ACE inhibitors for the treatment of hypertension

Drug selection by means of the SOJA method

Lesley Edgar, Senior Pharmaceutical Officer, DHSSPS, Belfast, Northern Ireland

Anita Hogg, Hospital Pharmacist, Northern Trust, Antrim, Northern Ireland
Mike Scott, Hospital Pharmacist, Northern Trust, Antrim, Northern Ireland
Mark Timoney, Principal Pharmaceutical Officer, DHSSPS, Belfast Northern Ireland
James Mc Elnay, School of Pharmacy, Queen’s University of Belfast Northern Ireland
Jill Mairs Regional Procurement Pharmacist, Northern Trust Whiteabbey,Northern Ireland
Rob Janknegt, Hospital Pharmacist, Sittard, the Netherlands

Regional Cardiology Expert Group Members:

Professor Jennifer Adgey, Consultant Cardiologist, Belfast Trust

Dr. Simon Baird, GP, NHSSB
Dr. Bryan Burke, GP, EHSSB
Miss Lesley Edgar, Principal Pharmaceutical Officer, DHSSPS
Dr. Damian Fogarty, Consultant Nephrologist, QUB/Belfast Trust
Dr. David Higginson, Consultant Cardiologist, South Eastern Trust
Professor Denis Johnston, Whitla Professor of Therapeutics and Pharmacology, QUB/Belfast
Trust
Mrs Lynn Keenan, Prescribing Information Pharmacist, COMPASS
Dr. Ursula Mason, GP, EHSSB
Dr. Ian Menown, Consultant Cardiologist, Southern Trust
Mr. Greg Miller, Locality Prescribing Adviser, EHSSB
Mrs Debbie McGivern, Locality Prescribing Adviser, SHSSB
Dr. Albert McNeill, Consultant Cardiologist, Western Trust
Dr. Heather Neagle, Medical Officer, DHSSPS
Ms Roisin O’Hare, Lead Teacher Practitioner (Pharmacist), QUB/ Southern Trust
Dr. George O’Neill, GP, EHSSB
Dr. Peter Passmore, Reader in Geriatric Medicine, QUB, Consultant, Belfast Trust
Dr. Michael Scott, Head of Pharmacy and Medicines Management, Northern Trust
Dr. Mark Timoney, Senior Principal Pharmaceutical Officer, DHSSPS

1
 Dr. Tom Trouton, Consultant Cardiologist, Northern Trust

Correspondence:
Dr. Robert Janknegt, Hospital Pharmacist, Sittard, the Netherlands
Orbis Medisch Centrum
Dr. H. van der Hoffplein 1
6162 BG Sittard-Geleen
The Netherlands
Tel  +31 88 4597709
Email r.janknegt@orbisconcern.nl

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Summary

ACE inhibitors have proven to be effective blood pressure lowering agents with an excellent
tolerability profile. The family of these drugs is still expanding, necessitating the definition of
selection criteria in order to choose the "right drug".
In this article the ACE inhibitors available in the United Kingdom (UK) are scored by means of
the SOJA method. The System of Objectified Judgement Analysis (SOJA) method is a model
for rational drug selection. The relevant selection criteria for a certain group of drugs are
defined and judged by a panel of experts and each selection criterion is given a relative weight.
The more important that a selection criterion is considered, the higher the relative weight that is
given to that criterion. The ideal properties for each selection criterion are determined and each
drug is scored as a percentage of the score of the ideal drug for all selection criteria. The
following selection criteria were used (relative weight): number of formulations (20), number of
indications (20), variation in bioavailability (40), interactions (40), trough/peak ratio diastolic
blood pressure lowering effect (20), efficacy (250), side-effects (150), dosage frequency (100),
documentation (100) and effect on clinical endpoints (260). Ramipril showed the highest score,
followed by perindopril, lisinopril and enalapril. The well documented effects on clinically
relevant end points, such as cardiovascular morbidity and mortality contributed to the high
score for ramipril.

3
INTRODUCTION
The renin-angiotensin system plays an important role in blood pressure regulation and fluid and
electrolyte balance. Angiotensin II is a very powerful vasoconstrictor. Other effects of
angiotensin II include sodium and water retention and increased sympathetic activity, all leading
to increased blood pressure. The angiotensin converting enzyme inhibitors (ACE inhibitors),
which inhibit the conversion of angiotensin I into the active compound angiotensin II were the
first antihypertensive agents targeted against angiotensin II. ACE inhibitors have proven to be
effective blood pressure lowering agents with an excellent tolerability profile; some of the ACE
inhibitors are standard drugs in the therapy of heart failure as well. The family of these drugs is
still expanding, necessitating the definition of selection criteria in order to choose the "drug of
choice" (1).
The System of Objectified Judgement Analysis (SOJA) method is a model for rational drug
selection (2). The relevant selection criteria for a certain group of drugs are defined and judged
by a panel of experts. The more important that a selection criterion is considered, the higher the
relative weight that is given to that criterion. The ideal properties for each selection criterion are
determined and each drug is scored as a percentage of the relative weight for all selection
criteria. The criteria, which were used in the present SOJA method and the weighting of the
authors is presented in Table 1.
The SOJA method was used as the first phase of the so-called STEPS methodology, which is
used in Northern Ireland to achieve optimal and cost-effective drug selection. See the
discussion section for further explanation.
A highly standardised procedure was used in the creation of the manuscript:
- Literature search in Medline, Embase, Cochrane, meta-analyses and review articles for relevant
publications using the names all of individual ACE inhibitors as key words.
- Consultation of EMEA Scientific Reports, NICE guidelines
- On the basis of these sources the most relevant publications were obtained. For the judgement
of clinical efficacy, only double-blind comparative studies in patients with hypertension between 2
ACE inhibitors, or between an ACE inhibitor and another antihypertensive drug were taken into
consideration. The number of included patients should be at least 25 per treatment arm. These
studies were screened by the first two authors and the last author.
All studies regarding effects on clinically relevant endpoints were screened and judged by the
same authors. The other authors served as sounding board for judgement on completeness and
correctness.

4
- Creation of the SOJA score by the authors
- In order to minimize bias, from whatever source, the final manuscripts was sent to a large group
of experts on the topic in question and to all pharmaceutical companies active in the field of ACE
inhibitors for a check on scientific correctness and completeness of the presented data.

In this article the ACE inhibitors available in the UK are scored by means of the SOJA method.
The following drugs were included in the score:

Captopril
Cilazapril
Enalapril
Fosinopril
Imidapril
Lisinopril
Moexipril
Perindopril
Quinapril
Ramipril
Trandolapril

The evaluation of the criteria in the SOJA method is highly standardised in order to promote
unbiased judgement of drugs from various pharmacotherapeutic categories based on clinically
relevant criteria. There will of course always be room for debate whether or not the correct scoring
system was used for each criterion and judgement may be arbitrary for most, if not all, criteria.
This is the case with any method used to quantify properties of drugs. The SOJA method is
intended as a tool for rational drug decision making, forcing clinicians and pharmacists to include
all relevant aspects of a certain group of drugs, thereby preventing formulary decisions being
based on only one or two criteria. Besides this, possible “hidden criteria” are excluded from the
decision making process. The outcome of this study should be seen as the basis for discussions
within formulary committees and not as the absolute truth. The present score is specific for the
UK, as the UK formulations and approved indications were used for calculation of the score.

5
 The selection criteria and the mean relative weights that are assigned by the authors are shown
in Table 1.

SELECTION CRITERIA

Formulations

To facilitate flexible dosing it is important to have more than one dosage strength available.
This is also true for a liquid or dispersible formulation in patients with swallowing problems.
Injectable formulations of these drugs are not used to any great extent and are not scored.
This criterion was scored as follows:

1 oral form 40%

More oral tablet/capsule strengths 60%
Combination with diuretic 20%
Liquid/dispersible oral form 20%

Number of indications

From a formulary point of view it may be relevant to include ACE inhibitors which are approved
for more than one single indication. Although it seems unlikely that there will be major
differences in efficacy or tolerance between different ACE inhibitors, not all ACE inhibitors are
approved for more indications than just hypertension.
This was scored as follows:

Hypertension 40%
Congestive heart failure (any form) 15%
Diabetic nephropathy 15%
Non-diabetic nephropathy 15%
Risk reduction in patients with 15%

6
cardiovascular disease

Pharmacokinetics

A wide variety of pharmacokinetic properties may be used for drug selection of ACE inhibitors,
but only a few have any clinical relevance. Factors such as protein binding, volume of
distribution, route of elimination and lipophilicity have little or no impact on efficacy and
tolerability of these drugs, although a combined renal and metabolic elimination may be
advantageous in patients with renal disease. Dose adaptation in renal disease is usually
relatively simple, so this is not clinically relevant in the treatment of hypertension, although it
might be of more importance in the treatment of heart failure or after myocardial infarction (1, 3-
7). The elimination half-lives of the various drugs are quite different. Elimination half-life as such
was not used as a selection criterion, as this criterion is incorporated in the criteria dosage
frequency and peak-trough ratio of antihypertensive effect. Moreover, half-life is probably of
less importance than the kinetics of binding to ACE.
Most ACE inhibitors are prodrugs, which have to be metabolised into the active "prilate". It is a
theoretical advantage if a drug is not a prodrug, as this may result in less variable serum
concentrations of the active compound.
The pharmacokinetic properties of ACE inhibitors are not identical.
The only pharmacokinetic criterion that was used was the variability of the bioavailability after
oral administration. A therapy may fail because of great differences in bioavailability and
incomplete absorption or a high variability will make dose titration more troublesome. The score
is based on the variability of bioavailability of the drugs after oral administration. This was
scored inversely proportional to the coefficient of variation.

Interactions

Drug interactions usually occur in a small minority of patients, but are relevant from a formulary
point of view in order to reduce the incidence and severity of these interactions.
If a drug has a high incidence of drug interactions, this may complicate therapy with this drug.
The lower the incidence and severity of drug interactions with each individual drug, the higher

7
 the score for this criterion. Besides drug interactions, the effect of food on the pharmacokinetic
properties of ACE inhibitors was also taken into consideration.

Trough/peak ratio diastolic blood pressure effect

The US Food and Drug Adminstration has suggested a definite and comprehensive index of
the antihypertensive effect. The trough effect (at the end of the dosage interval) should be at
least 50% of the peak effect, once appropriate adjustment has been made for placebo effect
and the circadian rhythm. If the net peak effect is limited (5mm Hg) the trough effect should be
at least 66% of the peak effect (8).
This was scored as follows:

Trough/peak ratio Score

> 0.75 100%
0.66-0.75 80%
0.5-0.65 60%
0.4-0.49 40%
0.25-0.39 20%
< 0.25 0%

Efficacy

Clinical efficacy is by definition a very important selection criterion for each group of drugs. The
relative efficacy of ACE inhibitors was determined from double-blind comparative studies
between these drugs. The number of mm Hg lowering of blood pressure was used for
comparison as well as the number of patients who show normalisation of blood pressure (%
responders) after treatment with the drugs.

Side-effects

8
 The relative tolerance was determined from double-blind comparative studies between ACE
inhibitors. For every % difference in tolerance, 3% of the maximum score was deducted for the
least tolerated drug. If one drug has an incidence of adverse reactions which is 5% higher than
that of another ACE inhibitor, the score for the drug with the poorest tolerance will be 15% (3 x
5%) lower.

Dosage frequency

A low dosage frequency is of great importance in life-long treatment such as that of

hypertension. Patient compliance is at its best at once daily dosing, although the difference
between once and twice daily dosing is not impressive. Patient compliance drops significantly
at higher dosage frequencies.
This was scored as follows:

1 x daily 100%
1-2 x daily 90%
2 x daily 80%
2-3 x daily 60%
3 x daily 40%
4 x daily 10%

Documentation

The score for this criterion was divided over 4 subcriteria.

9
The first two subcriteria are indicative of the overall clinical documentation of the drugs in
randomised controlled clinical studies. A large number of clinical studies and a large number of
patients included in these studies leave no doubt about the clinical efficacy and safety of this
drug in the studied population. The latter two criteria are indicative of the overall clinical
experience with the drug. These subcriteria may introduce a bias to the advantage of older
drugs, but this is done intentionally. The safety of a newly introduced drug cannot be
guaranteed from the results of clinical studies, in which only a relatively small number of
patients were included and most patients at risk for the development of adverse reactions (e.g.
patients with diminished renal function) were excluded. Both the number of patients that have
been treated on a world wide bases and the period that a certain drug has been available are of
importance, as it may take time until adverse reactions occur.

1. Number of double blind comparative studies

The number of double blind comparative clinical studies with other antihypertensive agents is
an important determinant of the clinical documentation.
5% of the relative weight for this subcriterion was awarded for each double-blind comparative
study.

2. Number of patients in these studies

Besides the number of clinical studies, the number of patients that were treated with the drug in
question must also be taken into consideration.
1% of the relative weight for this subcriterion was awarded for every 10 patients enrolled in
double-blind comparative studies.

3. Number of years marketed

The number of years that a product has been marketed in any country in the world provides
information on the clinical experience with the drug. If a product is on the market for more than
10 years it is very unlikely that serious adverse reactions will be observed that have not been
seen in the first 10 years after its introduction.

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 10% of the relative weight for this subcriterion was awarded for every year that the product is
available on the market.

4. Number of patient-days worldwide

Besides the number of years that a product is on the market, also the number of patient days
experience (on a world-wide level) with the drug plays a role.
1% of the relative weight for this subcriterion was awarded for every million patient-days
worldwide.

Effect on clinical endpoints

The ultimate goal of antihypertensive treatment is not to lower blood pressure, but to decrease
the incidence of cardiovascular morbidity and mortality.
The clinically documented effects of ACE inhibitors were classified as follows:

Reduction of mortality after myocardial infarction or during heart 10%

failure
Reduction of mortality in high risk patients 15%
Reduction of morbidity in high risk patients 15%
Effect on glomerular filtration rate in diabetics 10%
Effect on glomerular filtration rate in non-diabetics 10%
Reduction of cardiovascular mortality/morbidity in hypertension 40%

RESULTS

Formulations

The following formulations are available:

Drug Trade name Strengths Availability Availability Score

(mg) of of liquid

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 combination formulation
with diuretic
product
Captopril 12.5, 25, 50 + - 80%
Cilazepril Vascase 0.5, 1, 2.5, 5 - - 60%
Enalapril 2.5, 5, 10, + - 80%
20
Fosinopril Staril 10, 20 - - 60%
Imidapril Tanatril 5, 10, 20 - - 60%
Lisinopril 2.5, 5, 10, + - 80%
20
Moexipril Perdix 7.5, 15 - - 60%
Perindopril 2, 4, 8 + - 80%
Quinapril 5, 10, 20, 40 + - 80%
Ramipril 1.25, 2.5, 5, - - 60%
10
Trandolapril Gopten 0.5, 1, 2, 4 - - 60%

None of the drugs are available as a liquid or dispersible formulation.

All ACE inhibitors are available in more than one tablet strength.
A combination with a diuretic is available for 5 drugs, but not for the others. However, it was
noted (but not scored) that ramipril and trandolapril were available in combination with a
calcium channel blocker.

Number of indications

The following indications are approved in the UK:

Drug Hypertension Heart Nephropathy Nephropathy Risk Score

Failure Diabetic Non-diabetic Reduction
Captopril + + + - + 85%
Cilazepril + + - - - 55%

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Enalapril + + - - - 55%
Fosinopril + + - - - 55%
Imidapril + - - - - 40%
Lisinopril + + + - + 85%
Moexipril + - - - - 40%
Perindopril + + - - + 70%
Quinapril + + - - - 55%
Ramipril + + + + + 100%
Trandolapril + + - - - 55%

Ramipril is approved for all indications and captopril and lisinopril are approved for most
indications, whereas imidapril and moexipril are only approved for hypertension.

Pharmacokinetics

The pharmacokinetic properties of the ACE inhibitors are summarised in Table 2.

The variability of the serum concentration of the active compounds of the drugs is as follows:

Drug Variability Score

Captopril 13% 87%
Cilazepril 31% 69%
Enalapril 26% 74%
Fosinopril 24% 76%
Imidapril 35% 65%
Lisinopril 38% 62%
Moexipril 36% 64%
Perindopril 19% 81%
Quinapril 31% 69%
Ramipril 11% 89%
Trandolapril 8% 92%

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From references: 9-33

Trandolapril shows the lowest variability in the area under the serum concentration-time curve
(AUC) of the ACE inhibitors. Ramipril, captopril and perindopril also show a low variability in the
serum levels of the active compounds. The highest variablity is seen with imidapril, lisinopril,
cilazapril and quinapril.
No published data could be found for moexipril. This drug was arbitrarily awarded 60%.

Interactions

The pharmacokinetic drug interactions which may occur with ACE inhibitors have been
extensively reviewed by Shionori (34).

Interactions with cardiovascular drugs

No major pharmacokinetic interaction is seen with diuretics, but hyperkalemia may occur in
patients taking potassium supplements or potassium-sparing diuretics, especially in patients
with renal disease. Addition of ACE inhibitors to diuretic therapy may result in hypotension.
There appear to be no differences in the extent of these interactions between ACE inhibitors.
No major interactions (apart from the intended additive blood pressure lowering effect) are
observed when ACE inhibitors are combined with betablockers or calcium antagonists. Additive
blood pressure lowering effects are also seen with alpha blockers and central alpha 2-
adrenoceptor agonists. Although data are incomplete and sometimes conflicting, there seems
to be no clinically relevant effect of ACE inhibitors on the pharmacokinetics of digoxin (34). An
interaction between captopril and digoxin (25% increase of digoxin levels) was observed in
patients with severe heart failure, whereas no interaction was found in patients with
hypertension (35).

