Use of angiotensin converting enzyme inhibitors in heart failure with

reduced ejection fraction

Author:
Wilson S Colucci, MD
Section Editor:
Stephen S Gottlieb, MD
Deputy Editor:
Susan B Yeon, MD, JD, FACC

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Feb 2018. | This topic last
updated: Jan 30, 2018.

INTRODUCTION — Randomized trials have shown that angiotensin

converting enzyme (ACE) inhibitor therapy leads to symptomatic
improvement, reduced hospitalization, and enhanced survival in patients
with heart failure with reduced ejection fraction (HFrEF) [1-8]. Therefore,
ACE inhibitors are an important component of standard HF therapy in
patients with current or prior symptoms of HF and depressed left
ventricular systolic function.

The clinical data supporting the use of ACE inhibitors in patients with HF
will be reviewed here. The mechanisms of action of these agents in HF,
their role in patients with diastolic dysfunction, and their use in patients
with asymptomatic systolic dysfunction is discussed separately.
(See "Angiotensin converting enzyme inhibitors and receptor blockers in
heart failure: Mechanisms of action" and "Treatment and prognosis of
heart failure with preserved ejection fraction" and "Management and
prognosis of asymptomatic left ventricular systolic dysfunction".)

An overview of the treatment of HFrEF is discussed separately.

(See "Overview of the therapy of heart failure with reduced ejection
fraction".)

MECHANISM OF ACTION — The mechanism by which ACE inhibitors act

in HF is incompletely understood. The observation that other pure
vasodilators (ie, those that are not neurohumoral modulators) do not
improve survival (or do so to a lesser degree than ACE inhibitors) or may
actually worsen cardiac function and/or clinical outcomes has led to the
conclusion that ACE inhibitors work primarily by a mechanism other than
simply decreasing preload and afterload, or that detrimental effects due
to excessive vasodilation per se (eg, renin-angiotensin aldosterone
system or sympathetic activation) are countered by other actions of ACE
inhibitors.

The following are possible mechanisms for ACE inhibitor effects in

patients with HF:

●Improvements in arterial tone and/or compliance leading to

decreased left ventricular afterload [9], thereby contributing to
improved systolic function and/or decreased hypertrophy and
diastolic dysfunction.
●Modulation of myocyte response to the intracardiac renin-
angiotensin system [10] (see "Actions of angiotensin II on the heart").
This system may contribute to myocardial hypertrophy and
remodeling, which may be deleterious in the long term to ventricular
function. (See "Cardiac remodeling: Basic aspects".)
●Reduction in central sympathetic outflow and enhancement of
sympathoinhibitory responses to baroreceptor stimulation [11,12].
●Elevation in the concentration of kinins, most importantly bradykinin,
by inhibiting the kininase activity of ACE [13].
●Improvement in endothelial function leading to improved vascular
function [14].
●Alterations in protein composition of skeletal muscle [15], which
may contribute to improvement in exercise capacity [16,17].

CLINICAL USE

Indications — For patients with HF and reduced left ventricular ejection

fraction (LVEF ≤40 percent), we recommend an ACE inhibitor as part of
the initial treatment strategy (algorithm 1). This recommendation applies
to a variety of patient subgroups, including across the spectrum of New
York Heart Association functional class of HF. (See 'Use in
subgroups' below.)

This recommendation is consistent with major society guidelines,

including the 2017 American College of Cardiology/American Heart
Association focused update [18] and the 2016 European Society of
Cardiology task force guidelines [19].

As discussed separately, we suggest use of an ACE inhibitor (or single-

agent angiotensin II receptor blocker [ARB] (see "Use of angiotensin II
receptor blocker in heart failure with reduced ejection fraction")) rather
than sacubitril-valsartan as a component of initial medical therapy for
HFrEF. Some experts have suggested use of sacubitril-valsartan (rather
than ACE inhibitor) as a component of initial therapy for HFrEF. Transition
from ACE inhibitor to sacubitril-valsartan to improve outcomes in patients
with HFrEF is discussed separately. (See "Use of angiotensin receptor-
neprilysin inhibitor in heart failure with reduced ejection fraction".)

