This document summarizes a study that reviewed evidence on the effectiveness of different ACE inhibitors (ACEis) for treating essential hypertension. The study found: 1) No trials directly compared the main ACEis prescribed in England (ramipril, lisinopril, perindopril, enalapril). 2) Lisinopril is the only ACEi shown to be as effective as thiazide diuretics for outcomes like mortality, though it was inferior for stroke prevention. 3) Evidence suggests ramipril may be better than placebo for hypertension treatment and prevention, but the evidence is indirect. 4) Perindopril showed no benefit over placebo for hypertension treatment or

1. Are all ACE inhibitors ace in treatment of essential hypertension?
Nik Manassiev, Josep Vidal-Alaball, Benjamin Porter
Nik Manassiev, Goodrest Croft Surgery, 1 Goodrest Croft, Yardley Wood, Birmingham, UK;
Josep Vidal-Alaball, Department of Primary Care and Public Health, School of Medicine,
Cardiff University, Wales, UK; Benjamin Porter, FY1, Worcestershire Royal Hospital,
Charles Hastings’s Way, Newtown Road, Worcester, WR5 4DD
Abstract: ACE inhibitors (ACEi) are widely recommended and used for treatment of
hypertension. There are number of ACEi to choose from. It make sense to use the one that
that has been shown to be most effective in prevention of serious hypertension complication
such as stroke. If there is more that one choice it make sense to use the one with lower
acquisition cost. In this paper we are looking into the evidence for using ACEi as a first line
treatment for hypertension and to try and find out which ACEi has been associated with the
best clinical outcome. We found no long-term trials comparing ACEi and placebo for
treatment of hypertension. We found no head-to-head studies directly comparing the main
four ACEi’s, commonly prescribed in England. On the basis of the evidence presented,
lisinopril is the only commonly used ACEi that can be considered a first line treatment for
hypertension. There is some evidence for ramipril, although this is not as strong. There is no
substantial evidence of the effectiveness of enalapril and in the presence of a proven treatment
(lisinopril) it makes no sense to use it for the treatment of hypertension. There is no evidence
that perindopril improves mortality or stroke rate in patients with hypertension. Perindopril is
no better than placebo for treatment of patients with previous TIA or stroke.
Background.
Hypertension is a common condition and its prevalence increases with age (1, 2). It has been
shown that hypertension is a risk factor for stroke, myocardial infarction (MI), renal failure,
congestive heart failure, and dementia. The treatment of hypertension leads to decreased
incidence of cardiovascular events and prolongs life (3). The association between stroke and
hypertension is stronger than that of coronary vascular disease and hypertension (4). It is
currently recommended that blood pressure should be treated and the lower the blood
pressure, the better (5). For patients over 55 years old (the majority of hypertensive patients)
treatment with thiazide/thiazide type diuretic or dihydropiridine calcium channel blocker is
recommended, adding an Angiotensin Converting Enzyme inhibitor (ACEi) if a second drug
is necessary. For patients younger than 55 years of age initial treatment with an ACEi is
recommended (5,6). ACEi’s (perindopril and ramipril) are also recommended by the Royal
College of Physicians for secondary prevention of stroke (7). Previous literature has
concluded that the effect of ACEi’s on blood pressure and stroke is a ‘class effect’ (6).
In England in 2006 30.1 million prescriptions were issued for ACEi’s. The most commonly
used ACEi’s were ramipril (39.8%), lisinopril (25.2 %), perindopril (18.7%) and enalapril
(9.9%). Together, these accounted for 93.6% of all ACEi’s prescribed in 2006. Between 2002
and 2006 the prescription of these ACEi’s, as percentage of the total, increased with different
pace depending on the preparations; whilst the usage of perindopril increased by 140% and
ramipril by 111%, lisinopril only showed a 22% increase with enalapril decreasing in usage
by 13%. (8)

