Renin-angiotensin system inhibition in the treatment of hypertension

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Renin-angiotensin system inhibition in the treatment

of hypertension
Authors: Johannes FE Mann, MD, Karl F Hilgers, MD
Section Editors: George L Bakris, MD, William J Elliott, MD, PhD
Deputy Editor: John P Forman, MD, MSc

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2024. | This topic last updated: May 30, 2023.

INTRODUCTION

Inhibitors of the renin-angiotensin system (RAS), particularly angiotensin-converting

enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are commonly used in
the treatment of hypertension. The role of the RAS in hypertension and the use of specific
inhibitors of this system to treat hypertension will be reviewed here.

The use of RAS inhibitors in patients with kidney disease and diabetes is discussed
separately:
● (See "Choice of drug therapy in primary (essential) hypertension".)
● (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease
in adults".)
● (See "Treatment of hypertension in patients with diabetes mellitus".)
● (See "Treatment of diabetic kidney disease".)

The importance of local (ie, tissue) RAS activity in low-renin hypertension and the effects of
angiotensin II on the heart are presented elsewhere:
● (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on
'Renin-angiotensin system'.)

The safety of ACE inhibitors and ARBs in patients with coronavirus disease 2019 (COVID-19)
is discussed in another topic:

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Renin-angiotensin system inhibition in the treatment of hypertension
● (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and
hypertension", section on 'Renin angiotensin system inhibitors'.)

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

Since the introduction of captopril in 1977 [1], angiotensin-converting enzyme (ACE)

inhibitors have become widely used for the treatment of hypertension and three of its
major complications: acute myocardial infarction, congestive heart failure, and chronic
kidney disease. Fifty to 60 percent of White patients have a good response to monotherapy
with ACE inhibitors, a response rate similar to other first-line antihypertensive drugs [2].
ACE inhibitors have the additional advantages of having a more favorable side effect
profile than sympathetic blockers, beta blockers, and diuretics [3]. Various professional
societies have recommended ACE inhibitors and angiotensin II receptor blockers (ARBs) as
first- or second-line therapy in the treatment of hypertension [4-7]. (See "Choice of drug
therapy in primary (essential) hypertension" and "Chronic coronary syndrome: Overview of
care" and "Treatment of hypertension in patients with heart failure" and "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease in adults".)

Specific indications for use — There are a number of settings in which ACE inhibitors are
the antihypertensive drugs of choice because of possible benefits in addition to lowering
the blood pressure. (See "Choice of drug therapy in primary (essential) hypertension".)

These include:
● Heart failure with reduced ejection fraction (HFrEF) [8] (see "Use of diuretics in
patients with heart failure" and "Primary pharmacologic therapy for heart failure with
reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist' and
"Primary pharmacologic therapy for heart failure with reduced ejection fraction",
section on 'Beta blocker' and "Primary pharmacologic therapy for heart failure with
reduced ejection fraction", section on 'Primary components of therapy')
● Proteinuric chronic kidney disease, both diabetic and nondiabetic [9] (see
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in
adults" and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes
mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2
diabetes mellitus" and "Treatment of hypertension in patients with diabetes mellitus")
● After a myocardial infarction in most patients, particularly those with heart failure or
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Renin-angiotensin system inhibition in the treatment of hypertension

reduced systolic function [10] (see "Angiotensin converting enzyme inhibitors and
receptor blockers in acute myocardial infarction: Recommendations for use")

Antihypertensive response — The decline in blood pressure seen with ACE inhibitors
appears to be primarily due to decreased formation of angiotensin II, but decreased
degradation of kinins could contribute by both direct vasodilation and increasing the
production of vasodilator prostaglandins [11].

Black patients may be less sensitive than White patients to ACE inhibitors as monotherapy
for hypertension [12]. However, the addition of even a low dose of a thiazide diuretic to an
ACE inhibitor leads to a fall in blood pressure that is comparable with that seen in White
patients [13].