Interactions with other drugs

The absorption of captopril is diminished by about 35% by concomitant intake of antacids.

There are little data on the other ACE inhibitors. No pharmacokinetic drug interaction is

14
observed when ACE inhibitors are combined with cimetidine. No major kinetic interactions are
observed between ACE inhibitors and antihyperglycemic drugs, allopurinol, probenecide and
lipid lowering drugs such as the HMG-CoA reductase inhibitors. ACE inhibitors may affect the
clearance of lithium, resulting in higher serum concentrations of lithium. It is not clear whether
there are relevant differences between ACE inhibitors in the extent of this interaction. In general
the interaction appears to be of limited importance (35).
The blood pressure lowering effect of ACE inhibitors may be decreased to some extent by non-
steroidal anti-inflammatory drugs (NSAIDs). There seems to be no differences between ACE
inhibitors with respect to this interaction. Perindopril showed similar antihypertensive activity in
patients treated with NSAIDs or in patients who were not receiving NSAIDs treatment (36).
There are insufficient data on the potential interactions between ACE inhibitors and ciclosporin
or rifampin.

Food has limited or no effects on the absorption of most ACE inhibitors. Only the
bioavailabilities of captopril, cilazapril and perindopril are decreased to any significant extent.

There are few clinically relevant drug interactions between ACE inhibitors and other drugs,
apart from the (intended) additive blood pressure lowering effects of combinations with
diuretics, beta blockers or calcium antagonists. There is no conclusive data whether differences
are observed between ACE inhibitors in the extent of interaction with antacids, although this
interaction appears to be absent with ramipril.

An interaction with food has been described for captopril, cilazepril, moexipril and perindopril.
These drugs score 80%. All other ACE inhibitors score 90% for this criterion.

Trough/peak ratio

In the studies included in this section, the trough/peak ratio (TPR) was calculated by
substracting the blood pressure following drug treatment from that following placebo. The peak
is defined as the timepoint of the lowest blood pressure and the trough as the time point of the
highest blood pressure (37).
The most relevant data concerning the TPR of ACE inhibitors are summarised in Table 3. The
data in this table are extracted from a review by Zannad (38), who collected data using the

15
same methodology (patients with mild to moderate hypertension untreated for at least 2 weeks
prior to the study, ACE inhibitor monotherapy for at least 2 weeks, 24 hour ambulatory blood
pressure monitoring with hourly mean values of systolic and diastolic blood pressure). For 2
drugs (cilazepril and fosinopril) data were collected from other studies (39, 40). For several
drugs (captopril, lisinopril, perindopril and ramipril) higher TPRs were found in studies using
different methodologies from those of Zannad (38, 41-47).
As there are many differences in study methodology and the clinical relevance of this criterion
is still unclear (48, 49), we have given a low relative weight of 20 points to this criterion.
Relatively high doses were used for several drugs, such as captopril, lisinopril and ramipril. This
makes it difficult to draw any definite conclusions from these data. The results for TPRs are not
always consistent for all studies. Perindopril and trandolapril show the highest TPR and score
100%. Cilazepril, enalapril and ramipril score 60%, lisinopril and fosinopril score 40%, captopril
and quinapril score 20%.
Moexipril showed a very low TPR in the review by Zannad et al. This drug does not score for
this criterion.
Limited data are available on imidapril. In one study a TPR of 0.63-0.84 was found for dosages
of 2.5-20 mg (50). This drug is awarded 80%.

Efficacy

A large number of comparative clinical studies have been performed between ACE inhibitors.
The results of these studies are summarised in Table 4.
Not all drugs have been directly compared to each other. The number of comparative studies of
fosinopril with other ACE inhibitors is quite low. Most ACE inhibitors have been compared to
captopril and enalapril and to a lesser extent also with lisinopril. The size of most studies was
insufficient to exclude type II errors, but in general most drugs appear to have quite similar
antihypertensive efficacy, with the exception of captopril, which is consistently less effective
than other ACE inhibitors in almost all studies.
ACE inhibitors were no more effective than placebo in African Americans (100).
All compounds are given an identical score of 70% for clinical efficacy, corresponding to the
mean response rate. Captopril is awarded 60%.

Side effects

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ACE inhibitors are usually well tolerated. The most important side effects of ACE inhibitors
include: cough, headache, dizziness, weakness, nausea and skin reactions. Angioedema is
rarely observed and jaundice has also been described (101-116). Almost all studies have failed
to show any relevant differences in the incidence and severity of adverse reactions between
ACE inhibitors. Cough is the most common and "most irritating" side-effect of ACE inhibitors.
The incidence of cough is highly variable and ranges from 3% to more than 50% (30). The
incidence of cough is often underestimated (117). The mean incidence lies between 15 and
30% (118). There seem to be little, if any, differences between most ACE inhibitors in the
incidence of cough, although some studies suggest minor differences (119). Direct comparative
studies between imidapril and other ACE inhibitors showed a lower incidence of dry cough
(120).
There are some indications that the incidence of cough with fosinopril may be lower than those
of other ACE inhibitors (121, 122). The number of comparative studies with fosinopril is
however too low to allow definite conclusions.
Another well known side-effect of ACE inhibitors is the first-dose hypotension, which occurs
especially in patients with congestive heart failure. Although some (small scale) studies suggest
that there may be differences in the incidence of this reaction between ACE inhibitors, this
needs to be studied in more detail (55).
The most important serious adverse reaction to ACE inhibitors is angioedema. This is observed
more frequently than in other classes of antihypertensive drugs (123). In the large scale
ALLHAT study angioedema was observed in 0.42% of patients, whereas only 0.04% of patients
treated with chlorthalidone or amlodipine suffered from this side-effect (124). Angioedemia was
seen in 0.2% of ACE inhibitor users in a database study. The incidence was 1.97 cases per
1,000 person years. The incidence was 0.51 cases per 1,000 person years for other
antihypertensives (RR for ACE inhibitor use 3.56). Over 50% of cases was seen within 90 days
after start of the medication, but new cases were observed even after over 1 years’usage (125).
Hepatotoxicity has been described for ramipril. It is not clear whether there are differences
between the ACE inhibitors in the incidence of hepatotoxicity (126).
All drugs are awarded 70%.

Dosage frequency

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Most ACE inhibitors can be taken once daily: cilazapril, fosinopril, imidapril, lisinopril, moexipril,
perindopril, quinapril, ramipril, and trandolapril. These drugs score 100%. Other agents are
taken once or twice daily - these drugs are awarded 90%. Captopril has to be taken twice daily
and is awarded 80%.

Documentation

The clinical documentation of the drugs is summarised in Table 5 (From references 51-99, 127-
384). For the calculation of the number of studies and the number of patients involved in these
studies, the studies included in the Tables were taken into account as well as published double-
blind comparative studies with other antihypertensive agents, such as diuretics, betablockers,
calcium antagonists or angiotensin II antagonists. These data were collected from reviews on
each individual drug, plus recently published studies.
Most ACE inhibitors are very well documented.

Effect on clinical endpoints

Reduction of mortality after myocardial infarction or during heart failure

Several studies have shown beneficial effects of ACE inhibitors on these conditions (385-407).
The Consensus study showed a clear reduction of overall and cardiovascular mortality of
enalapril on a high risk group of patients with heart failure when compared with placebo (385).
The SOLVD study involved patients with a left ventricular ejection fraction of less than 25%.
This study also showed a significant reduction in cardiovascular and overall mortality, infarction
and the development of serious heart failure (386). These favourable effects were maintained
after long term (up to 12 years) treatment (387).

Several trials have studied the use of ACE inhibitors after myocardial infarction.
The Consensus II trial started within 24 hours after myocardial infarction (388). The lack of a
beneficial effect on mortality in Consensus II may have been caused by a variety of reasons,
such as increased myocardial ischaemia due to blood pressure lowering effect and a potential
role of angiotensin II in the healing process immediately after myocardial infarction (395).

18
Trandolapril reduced overall mortality in post myocardial infarction patients with left ventricular
dysfunction (397).

Perindopril 2-8 mg has been compared to placebo in 1,224 patients of 65 years or older after
myocardial infarction and with a left ventricular ejection fraction of over 40%. The combined
endpoint was death, hospital admission for heart failure or ventricular remodeling. Secondary
endpoints included cardiovascular death, hospitalisation for re-infarction or angina with
revascularisation. A significant reduction of the primary endpoint was observed from 57% to
35% in the perindopril group, an absolute risk reduction of 22%, p<0.001. It should be noted
that the risk reduction was caused almost entirely by the effect on remodeling (398).The
number of patients that has to be treated to save one life varies widely between the studies,
also because of the different patient populations (400).
Both captopril and ramipril significantly reduced mortality and morbidity after myocardial
infarction (163, 164) in patients with symptomatic heart failure.
An interesting observation is that ramipril was associated with a significantly lower hospital
mortality and a lower rate of nonfatal major adverse coronary and cerebrovascular events in
comparison with the pooled data for other ACE inhibitors in a multivariate analysis of the
MITRA PLUS registry of patients with ST-elevation acute myocardial infarction (401). The
relevance of these findings is still unclear.

In a retrospective cohort study, a higher mortality was found after use of enalapril, fosinopril,
captopril, quinapril and lisinopril in comparison with ramipril. No significant difference was
observed between ramipril and perindopril (402). The relevance of these findings is unclear, but
certainly makes it interesting for further investigation. The patients treated with ramipril or
perindopril had a lower incidence of heart failure en used more beta blockers in comparison
with the other ACE inhibitors (403).

Reduction of mortality and morbidity in high risk patients

Ramipril has demonstrated effects on cardiovascular morbidity and mortality in high risk
patients. The HOPE study (408, 409) showed a significant reduction of myocardial infarction,
stroke, and mortality in patients with vascular disease or diabetes and at least one other risk
factor for ramipril in comparison with placebo. The effect of ramipril was much more

19
pronounced than could be explained by its antihypertensive action. This effect was also
observed in women (410). The effect was more pronounced than could be explained on the
basis of the blood pressure lowering effects. There is still uncertainty about the mechanism
behind the relationship between blood pressure lowering effects of ramipril and the observed
favourable effects in the HOPE study (411, 412).

Perindopril has demonstrated a positive effect on survival in patients with end stage renal
failure, contrary to treatment with calcium antagonists or betablockers. This effect was
correlated with a reduction in aortic pulse wave velocity by perindopril. The risk ratio for ACE
inhibitor use was 0.19 (95% CI 0.14 to 0.43) for all cause mortality (413).

In the PROGRESS study, perindopril (4 mg daily during 4 years, if necessary combined with
indapamide) was compared to placebo in patients with previous stroke of transient ischaemic
attack. Blood pressure reduction by perindopril +/- indapamide was limited (9/4 mmg Hg), but a
significant reduction in the primary endpoint (total stroke) was found: 28% reduction (from 14%
to 10%) as well as a 26% reduction in total major vascular events, irrespective of initial blood
pressure of the patients. This reduction was found in the overall treatment group and in the
combination group, but not with the single-drug (perindopril) regimen. In the combination group
the stroke risk reduction was 43%, whereas no significant reduction of 5% was found in the
single-drug perindopril group (414). This study therefore does not provide evidence that
perindopril monotherapy results in a lower incidence of stroke.
In the EUROPA study, perindopril 8 mg daily (n=6,110) was compared with placebo (n=6,108)
in patients with coronary heart disease during 4.2 years on average. The primary endpoint was
cardiovascular death, myocardial infarction of cardiac arrest. A reduction of 20% was observed
on the primary endpoint (9.9% vs 8%, p=0.003) in comparison with the placebo group. A variety
of secundary endpoints was used of which significance was reached on the reduction of non-
fatal myocardial infarction by 22% (6.5% vs 4.8%, p=0.001) and a combined endpoint of total
mortality, non-fatal myocardial infarction, instable angina pectoris and cardiac arrest: a
reduction of 14% (17.1% vs 14.8%, p=0.0009). Total mortality (6.9% vs 6.1%) was not
significantly lower in the perindopril group (415). In the ADVANCE study, a fixed combination of
perindopril 4 mg and indapamide 1.25 mg or placebo was added to an existing therapy in patients
with diabetes mellitus with a mean follow-up of 4.3 years. The primary endpoints were composites
of major macrovascular and microvascular events, defined as death from cardiovascular disease,

20
non-fatal stroke or non-fatal myocardial infarction and new or worsening renal or diabetic eye
disease. The reduction in blood pressure (systolic 5.6mm Hg and diastolic 2.2mm Hg) was
significantly stronger in the active group. The primary endpoint was decreased by 9% in
comparison with placebo, p=0.04. The individual macrovascular and microvascular events were
not significantly different from placebo. The relative risk of death from cardiovascular disease was
reduced by 18% and all cause mortality was reduced by 14%, both p=0.03 (416). Because this is
a combination treatment, it is unclear what the contribution of perindopril to the observed effects
was.

In the large-scale (over 19.000 patients) Anglo-Scandinavian Cardiac Outcomes Trial- Blood
pressure lowering arm (ASCOT-BPLA) blood pressure lowering regimes based on amlodipine 5-
10mg or atenolol 50-100mg were compared concerning the incidence of fatal coronary diseases
and nonfatal myocardial infarction (primary endpoint) and coronary revascularisation and fatal plus
non-fatal stoke (secoundary endpoint). Patients with hypertension and at least three other
cardiovascular risk factors were included in the study. The average duration of the study was 5.5
years, pPerindopril 4-8mg could be added to amlodipine, whereas bendroflumethiazide 1.25-
2.5mg could be added to atenolol in case of inusufficient blood pressure control on monotherapy.
No significant difference was seen on the primary endpoint: 4.4% in the amlodipine group versus
4.9% in the atenolol group. It should be taken into consideration that the ACE inhibitor was only
second-line therapy in this study. Several secondary endpoints showed a signiifcant difference in
favour of amlodipine: non-fatal myocardial infarction (HR 0.87), total coronary endpoints (0.87),
total cardiovascular events and procedures (0.84), total mortality (0.89), cardiovascular mortality
(0.76) and stroke (0.77). The development of new cases of diabetes was lower in the amlodipine
group (HR 0.70) (417). The blood pressure lowering with the amlodipine regimen (28/18mm Hg)
was slightly stronger than that in the atenolol group (26/16mm Hg). The favourable effects on the
incidence of stroke were maintained after correction for the blood pressure lowering effects. If a
correction was made for other variables, the difference was no longer significant (418). The effects
of perindopril monotherapy could not be evaluated, because 82% of patients also received
amlodipine.

In the QUO VADIS study, quinapril 40 mg or placebo during one year were given to patients
undergoing coronary artery bypass grafting. The number of patients experiencing clinical
ischaemic events (death, repeat CABG, percutaneous revascularisation, myocardial infarction,

21
recurrent AP, ischaemic stroke or transient ischaemic attacks) was significantly reduced by
quinapril (419).
The QUIET study (in which the effects of quinapril 20mg for 3 years on the incidence of cardiac
ischaemic events and/or progression of coronary artery atherosclerosis were compared with
placebo in patients undergoing coronary angioplasty) yielded negativedisappointing results. No
significant reduction in the frequency of major cardiac events was observed (420).

Effect on glomerular filtration rate in diabetics/non-diabetics

Captopril, lisinopril and ramipril have demonstrated a positive effect on glomerular filtration rate
in both diabetic and non-diabetic patients (421-432). Most ACE inhibitors have shown a
reduction in microalbuminuria in patients with diabetes, but few have documented positive
effects on (maintaining) glomerular filtration rate.
Ramipril 2.5-10mg per day was more effective than amlodipine (5-10mg per day) in slowing
renal disease progression in patients with hypertensive renal disease and prote inuria (433) in a
large scale study.
In a comparative study between captopril, valsartan and placebo in patients with type 2
diabetes and microalbuminuria, no significant differences in the GFR were observed between
the 3 groups (434).
In a small scale study in patients with peritoneal dialysis, ramipril 5mg daily during 1 year
resulted in a significantly lower decrease in glomerular filtration rate in comparison with no
treatment (435).

Imidapril and captopril showed favourable effects on albumin excretion rate in comparison with
placebo, but no significant effects on GFR were seen at the end of the study (436).

As described above perindopril has demonstrated a positive effect on survival in patients with
end stage renal failure. Of these patients, 8% were also suffering from diabetes (413). This
effect can be regarded as being even more important than the effect on GFR. Because of this,
perindopril was also awarded the full score, despite the fact that no effect on GFR has been
proven in comparison with placebo (437, 438).
In a retrospective analysis, it has been shown that ACE inhibitors may reduce mortality of
hemodialysis patients in comparison with those not treated with ACE inhibitors. Blood pressure

22
reduction was similar in both groups, but mortality risk decreased by 52% in the ACE inhibitor-
treated patients. No specification of the ACE inhibitors, nor the applied dosages was given
(439).