2. In this paper we examine whether the most commonly prescribed ACEi’s in England have
similar effects regarding treatment of hypertension and reducing the risk of stroke.
Methods:
We searched Medline and Embase from 1985 onwards and searched all the relevant reviews,
guidelines, policy statements and recommendations for references. We also wrote to
manufacturers of ACEi’s asking for detailed information. We looked for randomised
controlled trials (RCT) published in English. We retrieved all relevant original publications
and tried to establish if all four of the most commonly prescribed ACEi’s in the England were
equally effective. The inclusion criteria were: 1) random allocation of patients to either an
ACEi or placebo 2) random allocation of patients to regimens based on different classes of
blood pressure lowering drugs that included an ACEi.
Trials that included patients who were selected mainly on the basis of high blood pressure,
diabetes mellitus, coronary heart disease, cerebrovascular disease, peripheral vascular disease
or renal disease were included. Trials that selected patients mainly on the basis of acute MI or
heart failure were not included, as often they did not report the effects of treatment separately
for hypertensive and non-hypertensive patients or the report is incomplete. Trials were
required to have at least 250 patients per group with a minimum duration of at least one year.
Trials were required to report at least total mortality, stroke incidence and MI incidence.
Results:
1. Ramipril
No RCT comparing ramipril with placebo for treatment of hypertension and satisfying the
inclusion criteria was identified.
We found one study, the HOPE study (9), that compared ramipril with placebo in patients
older than 55 with high risk for cardiovascular disease. The study randomised 9297 patients,
47% of them had hypertension and 11% had stroke on enrolment. The mean age of the
participants was 66 years with a mean follow-up of 5 years. There were significant reductions
in the rates of death of any cause (12.2% vs. 10.4%; p=0.005), death of cardiovascular causes
(8.1% vs. 6.1%; p<0.001), MI (12.3% vs. 9.9%; p<0.001) and stroke (3.9% vs. 3.4%;
p<0.001) in the group receiving ramipril. There were a number of pre-planned subgroup
analyses showing that ramipril was effective in decreasing events in patients with and without
hypertension, and with and without stroke at baseline.
2. Perindopril
There were no RCTs comparing perindopril with placebo that satisfied our inclusion criteria.
We found one paper, the PROGRESS trial (10), comparing perindopril, indapamide and
placebo in the secondary prevention of stroke. It enrolled 6105 participants and randomised
them as follows: 1770 to peridopril and indapamide, 1771 to double placebo, 1281 patient to
perindopril and 1280 to single placebo. 40% of the patients had a history of hypertension. The
mean age of the patients was 64 years and the mean follow-up was 3.9 years. Treatment with
perindopril lead to a reduction in blood pressure of 5/3mmHg compared with the placebo

3. group. There was no difference in the occurrence of stroke (157 [n=1281] vs. 165 [n=1280];
p>0.6) or major cardiovascular events (227 [n=1281] vs. 237 [n=1280]; p>0.6) between the
perindopril and placebo groups. Perindopril was no more effective than placebo in both
hypertensive and non-hypertensive patients at baseline. No effect on death rates was reported,
presumably because there was none.
The widely quoted ASCOT trial (11) tested amlodipine or a combination of amlodipine and
perindopril versus atenolol or a combination of atenolol and bendrofluazide. The way the
study reported its finding does not allow any conclusions to be drawn about the effects of
perindopril on hypertension.
The EUROPA study (12) compared perindopril, 8 mg per day, with placebo in patients with
stable coronary artery disease. In this study only patients with evidence of coronary artery
disease were recruited. 6110 of the study participants received perindopril and 6108 received
placebo. The mean age of the patients was 60 years and the mean follow-up period was 4.2
years. 27 % of the patients (1650 in the treatment and 1662 in the placebo group) had
hypertension (blood pressure >190/95 or receiving antihypertensive treatment). Treatment
with perindopril resulted in decrease of 5/2 mmHg in blood pressure in comparison with
placebo treatment. Although the study reported that perindopril treatment was associated with
a significant reduction in the combined end point of cardiovascular mortality, non-fatal MI
and resuscitated cardiac arrest (8% vs. 9.9%; p=0·0003) in patients with stable coronary
artery disease and without heart failure or notable hypertension, there was no significant
difference in reducing total mortality (6.1% vs. 6.9%; p=0.1) or stroke (1.6% vs. 1.7%)
between treatment and placebo group respectively.
3. Lisinopril
We were unable to find any studies comparing lisinopril with placebo in the treatment of
hypertension.
One large randomised controlled study, the ALLHAT (13) trial, compared lisinopril (9054
patients) with chlorthalidone (15225 patients) and amlodipine (9048 patients) for the
treatment of hypertension. The mean patient age was 67 years with a mean follow up of 4.9
years. The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal
MI analysed by intention to treat. Secondary outcomes were all-cause mortality, fatal and
nonfatal stroke, combined CHD and combined cardio vascular disease (CVD). 23% of
patients had a history of MI or stroke, and 36% were diabetic. There were a number of sub-
analyses conducted. The results showed that there was no difference between lisinopril and
chlorthalidone for the primary outcome or for the secondary outcomes of all-cause mortality
and combined CHD. The lisinopril group had a 15% higher risk of stroke and 10% higher risk
of combined CVD, both statistically significant (p=0.02 and p=<0.001 respectively). The
authors concluded that thiazide-type diuretics were superior to ACEi’s in preventing CVD
and should be used as the first step in the treatment of hypertension.
One Swedish study conducted in 1999 (14)compared the ACEi’s lisinopril or enalapril to
conventional treatment (β-blocker and/or hydrochlorothyazide) or a calcium antagonist
(felodipine or isradipine). The mean age of the patients was 76 years and the mean length of
follow up was 4.5 years. The study randomised 2208 to the ACEi group, 2213 to conventional
drugs group and 2196 to the calcium antagonist group. There was no statistically significant