Evaluation prior to initiation — Clinical evaluation prior to ACE inhibitor

initiation includes assessment of blood pressure, renal function, and
electrolytes to determine if a contraindication or condition that requires
caution and cardiology consultation is present.

Contraindications — An ACE inhibitor should not be prescribed for

patients with idiopathic or heritable angioedema or angioedema related
to prior ACE inhibitor use.

Cautions — ACE inhibitor use in the following clinical settings requires

caution [20]:

●Significant hyperkalemia (K+>5.0 mmol/L) – When hyperkalemia is

present prior to initiation of ACE inhibitor, potential causes should be
assessed and addressed, including presence of kidney disease and
use of potassium supplements or drugs that elevate serum potassium
levels. (See 'Drug interactions' below.)
●Bilateral renal artery stenosis – A patient with this condition can
initiate treatment with an ACE inhibitor, but careful monitoring is
required given the risk of decline in glomerular filtration rate (GFR).
The majority of patients with bilateral renal artery stenosis can
tolerate an ACE inhibitor with only a small decline in GFR. The
approach to renal dysfunction is discussed below. (See "Treatment of
bilateral atherosclerotic renal artery stenosis or stenosis to a solitary
functioning kidney", section on 'Medical therapy' and 'Use with renal
dysfunction' below.)
 ●Symptomatic or severe asymptomatic hypotension (systolic blood
pressure <90 mmHg) – Goals of treatment of hypotension include
avoidance of organ hypoperfusion and enabling initiation of ACE
inhibitor (or ARB) therapy. Management of hypotension includes
discontinuing any unnecessary vasodilators (eg, calcium channel
blockers should generally be avoided in patients with HFrEF) and
correcting intravascular volume depletion (eg, reducing or holding
diuretic dose if there are no signs of congestion). If hypotension
persists, cardiology consultation is recommended.

Use with renal dysfunction — The approach to renal dysfunction

depends upon the severity and time course of renal dysfunction. We avoid
ACE inhibitor therapy in nondialysis patients with serum creatinine
>3.5 mg/dL (310 micromol/L) or estimated GFR (eGFR) <20 mL/min/1.73
m2 [21]; for such patients, combination hydralazine-isosorbide dinitrate
(rather than an ARB) is suggested. (See "Hydralazine plus nitrate therapy
in patients with heart failure with reduced ejection
fraction" and "Overview of the therapy of heart failure with reduced
ejection fraction".)

Alterations in renal function and management of worsening renal function

during ACE inhibitor therapy is discussed below. (See 'Worsening renal
function' below.)

Patients treated with dialysis can be treated with ACE inhibitors.

(See "Therapy of heart failure in hemodialysis patients", section on
'Pharmacologic therapy for systolic dysfunction'.)

Choice of agent — The available evidence suggests that the beneficial

effect of ACE inhibitor therapy is a class effect, although the best
evidence supporting specific target doses is available for agents shown
to be effective in clinical trials. Evidence for a survival benefit from ACE
inhibitor therapy in patients with HF without recent myocardial infarction
(MI) is based largely on trials using enalapril. Additional support for long-
term ACE inhibitor therapy in patients with HF comes from trials in
patients with recent MI and either LV systolic dysfunction or HF; long-
term trials used captopril, ramipril, or trandolapril [22], and the largest
shorter-term trials used captopril or lisinopril. (See "Angiotensin
converting enzyme inhibitors and receptor blockers in acute myocardial
infarction: Clinical trials".)
Dose initiation and titration — For patients with HFrEF, ACE inhibitor
therapy is one component of combination therapy (along with beta
blocker therapy and, in selected patients, mineralocorticoid receptor
antagonist), which improves symptoms and prolongs survival. The ACE
inhibitor is usually initiated prior to beta blocker therapy, with titration to
a moderate dose. The beta blocker is then titrated to the maximum dose,
followed by uptitration of the ACE inhibitor to the maximum
recommended and tolerated dose. The approach to pharmacologic
therapy of HFrEF is discussed in detail elsewhere. (See "Overview of the
therapy of heart failure with reduced ejection
fraction" and "Pharmacologic therapy of heart failure with reduced
ejection fraction", section on 'ACE inhibitors or beta blockers
first' and 'Use with other drugs' below.)

