by
items: year to September 2009)32
30%
Proportion of practices
25%
15%
10%
6
95-100
90-95
85-90
80-85
75-80
70-75
65-70
Proportion of ACE-inhibitors prescribed (% total renin-angiotensin system drug items)
Combination therapy with an ACE inhibitor plus
an A2RA has been shown to significantly reduce
hospitalisations, but not mortality, in patients
with heart failure compared to monotherapy
with an ACE inhibitor.20 Hospitalisation is an
important clinical endpoint for these patients,
and a meta-analysis found that adding an A2RA
to an ACE inhibitor avoids one hospitalisation
for every 26 patients treated over one to three
years.20 The trade off with this benefit is the
greater risk of adverse effects with combination
therapy. Adding an A2RA to an ACE inhibitor
in people with heart failure increases the risk
of worsening renal function, hyperkalaemia
and hypotension.30 Therefore, careful patient
monitoring is again paramount.
to an A2RA. In uncomplicated hypertension,
a renin-angiotensin system drug in particular
may not necessarily be indicated and either a
thiazide diuretic or a calcium channel blocker
may be suitable.4
Looking at the data in England at practice
level, in the year to September 2009, 11.5% of
practices had ACE inhibitor prescribing rates of
at least 80%, showing this level of prescribing
is achievable (see Figure 2).32 However,
most practices have levels lower than this,
suggesting that improvements could be made.
Data from the NHS Information Centre’s report
on hospital prescribing33 suggest there is a
statistically significant correlation between
primary and secondary care in the proportion
of renin-angiotensin system drugs prescribed
as ACE inhibitors (based on cost). Figure 3 on
page 7, shows SHAs with a higher proportion
of ACE inhibitor prescribing in hospital also
have a higher proportion in primary care, and
vice versa.34 An integrated approach between
primary and secondary care in the prescribing
of renin-angiotensin system drugs would
therefore seem to be a vital component of any
approach to improve prescribing in this area.
A Better Care Better Value indicator related
to increasing low cost prescribing of drugs
affecting the renin-angiotensin system was
published in April 2009.3
What level of A2RA prescribing would seem
appropriate from the evidence?
An integrated
approach between
primary and
secondary care is
vital to improve
prescribing in this
area
60-65
55-60
50-55
45-50
40-45
35-40
30-35
25-30
0%
20-25
5%
15-20
It is reasonable
to expect ACE
inhibitors to make
up at least 80% of
renin-angiotensin
system drug
prescribing
20%
Based on the evidence outlined above, the
majority of renin-angiotensin system drug
prescribing should be for ACE inhibitors. In
2006, the full hypertension guidance from
NICE assumed (based on expert opinion)
that 80% of patients starting on ACE inhibitors
would continue with these,31 but this proportion
of ACE inhibitor prescribing is higher than the
current average. Currently, across primary care
in England an average of about 70% of reninangiotensin system drug prescribing is for
ACE inhibitors and 30% for A2RAs.32 However,
A2RAs account for 70% of the total spend on
renin-angiotensin system drugs.32 Given that
the major benefit of A2RAs over ACE inhibitors
is their lower rate of cough, and the percentage
of people reporting cough with ACE inhibitors
in RCTs is about 10%23 (and not all these
people will require the drug to be stopped) it is
reasonable to expect that at least 80% of reninangiotensin system drug prescribing should be
for an ACE inhibitor. If an ACE inhibitor has to
be discontinued in a patient because of cough,
it may be that another class of antihypertensive
could be considered before routinely switching
What savings could be made if the
proportion of ACE inhibitor prescribing
was increased?
The total cost of renin-angiotensin system drug
prescribing in primary care in England is about
£366 million per year (based on data to quarter
March 09).32 This reflects approximately 70% of
prescribing being for ACE inhibitors and 30% for
A2RAs. If the prescribing of ACE inhibitors was
increased to 80% (and A2RAs decreased to
20%), the total cost of renin-angiotensin system
drugs per year would be about £298 million – a
saving of about £68 million per year.