The utility of ACE inhibitors with diuretics is not limited to Black patients, since these drugs
have a synergistic effect, attaining goal blood pressure in up to 85 percent of patients with
mild hypertension [13]. The antihypertensive response to diuretics is often limited by the
hypovolemia-induced increase in renin release and subsequent angiotensin II production
[14]; this effect is prevented by converting enzyme inhibition, leading to a more prominent
reduction in blood pressure (see "Use of thiazide diuretics in patients with primary
(essential) hypertension"). For similar reasons, dietary sodium restriction can also enhance
the response to an ACE inhibitor [15].

ACE inhibitors minimize some of the metabolic changes induced by diuretic therapy.
Hypokalemia, for example, is less prominent because the reduction in angiotensin II
formation induced by the ACE inhibitor leads to decreased secretion of aldosterone. ACE
inhibitors also do not induce glucose intolerance, hyperlipidemia, or hyperuricemia; may
increase insulin sensitivity; and may minimize or prevent diuretic-induced elevations in
serum glucose, cholesterol and uric acid levels [16].

Apart from diuretics, calcium channel blockers can be used effectively with ACE inhibitors
and, as shown in the Avoiding Cardiovascular Events through Combination Therapy in
Patients Living with Systolic Hypertension (ACCOMPLISH) trial, may have clinical
advantages over diuretics when achieved blood pressure is similar. Combination of an ACE
inhibitor with a beta blocker may be less useful because of inferior antihypertensive
activity compared with other ACE inhibitor combinations [17]. This relative lack of efficacy
may be due in part to similar mechanisms of action, as angiotensin II formation and renin
secretion are respectively reduced. (See "Choice of drug therapy in primary (essential)
hypertension".)
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Renin-angiotensin system inhibition in the treatment of hypertension

Dose — As with other antihypertensive agents, proper dose can minimize the incidence of
side effects ( table 1). To minimize the risk of first-dose hypotension due to an abrupt
decline in angiotensin II levels, the patient should not be volume depleted. The initial dose
can be reduced by one-half in older adult patients or those with heart failure who are at
higher risk for hypotension. Side effects other than those related to hypotension can occur
with ACE inhibitors, the most common being cough [18], less commonly hyperkalemia, and
rarely angioedema [19]. ACE inhibitors are contraindicated during pregnancy [20]. (See
"Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers".)

The duration of action varies with different ACE inhibitors. Some ACE inhibitors can be
given once daily (eg, trandolapril, lisinopril, and benazepril). The use of longer-acting
agents once daily should improve patient compliance, reduce costs, maintain smoother
control, and ensure that the abrupt rise in pressure upon awakening in the early morning
is blunted, hopefully thereby reducing the incidence of serious cardiovascular events at
this time.

After the initiation of therapy, the patient should be reexamined in a few weeks to allow
the full antihypertensive effect to occur. If there is no or little fall in blood pressure with an
adequate dose, the drug can be stopped and different class of drug started, a concept
called "sequential monotherapy." Alternatively, another drug may be added, such as a
calcium channel blocker. (See "Choice of drug therapy in primary (essential) hypertension".)

If the patient's blood pressure is reduced by the ACE inhibitor but the goal pressure is not
achieved, the dose can be gradually increased to the maximum levels noted in the table (
table 1). However, the addition of a second drug from a different class will provide much
greater antihypertensive effect [21].

In patients with extensive atherosclerosis or kidney function impairment who are more
likely to have renovascular stenoses, a repeat plasma creatinine concentration should be
obtained within one to two weeks of ACE inhibitor or ARB initiation to ensure that kidney
perfusion has been maintained. However, a modest and nonprogressive increase in the
plasma creatinine in such patients should not prompt discontinuation of therapy. (See
"Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.)