4. difference in total mortality, cardiovascular mortality, MI or stroke between treatment groups.
The study did not report the results according to individual treatment agents and therefore it is
not possible to draw any conclusions about the individual effects of lisinopril.
4. Enalapril
We did not find a randomised control trial meeting our inclusion criteria that compared
enalapril and placebo for the treatment of hypertension.
The Swedish study (14), mentioned previously, reported that lisinopril and enalapril were
equivalent to β-blockers, diuretics or calcium antagonists in treating hypertension. However,
the results were not reported for individual medications and therefore it was not possible to
draw any conclusion about the effect of enalapril.
A further study (15) randomised 3044 patients to receive an ACEi and 3039 to receive a
diuretic. The mean age of the participants was 72 years and the follow-up lasted a median of
4.1 years. The patients were relatively low risk, with only 8% having CHD, 5%
cerebrovascular disease and 7% being current smokers. The recommended treatment agents
were enalapril for the ACEi group and hydrochlorothiazide for the diuretic group. However,
the choice of agent was left to the individual doctor. There was no difference in all cause
mortality (1.6% and 1.7%; p=0.27,), and stroke (0.92% and 0.88%; p=0.91) between the
ACEi group and the diuretic group respectively. There was a statistically significant 32%
reduction in the rate of nonfatal MI in the ACEi group compared to the diuretic group
(adjusted hazard ratio, 0.68; p=0.05). The authors did not publish how many patients were on
the different types of ACEi and diuretic and it is therefore not possible to draw any
conclusions about enalapril.
Conclusions:
We found no long-term trials comparing ACEi and placebo for treatment of hypertension.
We found no head-to-head studies directly comparing the main four ACEi’s, commonly
prescribed in England.
There is no evidence ( 10, 11, 12) that perindopril improves mortality or stroke rate in patients
with hypertension, or in patients with previous TIA or stroke in comparison to placebo.
No inferences can be drawn about Enalapril as there are no studies comparing this medication
to either placebo or another blood pressure lowering agent.
There is some evidence (9) that Ramipril may be better than placebo for the treatment of
hypertension in high risk patients. The evidence is indirect and difficult to quantify because of
the way the study has been reported and furthermore, because the treatment of hypertension
and stroke prevention was not a primary or secondary outcome of the study.
The strongest evidence we found about the use of ACEi’s for the treatment of hypertension is
for lisinopril (13). It has been shown that lisinopril is as effective as thiazide diuretics
regarding total mortality, but inferior regarding prevention of stroke.