Beginning ACE inhibitor therapy with low doses (eg, 2.5 mg

of enalapril twice daily, 6.25 mg of captopril three times daily, or 5 to
10 mg of lisinopril daily) will reduce the likelihood of complications such
as hypotension and azotemia [23,24]. In the screening phase of the
SOLVD trial, for example, a test dose of 2.5 mg of enalapril twice daily
produced symptomatic hypotension in 2.2 percent of almost 7500
patients with New York Heart Association class III or IV HF; cessation of
therapy for hypotension was required in only 0.5 percent of patients [23].

If initial therapy is tolerated, the dose is then gradually increased (after

maximization of beta blockers) to a maintenance dose of 10 mg twice
daily of enalapril, 50 mg three times daily of captopril, or up to
40 mg/day of lisinopril or quinapril unless side effects occur [1-3,5,25].
These relatively high doses reflect those used in the successful trials
described above [25]. Although there is uncertainty if these doses are
more beneficial than lower doses, maximum-dose therapy, if tolerated, is
recommended [26]. If the target doses cannot be administered or are
poorly tolerated, lower doses should be used with the expectation that
there are likely to be only small differences in efficacy between low and
high doses [25,27]. (See 'Effect of dose' below.)

MANAGEMENT OF USE

Monitoring — Monitoring for potential side effects should include routine

laboratory assessment of serum electrolytes and renal function prior to
and following initiation and uptitration of an ACE inhibitor. The risk of
hyperkalemia is increased if an aldosterone antagonist is administered
concomitantly. On the other hand, concomitant potassium-wasting
diuretic therapy can cause hypokalemia. One suggestion is to check
serum electrolytes and renal function at one week and at one month
following increases in ACE inhibitor dose and then periodically (eg, every
three to six months), depending on the patient's stability and baseline
renal function.

Side effects — Side effects of ACE inhibitors include hypotension,

worsening renal function (discussed below), hyperkalemia, cough, and
angioedema. (See "Major side effects of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers", section on 'ACE
inhibitors'.)

Worsening renal function

Frequency — ACE inhibitor therapy has a variable effect on the

glomerular filtration rate (GFR) in patients with HF, as usually estimated
from the serum creatinine concentration. Worsening renal function as
evidenced by increases in serum creatinine is observed in approximately
10 to 35 percent of patients with HFrEF after initiation of an ACE inhibitor
[28]. The major mechanism is a preferential reduction in resistance at the
efferent glomerular arteriole, which will lower the intraglomerular
pressure that is the primary driving force to glomerular filtration.
However, some patients have no change in serum creatinine, and
approximately 10 to 25 percent have a reduction in serum creatinine [29-
31]. (See "Renal effects of ACE inhibitors in heart failure", section on
'Effect on glomerular filtration rate'.)

As an example, the effect of enalapril on renal function was evaluated in

an analysis from the CONSENSUS trial of 123 patients with severe HF
(New York Heart Association class IV) [29]. The mean baseline serum
creatinine concentration was 1.5 mg/dL (133 micromol/L). The serum
creatinine increased by an average of 10 to 15 percent within the first
three weeks, but there was substantial variability in the renal response:
The serum creatinine fell (ie, GFR improved) in 24 percent of patients,
increased by less than 30 percent in 41 percent, by 30 to 100 percent in
24 percent, and by more than 100 percent in 11 percent, most often due
to concurrent disease. In another report, in which 34 of 104 HF patients
developed a decline in GFR on ACE inhibitor therapy, the serum creatinine
returned to pretreatment values with a reduction in diuretic dose and
liberalization of salt intake [30]. In some patients, the addition of an ACE
inhibitor may lead to volume depletion by increasing the response to the
current dose of diuretic.

Risk factors for a rise in serum creatinine in CONSENSUS and other

studies included signs of volume depletion (lower central venous and left
ventricular [LV] filling pressures), as well as signs of more severe HF [29-
31]. These included lower arterial pressures, higher doses of loop
diuretics, and hyponatremia, the severity of which varies directly with the
severity of the HF. The presence of bilateral renal artery stenosis is a less
common cause for worsening renal function on ACE inhibitor therapy.
(See "Hyponatremia in patients with heart failure" and "Treatment of
bilateral atherosclerotic renal artery stenosis or stenosis to a solitary
functioning kidney", section on 'Medical therapy'.)