ANGIOTENSIN II RECEPTOR BLOCKERS

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Renin-angiotensin system inhibition in the treatment of hypertension

Angiotensin II receptor blockers (ARBs) interfere with the RAS by impairing the binding of
angiotensin II to the AT1 receptor on the cell membrane, thereby inhibiting the action of
angiotensin II [22]. Blockade of the action of angiotensin II leads to elevations in plasma
levels of renin, angiotensin I, and angiotensin II. However, this build-up of precursors does
not overwhelm the receptor blockade, as evidenced by a persistent fall in both blood
pressure and plasma aldosterone levels [23].

Differences between ACE inhibitors and ARBs — There are substantial pharmacologic
differences in the actions of angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs), but few clinical differences have been
documented. At least three factors may contribute to the pharmacologic differences (
figure 1):
● ACE is a kininase. Thus, inhibiting this enzyme, which normally degrades bradykinin,
with an ACE inhibitor leads to increased kinin levels, an effect not seen with an ARB.
This is likely responsible for the cough that may be seen with ACE inhibitors (but not
with ARBs), although high bradykinin levels may also provide additional vasodilation
and other benefits not observed with ARBs.
● By decreasing angiotensin II production, ACE inhibitors reduce the effect of both AT1
and AT2 receptors; only the former are inhibited by the ARBs.
● In the heart, kidney, and perhaps the blood vessels, the production of angiotensin II
may be catalyzed by enzymes other than ACE, such as chymase [24]. The effect of the
angiotensin II produced by this reaction can be inhibited by the ARBs but not by ACE
inhibitors. However, the role of these non-ACE enzymes for the generation of
angiotensin II in vivo, if any, is uncertain.

Efficacy and dose — The ARBs have an effect similar to that seen with monotherapy with
other antihypertensive drugs ( table 1) [25]. However, several studies have shown that
losartan, when given once daily, does not control blood pressure to the same magnitude
as other ARBs (irbesartan, telmisartan, candesartan, and valsartan) [26-29]. On the other
hand, losartan produces a slight fall in plasma uric acid that does not occur with the other
ARBs, an effect that is due to enhanced uric acid excretion [30]. This appears to be
mediated at least in part by direct inhibition of the proximal urate-anion exchanger that is
responsible for urate reabsorption [31].

The antihypertensive efficacy of ARBs appears to be roughly equivalent to that of the ACE
inhibitors. A meta-analysis of 61 studies that directly compared angiotensin II receptor
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Renin-angiotensin system inhibition in the treatment of hypertension

blockers and ACE inhibitors reported no difference in the antihypertensive effects of these
agents [25].

In addition, the effects of ARBs and ACE inhibitors on cardiovascular events appear similar.
The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial
(ONTARGET) compared telmisartan (80 mg/day), ramipril (10 mg/day), and combination
therapy (80 + 10 mg/day) with both agents in 25,620 patients with vascular disease or
diabetes [32]. The primary outcome was death from cardiovascular causes, myocardial
infarction, stroke, or hospitalization for heart failure. Achieved mean blood pressure was
lower in patients who received telmisartan compared with ramipril (by 0.9/0.6 mmHg) and
in patients who received both agents compared with ramipril (2.4/1.4 mmHg). The
cardiovascular outcomes were similar in all three groups, while cough was more common
with ramipril, and both hyperkalemia and acute kidney injury were more common with
combined therapy. (See "Major side effects of angiotensin-converting enzyme inhibitors
and angiotensin II receptor blockers".)

In addition, a meta-analysis of nine trials and 11,007 patients that directly compared ACE
inhibitors with ARBs in hypertensive patients found similar rates of all-cause mortality and
cardiovascular mortality [33]. By contrast, drug withdrawal due to adverse events was
significantly more frequent with ACE inhibitors (one additional withdrawal from therapy for
every 55 patients treated with ACE inhibitors over four years), mostly due to dry cough.
Thus, ARBs are a reasonable alternative to ACE inhibitor therapy in hypertensive patients.