Trandolapril 2 mg (with or without verapamil) had a favourable effect on the development of

microalbuminuria in a 3-year study in patients with type 2 diabetes in comparison with
verapamil monotherapy or placebo. Microalbuminuria was seen in 6.0% of patients with
trandolapril vs 11.9% on verapamil. The study did no show an effect on glomerular filtration rate
(440).

In a systematic review it was concluded that ACE inhibitors reduce total mortality by 21% in
comparison with placebo in patients with diabetic nephropathy. No significant differences were
found between angiotensin II antagonists and placebo (441).
In a double-blind study between telmisartan 80mg daily (n=130) and enalapril 20mg daily
(n=130) for 5 years, no statistical differences were observed between both drugs in their effects
on glomerular filtration rate, serum creatinine, albuminuria, blood pressure, renal failure and
cardiovascular events or mortality (442).

Reduction of cardiovascular mortality/morbidity in hypertension

In a large subpopulation of the HOPE study, ramipril showed a significant reduction of

cardiovascular morbidity and mortality in comparison with placebo. These patients were already
treated with another antihypertensive drug, but the addition of ramipril lowered mortality in
comparison with placebo (443).

No other ACE inhibitor has been compared with placebo in hypertension. In two studies, ACE
inhibitors were compared with other antihypertensive drugs (often in combination therapy). In
the CAPPP study captopril showed similar effects on cardiovascular mortality than betablockers
or diuretics (444). The incidence of stroke was higher in the captopril group, whereas captopril
performed better in patients with diabetes. In the STOP hypertension II trial, enalapril and
lisinopril were compared with betablockers, diuretics or calcium antagonists in hypertension. No

23
differences were observed between the drugs in their effects on cardiovascular morbidity and
mortality (445).
The largest study ever, involving 42,448 patients investigated the effects of antihypertensive
agents in patients with hypertension and at least one additional risk factor of coronary heart
disease or myocardial infarction (ALLHAT). This study compared chlorthalidone, amlodipine,
lisinoenalapril and doxazosin. Of these, 9,054 patients were treated with lisinopril; 12,255 with
chlorthalidone and 9,048 with amlodipine. The follow-up period was 4.9 years.
The primary outcome was combined fatal CHD or non-fatal myocardial infarction (intention-to-
treat analysis). Secondary outcomes were all-cause mortality, stroke, combined CHD (primary
outcome, coronary revascularisation, or angina with hospitalisation), and combined CVD
(combined CHD, stroke, treated angina without hospitalisation, heart failure, and peripheral
arterial disease) (124).
No difference was found between treatments concerning primary outcome. Compared with
chlorthalidone (6-year rate, 11.5%), the relative risk (RR) was 0.99 (95% CI, 0.91-1.08) for
lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-
year systolic blood pressures were significantly higher in the lisinopril (2mm Hg, P<.001) group
compared with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with
amlodipine (0.8mm Hg, P<.001) (124). For lisinopril vs chlorthalidone, lisinopril had higher 6-
year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs
5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31)
(137A). In summary, the results of lisinopril were similar to those achieved with chlorthalidone
concerning the primary endpoint, but were less favourable in comparison with those of
chlorthalidone concerning the secondary endpoint (446). Lisinopril was awarded 30% of the
available 40% for this subcriterion because of the less favourable results on stroke and heart
failure in comparison with chlorthalidone.
In a subgroup analysis, lisinopril was much less effective in Afro-Caribbeans than in
Caucasians. This was not the case for chlorthalidone. In this subgroup chlorthalidone was also
more effective in reducing the incidence of stroke and combined cardiovascular events (447).
In an open study in elderly patients with hypertension, ACE inhibitors (n=3,044), mainly
enalapril were compared to diuretics (n=3,039), mainly hydrochlorothiazide. The incidence of
cardiovascular events was lower in the group treated with an ACE inhibitor (RR 0.89, p=0.05).
In the subgroup of males, the difference between both groups reached significance (RR 0.82,
p=0.02). No differences were observed in women. The incidence of non-fatal cardiovascular

24
events (RR 0.86, p=0.03) was lower in patients treated with an ACE inhibitor, but the incidence
of fatal stroke was significantly higher in the ACE inhibitor group: RR 1.91, p=0.04 (448). No
details were presented on which ACE inhibitors were used, nor on the applied dosages.

Because perindopril only showed significant effects on morbidity and mortality in combination
with indapamide, the drug was assigned a +/- for its effect in hypertension.

Ramipril did not show a significant decrease in the development of diabetes in a 3-year, placebo-
controlled study in patients without cardiovascular diseases, but with increased fasting blood
glucose (449).

The effects of ACE inhibitors on clinical endpoints are summarised in Table 6.

The SOJA score

The SOJA score is shown in Table 7. The selection criteria may be divided into "intrinsic"
criteria (bioavailability, drug interactions, TPR, efficacy and side-effects) which do not change
with time and are valid for all countries and "extrinsic" criteria (number of formulations, number
of indications, dosage frequency and documentation) which may vary from country to country
and are also time dependent (especially documentation).
This score is specific for the UK situation as the extrinsic criteria may be different in other
countries. The SOJA score is also time dependent as documentation and survival studies may
change when the results of new studies become available.

DISCUSSION

The relative weight that is given to each selection criterion is the result of consultation of a
panel of experts on ACE inhibitors, but will always be a matter of discussion. This is the reason
why an interactive program has been made available, in which each physician may enter his
own weighting factor to each criterion, thereby making his own personal selection of these
drugs. Debate is always possible (and even desirable) on the relative importance of the applied
selection criteria. If one considers that there is a 1:1 relationship between antihypertensive
efficacy and observed clinical outcomes, such as reduction of cardiovascular morbidity and

25
mortality, there is no need to assign a high weight (or even any weight at all) to the selection
criterion documented effects on clinical endpoints. Most authors of the present paper
considered this criterion to be an important, if not the most important, criterion. In any case it is
illogical to assign a moderate high weight to this criterion. There can be no doubt that the effect
on clinical endpoints is important (high weight), but it can be considered to be a class effect
(low weight). In a preliminary version of the SOJA score for ACE inhibitors, the criterion effect
on clinical endpoints was not included, leading to an entirely different score (450). The authors
believe that the present score is a much better one. The previous version also contained cost
as a criterion. This criterion is deleted in the present score as is explained further on during this
section.
The authors decided to include all relevant clinical endpoints studies with ACE inhibitors ,
irrespective of the effects in hypertensive patients, although this subcriterion was assigned a
much higher relative weight than documented effects in other patient categories. This was
based on the fact that many hypertensive patients have comorbidities and that documented
favourable effects on these comorbidities can be seen as advantageous. Debate on this
decision is of course possible.
The criteria clinical efficacy and side-effects, although being the most important selection
criteria, are not discriminating between drugs belonging to one class show very similar clinical
efficacy and tolerance.
The SOJA method is used in Northern Ireland (N.I.) as part of the Safe Therapeutic Economic
Pharmaceutical Selection (STEPS) methodology. During 2007, as part of the Departmental
Pharmaceutical Clinical Effectiveness Programme, an EU Restricted Tender for all ACE
Inhibitors was issued on behalf of both primary and secondary care sectors in N.I. In the first
phase of STEPS a preselection of available drugs within this therapeutic class was performed
by means of the SOJA method. The criterion acquisition costs was willingly not included in the
first stage, to alllow preselection of drugs on quality aspects only. The eleven different ACE
Inhibitors chemical entities were evaluated and ranked , Only the five chemical entities
(ramipril, perindopril, enalapril, lisinopril, captopril) with the highest clinical evaluation scores
proceeded to the next phase.
In the second phase of STEPS, a structured risk assessment of the tendered products (13
products from 6 different manufacturers), which had passed the clinical evaluation phase, was
performed. This included judgement of critical information (labelling, , storage conditions,
blisters and patient information leaflets. A number of added value criteria such as calendar

26
packs, EAN barcode,pack size, tablet/capsule colouring and marking and label instruction
space are also taken into consideration.
In the third phase the tendered costs of each available strength of each individual product was
determined and related to the Defined Daily Dose (DDD), as laid down by the World Health
Organisation, in order to estimate the expected overall costs of each of these drugs. This was
carried out to ensure that true cost comparisons were calculated as the equivalent DDD varies
from one therapeutic agent to another. The total annual costs were calculated on the tendered
price for secondary care and where the product offered was a generic product, for primary
care, If the tendered product was a branded product the current NHS List Price as set by the
PPRS, applies to primary care.
In the final phase the expert panel decided on the basis of the budgetary impact analysis which
of the tendered products that had passed STEPS I and II and represented Best Value for
money for both primary and secondary care, should be recommended to constitute 70% of the
requirement for that therapeutic class. The rationale for a 70% target was to ensure that there
was sufficient scope to enable the treatment of both more complex (primarily in secondary
care) and well stabilised (chiefly in primary care) patients to be accommodated, thereby
ensuring that all patients can be treated optimally (4510). The new Regional Contract for ACE
Inhibitors for primary and secondary care in N.I. commenced on the 1 st January 2008.
The present process has led to much greater uniformity in prescribing (evidence based) ACE
inhibitors and has also resulted in significant savings in the overall cost of the use of ACE
inhibitors in primary and hospital care.

Regional Prescribing Guidance was issued to the Service and was published on the
Department of Heath website http://www.dhsspsni.gov.uk/acei_and_atiira_guideline_final.pdf

Conclusions

The SOJA method has proven to be a very interesting and easy to perform method to allow a
preselection of drugs within a class on quality aspects only. The Regional Carradiology Expert
Group in N.I. recommended Lisinopril, Perindopril and Ramipril as the ACE inhibitors of choice.,

Conflict of interests
None to declare

27
References

1. Leonetti G, Cuspidi C. Choosing the right ACE inhibitor. A guide to selection. Drugs 1995;49 :516-35.

2. Janknegt R, Steenhoek A. The System of Objectified Judgement Analysis. A tool in rational drug selection for formulary purposes. Drugs
1997;53:550-62.

3. Anonymous. Who needs nine ACE inhibitors? Drug Ther Bull 1995;33:1-3.

4. Van Veen A. Welke ACE remmer bij hypertensie? Modern Med 1993;31:61-3.

5. Bet PM, Steenhoek A. ACE remmers. Een preparaatkeuze volgens de SOJA methode. Pharm Weekbl 1992;127:1262-71.

6. Burnier M, Biolloaz J. Pharmacokinetic optimisation of angiotensin converting enzyme (ACE) inhibitor therapy. Clin Pharmacokinet1992;22:375-
84.

7. Van Schaik BAM. ACE remmers: huidige stand van zaken en een blik in de toekomst. Pharm Weekbl 1992;127:1108-13.

8. Division of Cardio Renal Drugs Products, Food and Drug Administration. Proposed guidelines for the clinical evaluation of antihypertensive
drugs. Rockville MD, US Department of Health and Human Services, 1988.

9. Schweizer C, Kaiser G, Dieterle W et al. Pharmacokinetics and pharmacodynamics of benazepril HCl in patients with proteinuria. Eur J Clin
Pharmacol 1993;44:463-66.

10. Shionoiri H, Ueda S, Minamisawa K et al. Pharmacokinetics and pharmacodynamics of benazepril in hypertensive patients with normal and
impaired renal function. J Cardiovasc Pharmacol 1992;20:348-57.

11. Edeki T, Johnston A, Kam Wa E et al. Enalapril pharmacokinetics and ACE inhibition following single and chronic oral dosing. Int J Clin
Pharmacol Ther 1994;32:142-6.

12. Nakamura H, Ishii M, Sugimura T et al. The kinetic profiles of enalapril and enalaprilat and their possible developmental changes in pediatric
patients with congestive heart failure. Clin Pharmacol Ther 1994;56:160-8.

13. Witte K, Weisser K, Neubeck M et al. Cardiovascular effects, pharmacokinetics and converting enzyme inhibition of enalapril after morning
versus evening administration. Clin Pharmacol Ther 1993;54:177-86.

14. Louis WJ, Conway EL, Krum H et al. Comparison of the pharmacokinetics and pharmacodynamics of perindopril, cilazapril and enalapril. Clin
Exp Pharmacol Physiol 1992;19 suppl. 19:55-60.

15. Ford N, Lasseter KC, Van Harken D et al. Single-dose and steady-state pharmacokinetics of fosinopril and fosinoprilat in patients with hepatic
impairment. J Clin Pharmacol 1995;35:145-50.

16. Hui K, Duchin KL, Kripalani KJ et al. Pharmacokinetics of fosinopril in patients with various degrees of renal function. Clin Pharmacol Ther
1991;49:457-67.

17. Neubeck M, Fliser D, Pritsch M et al. Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure. Wur J Clin Pharmacol
1994;46:537-43.

18. Louis WJ, Workman BS, Conway EL et al. Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive
subjects. J Cardiovasc Pharmacol 1992;20:505-11.

28
19. Lees KR, Green ST, Reid J. Influence of age on the pharmacokinetics and pharmacodynamics of perindopril. Clin Pharmacol Ther 1988;44:418-
25.

20. Halstenson CE, Opsahl JA, Rachael K et al. The pharmacokinetics of quinapril and its active metabolite, quinalaprilat, in patients with various
degrees of renal function. J Clin Pharmacol 1992;32:344-50.

21. Begg EJ, Robson RA, Kram H et al. The pharmacokinetics of quinalapril and quinalaprilat in patients wtih congestive heart failure. Br J Clin
Pharmac 1994;37:302-4.

22. Elliott HL, Macdonald NJ, Meredith PA et al. Dose responses and pharmacokinetics for the angiotensin converting enzyme inhibitor quinapril. Clin
Pharmacol Ther 1992;51:260-5.

23. Verho M, Luck C, Stelter WJ et al. Pharmacokinetics, metabolism and biliary and urinary excretion of oral ramipril in man. Curr Med Res Opin
1995;13:264-73.

24. Van Griensven JM, Schoemaker RC, Cohen AF et al. Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril. Eur
J Clin Pharmacol 1995;47:513-8.

25. Arner P, Wade A, Engfeldt P et al. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and
elderly patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol 1994;23 suppl. 4:S44-9.

26. Lenfant B, Mouren M, Bryce T et al. Trandolapril; pharmacokinetics of single oral doses in healthy male volunteers. J Cardiovasc Pharmacol
1994;23 suppl. 4:S38-43.

27. Bevan EG, McInnes GT, Aldigier JC et al. Effect of renal function on the pharmacokinetics and pharmacodynamics of trandolapril. Br J Clin
Pharmac 1993;35:128-35.

28 Marzo A, Dal Bo L, Mazzuchelli P et al. Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers. Arznim Forsch
1999;49:992-6.

29 Hoogkamer JF, Kleinbloesem CH, Nokhodian A et al. Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose
and during steady state in patients with chronic renal failure. Eur J Clin Pharmacol 1998;54:59-61.

30 Hoogkamer JF, Kleinbloesem CH, Nokhodian A et al. Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose
and during steady state in patients with impaired liver function. Eur J Clin Pharmacol 1997;51:489-91.

31 Harder S, Thurmann PA, Ungethum W. Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in
hypertensive patients. Br J Clin Pharmacol 1998;45:377-80.

32 Breithaupt-Grogler K, Ungethum W, Meurer-Witt B, Belz GG. Pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme
inhibitor imidapril with hydrochlorothiazide, bisoprolol and nilvadipine. Eur J Clin Pharmacol 2001;57:275-84.

33 Hutt V, Michaelis K, Verbesselt R et al. Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide. Eur J Clin Pharmacol
1996;51:339-44.

34. Shionori H. Pharmacokinetic drug interactions with ACE inhibitors. Clin Pharmacokinet 1993;25:20-58.

35. Opie LH. Angiotensin converting enzyme inhibitors. Scientific basis for clinical use. Wiley Liss, New York, 1994. 316 pp

36. Overlack A, Adamczak M, Bachmann W et al. ACE inhibition with perindopril in essential hypertensive patients with concomitant diseases. Am J
Med 1994;97:126-34.

29
37. Elliott HL, Meredith PA. Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995;13:279-83.

38. Zannad F, Matzinger A, Larche J. Trough/peak ratios of once daily ACE inhibitors and calcium antagonists. Am J Hypertens 1996;9:633-43.

39. Guntzel P, Kobrin I, Pasquier C et al. The effect of cilazapril, a new angiotensin converting enzyme inhibitor, on peak and trough blood pressure
measurements in hypertensive patients. J Cardiovasc Pharmacol 1991;17:8-12.

40. Ford NF, Fulmor IE, Nichola PS et al. Fosinopril monotherapy: relationship between blood pressure reduction and time of administration. Clin
Cardiol 1993;16:324-30.

41. Morgan T, Anderson A. Duration of antihypertensive effect of perindopril, enalapril and captopril. Hypertension 1993;21:658.

42. Salvetti A, DiVenanzio LD, Arrighi P et al. Trough:peak raio of the blood pressure response to ACE inhibitors. J Hypertens 1994;12 suppl. 8:S91-
5.

43. Martell N, Gill B, Marin R et al. Trough to peak ratio of once-daily lisinopril and twice-daily captopril in patients with essential hypertension. J
Hum Hypertens 1998;12:69-72.

44. Zannad F, Bernaud CM, Fay R. Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic
coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators' Group. J Hypertens 1999;17:137-46.