The time course and clinical significance of worsening renal function is

discussed below. (See 'Effect of renal dysfunction' below.)

Approach to management — We suggest the following approach to

worsening renal function in patients with HFrEF treated with ACE
inhibitor.

●Precautionary measures should be taken to reduce the risk of

worsening renal function in patients with HFrEF treated with ACE
inhibitor. These include avoiding concomitant nephrotoxic drugs (eg,
nonsteroidal anti-inflammatory drugs [NSAID]), evaluating and treating
other causes of worsening renal function (eg, intrinsic kidney
disease), and avoiding volume depletion (ie, if no congestion is
present, reducing or suspending diuretic) at the time of ACE inhibitor
initiation.
●If serum creatinine increases by >50 percent above baseline or if
serum creatinine is >3 mg/dL (266 micromol/L) or estimated GFR
(eGFR) is <25 mL/min/1.73 m2, decrease dose of ACE inhibitor by one-
half, evaluate volume status, and determine the appropriateness of
decreasing the diuretic dose, then recheck laboratory tests. Serum
creatinine, blood urea nitrogen (BUN), and serum potassium should be
rechecked frequently (at least weekly) until levels have stabilized.
After renal function has stabilized, the appropriateness of uptitrating
ACE inhibitor dose should be assessed.
 ●If serum creatinine increases by >100 percent above baseline or if
serum creatinine is >3.5 mg/dL (310 micromol/L) or eGFR is
<20 mL/min/1.73 m2, stop ACE inhibitor; evaluate volume status;
determine the appropriateness of decreasing the diuretic dose; and
recheck laboratory tests. Serum creatinine, BUN, and serum
potassium should be rechecked frequently (at least weekly) until
levels have stabilized. After renal function has stabilized, the
appropriateness of rechallenge with ACE inhibitor should be
assessed.

If cessation of angiotensin inhibition is required, hydralazine plus a

nitrate is a suggested alternative. (See "Pharmacologic therapy of heart
failure with reduced ejection fraction", section on 'Hydralazine plus
nitrate'.)

Alternatives for patients with ACE inhibitor intolerance — For patients

with HFrEF who are ACE-inhibitor intolerant due to cough, we recommend
an ARB as an alternative. For patients who have developed angioedema
on an ACE inhibitor, we suggest cautiously substituting an ARB since
angioedema has been infrequently reported with ARB therapy. Among
patients who develop angioedema while taking an ACE inhibitor, there is
a low risk of angioedema when an ARB is taken.

If ACE inhibitor intolerance is due to hyperkalemia, hypotension, or renal

insufficiency, switching to combination hydralazine-isosorbide dinitrate
(rather than an ARB) is suggested.

Drug interactions — Adverse drug interactions with ACE inhibitors

include the following:

●The combination of an ACE inhibitor and an NSAID increases the risk

of acute kidney injury. NSAIDs should be avoided in patients with HF
since NSAID use in this population is associated with increased risk
of HF exacerbation, acute kidney injury, hyperkalemia, impaired
responses to ACE inhibitor and diuretics, and mortality. (See "Drugs
that should be avoided or used with caution in patients with heart
failure", section on 'Nonsteroidal anti-inflammatory
drugs' and "NSAIDs: Acute kidney injury (acute renal failure)",
section on 'Risk factors'.)
 ●Drugs that increase the risk of hyperkalemia when used with an ACE
inhibitor:
•Potassium supplements should be used only when required to
maintain serum potassium levels. (See "Drugs that should be
avoided or used with caution in patients with heart failure",
section on 'Drugs that may cause hyperkalemia'.)
•The potassium-sparing
diuretics amiloride and triamterene should generally be avoided
given the potential risk of hyperkalemia.
•Selected patients treated with ACE inhibitors for HFrEF (including
those with symptomatic HF with LVEF ≤35 percent) are
candidates for mineralocorticoid receptor antagonist therapy, but
careful monitoring of serum potassium and renal function is
required to avoid hyperkalemia. (See "Use of mineralocorticoid
receptor antagonists in heart failure with reduced ejection
fraction", section on 'Selection of patients'.)
●In the patient taking an ACE inhibitor,  trimethoprim/trimethoprim-
sulfamethoxazole should be avoided or used with caution with
careful monitoring given the increased risk of hyperkalemia and acute
kidney injury with this combination of drugs. (See "Drugs that should
be avoided or used with caution in patients with heart failure",
section on 'Trimethoprim-sulfamethoxazole'.)