As with other agents that inhibit the RAS, the efficacy of ARBs is enhanced by concomitant
administration of low doses of a diuretic [34] and by a reduction in dietary sodium intake.
As with ACE inhibitors, ARBs appear to minimize the hypokalemia and hyperuricemia
induced by diuretic therapy [34].

SIDE EFFECTS

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers

(ARBs) are generally well tolerated. Cough and angioedema are less common with ARBs
[32]. Both ACE inhibitors and ARBs are contraindicated in pregnancy. These issues, as well
as other side effects from these medications, are discussed in detail separately:
● (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin
II receptor blockers".)
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Renin-angiotensin system inhibition in the treatment of hypertension
● (See "Adverse effects of angiotensin-converting enzyme inhibitors and receptor
blockers in pregnancy".)

ACE inhibitors plus ARBs — A separate issue is the side effects associated with combined
angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB)
therapy compared with either drug alone. The Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint Trial (ONTARGET) cited above of high-risk
patients [32,35] found a significant increase in adverse effects (including a possible
increase in mortality) with combined therapy compared with an ACE inhibitor alone. As a
result, combined therapy is not recommended for the treatment of hypertension.

The data supporting adverse effects and the possible role of combined therapy to slow
progression in patients with proteinuric chronic kidney disease are discussed elsewhere:
● (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin
II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)
● (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease
in adults", section on 'Combination of ACE inhibitors and ARBs'.)

DIRECT RENIN INHIBITORS

The first effective oral direct renin inhibitor, aliskiren, became available in the United States
in March 2007. However, it is rarely used and is no longer available in some countries.

Aliskiren lowers blood pressure to a degree comparable with most other agents [36]. A
number of studies have evaluated the blood pressure-lowering effect of aliskiren in
combination with other antihypertensive drugs [36-39]. In one report, the combination of
maximum doses of aliskiren and valsartan decreased blood pressure more than maximum
doses of either agent alone but not more than would be expected with dual therapy using
drugs from different classes [40]. Aliskiren, as with other inhibitors of the RAS, should not
be used in pregnancy.

In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial, aliskiren plus
losartan was associated with a significant 20 percent greater reduction in proteinuria
compared with losartan alone in patients with type 2 diabetes and nephropathy, in the
absence of a significantly greater effect on blood pressure [41]. However, this effect on
proteinuria did not translate into a clinical benefit. In the Aliskiren Trial in Type 2 Diabetes

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Using Cardiorenal Endpoints (ALTITUDE), 8600 patients with type 2 diabetes and kidney
disease already taking either an angiotensin-converting enzyme (ACE) inhibitor or
angiotensin II receptor blocker (ARB) were randomly assigned to additional therapy with
aliskiren or placebo [42]. The ALTITUDE trial was stopped early because of futility (no
benefit on the primary cardiovascular and kidney outcomes) and because aliskiren therapy
produced a nonsignificantly higher rate of adverse events (ie, nonfatal stroke,
hypotension). The ALTITUDE trial is discussed in detail elsewhere. (See "Treatment of
diabetic kidney disease".)

The effect of aliskiren on progression of atherosclerotic coronary artery disease in patients

with controlled hypertension was examined in the Aliskiren Quantitative Atherosclerosis
Regression Intravascular Ultrasound Study (AQUARIUS) [43]. In this trial, 613 patients with
a systolic blood pressure between 125 and 139 mmHg (most of whom were treated with
antihypertensive medications) and two other cardiovascular risk factors were randomly
assigned to aliskiren (300 mg/day) or placebo. After 18 months, the atherosclerotic burden
and progression of atherosclerosis (measured by coronary intravascular ultrasound) was
similar between the groups. In a secondary analysis based upon a small number of events,
aliskiren appeared to reduce the rate of cardiovascular events. However, this analysis
excluded diabetic patients who were treated with angiotensin inhibitors (approximately 15
percent of the study population), as such patients were removed from the study after
publication of the ALTITUDE trial [44]. In addition, adverse events were more common with
aliskiren.