45. Staessen JA, Bieniaszewski L, Buntinx F et al. The trough-to-peak ratio as an instrument to evaluate antihypertensive drugs. Hypertension
1995;26:942-9.

46. Diamant M, Vincent HH. Lisniopril versus enalapril: evaluation of trough:peak ratio by ambulatory blood pressure monitoring. J Hum Hypertens
1999;13:405-11.

47. Sica DA. Dosage considerations with perindopril for systemic hypertension. Am J Cardiol 2001;88 suppl.:13i-18i.

48. Frishman WH. Twenty-four hour blood pressure control. Apporaches to assesment and efficacy of ACE inhibitors. Adv Ther 1996;13:110-23.

49. Meredith PA, Elliott HL. Antihypertensive treatment and trough:peak ratio: genral considerations. J Hypertens 1994;12 suppl. 8:S79-83.

50. Vandenburg MJ, McKay EM, Dews I et al. Dose finding studies with indapamil: a new ACE inhibitor. Br J Clin Pharmacol 1994;37:265-72.

51. Stevenson JG, Chideckel EW. Evaluation of cilazapril versus captopril in patients with mild to moderate essential hypertension. Clin Exp
Hypertens 1994;16:179-96.

52. Al-Idrissi HY, Ibrahim EM, Hassan F et al. A randomised double blind crossover study of cilazapril and captopril in mild to moderately severe
hypertension in Saudis. J Drug Dev 1993;5:215-23.

53. Garanin G. A comparison of once-daily antihypertensive therapy with captopril and enalapril. Curr Ther Res 1986;40:567-75.

54. Steiner SS, Friedhoff AJ, Wilson BL et al. Antihypertensive therapy and quality of life; a comparison of atenolol, captopril, enalapril and
propranolol. J Hum Hypertens 1990;4:217-25.

55. Walker JF, Kulage SF, Kramsch DM. The efficacy and safety of enalapril in moderate to severe essential hypertension. J Hypertens 1984;2
suppl. 2:107-11.

30
56. Thind GS, Johnson A, Bhatnagar D et al. A parallel study of enalapril and captopril and 1 year of experience with enalapril treatment of moderate
to severe essential hypertension. Am Heart J 1985;109:852-8.

57. Rumboldt Z, Marinkovic M, Drinovec J. Enalapril versus captopril: a double-blind multicentre comparison in essential hypertension. Int J Clin
Pharmacol Res 1988;8:181-8.

58 Huang PJ, Chien KL, Chen MF et al. Efficacy and safety of imidapril in patients with essential hypertension: a double-blind comparison with
captopril. Cardiology 2001;95:146-50.

59. Rumboldt Z, Simunic N, Bagatin J et al. Controlled multicentre comparison of captopril versus lisinopril in the treatment of mild-to-moderate
arterial hypertension. Int J Clin Pharmacol Res 1993;13:35-41.

60. Whelton A, Miller WE, Dunne B et al. Once daily lisinopril compared with twice daily captopril in the treatment of mild to moderate hypertension:
assessment of office and ambulatory blood pressures. J Clin Pharmacol 1990;30:1074-80.

61. Siche JP, Gaudemaris de R, Lorraine de A et al. Comparative trial of lisinopril and captopril (once daily) in mild to moderate hypertension:benefit
of 24-hour ambulatory blood pressure monitoring. In: A Focus on the clinical effects of a long-acting ACE inhibitor hypertension. Keane WF (ed). Raven
Press Ltd, New York, 1990 pp 31-9.

62. Rumbolot Z, Simunic M, Bagatin J et al. Controlled multicentre comparison of captopril versus lisinopril in the treatment of mild-to-moderate
arterial hypertension. Int J Clin Pharmacol Res 1993;13:35-41.

63. Gosse P, Dallocchio M, Gourgon R. ACE inhibitors in mild to moderate hypertension: comparison of lisinopril and captopril administered once
daily. J Hum Hypertens 1989;3:25-8.

64. Stimpel M, Koch B, Jansen T et al. Moexipril versus captopril in patients with mild to moderate hypertension. J Cardiovasc Pharmacol.
1996 ;28:769-73.

65. Lees KR, Reid JL, Scott MG et al. Captopril vs perindopril: a double blind study in essential hypertension. J Hum Hypertens 1989;3:17-22.

66. Agabiti-Rosei E, Ambrosioni E, Finardi G et al. Perindopril versus captopril efficacy and acceptability in an italian multicenter trial. Am J Med
1992;92 suppl. 4B:S79-83.

67. Anastacio RV, Mendoza CM, Katigbak-Cancayco B. A parallel group double blind study of once daily quinapril versus twice daily captopril in the
treatment of mild to moderate essential hypertension. Philipp J Int Med 1993;31:41-52.

68. Schnaper HW. Comparison of the efficacy and safety of quinapril vs captopril in treatment of moderate to severe hypertension. Angiology
1989;40:389-95.

69. Taylor SH. The treatment of mild to moderate hypertension with ACE inhibitors. J Cardiovasc Pharmacol 1990;15 suppl. 2:S24-8.

70. Frishman WH, Greenberg S. Angiotensin converting enzyme inhibitors as initial monotherapy in severe hypertension. Quinapril and captopril. Am
J Hypertens 1991;4:827-31.

71. Witte PU, Walter U. Comparative double blind study of ramipril and captopril in mild to moderate essential hypertension. Am J Cardiol
1987;59:115-20.

72. Yajnik VH, Vatsraj D, Acharya HK. Ramipril vs captopril in mild to moderate hypertension. J Ass Phys Ind 1994;42:1203.

73. Pauly NC. Comparison of the efficacy and safety of trandolapril and captopril for 16 weeks in mild to moderate essential hypertension. J
Cardiovasc Pharmacol 1994;23 suppl. 4:S73-6.

31
74. Yoshinaga K, Saruta T, Kaneko Y et al. Evaluation of efficacy and safety of cilazapril versus enalapril in patients with essential hypertension. J
Clin Ther Med 1989;5:1873-1913.

75. Goldstein RJ. A multicentre, randomized, double-blind parallel comparison of fosinopril sodium and enalapril maleate for the treatment of mild to
moderate essential hypertension. Drug Invest 1991;3 suppl. 4:38-44.

76. Hansson L, Forslund T, Hoglund C et al. Fosinopril versus enalapril in the treatment of hypertension: a double blind study in 195 patients. J
Cardiovasc Pharmacol 1996;28:1-5.

77. Saruta T, Omae T, Kuramochi M et al. Imidapril hydrochloride in essential hypertension: a double-blind comparative study using enalapril
maleate as a control. J Hypertens 1995;13 Suppl 3:S23-30.

78. Van der Does R, Euler R, Comparison of the antihypertensive effect of imidapril and enalapril in the treatment of mild-to-moderate hypertension:
a randomized, parallel-group double-blind study. Curr Ther Res Clin Exp 2001;29:437-50.

79 Espinel CH, Williams JL, Coughlin SS. Enalapril and lisinopril in the treatment of mild to moderate essential hypertension. Clin Ther 1990;12:181-
90.

80. Gourlat S, McNeil J, Forbes A et al. Differences in the acute and chronic antihypertensive effects of lisinopril amd enalapril assessed by
ambulatory blood pressure monitoring. Clin Exp Hypertens 1993;15:71-89.

81. Whelton A, Dunne B, Glazer N et al. Twenty-four hour blood pressure effect of once-daily lisinopril, enalapril, and placebo in patients with mild to
moderate hypertension. J Hum Hypertens 1992;6:325-31.

82. Enstrom I, Thulin T, Lindholm LH. Comparison between enalapril and lisinopril in mild-moderate hypertension. A comprehensive model for
evaluation of drug efficacy. Blood Press 1992;1:102-7.

83. Yoshinaga K, Saruta T, Abe K et al. Clinical evaluation of monotherapy with perindopril, an ACE inhibitor in the treatment of essential
hypertension. Double blind parallel comparison with enalapril maleate. Rins Iyak 1997;13:4259-97.

84. Alcocer L, Campros C, Bahrena JH et al. Clinical aceptability of ACE inhibitor therapy in mild to moderate hypertension, a comparison between
perindopril and enalapril. Cardiovasc Drugs Ther 1995;9:431-6.

85. Yusuff K, Razak TA, Yusuf N et al. Comparative efficacy of perindopril and enalapril once daily using 24-hour ambulatory blood pressure
monitoring. Int J Clin Pract 1999;53:277-80.

86. Taylor SH. A comparison of the efficacy and safety of quinapril with that of enalapril in the treatment of mild and moderate essential hypertension.
Angiol 1989;40:382-8.

87. Durante M, Yulde J, Crisostomo M et al. A parallel group double-blind study of once daily quinalapril versus enalapril in the treatment of mild to
moderate essential hypertension. Philipp J Int Med 1991;29:173-84.

88. Sanchez S, Luna A, Orozco R. Quinalapril versus enalapril in the treatment of mild to moderate essential hypertension. Clin Ther 1991;13:651-5.

89. Zabludowski J, Rozenfeld J, Akbary MA et al. A multi-centre comparative study between ramipril and enalapril in patients with mild to moderate
essential hypertension. Curr Med Res Opin 1988;11:93-106.

90. Todd PA, Benfield P. Ramipril: a review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs
1990;39:110-35.

32
91. Ruddy MC, Mroczek WJ. Comparison of ramipril and enalapril in patients with esential hypertension. Pharmacother 1993;13:224-8.

92. Yasky J, Verho M, Erasmus TP et al. Efficacy of ramipril versus enalapril in patients with mild to moderate essential hypertension. Br J Clin Pract
1996;50:302-10.

93. Nami R, Pavese G, Panza F et al. Comparative evaluation of the antihypertensive effect and the tolerability of different ACE inhibitors in the
medium term treatment of essential hypertension. G Ital Ric Clin Ter 1992;13:107-16.

94. Arakawa K, Saruta T, Iimura O. Clinical evaluation of ACE inhibitors trandolapril in patients with essential hypertension. Multicentred double-blind
comparative study in comparison with enalapril maleate. Rins Hyok 1992;20:477-511.

95. De Leeuw PW, Pauly NC. Double-blind comparison of efficacy and safety of trandolapril 2 mg and hydrochlorothiazide 25 mg in patients with mild
to moderate hypertension. J Hypertens 1992;10 suppl.4:199.

96. Poirier L, Bourgeois J, Archambault F et al. ACE inhibitors as first-line treatment agents: a comparative study of trandolapril and enalapril on
casual and ambulatory blood pressures. Am J Ther 1995;2:159-64.

97. Papageorgiou A, Karayiannis A, Athyros V. A comparative study of the efficacy and safety of quinapril and lisinopril in patients with mild to
moderate hypertension. Drug Invest 1994;7:13-7.

98. Langan J, Laws D, Llivingstone ED. Quinapril and lisinopril in elderly patients with mild-to-moderate hypertension: a randomised double-blind
comparison. Br J Clin Res 1995;6:191-9.

99. Koenig W, Feldmann M, Krohn J. Ramipril vs lisinopril in the treatment of mild to moderate hypertension. A randomised double blind multicentre
trial. Drug Invest 1992;4:450-7.

100. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med 2004;141:614-
27.

101. Balfour JA, Goa K. Benazepril. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension and
congestive heart failure. Drugs 1991;42:511-39.

102. Deget F, Brogden RN. Cilazapril. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension and
congestive heart failure. Drugs 1991;41:799-820.

103. Wadworth AN, Murdoch D, Brogden RN. Atenolol. A reppraisal of its pharmacological properties and therapeutic use in cardiovacular disorders.
Drugs 1991;42:468-510.

104. Todd PA, Goa K. Enalapril. A reppraisal of its pharmacology and therapeutic use in hypertension. Drugs 1992;43:346-81.

105. Murdoch D, McTavish D. Fosinopril. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in essential
hypertension. Drugs 1992;43:123-40.

106. Wagstaff AJ, Davis R, Mc Tavish D. Fosinopril. A reappraisal of its pharmacology and therapeutic efficacy in essential hypertension. Drugs
1996;51:777-91.

107. Todd PA, Fitton A. Perindopril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs 1991;42:90-
114.

108. Plosker GL, Sorkin EM. Quinapril. A reappraisal of its pharmacology and therapeutic efficacy in cardiovascular disorders. Drugs 1994;48:227-52.

33
109. Frampton JE, Peters DH. Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure. Drugs 1995;49:440-66.

110. Oparil S. Efficacy of perindopril in the treatment of systemic hypertension. Am J Cardiol 2001;88 suppl.:23i-12i.
111 Clark LT. Safety profile of perindopril. Am J Cardiol 2001;88 suppl.:36i-40i.

112. Poudit C, Girgrah N, Allard J. ACE inhibitor-induced angioedema of the intestine: case report, incidence, pathophysiology, diagnosis and
management. Can J Gastroenterol 2001;15:827-32.

113. Schattner A, Kozak N, Friedman J. Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature. Am J Med
Sci 2001;332:236-40.

114. Culy CR, Jarvis B. Quinapril. A further update of its pharmacology and therapeutic use in cardiovascular disorders. Drugs 2002;62:339-85.

115. Hurst M, Jarvis B. Perindopril. An updated review of its hypertension. Drugs 2001;61:867-96.

116. Kostis JB, Kim HJ, Rusnak J et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 2005;165:1637-42.

117. Johns Cupp M, Moherman LJ. Lessons from low enrollment in ACE inhibitor cough study. Ann Pharmacother 1996;30:413-4.

118. Lombardi C, Crivellaro M, Dama A et al. Are physcians aware of the side effects of ACE inhibitors? Chest 2005;128:976-9.

119. Tumanan-Mendoza BA, Dans AL, Villacin LL et al. Dechallenge and rechallenge method showed different incidences of cough among four ACE-
Is. J Clin Epidemiol 2007;60:547-53.

120. Robinson DM, Curran MP, Lyseng-Williamson KA. Imidapril: a review of its use in essential hypertension, Type 1 diabetic nephropathy and
chronic heart failure. Drugs 2007;67:1359-78.

121. Germino FW, Lastra J, Pool P et al. Evaluation of the cough profile of fosinopril in hypertensive patients with ACE inhibitor-associated cough. A
pilot study. Curr Ther Res 1993;54:469-75.

122. David D, Jallad N, Germino FW et al. A comparison of the cough profile of fosinopril and enalapril in hypertensive patients with a history of ACE
inhibitor-associated cough. Am J Ther 1995;2:806-13.

123. Weber MA, Messerli FH. Angiotensin-converting enzyme inhibitors and angioedema: estimating the risk. Hypertension 2008;51:1465-7.

124. ALLHAT officers. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel
blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2992;288:2981-97.

125 Miller DR, Oliveria SA, Berlowitz DR et al. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors.
Hypertension 2008;51:1624-30.

126. Yeung E, Wong FS, Wanless IR et al. Ramipril-associated hepatoxicity.Arch Pathol Lab Med 2003;127:1493-7.

127. Franke H. Antihypertensive effects of candesartan cilexetil, enalapril and placebo. J Hum Hypertens 1997;11 suppl. 2:S61-2.

128. Zanchetti A, Omboni S, Di Biagio C. Candesartan cilexetil and enalapril are of equivalent efficacy in patients with mild to moderate hypertension.
J Hum Hypertens 1997;11 suppl.2:S57-9.

129. Tanser PH, Campbell LM, Carranza J et al. Candesartan celexetil is not associated with cough in hypertensive patients with enalapril-induced
cough. Am J Hypertens 2000;13:214-8.

34
130. Himmelmann A, Keinanen-Kiukaanniemi S, Wester A et al. The effect duration of candesartan cilexetil once daily in comparison with enalapril
once daily, in patients with mild to moderate hypertension. Blood Press 2001;10:43-51.

131. Zanchetti A, Omboni S. Comparison of candesartan versus enalapril in essential hypertension. Am J Hypertens 2001;14:129-34.

132. Malmqvist K, Kahan T, Dahl M. Angiotensin II Type I receptor blcokade in hypertensive women: benefits of candesartan cilexetil versus enalapril
or hydrochlorothiazide. Am J Hypertens 2001;13:504-11.

133. Argenziano L, Trimarco B. Effect of eprosrtan and enalapril in the treatment of elderly hypertensive patients: subgroup analysis of a 26 week,
double-blind, multicentre study. Curr Med Res Opin 1999;15:9-14.

134. Oparil S. Eprosartan versus enalapril in hypertensive patients with ACE inhibitor-induced cough. Curr Ther Res 1999;60:1-14.

135. Sega R. Efficacy and safety of eprosartan in severe hypertension. Blood Press 1999;8:114021.

136. Larochelle P, Flack JM, Marbury TC et al. Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Am J Cardiol
1997;80:1613-5.

137. Mimran A, Ruilope L, Kerwin L et al. A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full
dose range of enalapril for the treatment of mild-to-moderate hypertension. J Hum Hypertens 1998;12:203-8.

138. Chiou KR, Chen CH, Ding PY et al. Randomized, double-blind comparison of irbesartan and enalapril for treatment of mild to moderate
hypertension. Chung Hua I Hsueh Tsa Chih (Taipei) 2000;63:368-76.

139. Roca-Cusachs A, Oigman W, Lepe L et al. A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily
losartan compared to twice-daily captopril in mild to moderate hypertension. Acta Cardiol 1997;6:495-506.