5. Discussion
ACEi’s are drugs approved for the treatment of hypertension. However, at the time of
regulatory approval, it is not clear whether a short term decrease in blood pressure would
translate into improvements in hard clinical outcomes, such as mortality rates and stroke rates.
It is surprising therefore, to find that ACEi’s are recommended as the first line treatment of
hypertension by national guidelines (5,6, 16), despite the fact that evidence for the
recommendation (other than lisinopril) is either lacking or unconvincing. Surprisingly, the
recommendations do not distinguish between different ACEi’s, even though there is no
evidence that either perindopril or enalapril improve stroke rates in people with hypertension.
Inexplicably, the National Clinical Guidelines for Stroke (7) specifically recommends
perindopril for secondary prevention of stroke in patients with hypertension, when well
conducted studies conclusively shows that perindopril has no effect on stroke (10,12). Perhaps
the author’s of the guidelines were assuming a class effect present in all ACEi’s? However, a
class effect does not always exist in similar groups of drugs (e.g. metoprolol (17) vs. atenolol
(18) and simvastatin (19) vs. pravastin (20)). It should be noted that all papers reviewed other
than the study conducted by Dahlof and colleagues (11) were published at the time of drawing
the guidelines.
In diabetics, hypertension is a stronger risk factor than blood sugar levels. For this reason it
seems reasonable to use only drugs proven for the treatment of hypertension and with proven
beneficial renal effects. Only lisinopril has a licence for nephropathy and microalbuminuria in
hypertensive Type 2 diabetics.
On the basis of the evidence presented, lisinopril is the only commonly used ACEi that can be
clearly considered a first line treatment for hypertension. There is some evidence for ramipril,
although this is not as strong. There is no substantial evidence of the effectiveness of enalapril
and in the presence of a proven treatment (lisinopril) it makes no sense to use it for the
treatment of hypertension. There is clear evidence that perindopril is not effective and should
not be used for treating hypertension. Furthermore, because (at the time of writing)
perindopril is still on patent, it is over three times the cost of either ramipril or lisinopril.

6. References:
1. Burt VL, Whelton PK, Roccella EJ et all. Prevalence of hypertension in the US adult
population. Results from the Third National Health and Nutrition Examination Survey, 1988-
1991. Hypertension 1995; 25: 305-313
2. SIGN. Hypertension in older people. A national clinical guideline. 2001, page 3
3. Pearce KA, Furberg CD, Rushing J. Does antihypertensive treatment of the elderly prevent
cardiovascular event or prolong life. Arch Fam Med 1995; 4: 943-950
4. MacMahon S, Peto R, Cutler J et all. Epidemiology: blood pressure, stroke and coronary
heart disease. Lancet 1990; 335: 765-774
5. Williams B, Poulter NR, Brown MJ et all. Guidelines for management of hypertension:
report of the fourth working party of the British Hypertension Society, 2004 – BHS IV. J
Hum Hyper 2004;18:139-185
6. The National Collaborating Centre for Chronic Conditions. Hypertension. Management of
hypertension in adults in primary care: partial update of NICE Clinical Guideline 18. Royal
College of Physicians, 2006
7. Intercollegiate Stroke Working Party. National Clinical Guidelines for Stroke. Royal
College of Physician Press, Second Edition, 2004
8. David Cracknell, Office for National Statistics, personal communication 2007
9. The Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J
Med 2000;342:145-53
10. PROGRESS Collaborative group. Randomised trial of perindopril-based blood pressure
lowering regimen among 6105 individuals with previous stroke or transient ischemic attack.
Lancet 2001;358:1033-1041
11. 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
12. The EURopean trial On reduction of cardiac events with Perindopril in stable coronary
Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events
among patients with stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial ( the EUROPA study). Lancet 2003;362: 782-88
13. The antihypertensive and lipid-lowering treatment to prevent heart attack trial
(ALLHAT). Major outcomes in high-risk hypertensive patients randomised to angiotensin-
converting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002;288:2981-
2997
14. Hansson L, Lindholm LH, Ekbom T et al. Randomised trial of old and new
antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish
Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-56
15. Wing LMH, Reid CM, Ryan P et al. A comparison of outcomes with angiotensin-
converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med
2003;348:583-92
16. JBS 2: Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease in
Clinical Practice. Heart 2005;91:suppl V ( v1-v51)
17. Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G. Primary
prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY
study. JAMA 1988;259:1976-82

7. 18 MRC Working Party. Medical research council trial of treatment of hypertension in older
adults: principal results. BMJ 1992;304:405-412
19. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of
cholesterol lowering with simvastatin in 20 536 high risk individuals: a randomised placebo-
controlled trial. Lancet 2002;360:7-22
20. The ALLHAT Officers and coordinators for the ALLHAT collaborative research group.
Major outcome in moderately hypercholesterolemic, hypertensive patients randomised to
pravastatin versus usual care. The Antihypertensive and Lipid Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007
WORD COUNT: 2076
Corresponding author: Dr Nik Manassiev. E-mail address: d_manassieva@hotmail.com
January 2009