An increased risk of hyperkalemia when aliskiren is combined with ACE inhibitors or ARBs
has been described in the ALTITUDE trial and in other studies [42,45]. Thus, aliskiren
should not be combined with ACE inhibitors or ARBs [46]; it may be used as a third-line
agent if patients do not tolerate ACE inhibitors or ARBs.

SUMMARY AND RECOMMENDATIONS

● Inhibitors of the renin-angiotensin system (RAS), including angiotensin-converting

enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin
inhibitors are commonly used in the treatment of hypertension. (See 'Introduction'
above.)
● There are a number of settings in which ACE inhibitors are the antihypertensive drugs

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Renin-angiotensin system inhibition in the treatment of hypertension

of choice because of possible benefits in addition to lowering the blood pressure (see
'Specific indications for use' above):

• Heart failure with reduced ejection fraction (HFrEF)

• Proteinuric chronic kidney disease, both diabetic and nondiabetic
• After a myocardial infarction in most patients, particularly those with heart failure
or reduced systolic function
● Proper dose of ACE inhibitors can minimize the incidence of side effects ( table 1).
The duration of action varies with different ACE inhibitors. Some ACE inhibitors can be
given once daily (eg, trandolapril, lisinopril, and benazepril). (See 'Dose' above.)
● There are pharmacologic differences in the actions of ACE inhibitors and ARBs. Except
for the cough associated with ACE inhibitors, these pharmacologic differences are not
associated with clinically meaningful differences in therapeutic effects. At least three
factors may contribute to the pharmacologic differences ( figure 1) (see
'Differences between ACE inhibitors and ARBs' above):

• ACE is a kininase. Thus, inhibiting this enzyme, which normally degrades

bradykinin, with an ACE inhibitor leads to increased kinin levels, an effect not seen
with an ARB. This is likely responsible for the cough that may be seen with ACE
inhibitors (but not with ARBs), although high bradykinin levels may also provide
additional vasodilation and other benefits not observed with ARBs.

• By decreasing angiotensin II production, ACE inhibitors reduce the effect of both

AT1 and AT2 receptors; only the former are inhibited by the ARBs.

• In the heart, kidney, and perhaps the blood vessels, the production of angiotensin
II may be catalyzed by enzymes other than ACE, such as chymase. The effect of the
angiotensin II produced by this reaction can be inhibited by the ARBs but not by
ACE inhibitors.
● The ARBs have an effect similar to that seen with monotherapy with other
antihypertensive drugs, including ACE inhibitors ( table 1).
● The antihypertensive effect of both ACE inhibitors and ARBs is enhanced by
concomitant administration of low doses of a diuretic and by a reduction in dietary
sodium intake. Both drugs also appear to minimize the hypokalemia and
hyperuricemia induced by diuretic therapy. (See 'Dose' above and 'Efficacy and dose'
above.)

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Renin-angiotensin system inhibition in the treatment of hypertension
● Both ACE inhibitors and ARBs are generally well tolerated. Side effects other than
those related to hypotension can occur with both drugs, including hyperkalemia and
rarely angioedema, as well as acute kidney injury in patients with low effective arterial
blood volume (eg, diarrhea, vomiting, and heart failure). Cough is a common side
effect of ACE inhibitors. ACE inhibitors and ARBs are contraindicated during
pregnancy. (See 'Side effects' above and "Major side effects of angiotensin-converting
enzyme inhibitors and angiotensin II receptor blockers".)
● Combined therapy with both an ACE inhibitor and ARB is not recommended for the
treatment of hypertension. (See 'ACE inhibitors plus ARBs' above.)
● The first effective oral direct renin inhibitor, aliskiren, lowers blood pressure to a
degree comparable with most other agents. In combination with an ACE inhibitor or
ARB, aliskiren increases the risk of adverse effects and does not lower the risk of
cardiovascular event. Thus, aliskiren should not be combined with ACE inhibitors or
ARBs. (See 'Direct renin inhibitors' above.)

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