140. Mallion JM, Bradstreet DC, Makris L et al. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with captopril in
patients with mild to moderate hypertension. J Hypertens 1995;13 Suppl. 1:S35-41.

141. Ruff D, Gazdick LP, Berman R et al. Comparative effects of combination drug therapy regimens commencing with either losartan potassium, an
angiotensin II receptor antagonist, or enalapril maleate for the treatment of severe hypertension. J Hypertens 1996;14:263-70.

142. Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril
in patients with essential hypertension. J Hypertens 1995;13:1343-51.

143. Townsend R, Haggart B, Liss C et al. Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in
patients with essential hypertension. Clin Ther 1995;17:911-23.

144. Ogihara T, Yoshinaga K. The clinical efficacy and tolerability of the angiotensin II receptor antagonist losartan in Japanese patients with
hypertension. Blood Press 1996;5 suppl. 2:78-81.

145. Karlberg BE, Lins LE, Hermansson K. Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly
patients with primary hypertension. J Hypertens 1999;17:293-302.

146. Smith DH, Neutel JM, Morgenstern P. Once daily telmisartan compared with enalapril in the treatment of hypertension. Adv Ther 1998;15:229-40.

147. Lacourciere Y. The incidence of cough. A comparison of lisinopril, placebo and telmisartan, a novel angiotensin II antagonist. Int J Clin Pract
1999;53:1-5.

35
148. Neutel JM, Frishman WH, Oparil S et al. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Ther
1999;6:161-6.

149. Holwerda NJ, Fogari R, Angeli P et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety
compared with placebo and enalapril. J Hypertens 1996;14:1147-51.

150. Mallion JM, Boutelant S, Chabreux P et al. Valsartan, a new angiotensin II antagonist; blood pressure reduction in essential hypertension
compared with an angiotensin converting enzyme inhibitor, enalapril. Blood Press Monit 1997;2:179-84.

151. Black HR, Graff A, Shute D et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and
safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J Hum Hypertens 1997;11:483-9.

152. Perico N, Spormann D, Peruzzi E et al. Efficacy and tolerability of valsartan compared with lisinopril in patients with hypertension and renal
insufficiency. Clin Drug Invest 1997;4:252-9.

153. Benz J, Oshrain C, Avery C et al. Valsartan, a new angiotensin II receptor antagonist: a double-blind study comparing the incidence of cough with
lisinopril and hydrochlorothiazide. J Clin Pharmacol 1997;17:101-7.

154. Bremner AD, Baur M, Oddou-Stock P et al. Valsartan: long term efficacy and tolerability compared to lisinopril in elderly patients with essential
hypertension. Clin Exp Hypertens 1997;19:1263-85.

155. Conlin PR, Spence JD, Williams B et al. Angiotensin II antagonists for hypertension: are there differences in efficacy? Am J Hypertens
2000;13:418-26.

156. Van Nueten L, Rishoj Nielsen M, Vertommen C et al. Nebivolol versus enalapril in essential hypertension: a long-term double-blind comparative
trial. Acta Clin Belg 1999;54:19-25.

157. Prisant LM, Neutel JM, Papademetriou V et al. Low-dose combination treatment for hypertension versus single-drug
treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies. Am J Ther 1998;5:313-21.

158. Radevski I, Skudicky D, Candy G et al. Antihypertensive monotherapy with nisoldipine CC is superior to enalapril in black patients with severe
hypertension. Am J Hypertens 1999;12:194-203.

159. Andersson OK. Improved efficacy with maintained tolerability in the treatment of primary hypertension. Comparison between the felodipine-
metoprolol combination tablet and monotherapy with enalapril. Swedish Multicentre Group. J Hum Hypertens 1999;13:55-60.

160. Cushman WC, Cohen JD, Jones RP et al. Comparison of the fixed combination of enalapril/diltiazem ER and their monotherapies in stage 1 to 3
essential hypertension. Am J Hypertens 1998;11:23-30.

161. Estacio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-
insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645-52.

162. Van Nueten L, Schelling A, Vertommen C et al. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial.
J Hum Hypertens 1997;11:813-9.

163. Tan KW, Frise SA. Efficacy and tolerability of doxazosin versus enalapril in the treatment of patients with mild-to-moderate hypertension. Clin
Ther 1997;19:459-70.

164. Kuschnir E, Acuna E, Sevilla D et al. Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 20 mg compared with
amlodipine 5 mg, benazepril 20 mg, and placebo. Clin Ther 1996;18:1213-24.

36
165. Devereux RB, Dahlof B, Levy D et al. Comparison of enalapril versus nifedipine to decrease left ventricular hypertrophy in systemic hypertension
(the PRESERVE trial). Am J Cardiol 1996;78:61-5.

166. Naidu MU, Usha PR, Rao TR et al. Evaluation of amlodipine, lisinopril, and a combination in the treatment of essential hypertension. Postgrad
Med J 2000;76:350-3.

167. Beltman FW, Heesen WF, Smit AJ et al. Effects of amlodipine and lisinopril on left ventricular mass and diastolic function in previously untreated
patients with mild to moderate diastolic hypertension. Blood Press 1998;7:109-17.

168. Ruddy TD, Fodor JG. Nisoldipine CC and lisinopril alone or in combination for treatment of mild to moderate systemic hypertension. Canadian
Nisoldipine CC Hypertension Trial Group. Cardiovasc Drugs Ther 1997;11:581-90.

169. Karlberg BE, Andrup M, Oden A. Efficacy and safety of a new long-acting drug combination, trandolapril/verapamil as compared to monotherapy
in primary hypertension. Swedish TARKA trialists. Blood Press 2000;9:140-5.

170. Messerli F, Frishman WH, Elliott WJ. Effects of verapamil and trandolapril in the treatment of hypertension. Trandolapril Study Group. Am J
Hypertens 1998;11:322-7.

171. DeQuattro V, Lee D, Messerli F. Efficacy of combination therapy with trandolapril and verapamil sr in primary hypertension: a 4 x 4 trial design.
The Trandolapril Study Group. Clin Exp Hypertens 1997;19:373-87.

172. Andrejak M, Santoni JP, Carre A et al. A double-blind comparison of perindopril hydrochlorothiazide-amiloride in mild to moderate essential
hypertension. Fundam Clin Pharmacol 1991;5:185-92.

173. Morgan TO, Louis WJ, MacDonald GJ et al. Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension:
results of a double-blind multicenter study versus atenolol. Am J Med 1992;92 suppl. 4B:73S-8S.

174. Brown CL, Backhouse CI, Grippat JC et al. The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on
the renin-angiotensin system in hypertensive subjects, Eur J Clin Pharmacol 1990;39:327-32.

175. Zannad F, Bernaud CM, Fay R. Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic
coverage and beyond in patients with mild to moderate hypertension. J Hypertens 1999;17:137-46.

176. Thurston H, Mimran A, Zanchetti A et al. A double-blind comparison of perindopril and atenolol in essential hypertension. J Hum Hypertens
1990;4:547-52.

177. Martinez-Castelao A, Hueso M, Sanz V et al. Double-blind, crossover,comparative study of doxazosin and enalapril in the treatment of
hypertension in renal transplant patients under cyclosporin immunosuppression. Transplant Proc 2002;34:403-6.

178. Chien KL, Huang PJ, Chen MF et al. Assessment of quality of life in a double-blind, randomized clinical trial of imidapril and captopril for
hypertensive Chinese in Taiwan. Cardiovasc Drugs Ther 2002;16:221-6.

179. Pitt B, Reichek N, Willenbrock R et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left
ventricular hypertrophy. The 4E left ventricular hypertrophy study. Circulation 2003;108:1831-8.

180. Mourad JJ, Waeber B, Zannad F et al. Comparison of different strategies in hypertension: a low-dose combination of perindopril/indapamide
versus a sequential monotherapy or a stepped-care approach. J Hypertens 2004;22:2379-86.

181. Anichkov DA, Shostak NA, Schastnaya OV. Comparison of rilmenidine and lisinopril on ambulatory blood pressure and plasma lipid and glucose
levels in hypertensive women with metabolic syndrome. Curr Med Res Opin 2005;21:113-9.

37
182. Gradman AH, Arcuri KE, Goldberg AI, Ikeda LS, Nelson EB, Snavely DB. A randomized, placebo-controlled, double-blind, parallel study of various
doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertens 1995;25:1345-50.

183. Martinez Castelao A, Ibernon M et al. Doxazosin GITS trough to peak ratio and 24-hour blood pressure monitoring in the management of
hypertension in renal transplant patients. Transplant Proc 2003;35:1736-8.

184. Franke H. Antihypertensive effects of candesartan cilexetil, enalapril and placebo. J Hum Hypertens 1997;11 suppl. 2:S61-2.

185. Zanchetti A, Omboni S, Di Biagio C. Candesartan cilexetil and enalapril are of equivalent efficacy in patients with mild to moderate hypertension. J
Hum Hypertens 1997;11 suppl.2:S57-9.

186. Tanser PH, Campbell LM, Carranza J et al. Candesartan celexetil is not associated with cough in hypertensive patients with enalapril-induced
cough. Am J Hypertens 2000;13:214-8.

187. Cuspidi C, Muiesan ML, Valagussa L et al. Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential
hypertension: the candesartan assessment in the treatment of cardiac hypertrophy study. J Hypertens 2002;20:2293-2300.

188. Neldam S, Forsen B. Antihypertensive treatment in elderly patients aged 75 years or over. Drugs and Aging 2001;18:225-32.

189. Gradman AH, Gray J, Maggiacone D et al. Assessment of once-daily eprosartan, an angiotensin II antagonist, in patients with systemic hypertension.
Clin Ther 1999;21:442-53.

190. Ruilope L, Jaeger B, Prichard B. Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial. Blood Press
2001;10:223-9.

191. Coca A, Calvo C, Garcia-Puig J et al. A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in
adults with mild to moderate essential hypertension, as asse4ssed by ambulatory blood pressure monitoring: the MAPAVEL study. Clin Ther 2002;24:126-
38.

192. Smith DH, Matzek KM, Kempthorne-Rawson J. Dose-response and safety of telmisartan in patients with mild-to-moderate hypertension. J Clin
Pharmacol 2000;40:1380-90.

193. Bellet M, Friedrichs D, Bodin F et al. Benazepril: clinical response compared with other ACE inhibitors. In: Brunner HR, et al. (eds) Benazepril:
profile of a new ACE inhibitor. pp 99-109. Royal Soc Med Ser Int Congr Symp Series No 166. Royal Soc Med 1990.

194. Fagher B, Katzman P, Hulthen UL, Henningsen NC, Thulin T. Antihypertensive efficacy and tolerability of enalapril and slow-release verapamil in
essential hypertension: A double-blind, cross-over study. J Intern Med 1991;230:219-26.

195. Palmer A, Fletcher A, hamilton G, Muriss S, Bulpitt C. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a
converting enzyme inhibitor in hypertensive blacks. Arch Intern Med 1990;150:1707-13.

196. Morgan TO, Anderson A, Jones E. Comparison and interaction of low dose felodipine and enalapril in the treatment of essential hypertension in
elderly subjects. Am J Hypertens 1992;5:238-43.

197. Rodriguez-Manaz L, Guillon F, Caballero JC, Tobares N, Sempere R. A comparison of the efficacy, tolerability and effect on quality of life of
nisoldipine CC and enalapril in elderly patients with mild-t-moderate hypertension. Acta Ther 1996;22:89-106.

198. Verkaaik R, Hogewind BL, Woittiez AJ. A comparative study of the effects of nitrendipine and enalapril in essential hypertension. J Cardiovasc
Pharmacol 1991;18 suppl. 1:63-6.

38
199. Philipp T, Anlauf M, Distler A, Holzgreve H, Michaeles J, Wellek S. Randomized, double-blind, multicentre comparison of hydrochlorothiazide,
atenolol, nitrendipine and enalapril in antihypertensive treatment: results of the HANE study. Br Med J 1997;315:154-9.

200. De Quattro V, Lee DP. Equivalent reduction of proteinuria in hypertensives by either nifedipine GITS or enalapril: disparate effects on
neurohormones and ambulatory blood pressure and the influence of salt. Cardiol 1997;88 suppl. 3:38-42.

201. Devereux RB, Palmieri V, Sharpe N et al. Effects of once-daily angiotensin-converting enzyme inhibition and calciumchannel blockade-based
antihypertensive treatment regimens on LVH and diastolic filling in hypertension: the prospective randomized enalapril study evaluating regression of
ventricular enlargement (preserve) trial. Circulation 2001;104:1248-54.

202. White WB, Sica DA, Calhoun D et al. Preventing increases in early-morning blood pressure, heart rate, and the rate-pressure product with controlled
onset extended release verapamil at bedtime versus enalapril, losartan and placebo at arising. Am Heart J 2002;144:657-65.

203. Mroczek WJ. Efficacy and safety of a new angiotensin-converting enzyme inhibitor, ramipril, vs. enalapril in essential hypertension: a
multicenter trial. J Cardiovasc Pharmacol 1991;18 Suppl 2:S147-9.

204. Frick MH, Halttunen P, Himanen P et al. A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate
essential hypertension. Br J Clin Pharmacol 1986;21 Suppl 1:55S-62S.

205. Fukiyama K, Omae T, Iimura O, et al. A double-blind comparative study of doxazosin and prazosin in the treatment of essential hypertension.
Am Heart J 1991;121:317-22.

206. Neaton JD, Grimm JRH, Prineas RJ et al. Treatment of mild hypertension study. Final results. JAMA 1993;270:713-34.

207. Taylor SH, Lee PS, Sharma SK. A comparison of doxazosin and enalapril in the treatment of mild and moderate essential hypertension.
1988;116:1820-5.

208. Aberg H, Morlin C, Lithell H. Different long-term metabolic effects of enalapril and atenolol in patients with mild hypertension. EGTA Group. J
Hum Hypertens. 1995;9:149-53.

209. Jackson G, Thirkettle JL, Taylor DJ et al. A double-blind crossover trial of atenolol, enalapril and the fixed combination of atenolol and nifedipine
in mild and moderate hypertension. Br J Clin Pract 1993;47:66-70.

210. Herrick AL, Waller PC, Berkin KE et al. Comparison of enalapril and atenolol in mild to moderate hypertension.
Am J Med 1989;86:421-6.

211. The Canadian Enalapril Study Group. Comparison of monotherapy with enalapril and atenolol in mild to moderate
hypertension.. CMAJ 1987;137:803-8.

212. Edmonds D, Greminger P, Locher R et al. Enalapril as a first-step agent in essential hypertension: a comparative study with atenolol. J
Hypertens Suppl 1986;4:S406-9.

213. Helgeland A, Strommen R, Hagelund CH et al. Enalapril, atenolol, and hydrochlorothiazide in mild to moderate hypertension. A comparative
multicentre study in general practice in Norway. Lancet 1986;1:872-5.

214. Larochelle P, Carruthers SG, Alexander M et al. Comparison of monotherapy with enalapril and atenolol in mild to moderate hypertension. CAMJ
1987;137:803-8.

215. Bakris G, Sica D, Ram V et al. A comparative trial of controlled-onset, extended-release verapamil, enalapril,
and losartan on blood pressure and heart rate changes. Am J Hypertens 2002;15:53-7.

39
216. Nielsen S, Dollerup J, Nielsen B et al. Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 months
study. Nephrol Dial Transplant 1997;12 Suppl 2:19-23.

217. Byyny RL, Merrill DD, Bradstreet TE et al.. An inpatient trial of the safety and efficacy of losartan compared with placebo and enalapril in patients
with essential hypertension. Cardiovasc Drugs Ther 1996;10:313-9.

218. Ramsay LE, Yeo WW. ACE inhibitors, angiotensin II antagonists and cough. The Losartan Cough Study Group. J Hum Hypertens 1995 Nov;9
Suppl 5:S51-4.

219. Tomlinson B, Woo J, Thomas GN et al. Randomized, controlled, parallel-group comparison of ambulatory and clinic
blood pressure responses to amlodipine or enalapril during and after treatment in adult chinese patients with hypertension. Clin Ther 2004;26:1292-304.

220. Ding YA, Chang SM, Chou TC. Comparison of amlodipine and quinapril on ambulatory blood pressure and
platelet function in hypertension. J Hum Hypertens 1995;9:637-41.

221. Del Vecchio L, Pozzi M, Salvetti A et al. Efficacy and tolerability of manidipine in the treatment of hypertension in patients with non-diabetic
chronic kidney disease without glomerular disease. Prospective, randomized, double-blind study of\ parallel groups in comparison with enalapril. J Nephrol
2004;17:261-9.

222. Kostis JB, Packer M, Black HR et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs.
Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-11.

223. Breeze E, Rake EC, Donoghue MD et al. Comparison of quality of life and cough on eprosartan and enalapril in people with moderate
hypertension. J Hum Hypertens 2001;15:857-62.

224. Himmelmann A, Keinanen-Kiukaanniemi S, Wester A et al. The effect duration of candesartan cilexetil once daily, in comparison with enalapril
once daily, in patients with mild to moderate hypertension. Blood Press 2001;10:43-51.

225. Zanchetti A, Omboni S. Comparison of candesartan versus enalapril in essential hypertension. Italian
Candesartan Study Group. Am J Hypertens 2001;14:129-34.