EVIDENCE

General efficacy — ACE inhibitors are recommended to treat HFrEF

dysfunction because multiple large, prospective, randomized trials have
consistently demonstrated a significant reduction in mortality (table
1) [1-5] as well as alleviation of symptoms and improvement in clinical
status [6-8]. The benefit of ACE inhibitors has been demonstrated in all
severities of symptomatic HF and in patients with asymptomatic left
ventricular (LV) dysfunction; a benefit has also been demonstrated after
myocardial infarction (MI).

A meta-analysis evaluated five trials (three starting during the first one to
three weeks post-MI) involving 12,763 patients with LV ejection fraction
(LVEF) ≤35 percent or <40 percent and/or clinical HF. ACE inhibition had
the following benefits compared with placebo [22]:
 ●A lower total mortality (23 versus 27 percent for placebo, odds ratio
[OR] 0.80, 95% CI 0.74-0.87) (figure 1). Most of the mortality benefit
was due to fewer deaths from progressive HF. This benefit of
treatment was apparent soon after the start of treatment and
continued to increase after more than four years.
●A lower rate of readmission for HF (14 versus 19 percent, OR 0.67,
95% CI 0.61-0.74).
●A lower incidence of MI (9 versus 11 percent, OR 0.79, 95% CI 0.70-
0.89), but no difference in stroke.

Overall, there was a significant reduction in death, MI, and hospital

admission for HF (OR 0.72, 95% CI 67-78 percent). This translates into
seven patients with at least one event prevented for every 100 patients
treated.

Effect of dose — As described above, we titrate ACE inhibitor therapy to

the highest tolerated dose up to the doses used in clinical trials, although
there is limited evidence on the efficacy of higher doses compared with
lower doses.

Support for the use of high doses comes from the observation that, in
patients on chronic ACE inhibitor therapy, gradual reactivation of
vascular tissue formation of angiotensin II occurs over time [32,33]. This
is seen in those with progressive HF as well as those who are clinically
stable. Conversion can be suppressed by increasing the dose of the ACE
inhibitor. However, high and low ACE inhibitor doses may be associated
with similar plasma angiotensin II and aldosterone concentrations [34].

One analysis evaluated observational data on 16,539 patients with a first

HF hospitalization [35]. During one year of follow-up, 4186 (25 percent)
died. Compared with patients on a low-dose ACE inhibitor, those on a high
dose had a significant reduction in mortality (hazard ratio [HR] 0.76).

Three controlled trials have addressed the issue of optimal dosing (low
compared with standard or high doses) and clinical outcome, with
conflicting results:

●The largest trial (ATLAS) suggested that there may be a decrease in

morbidity but not mortality with higher doses. The ATLAS trial
randomly assigned 3164 patients to either low- (2.5 to 5 mg) or high-
 dose (32.5 to 35 mg) lisinopril. Compared with the low-dose regimens,
high-dose lisinopril reduced mortality by an insignificant 8 percent,
although it significantly lowered the combined end point of mortality
and hospitalization for any cause by 12 percent and hospitalizations
for HF by 24 percent [27]. These benefits of high-dose lisinopril were
also seen in high-risk patients, including those with diabetes,
hypotension, hyponatremia, renal dysfunction, and elderly patients
[36].
●One trial randomly assigned 1532 patients with HF to three different
doses of enalapril (2.5, 5, and 10 mg twice per day) for six months;
the incidence of the primary end point of death, HF-related
hospitalization, or worsening of HF was similar in the three groups
(12, 13, and 15 percent, respectively) [37].
●A similar lack of dose dependence was noted in a second study of
248 patients that compared standard doses
of enalapril (20 mg/day) with high doses of up to 60 mg/day (mean
dose achieved 42 mg/day) [38].