MeReC Bulletin Volume 20, Number 2
Angiotensin-II receptor antagonists: what is the evidence for their place in therapy?
Primary care prescribing by SHA, % of net ingredient cost
of renin-angiotensin system drugs which are ACE inhibitors
Figure 3. Correlation between hospital and primary care renin-angiotensin system
drug prescribing at SHA level (by net ingredient cost)33,34
45
40
R² = 0.7768
P = 0.0007
35
30
25
20
25
30
35
40
45
50
55
60
65
Hospital prescribing by SHA, % of net ingredient cost of renin-angiotensin
system drugs which are ACE inhibitors
R2 = correlation coefficient
These figures are estimates, but they show that
significant savings could be made by reviewing
the prescribing of renin-angiotensin system
drugs. However, implementing changes to
prescribing in this area is not straightforward,
and a simple switch programme is not
appropriate. For new patients, the evidencebased position is that ACE inhibitors are the firstline renin-angiotensin system drug of choice in
all indications. However, for patients already
being treated with renin-angiotensin system
drugs any changes need to be individualised,
as this is a complex area in which to optimise
the use of medicines. More information and
materials on implementing better practice in
this area can be found on the National Support
Materials floor of the NPCi website.
References
1. Aliskiren Summary of Product Characteristics.
Accessed from www.emc.medicines.org.uk/
on 08/02/10
2. Barber N. What constitutes good prescribing?
BMJ 1995;310:923–25
3. NHS Institute for Innovation and Improvement
website. Accessed from www.productivity.nhs.
uk/ on 08/02/10
4. NICE. Hypertension: management of hypertension in adults in primary care. Clinical
guideline 34. June 2006. Accessed from www.
nice.org.uk/cg34 on 08/02/10
5. The ONTARGET investigators. Telmisartan,
ramipril or both in patients at high risk for vascular
events. N Engl J Med 2008;358:1547–59
6. Mann JFE, et al. Renal outcomes with telmisartan,
ramipril, or both, in people at high vascular
risk (the ONTARGET study): a multicentre,
randomised, double-blind, controlled trial. Lancet
2008;372:547–53
7. NICE. Chronic heart failure: management of
chronic heart failure in adults in primary and
secondary care. Clinical guideline 5. July
2003. Accessed from www.nice.org.uk/cg5 on
08/02/10
8. SIGN. Management of chronic heart failure.
Guideline No. 95. February 2007. Accessed from
www.sign.ac.uk/guidelines/fulltext/95/index.html
MeReC Bulletin Volume 20, Number 2
on 08/02/10
9. NICE. Myocardial infarction: secondary prevention. Clinical guideline 48. May 2007. Accessed
from www.nice.org.uk/cg48 on 08/02/10
10. NICE. Type 2 diabetes: the management of
type 2 diabetes. Clinical guideline 87. May
2009. Accessed from www.nice.org.uk/cg87 on
08/02/10
11. NICE. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young
people and adults. Clinical guideline 15. July
2004. Accessed from www.nice.org.uk/CG15 on
08/02/10
12. NICE. Chronic kidney disease: early identification
and management of chronic kidney disease in
adults in primary and secondary care. Clinical
guideline 73. September 2008. Accessed from
www.nice.org.uk/cg73 on 08/02/10
13. National Collaborating Centre for Chronic
Conditions. Chronic kidney disease: national
clinical guideline for early identification and
management in adults in primary and secondary
care. London: Royal College of Physicians,
September 2008. Accessed from http://guidance.
nice.org.uk/CG73/Guidance/pdf/English
on 08/02/10
14. Law MR, et al. Use of blood pressure lowering
drugs in the prevention of cardiovascular
7
Document
Angiotensin-II
Title receptor antagonists: what is the evidence for their place in therapy?