226. Chiou KR, Chen CH, Ding PY et al. Randomized, double-blind comparison of irbesartan and enalapril for treatment
of mild to moderate hypertension. Zhonghua Yi Xue Za Zhi (Taipei) 2000;63:368-76.

227. Gerritsen TA, Bak AA, Stolk RP et al. Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulin-dependent diabetes
mellitus and hypertension. J Hypertens. 1998 May;16(5):689-96.

228. Van Nueten L, Schelling A, Vertommen C et al. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial.
J Hum Hypertens 1997;11:813-9.

229. Akopov SE, Simonian NA. Comparison of isradipine and enalapril effects on regional carotid circulation in patients with hypertension with
unilateral internal carotid artery stenosis. J Cardiovasc Pharmacol 1997;30:562-70.

230. Guitard C, Lohmann FW, Alfiero R et al. Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension.
Cardiovasc Drugs Ther 1997;11:449-57.

231. Kuppers HE, Jager BA, Luszick JH et al. Placebo-controlled comparison of the efficacy and tolerability of once-daily moxonidine and enalapril in
mild-to-moderate essential hypertension. J Hypertens 1997;15:93-7.

232. Johnson BF, Eisner GM, McMahon FG et al. A multicenter comparison of adverse reaction profiles of isradipine and enalapril at equipotent
doses in patients with essential hypertension. J Clin Pharmacol 1995;35:484-92.

40
233. Nielsen S, Schmitz A, Knudsen RE et al. Enalapril versus bendroflumethiazide in type 2 diabetes complicated by hypertension. QJM
1994;87:747-54.

234. Testa MA, Anderson RB, Nackley JF et al. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The
Quality-of-Life Hypertension Study Group. N Engl J Med 1993;328:907-13.

235. Johnston GD, Banks DC, Davies S et al. A double blind comparative study of lisinopril and enalapril in patients with essential hypertension. J
Hum Hypertens 1991;5:405-10.

236.I Eisner GM, Johnson BF, McMahon FG et al. A multicenter comparison of the safety and efficacy of isradipine and enalapril in the treatment of
hypertension. Am J Hypertens 1991;4:154S-157S.

237. Rodriguez-Saavedra M, Zannad FM, Guerrero-Sierra J et al. Comparison of dilevalol and enalapril administered once daily for mild hypertension.
Am J Cardiol suppl 1989;63:50I-53I.

238. Enalapril in Hypertension Study Group (UK). Enalapril in essential hypertension: a comparative study with propranolol. Br J Clin Pharmacol
1984;18:51-6.

239. Otero ML, Claros NM; Study Investigators Group. Manidipine versus enalapril monotherapy in patients with hypertension and type 2 diabetes
mellitus: a multicenter, randomized, double-blind, 24-week study. Clin Ther 2005;27:166-73.

240. Chen JH, Cheng JJ, Chen CY et al. Comparison of the efficacy and tolerability of telmisartan 40 mg vs. enalapril 10 mg in the treatment of mild-
to-moderate hypertension: a multicentre, double-blind study in Taiwanese patients. Int J Clin Pract Suppl 2004;145:29-34.

241. Schram MT, van Ittersum FJ, Spoelstra-de Man A et al. Aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or
lisinopril as initial choice in hypertensive type II diabetic individuals: effects on albumin excretion, endothelial function and inflammation in a double-blind,
randomized clinical trial. J Hum Hypertens 2005;19:429-37.

242. Izzo JL Jr, Weinberg MS, Hainer JW et al. Antihypertensive efficacy of candesartan-lisinopril in combination vs. up-titration of lisinopril: the
AMAZE trials. J Clin Hypertens (Greenwich) 2004;6:485-93.

243. Malacco E, Santonastaso M, Vari NA et al. Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril Study.
Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood
Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study. Clin Ther 2004;26:855-65.

244. Rosei EA, Rizzoni D, Comini S et al. Evaluation of the efficacy and tolerability of nebivolol versus lisinopril in the treatment of essential arterial
hypertension: a randomized, multicentre, double-blind study. Blood Press Suppl 2003;1:30-5.

245. Deary AJ, Schumann AL, Murfet H et al. Influence of drugs and gender on the arterial pulse wave and natriuretic peptide secretion in untreated
patients with essential hypertension. Clin Sci (Lond) 2002;103:493-9.

246. Ferrario CM, Smith RD, Brosnihan B et al. Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension. Am J Hypertens
2002;15:557-64.

247. Deary AJ, Schumann AL, Murfet H et al. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J
Hypertens 2002;20:771-7.

248. Sever PS, Chang CL. Discordant responses to two classes of drugs acting on the renin-angiotensin system. J Renin Angiotensin Aldosterone
Syst 2001;2:25-30.

41
249. Campese VM, Lasseter KC, Ferrario CM et al. Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive hypertensive
patients. Hypertension 2001;38:1342-8.

250. Midtvedt K, Hartmann A, Foss A et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients
treated with nifedipine as compared to lisinopril. Transplantation 2001;72:1787-92.

251. Midtvedt K, Hartmann A, Holdaas H et al. Efficacy of nifedipine or lisinopril in the treatment of hypertension after renal transplantation: a double-
blind randomised comparative trial. Clin Transplant 2001;15:426-31.

252. Stanton AV, Chapman JN, Mayet J et al. Effects of blood pressure lowering with amlodipine or lisinopril on vascular structure of the common
carotid artery. Clin Sci (Lond) 2001;101:455-64.

253. Midtvedt K, Ihlen H, Hartmann A et al. Reduction of left ventricular mass by lisinopril and nifedipine in hypertensive renal transplant recipients: a
prospective randomized double-blind study. Transplantation 2001;72:107-11.

254. Asberg A, Midtvedt K, Vassbotn T et al. Better microvascular function on long-term treatment with lisinopril than with nifedipine in renal transplant
recipients. Nephrol Dial Transplant 2001;16:1465-70.

255. Terpstra WF, May JF, Smit AJ et al. Long-term effects of amlodipine and lisinopril on left ventricular mass and diastolic function in elderly,
previously untreated hypertensive patients: the ELVERA trial. J Hypertens 2001;19:303-9.

256. McInnes GT, O'Kane KP, Istad H et al. Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed
combination with low dose hydrochlorothiazide in hypertensive patients. J Hum Hypertens 2000;14:263-9.

257. Neutel JM, Frishman WH, Oparil S et al. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Ther
1999;6:161-6.

258. Norton GR, Woodiwiss AJ, Hartford C et al. Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase
inhibitor, sampatrilat, in black hypertensive subjects. Am J Hypertens 1999;12:563-71.

259. Lacourciere Y. The incidence of cough: a comparison of lisinopril, placebo and telmisartan, a novel angiotensin II antagonist. Telmisartan Cough
Study Group. Int J Clin Pract 1999;53:99-103.

250. Fogari R, Zoppi A, Corradi L et al. Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive
patients. Br J Clin Pharmacol 1998;46:467-71.

261.I Paster RZ, Snavely DB, Sweet AR et al. Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-
converting enzyme inhibitors. Clin Ther. 1998 Sep-Oct;20(5):978-89.

262. Fogari R, Zoppi A, Corradi L et al. Sexual function in hypertensive males treated with lisinopril or atenolol: a cross over study. Am J Hypertens
1998;11:1244-7.

263. Wallis EJ, Ramsay LE, Hettiarachchi J. Combined inhibition of neutral endopeptidase and angiotensin-converting enzyme by sampatrilat in
essential hypertension. Clin Pharmacol Ther 1998;64:439-49.

264. Weir MR, Reisin E, Falkner B et al. Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin
converting enzyme inhibitor in obese hypertensive patients. TROPHY Study Group. Am J Hypertens 1998;11:914-20.

265. Ruddy TD, Fodor JG. Nisoldipine CC and lisinopril alone or in combination for treatment of mild to moderate systemic hypertension. Canadian
Nisoldipine CC Hypertension Trial Group. Cardiovasc Drugs Ther 1997;11:581-90.

42
266. Chan P, Lin CN, Tomlinson B et al. Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate
hypertension. Am J Hypertens 1997;10:743-9.

267. Nielsen FS, Rossing P, Gall MA et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic
nephropathy. Diabetes 1997;46:1182-8.

268. Vaisse B, Herpin D, Asmar R et al. Assessment of antihypertensive effect by blood pressure monitoring: applications to bisoprolol and lisinopril
in a double-blind study. J Cardiovasc Pharmacol 1997;29:612-7.

269. Agardh CD, Garcia-Puig J, Charbonnel B et al. Greater reduction of urinary albumin excretion in hypertensive type II diabetic patients with
incipient nephropathy by lisinopril than by nifedipine. J Hum Hypertens 1996;10:185-92.

270. Crepaldi G, Carraro A, Brocco E et al. Hypertension and non-insulin-dependent diabetes. A comparison between an angiotensin-converting
enzyme inhibitor and a calcium antagonist. Acta Diabetol 1995;32:203-8.

271. Lacourciere Y, Brunner H, Irwin R et al. Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study
Group. J Hypertens 1994;12:1387-93.

272. Os I, Bratland B, Dahlof B et al. Female preponderance for lisinopril-induced cough in hypertension. Am J Hypertens. 1994;7:1012-5.

273. Predel HG, Kramer HJ. Lisinopril versus slow release nifedipine in patients with essential hypertension: a multicentre study. J Hum Hypertens
1994;8:777-80.

274. Nielsen FS, Rossing P, Gall MA et al. Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic
nephropathy. Diabetes 1994;43:1108-13.

275. Weir MR, Fagan T, Chrysant S, et al. Comparison of the efficacy and tolerability of an angiotensin converting enzyme inhibitor (lisinopril) versus
a calcium channel antagonist (diltiazem SR) in the treatment of moderate to severe hypertension. J Hum Hypertens 1994;8:531-7.

276. Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-
Hydrochlorothiazide Group. Arch Intern Med 1994;154:737-43.

277. Cappuccio FP, Markandu ND, Singer DR et al. Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and
predictors of response. J Hypertens 1993;11:839-47.

278. Hart W, Clarke RJ. ACE inhibition versus calcium antagonism in the treatment of mild to moderate hypertension: a multicentre study. Ireland-
Netherlands Lisinopril-Nifedipine Study Group. Postgrad Med J 1993;69:450-5.

279. Anonymous. Randomised, double-blind crossover comparison of once-daily captopril and lisinopril in patients with mild to moderate
hypertension--a community-based study. Hunter Hypertension Research Group. Clin Exp Hypertens 1993;15:423-34.

280. Hart W. Lisinopril-hydrochlorothiazide combination compared with the monocomponents in elderly hypertensive patients. J Hum Hypertens
1991;5 Suppl 2:85-9.

281. Lang H. The results of a large multicentre study comparing low-dose lisinopril-hydrochlorothiazide with the monocomponents. J Hum Hypertens
1991;5 Suppl 2:73-6.

282. Graham RD. Treating mild-to-moderate hypertension: a comparison of lisinopril-hydrochlorothiazide fixed combination with captopril and
hydrochlorothiazide free combination. J Hum Hypertens 1991;5 Suppl 2:59-61.

43
283. Os I, Bratland B, Dahlof B et al. Lisinopril or nifedipine in essential hypertension? A Norwegian multicenter study on efficacy, tolerability and
quality of life in 828 patients. J Hypertens 1991;9:1097-104.

284. Frimodt-Moeller J, Poulsen DL, Kornerup HJ et al. Quality of life, side effects and efficacy of lisinopril compared with metoprolol in patients with
mild to moderate essential hypertension. J Hum Hypertens 1991;5:215-21.

285. Witchitz S, Serradimigni A. Lisinopril versus slow-release nifedipine in the treatment of mild to moderate hypertension: a multicentre study. The
Cooperative Study Group. J Hum Hypertens 1989;3 Suppl 1:29-33.

286. Gosse P, Dallocchio M, Gourgon R. ACE inhibitors in mild to moderate hypertension: comparison of lisinopril and captopril administered once
daily. French Cooperative Study Group. J Hum Hypertens 1989;3 Suppl 1:23-8.

287. Zachariah PK, Bonnet G, Chrysant SG et al. Evaluation of antihypertensive efficacy of lisinopril compared to metoprolol in moderate to severe
hypertension. J Cardiovasc Pharmacol 1987;9 Suppl 3:S53-8.

288. Morlin C, Baglivo H, Boeijinga JK et al. Comparative trial of lisinopril and nifedipine in mild to severe essential hypertension. J Cardiovasc
Pharmacol 1987;9 Suppl 3:S49-52.

289. Lacourciere A. A multicenter, randomized, double-blind study of the antihypertensive efficacy and tolerability of irbesartan in patients aged > or =
65 years with mild to moderate hypertension. Clin Ther 2000;22:1213-24.

290. Bainbridge AD, McFadyen RJ, Stark S, Lees KR, Reid JL. The antihypertensive efficacy of a low dose combination of ramipril and felodipine ER in
mild to moderate hypertension. Br J Clin Pharmacol 1993;36:323-30.

291. Poisson P, Bauer B, Schueler E, Rangoonwala B. Ramipril and felodipine: a comparison of the efficacy and safety of monotherapy versus
combination therapy. Curr Med Res Opin 1996;14:445-56.

292. Scholze J, Bauer B, Massaro J. Antihypertensive profles of ascending dose combinations of ramipril and felodipine ER. Clin Exp Hypertens
1999;21:1447-62.

293. Agodoa LY, Appel L, Bakris GL et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled
trial. JAMA 2001;285:2719-28.

294. Thijs L, Celis H, Kiowski W et al. Double-blind comparison of antihypertensive treatment with ramipril and piretanide, given alone or in
combination. J Cardiovasc Pharmacol 1995;26:33-8.

295. Genthon R. Study of the efficacy and safety of the combination ramipril 2.5 mg plus hydrochlorothiazide 12.5 mg in patients with mild-to-
moderate hypertension. ATHES Study Group. Int J Clin Pharmacol Res. 1994;14(1):1-9.

296. Homuth V, Faulhaber HD, Loose U et al. Usefulness of piretanide plus ramipril for systemic hypertension: a multicenter trial. Am J Cardiol
1993;72:666-71.

297. Weidmann P, Frank J, Graf W et al. [Monotherapy with the ACE-inhibitor ramipril or the calcium antagonist nitrendipine in essential
hypertension] Schweiz Med Wochenschr 1992;122:1497-503.

298. Carre A, Zannad F, Vasmant D. The French multicentre study of ramipril in ambulatory patients with mild-to-moderate hypertension. Clin Physiol
Biochem 1992;9:105-12.

299. Lenox-Smith AJ, Street RB, Kendall FD. Comparison of ramipril against atenolol in controlling mild-to-moderate hypertension. J Cardiovasc
Pharmacol 1991;18 Suppl 2:S150-2.

44
300. Bolzano K, Arriaga J, Bernal R et al. The antihypertensive effect of lisinopril compared to atenolol in patients with mild to moderate hypertension.
J Cardiovasc Pharmacol 1987;9 Suppl 3:S43-7.

301. Seedat YK, Veravia Y, Cohen JD et al. Evaluation of the antihypertensive effect of lisinopril compared to atenolol in black, mixed and Indian patients
with mild-to-moderate hypertension. Curr Ther Res 1987;41:852-64.

302. Reisin E, Weir MR, Falkner B et al. Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial.
Treatment in Obese Patients With Hypertension (TROPHY) Study Group. Hypertension 1997;30:140-5.

303. Yu H, Lin S, Liu G et al. T1198C polymorphism of the angiotensinogen gene and antihypertensive response to angiotensin converting enzyme
inhibitors. Hypertens Res 2005;28:981-6.

304. Neutel JM, Smith DH, Weber MA et al. Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension:
the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study. J Clin Hypertens (Greenwich) 2005;7:641-6.

305. Nalbantgil I, Nalbantgil S, Ozerkan F et al. The efficacy of telmisartan compared with perindopril in patients with mild-to-moderate hypertension.
Int J Clin Pract Suppl 2004;145:50-4.

306. Mallion JM, Chamontin B, Asmar R et al. Twenty-four-hour ambulatory blood pressure monitoring efficacy of perindopril/indapamide first line
combination in hypertensive patients: the REASON study. Am J Hypertens 2004;17:245-51.

307. Yu H, Zhang Y, Liu G. Relationship between polymorphism of the angiotensin-converting enzyme gene and the response to angiotensin
converting enzyme inhibition in hypertensive patients. Hypertens Res 2003;26:881-6.

308. Derosa G, Cicero AF, Ciccarelli L et al. A randomized, double-blind, controlled, parallel-group comparison of perindopril and candesartan in
hypertensive patients with type 2 diabetes mellitus. Clin Ther 2003;25:2006-21.

309. Radauceanu A, Virion JM, Boivin JM et al. Time-effect profile of antihypertensive agents assessed with trough/peak ratio, smoothness index and
dose omission: an ambulatory blood pressure monitoring study with trandolapril vs. quinapril. Fundam Clin Pharmacol 2002;16:545-54.

310. Malacco E, Piazza S, Carretta R et al. Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-
moderate hypertension. Int J Clin Pharmacol Ther 2002;40:263-9.

311. Pahor M, Franse LV, Deitcher SR et al. Fosinopril versus amlodipine comparative treatments study: a randomized trial to assess effects on
plasminogen activator inhibitor-1. Circulation 2002;105:457-61.

312. Asmar RG, London GM, O'Rourke ME et al. Improvement in blood pressure, arterial stiffness and wave reflections with avery-low-dose
perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001;38:922-6.

313. Fogari R, Zoppi A, Preti P et al. Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in
hypertensive postmenopausal women. Am J Hypertens 2001;14:921-6.

314. Pieniazek W, Dimitrow PP, Jasinski T. Comparison of the effect of perindopril and acebutolol on cerebral hemodynamics in hypertensive
patients. Cardiovasc Drugs Ther 2001;15:63-7.

315. Pool J, Kaihlanen P, Lewis G et al. Once-daily treatment of patients with hypertension: a placebo-controlled study of amlodipine and benazepril
vs amlodipine or benazepril alone. J Hum Hypertens 2001;15:495-8.

316. Chanudet X, De Champvallins M. Antihypertensive efficacy and tolerability of low-dose perindopril/indapamide combination compared with
losartan in the treatment of essential hypertension. Int J Clin Pract 2001;55:233-9.

45
317. Paterna S, Di Pasquale P, Parrinello G et al. Comparison of the effects of felodipine and cilazapril on exercise performance in patients with mild
to moderate hypertension. A crossover study. Drugs Exp Clin Res 2000;26:125-31.

318. Messerli FH, Oparil S, Feng Z. Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor
(benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension. Am J
Cardiol 2000;86:1182-7.

319. Bauduceau B, Mayaudon H, Dupuy O. Rilmenidine in the hypertensive type-2 diabetic: a controlled pilot study versus captopril. J Cardiovasc
Risk 2000;7:57-61.

320. Reneland R, Alvarez E, Andersson P et al. Induction of insulin resistance by beta-blockade but not ACE-inhibition: long-term treatment with
atenolol or trandolapril. J Hum Hypertens. 2000;14:175-80.

321. Mallion JM, Chastang C, Unger P. Efficacy and safety of a fixed low dose perindopril/indapamide combination in essential hypertension. A
randomised controlled study. Clin Exp Hypertens 2000;22:23-32.

322. Klein G. Combination therapy with felodipine and metoprolol compared with captopril and hydrochlorothiazide. German MC Study Group. Blood
Press 1998;7:308-12.

323. Ostman J, Asplund K, Bystedt T et al. Comparison of effects of quinapril and metoprolol on glycaemic control, serum lipids, blood pressure,
albuminuria and quality of life in non-insulin-dependent diabetes mellitus patients with hypertension. Swedish Quinapril Group. J Intern Med 1998;244:95-
107.

324. Scholze J, Zilles P, Compagnone D. Verapamil SR and trandolapril combination therapy in hypertension--a clinical trial of factorial design.
German Hypertension Study Group. Br J Clin Pharmacol 1998;45:491-5.

325. Leonetti G, Trimarco B, Collatina S et al. An effective approach for treating elderly patients with isolated systolic hypertension: results of an Italian
multicenter study with fosinopril. Am J Hypertens 1997;10:230S-235S.

326. DeQuattro V, Lee D. Fixed-dose combination therapy with trandolapril and verapamil SR is effective in primary hypertension. Trandolapril Study
Group. Am J Hypertens 1997;10:138S-145S.

327. Preston RA, Materson BJ, Reda DJ et al. Proteinuria in mild to moderate hypertension: results of the VA cooperative study of six
antihypertensive agents and placebo. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Clin Nephrol 1997;47:310-5.

328. Anonymous. Effects of verapamil SR, trandolapril, and their fixed combination on 24-h blood pressure: the Veratran Study. Am J Hypertens
1997;10:492-9.

329. Gottdiener JS, Reda DJ, Massie BM et al. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension:
comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation
1997;95:2007-14.

330. Roca-Cusachs A, Oigman W, Lepe L et al. A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily
losartan compared to twice-daily captopril in mild to moderate essential hypertension. Acta Cardiol 1997;52:495-506.

331. Pool JL, Cushman WC, Saini RK et al. Use of the factorial design and quadratic response surface models to evaluate the fosinopril and
hydrochlorothiazide combination therapy in hypertension. Am J Hypertens 1997;10:117-23.

332. Bouhanick B. Equivalent effects of nicardipine and captopril on urinary albumin excretion of type 2, non-insulin-dependent diabetic subjects with
mild to moderate hypertension. Therapie 1996;51:41-7.

46
333. Zannad F, Vaur L, Dutrey-Dupagne C et al. Antihypertensive effects of trandolapril and nitrendipine in the elderly: a controlled trial with special
emphasis on time effect profiles. J Hum Hypertens 1996;10:51-5.

334. Chrysant SG, Fagan T, Glazer R et al. Effects of benazepril and hydrochlorothiazide, given alone and in low- and high-dose combinations, on
blood pressure in patients with hypertension. Arch Fam Med 1996;5:17-24.

335. Nicaise J, Neveux E, Blondin P. Antihypertensive efficacy and safe use of once-daily sustained-release diltiazem in the elderly: a comparison
with captopril. The Dilcacomp Study Group. J Int Med Res 1995;23:244-53.

336. Romero R, Castellote E, Ocon J et al. Controlled multicenter study with quinapril, hydrochlorothiazide, and combination in patients with moderate
to severe hypertension. J Cardiovasc Pharmacol 1995;26:114-8.

337. Chen CH, Ting CT, Lin SJ et al. Different effects of fosinopril and atenolol on wave reflections in hypertensive patients. Hypertension
1995;25:1034-41.

338. Himmelmann A, Hansson L, Hansson BG et al. ACE inhibition preserves renal function better than beta-blockade in the treatment of essential
hypertension. Blood Press 1995;4:85-90.

339. Hansson L. Effects of angiotensin-converting enzyme inhibition versus conventional antihypertensive therapy on the glomerular filtration rate.
Cardiology 1995;86 Suppl 1:30-3.

340. Lenz T, Schulte KL, Wagner B et al. Quinapril, hydrochlorothiazide, and combination in patients with moderate to severe hypertension. Eur Heart
J 1994;15:940-6.

341. Canter D, Frank GJ, Knapp LE et al. Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design.
Quinapril Investigator Group. J Hum Hypertens 1994;8:155-62.

342. Starr JM, Whalley LJ, Inch S et al. A double-blind trial of captopril or bendrofluazide in newly diagnosed senile hypertension. Curr Med Res Opin
1994;13:214-21.

343. Pordy RC. Cilazapril plus hydrochlorothiazide: improved efficacy without reduced safety in mild to moderate hypertension. A double-blind
placebo-controlled multicenter study of factorial design. Cardiology 1994;85:311-22.

344. Leonetti G, Salvetti A. Effects of cilazapril and nitrendipine on blood pressure, mood, sleep, and cognitive function in elderly hypertensive
patients: an Italian multicenter study. J Cardiovasc Pharmacol 1994;24 Suppl 3:S73-7.

345. Meyer BH, Pauly NC. Double-blind comparison of the efficacy and safety of trandolapril 2 mg and hydrochlorothiazide 25 mg in patients with
mild-to-moderate essential hypertension. Investigator Study Group. J Cardiovasc Pharmacol 1994;23 Suppl 4:S77-80.

346. Lumme JA, Jounela AJ. Left ventricular mass, serum electrolyte levels and cardiac arrhythmias in patients with mild hypertension treated with
cilazapril or hydrochlorothiazide. Int J Cardiol 1993;42:71-8.

347. Materson BJ, Reda DJ, Cushman WC et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with
placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med 1993;328:914-21.

348. Hauf-Zachariou U, Widmann L, Zulsdorf B et al. A double-blind comparison of the effects of carvedilol and captopril on serum lipid concentrations
in patients with mild to moderate essential hypertension and dyslipidaemia. Eur J Clin Pharmacol 1993;45:95-100.

349. Moser M, Abraham PA, Bennett WM et al. The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate
essential hypertension: a multicenter study. Clin Pharmacol Ther 1991;49:322-9.

47
350. Havinga TK, ten Berge BS, May JF et al. Captopril compared to atenolol in mild to moderate hypertension in a randomized double-blind controlled
trial. Neth J Med 1991;38:13-7.

351. Thurston H, Desche P. Assessment of antihypertensive efficacy of perindopril: results of double-blind multicenter studies versus reference
drugs. J Cardiovasc Pharmacol 1991;18 Suppl 7:S45-9.

352. McGrath BP, Matthews PG, Louis W et al. Double-blind study of dilevalol and captopril, both in combination with hydrochlorothiazide, in patients
with moderate to severe hypertension. J Cardiovasc Pharmacol 1990;16:831-8.

353. Lacourciere Y, Poirier L, Boucher S et al. Comparative effects of diltiazem sustained-release and captopril on blood pressure control and plasma
lipoproteins in primary hypertension: a randomized, double-blind, crossover study. J Hum Hypertens 1990;4:553-6.

354. Saunders E, Weir MR, Kong BW et al. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting
enzyme inhibitor in hypertensive blacks. Arch Intern Med 1990;150:1707-13.

355. Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with
hypertension. N Engl J Med 1989;321:868-73.

356. Wolfson P, Abernethy D, DiPette DJ et al. Diltiazem and captopril alone or in combination for treatment of mild to moderate systemic
hypertension. Am J Cardiol 1988;62:103G-108G.

357. Rosenthal J, Haerlin R, Schafer N et al. Efficacy of urapidil in the management of essential hypertension. A comparisonwith captopril. Drugs.
1988;35 Suppl 6:147-55.

358. Muiesan G, Agabiti-Rosei E, Buoninconti R et al. Antihypertensive efficacy and tolerability of captopril in the elderly: comparison with
hydrochlorothiazide and placebo in a multicentre, double-blind study. J Hypertens Suppl 1987;5:S599-602.

359. Kayanakis JG, Baulac L. Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in
mild to moderate hypertension. Br J Clin Pharmacol 1987;23 Suppl 1:89S-92S. 159GG Messerli F, Frishman WH, Elliott WJ et al. Antihypertensive
properties of a high-dose combination of trandolapril and verapamil SR. Blood Press Suppl 2007;1:6-9.

360. Messerli F, Frishman WH, Elliott WJ et al. Antihypertensive properties of a high-dose combination of trandolapril and verapamil SR. Blood Press
Suppl 2007;1:6-9.

361. Narkiewicz K. Comparison of home and office blood pressure in hypertensive patients treated with zofenopril or losartan. Blood Press Suppl
2007;2:7-12.

362. Farsang C. Blood pressure control and response rates with zofenopril compared with amlodipine in hypertensive patients. Blood Press Suppl
2007;2:19-24.

363. Nilsson P. Antihypertensive efficacy of zofenopril compared with atenolol in patients with mild to moderate hypertension. Blood Press Suppl
2007;2:25-30.

364. Verdecchia P, Calvo C, Möckel V et al. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension. Blood
Press 2007;16:381-91.

365. Malacco E, Omboni S. Antihypertensive efficacy of zofenopril plus hydrochlorothiazide fixed combination for treatment in metabolic syndrome.
Adv Ther 2007;24:1006-15.

48
366. White WB, Cleveland JM, Rolleri RL. Utility of semiautomatic clinic and 24-h ambulatory blood pressure measurements to evaluate combination
therapy: the Ramipril-Hydrochlorothiazide Hypertension Trial. J Hum Hypertens 2008;22:559-68.

367. Mao G, Hong X, Xing H et al. Efficacy of folic acid and enalapril combined therapy on reduction of blood pressure and plasma glucose: a
multicenter, randomized, double-blind, parallel-controlled, clinical trial. Nutrition 2008;24:1088-96

368. Guerrero P, Fuchs FD, Moreira LM, et al.Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in patients with
uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp Hypertens 2008;30:553-64.

369. Miranda RD, Mion D Jr, Rocha JC et al. An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination
versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study. Clin Ther
2008;30:1618-28.

370. Palatini P, Jung W, Shlyakhto E et al. Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril:
results of a randomized, double-blind study. J Hum Hypertens. 2009 May 21. [Epub ahead of print]

371. Sabharwal NK, Swinburn J, Lahiri A et al. Effect of imidapril and nifedipine on left ventricular hypertrophy in untreated hypertension. Clin Drug
Investig 2005;25:367-75.

372. Palma-Gamiz JL, Pego M, Marquez E et al. A multicentre, 12-week study of imidapril and candesartan cilexetil in patients with mild to moderate
hypertension using ambulatory blood pressure monitoring. Clin Drug Investig 2007;27:407-17.

373. Palma Gamiz JL, Pego M, Contreras EM et al. A twelve-week, multicenter, randomized, double-blind, parallel-group, noninferiority trial of the
antihypertensive efficacy and tolerability of imidapril and candesartan in adult patients with mild to moderate essential hypertension: the Iberian Multicenter
Imidapril Study on Hypertension (IMISH). Clin Ther 2006;28:2040-51.

374. van der Does R, Euler R. A randomized, double-blind, parallel-group study to compare the anti-hypertensive effects of imidapril and nifedipine in
the treatment of mild-to-moderate essential hypertension. J Int Med Res 2001;29:154-62.

375. Dews I, VandenBurg M. A 24-week dose-titration study of the angiotensin-converting enzyme inhibitor imidapril in the treatment of mild-to-
moderate essential hypertension in the elderly. J Int Med Res 2001;29:100-7.

376. Agabiti-Rosei E, Ambrosioni E, Pirelli A et al. Efficacy and tolerability of moexipril and nitrendipine in postmenopausal women with hypertension.
MADAM study group. Moexipril as Antihypertensive Drug After Menopause. Eur J Clin Pharmacol 1999;55:185-9.

377. Stimpel M, Koch B, Weber MA. Comparison between moexipril and atenolol in obese postmenopausal women with hypertension. Maturitas
1998;30:69-77.

378. Stimpel M, Koch B, Oparil S. Antihypertensive treatment in postmenopausal women: results from a prospective,randomized, double-blind,
controlled study comparing an ACE inhibitor (moexipril) with a diuretic (hydrochlorothiazide). Cardiology 1998;89:271-6.

379. White WB, Koch B, Stimpel M. Usefulness of moexipril and hydrochlorothiazide in moderately severe essential hypertension. Am J Ther
1997;4:123-9.

380. Chrysant SG, Stimpel M. A comparison of the antihypertensive effectiveness of a combination of moexipril or sustained-release verapamil with
low dose hydrochlorothiazide. J Clin Pharmacol. 1996;36:701-6.

381. Persson B, Stimpel M. Evaluation of the antihypertensive efficacy and tolerability of moexipril, a new ACE inhibitor, compared to
hydrochlorothiazide in elderly patients. Eur J Clin Pharmacol 1996;50:259-64.

49
382. Abernethy DR, Fox AA, Stimpel M. Moexipril in the treatment of mild to moderate essential hypertension: comparison with sustained-release
verapamil. J Clin Pharmacol 1995;35:794-9.

383. Chrysant SG, Fox AA, Stimpel M. Comparison of moexipril, a new ACE inhibitor, to verapamil-SR as add-on therapy to low dose
hydrochlorothiazide in hypertensive patients. Am J Hypertens 1995;8:418-21.

384. Mroczek WJ, Stimpel M. A double-blind evaluation of moexipril versus hydrochlorothiazide in hypertension. Adv Ther 1996;13-79-87.

385.. Consensus trial study group. Effect of enalapril on mortality in severe congestive heart failure. Results of the cooperative North Scandinavian
Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35.

386. SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J
Med 1991;325:293-302.

387. Jong P, Yusuf S, Rousseau MF et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic
dysfunction: a follow-up study. Lancet 2003;361:1843-8.

388. Swedberg K, Held P, Kjekshus J et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction.
Results of CONSENSUS II. N Engl J Med 1992;327:678-84.

389. Pfeffer MA, Braunwald E, Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial
infarction. N Engl J Med 1992;327:669-77

390. Tokmakova MP, Skali H, Kenchaia S et al. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme
inhibition after myocardial infarction. The SAVE study. Circulation 2004;110:3667-73.

391. Acute infarction ramipril efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity in survivors of acute myocardial infarction
with clinical evidence of heart failure. Lancet 1993;342:821-8.

392. Gruppo Italiano per lo studio della soprawivenza nellínfarcto myocardio. GISSI-3: effects of lisinopril and transdermal glyceryltrinitrate singly and
togther on 6 week mortaility and ventricular function after acute myocardial infarction. Lancet 1994;343:1115-22.

393. Packer MA, Poole_wilson PA, Armstrong PW et al. Comparative effects of low and high doses of the ACE inhibitor lisniopril on morbidity and
mortality in chronic heart failure. Circulation 1999;100:2312-8.

394. Colloborative Group. ISIS 4: a randomised factorial trial assessing early oral captopril, oral mononitrate and intravenous magnesium suphate in
58,050 patients with suspected myocardial infarction. Lancet 1995;18:669-85.

395. Kober L, Torp-Pedersen C, Carlsen JE et al. A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left
ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

396. Buch P, Rasmussen S, Abildstrom SZ et al. The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and
hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J 2005;26:145-52.

397. Anonymous. ACE inhibitors: increasingly applicable in haert failure. Drug Ther Persp 1994;3:no7: 6-9.

398. Ferrari R; Perindopril and Remodeling in Elderly with Acute Myocardial Infarction Investigators. Effects of angiotensin-converting enzyme
inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute
Myocardial Infarction (PREAMI) Study. Arch Intern Med 2006;166:659-66.