disease: meta-analysis of 147 randomised trials
in the context of expectations from prospective
epidemiological studies. BMJ 2009;338:b1665
25. Dickstein K, et al. Effects of losartan and captopril
on mortality and morbidity in high-risk patients
after acute myocardial infarction: the OPTIMAAL
randomised trial. Lancet 2002;360:752–60
15. Flather MD, et al. Long-term ACE-inhibitor therapy
in patients with heart failure or left-ventricular
dysfunction: a systematic overview of data from
individual patients. Lancet 2000;355:1575–81
26. Pfeffer MA, et al. Valsartan, captopril, or both in
myocardial infarction complicated by heart failure,
left ventricular dysfunction, or both. N Engl J Med
2003;349:1893–906
16. Baker WL, et al. Systematic review: comparative
effectiveness of angiotensin-converting enzyme
inhibitors or angiotensin II-receptor blockers
for ischaemic heart disease. Ann Intern Med
2009;151:861–71
27. Kunz R, et al. Meta-analysis: effect of monotherapy
and combination therapy with inhibitors of the
renin-angiotensin system on proteinuria in renal
disease. Ann Intern Med 2008;148:30–48
17. Lee VC, et al. Meta-analysis: angiotensinreceptor blockers in chronic heart failure and
high-risk acute myocardial infarction. Ann Intern
Med 2004;141:693–704
28. Pfeffer MA, et al. Effects of candesartan on
mortality and morbidity in patients with chronic
heart failure: the CHARM-Overall programme.
Lancet 2003;362: 759–66
18. The TRANSCEND Investigators. Effects of
the angiotensin-receptor blocker telmisartan
on cardiovascular events in high-risk patients
intolerant to angiotensin-converting enzyme
inhibitors: a randomised controlled trial. Lancet
2008;372:1174–83
29. McMurray JJV, et al. Effects of candesartan
in patients with chronic heart failure and
reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the
CHARM-Added trial. Lancet 2003;362:767–71
30. Lakhdar R, et al. Safety and tolerability of
angiotensin-converting
enzyme
inhibitor
versus the combination of angiotensinconverting enzyme inhibitor and angiotensin
receptor blocker in patients with left ventricular
dysfunction: a systematic review and metaanalysis of randomized controlled trials. J Card
Fail 2008;14:181–88
19. Volpe M, et al. Angiotensin II receptor blockers
and myocardial infarction: an updated analysis
of randomized clinical trials. J Hypertens
2009;27:941–46
20. Shibata MC, et al. The effects of angiotensinreceptor blockers on mortality and morbidity in
heart failure: a systematic review. Int J Clin Pract
2008;62:1397–402
31. National Collaborating Centre for Chronic
Conditions. Hypertension: management in
adults in primary care: pharmacological update.
London: Royal College of Physicians, 2006.
Accessed from http://guidance.nice.org.uk/index.
jsp?action=download&o=30111
21. BNF 58, September 2009. Accessed from www.
bnf.org on 08/02/10
22. UKMI patents database. Accessed from
www.ukmicentral.nhs.uk/pressupp/pe.htm
on 08/02/10
32. Personal communication. Prescription Services
NHS Business Services Authority. October 2009
23. Matchar DB, et al. Systematic review: comparative
effectiveness of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers for
treating essential hypertension. Ann Intern Med
2008;148:16–29
33. NHS Information Centre. Hospital Prescribing,
2008: England. October 2009. Accessed from
www.ic.nhs.uk/statistics-and-data-collections/
primary-care/prescriptions/hospital-prescribing2008:-england on 08/02/10
24. Pitt B, et al. Effect of losartan compared with
captopril on mortality in patients with symptomatic
heart failure: randomised trial – the losartan
heart failure survival study ELITE II. Lancet
2000;355:1582–87
34. Personal communication.
Centre. January 2010
NHS
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MeReC Bulletin Volume 20, Number 2