50
399. Ambrosioni E, Borghi C, Magnani B. The effect of the ACE inhibitor on mortality and morbidity after anterior myocardial infarction. N Engl J Med
1995;332:80-5.

400. Latini R, Maggioni AP, Flather M et al. ACE inhibitor use in patients with myocardial infarction. Circulation 1995;92:3132-7.

401. Wienbergen H, Schiele R, Gitt AK et al. Impact of ramipril versus other ACE inhibitors on outcome of unselected patients with ST-elevation acute
myocardial infarction. Am J Cardiol 2002;90:1045-9.

402. Pilote L, Abrahamovicz M, Rodriguez E et al. Mortality rates in elderly patients who take different ACE inhibitors after acute myocardial infarction:
a class effect? Ann Intern Med 2004;141:102-12.

403. Hennesy S, Kimmel SE et al. Is improved survival a class effect of ACE inhibitors? (Editorial) Ann Intern Med 2004;141:157-9.

404. Borghi C, Marino P, Zardini P et al. Post Acute Myocardial Infarction. The fosinopril in acute myocardial infarctio study (FAMIS). Am J Hypertens
1997;10:247S-54S.

405. Hall AS, Murray GD, Ball SG. Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction:
AIRE extension (AIREX) study. Lancet 1997;349:1493-7.

406. Torp-Pedersen C, Kober L, TRACE study group. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular
function after acute myocardial infarction. Lancet 1999;354:9-12.

407. Bungard TJ, MaAlister FA, Johnson JA et al. Underutilisation of ACE inhibitors in patients with congestive heart failure. Drugs 2001;61:2021-
2033.

408. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.

409. Bosch J, Yusuf S, Pogue J et al. Use of ramipril in preventing stroke: double blind randomised trial. Br Med J 2002;324:699-701.

410. Lonn E, Roccaforte R, Dagenais G et al. Effect of long-term therapy with ramipril in high-risk women. J Am Coll Cardiol 2002;40:693-702.

411. Taylor R. Conundrum of the HOPE study. Time of taking ramipril may account for lack of relation between blood pressure and outcome. BMJ
2003;327:681-2.

412. Bosch J, Yusuf S. Conundrum of the HOPE study. Auhor’s reply. BMJ 2003;327:682.

413. Guerin AP, Blacher J, Pannier B et al. Impact of aortic stiffness on survival of patients in end-stage renal failure. Circulation 2001;103:987-92.

414. Progress Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 individuals with previous
stroke of transient ischaemic attack. Lancet 2001;358:1033-41.

415. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease:
randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2003;362:782-8.

416. ADVANCE collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in
patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829-40.

51
417 Dahlof B, Sever PS, Poulter NR et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as
required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906.

418 Poulter NR, Wedel H, Dahlof B et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-
Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet 2005;366:907-13.

419. Oostenga M, Voors AA, Pinto YM et al. Effects of quinapril on clinical outcome after CABG. Am J Cardiol 2001;87:542-6.

420. Pitt B, O’Neill B, Feldman R et al. The QUIET trial. Am J Cardiol 2001;87:1058-63.

421. Maschino G, Alberti D, Janin G et al. Effect of the angiotensin converting enzyme inhibitor benazepril on the progression of chronic renal failure.
N Engl J Med 1996;334:939-45.

422. Ravid M, Brosh D, Levi Z et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2
diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-8.

423. Nielsen FS, Rossing P, Gall MA et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic
nephropathy. Diabetes 1997;46:1182-8.

424. Schnack C, Hoffmann W, Hopmeier P et al. Renal and metabolic effects of 1-year treatment with ramipril or atenolol in NIDDM patients with
microalbuminuria. Diabetol 1996;39:1611-6.

425. The GISEN group. Randomized placebo-controlled trial of effect of ramipril on decline of glomerular filtration rate and risk of terminal renal failure
in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857-63.

426. Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN
follow-up trial. Lancet 1998;253:1252-6.

427. Cordonnier DJ, Zaoui P, Halami S. Role of ACE inhibitors in patients with diabetes mellitus. Drugs 2001;61:1883-92.

428. Anonymous. ACE inhibitors prove beneficial for an increasing range of complications of diabetes mellitus. Drugs Ther Perspect 2002;18(6):11-13.

429. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of ACE inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62.

430. Heinig RE. What should the role of ACE inhibitors be in the treatment of diabetes? Lessons from HOPE and MICRO_HOPE. Diab Obes Metab
2002;4 suppl. 1:S19-S25.

431. Chiurchiu C, Remuzzi G, Ruggenenti P. ACE inhibition and renal protection in nondiabetic patients: the data of the meta-analyses. J Am Soc
Nephrol 2005:16:S58-63.

432. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazepril for advanced chronic renal insuffiency. N Engl J Med 2006;354:131-40.

433. Agodoa LY, Appel L, Bakris GL et al. Effect of ramipril vs amlodipine on renal outomes in hypertensive nephrosclerosis. JAMA 2001;285:2774-6.

434. Muirhead N, Feagan BF, Mahon J et al. The effects of valsartan and captopril on reducing microalbuminuria in patients with type 2 diabetes
mellitus: a placebo-controlled trial. Curr Ther Res 1999;60:650-60.

435. Li PK, Chow KM, Wong TY et al. Effects of an ACE inhibitor on residual renal function in patients receiving peritoneal dialysis. Ann Intern Med
2003;139:105-12.

52
436. Katayama S, Kikkawa R, Isogai S et al. Effect of captopril or imidapril on the progression of diabetic nephropathy in Japanese with type 1
diabetes mellitus: a randomized controlled study (JAPAN-IDDM). Diabetes Res Clin Pract 2002 ;55:113-21.

437. Kvetny J, Gregersen G, Smith Pedersen R. Randomized placebo controlled trial of perindopirl in normotensive, normoalbuminuric patients with
type 1 diabetes mellitus. Q J Med 2001;94:88-94.

438. Nankervis A, Nichols K, Klimartin G et al. Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year
okacebo-controlled biopsy study. Metab 1998;47:12-5.

439. Efrati S, Zaidenstein R, Dishy V et al. ACE inhibitors and survival of hemodialysis patients. Am J Kidney Dis 200240:1023-9.

440. Ruggenenti P, Fassi A, Ilieva AP et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-51.

441. Strippoli GF, Craig M, Deeks JJ et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality
and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004;329:828. Epub 2004 Sep 30:1-11.

442. Barnett AH, Bain SC, Bouter P et al. Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus
converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952-61.

443. Sihm I, Thygesen K, Krusell LR et al. Long-term renal and cardiovascular effects of antihypertensive treatment regimens based upon isradipine,
perindopril and thiazide. Blood Press 2000;9:346-54.

444. Hansson L, Lindholm LH, Niskanen L et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on
cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomised trial. Lancet 1999;353:611-6.

445. Hansson L, Lindholm LH, Ekbom T et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular morbidity and
mortality the Swedish Trial in Old Patients with hypertension –2 study. Lancet 1999;354:1751-6.

446. Messerli FH. ALLHAT, or the soft science of the seconday endpoint. Ann Intern Med 2003;139:777-80.

447. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine and lisinopril.
JAMA 2005;293:1595-1608.

448. Wing LM, Reid CM, Ryan P et al. A comparison of outcomes with ACE inhibitors and diuretics for hypertension in the elderly. N Engl J Med
2003;348:583-92.

449. Dream Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006;355:1551-62.

450. Alabbadi I, Crealey G, Scott M et al. Impact of Modified System of Objectified Judgement Analysis (SOJA) methodology on prescribing costs of
ACE inhibitors. Clin Drug Investig. 2006;26(9):485-94.

4510. Scott M, Timoney M, Mairs J, Crealey G, Al Abaddi I, Brenninkmeijer R, Janknegt R, McElnay J. Safe Therapeutic Economic Pharmaceutical
Selection (STEPS): development, introduction and use in Northern Ireland. Expert Opin Pharmacother 2007;8 Suppl 1:S57-63.

53
 Table 1
Selection criteria for ACE inhibitors

Selection criterion Mean relative weight

Formulations 20
Number of registrations 20
Variability of bioavailability 40
Interactions 40
Trough to peak ratio 20
Efficacy 250
Side-effects 150
Dosage frequency 100
Documentation 100
Effect on clinical endpoints 260

54
 Table 2
Pharmacokinetics of ACE inhibitors

Drug Prodrug Bioavailabilit Effect of foodReduction of Half life (hours)

y bioavailability when taken
with food
Captopril - 75-85% 25-50% 2-3
Cilazepril + 40-75% 20% 30-50
Enalapril + 60-70% -- 11
Fosinopril + 36% -- 11
Imidapril + 42% -- 8-14
Lisinopril - 25-30% -- 12
Moexipril + 40% 40% 10
Perindopril + 80% 30% 25
Quinapril +* 60% -- 3
Ramipril + 50-60% -- 13-17
Trandolapril + 40-60% -- 16-24

From references: 9-47

* Quinapril also has ACE inhibitory effects, comparable to captopril

55
 Table 3
Trough/peak ratios of ACE inhibitors for diastolic blood pressure calculated from 24
hour blood pressure monitoring

Drug Number Dose Ratio Score

of range (%)
patients (mg)
Captopril 52 25-100 bid 25 20%
Cilazepril 85 2.5-5 59-62 60%
Enalapril 127 5-20 40-79 60%
Fosinopril 64 10-40 32-44 40%
Imidapril 91 2.5-20 63-84 80%
Lisinopril 175 10-80 30-70 40%
Moexipril 34 7.5-15 <10 0%
Perindopril 182 4-8 34-100 100%
Quinapril 49 10-40 30-40 20%
Ramipril 84 5-10 50-63 60%
Trandolapril 84 1-2 50-100 100%

56
 Table 4
Double-blind comparative studies between ACE inhibitors in hypertension

Dose Type N DBP Response Reference

(mg) Reduction (%)
(mm Hg) #
Captopril 25-50 bid MM 62 7 26 51
Cilazepril 2.5-5 qd 132 8 37
Captopril 25-50 bid MM 15 13 63 52
Cilazepril 2.5-5 qd 15 17 83
Captopril 50-100 qd MM 66 16 78 53
Enalapril 10-20 qd 69 14 79
Captopril 25-100 bid MM 75 8 54
Enalapril 5-20 bid 74 11
Captopril 25-50 tid MS 82 16 60 55
Enalapril 5-20 bid 79 16 66
Captopril 25-100 tid MS 16 16 75 56
Enalapril 5-20 bid 16 18 75
Captopril 25-50 bid MS 34 21 97 57
Enalapril 20-40 qd 35 26 100
Captopril 25-50 bid MM 28 9 46 58
Imidapril 5-10 qd 29 10 48
Captopril 25-100 bid MM 45 15 59
Lisinopril 10-40 45 17
Captopril 25-100 bid MM 35 6 60
Lisinopril 10-40 qd 35 10
Captopril 50-100 bid MM 63 10 81 61
Lisinopril 20-40 qd 54 12 76
Captopril 12.5-50 MM 46 12 72 62
Lisinopril bid 45 16 80
10-40 qd

57
Captopril 50 qd MM 154 12 67 63
Lisinopril 20 qd 150 14 80
Captopril 25-50 bid MM 54 9 60 64
Moexipril 7.5-15 qd 105 10 65
Captopril 25-50 bid MM 79 12 57 65
Perindopril 4-8 qd 80 17 75
Captopril 25-50 bid MM 54 14 47 66
Perindopril 4-8 qd 54 14 67
Captopril 12.5-50 MM 19 14 53 67
Quinapril bid 21 18 62
10-40 qd
Captopril 25-100 bid MS 84 15 75 68
Quinapril 10-40 bid 88 19 78
Captopril 25-75 bid MM 102 9 55 69
Quinapril 10-40 qd 98 8 52
Quinapril 10-20 bid 102 9 62
Captopril 25-100 bid S 48 10 44 70
Quinapril 5-20 bid 40 12 58
Captopril 50 bid MM 111 14 65 71
Ramipril 10 qd 121 15 65
Captopril 50 bid MM 30 12 84 72
Ramipril 5 qd 30 8 71
Captopril 50 bid MM 83 10 44 73
Trandolapril 4 qd 86 14 61
Cilazepril 0.5-4 qd MM 157 70 74
Enalapril 2.5-20 qd 153 68
Enalapril 5-10 qd MM 116 10 52 75
Fosinopril 10-20 qd 115 9 50
Enalapril 10-20 qd MM 97 11 76
Fosinopril 20-40 qd 98 11
Enalapril 5-10 qd MM 115 13 66 77
Imidapril 5-10 qd 108 13 71
Enalapril 5-10 qd MM 177 13 74 78

58
Imidapril 5-10 qd 175 13 75
Enalapril 5-40 qd MM 48 16 98 79
Lisinopril 10-40 qd 49 17 96
Enalapril 10 qd MM 14 6 80
Lisinopril 10 qd 14 7
Enalapril 10 qd MM 36 7 42 81
Lisinopril 10 qd 37 11 70
Enalapril 20 qd MM 29 9 82
Lisinopril 20 qd 29 7
Enalapril 5-20 qd MM 125 12 56 83
Perindopril 2-8 qd 125 13 69
Enalapril 10-20 MM 81 16 56 84
Perindopril 4-8 80 15 65
Enalapril 10-20 MM 41 co 8 85
Perindopril 4-8 7
Enalapril 10-40 qd MM 130 16 80 86
Quinapril 10-40 qd 128 14 90
Enalapril 10-40 qd MM 27 17 67 87
Quinapril 10-40 qd 27 19 78
Enalapril 10-40 qd MM 26 17 88
Quinapril 10-40 qd 23 17
Enalapril 10-20 qd MM 86 11 69 89
Ramipril 5-10 qd 88 11 55
Enalapril 10 qd MM 48 16 58 90
Enalapril 10 qd 49 17 63
Ramipril 5 qd 51 16 71
Ramipril 10 qd 45 17 71
Enalapril 5 qd MM 26 5 91
Enalapril 10 qd 26 7
Enalapril 20 qd 27 7
Ramipril 2.5 qd 28 5
Ramipril 5 qd 26 6
Ramipril 10 qd 25 8

59
Enalapril 10 qd MM 30 co 10 92
Ramipril 2.5 qd 12
Enalapril 16 qd MM 20 15 60 93
Lisinopril 13 qd 20 13 65
Quinapril 15 qd 20 14 75
Ramipril 3 qd 20 12 75
Enalapril 2.5-10 qd MM 155 45 94
Trandolapril 0.5-2 qd 131 41
Enalapril 20 qd MM 78 76 95
Trandolapril 4 qd 81 57
Enalapril 2.5-20 qd MM 37 8 96
Trandolapril 0.4-4 qd 34 8
Lisinopril 10 qd MM 21 10 97
Quinapril 10 qd 21 20
Lisinopril 2.5-20 MM 39 16 75 98
Quinapril 5-40 36 14 69
Lisinopril 5 qd MM 55 2 0 99
Lisinopril 10 qd 34 11 49
Ramipril 2.5 qd 38 15 67

Legends to Table 4

MM mild to moderate hypertension

MS moderate to severe hypertension
S severe hypertension

#Various definitions were used for the percentage responders, such as reaching a diastolic
blood of lower dan 90mmHg or a lowering of the diastolic blood pressure by at least 10mmHg.

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 Table 5
Documentation

Drug Studies Patients Years Patient Score

Days
(millions)
Captopril >20 >1000 >10 >100 100%
Cilazepril >20 >1000 >10 >100 100%
Enalapril >20 >1000 >10 >100 100%
Fosinopril 8 >1000 >10 >100 85%
Imidapril 9 >1000 >10 >100 86%
Lisinopril >20 >1000 >10 >100 100%
Moexipril 10 >1000 >10 >100 88%
Perindopril >20 >1000 >10 >100 100%
Quinapril >20 >1000 >10 >100 100%
Ramipril >20 >1000 >10 >100 100%
Trandolapril 19 >1000 >10 >100 99%

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 Table 6
Documented clinical effects of ACE inhibitors

Drug Myocardial Mortality Morbidity Diabetics Non- Hypertensio Score

Infarction High risk High risk diabetics n
Captopril + + + + 70%
Cilazepril 0%
Enalapril + + + 60%
Fosinopril + 10%
Imidapril 0%
Lisinopril + + + +/- 60%
Moexipril 0%
Perindopril + + + +/- 60%
Quinapril + 15%
Ramipril + + + + + + 100%
Trandolapril + 10%

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 Table 7
SOJA score for ACE inhibitors in hypertension

Drug Form Ind Var Int TPR Eff Side Dos Doc Clin Score
Captopril 16 17 35 32 4 150 105 80 100 182 721
Cilazepril 12 11 28 32 12 175 105 100 100 0 575
Enalapril 16 11 30 36 12 175 105 90 100 156 731
Fosinopril 12 11 30 36 8 175 105 100 85 26 588
Imidapril 12 8 26 36 16 175 105 100 86 0 564
Lisinopril 16 17 25 36 8 175 105 100 100 156 738
Moexipril 12 8 26 32 0 175 105 100 88 0 546
Perindopril 16 14 32 32 20 175 105 100 100 156 750
Quinapril 16 11 28 36 4 175 105 100 100 39 614
Ramipril 12 20 36 36 12 175 105 100 100 260 856
Trandolapril 12 11 37 36 20 175 105 100 99 26 621

63