Use in subgroups — Evidence from clinical trials suggests that ACE

inhibitor therapy for HFrEF is beneficial across various patient subgroups
including varying functional classes of HF, elderly patients, patients with
diabetes mellitus, and after MI. Although there are less data available on
the efficacy of ACE inhibitor therapy among women and black patients
with HFrEF, the available data suggest that recommendations for ACE
inhibitor therapy for HFrEF are appropriate regardless of gender or race.

Severity of HF — In randomized controlled trials studying patients with

New York Heart Association (NYHA) functional class ranging from II to IV,
ACE inhibitor therapy reduced mortality compared with placebo [1,2,39]:

●The CONSENSUS study group evaluated 253 patients with advanced

NYHA III or IV HF who were being treated with diuretics, digitalis, and
vasodilating agents, primarily nitrates [1]. The administration
of enalapril significantly reduced the six-month mortality by 40
percent when compared with placebo (26 versus 44 percent) and the
12-month mortality by 31 percent (36 versus 52 percent) (figure 2).
This benefit was sustained for at least four years, and the risk
reduction averaged over the 10-year duration of the trial was 30
percent (figure 3) [40]. In addition to the mortality benefit, enalapril
 was associated with significant reductions in NYHA class and in the
requirement for other HF therapies.
●The SOLVD treatment trial evaluated 2569 patients with
symptomatic NYHA class II to III HF with LVEF ≤35 percent [2]. When
compared with placebo, enalapril resulted in a significant reduction
in all-cause mortality (35 versus 40 percent, risk reduction 16
percent, 95% CI 5-26 percent) (figure 4).
A subsequent analysis, called XSOLVD, followed the patients in the
SOLVD treatment trial up to a median of 12 years; the outcome was
determined in virtually all of the original participants [39]. The
reduction in all-cause mortality in the enalapril group narrowed over
time and was no longer significant at 12 years, at which time 80
percent of patients in both groups had died (HR 0.93, 95% CI 0.85-
1.01). Overall, enalapril significantly increased median life
expectancy by 8.6 months.

In one randomized controlled trial in patients with NYHA class II or III HF,
ACE inhibitor therapy reduced mortality compared with the combination
of hydralazine and isosorbide dinitrate. The efficacy of ACE inhibitors
compared with hydralazine plus isosorbide dinitrate in patients with
NYHA class II and III HF was evaluated in the V-HeFT II trial of 806 men
[3]. After two years, the mortality rate was significantly lower
with enalapril (18 versus 25 percent with isosorbide/hydralazine) (figure
5). Subgroup analyses revealed a survival benefit from enalapril versus
hydralazine plus isosorbide dinitrate in white patients but not black
patients, although the interaction between race and treatment was not
statistically significant (p = 0.09) [41]. (See 'Influence of race' below.)

Effect of renal dysfunction — A reduced glomerular filtration rate (GFR)

is associated with a worse prognosis in patients with HF, at least in part
because it reflects decreased renal perfusion due to more severe cardiac
disease. (See "Cardiorenal syndrome: Prognosis and treatment", section
on 'Reduced GFR and prognosis'.)

Clinical trials of ACE inhibitor therapy for HFrEF have included patients
with mild renal dysfunction (Kidney Disease Outcomes Quality Initiative
[KDOQI] stage 1 [GFR ≥90 mL/min/1.73 m2] or stage 2 [GFR 60 to
89 mL/min/1.73 m2] chronic kidney disease [CKD]), who have represented
approximately one-third of patients in randomized trials [28]. Thus, there
is strong evidence of benefit from ACE inhibitor therapy in patients with
HFrEF with mild CKD.

There is also evidence of benefit from ACE inhibitor therapy in patients

with HFrEF with moderate renal dysfunction (stage 3 CKD; estimated GFR
[eGFR] 30 to 59 mL/min/1.73 m2), as some clinical trials of ACE inhibitor
therapy for HFrEF have included these patients. In the CONSENSUS trial
in patients with severe HF, the mean eGFR was approximately
47 mL/min/1.73 m2 [1]. Substudy analyses of data from CONSENSUS of
the impact of serum creatinine on ACE inhibitor effect have yielded mixed
results [42,43]. In the SOLVD, ATLAS, and SAVE trials, moderate renal
dysfunction did not significantly modify the clinical effect of ACE inhibitor
therapy [28,44-46].

By contrast, evidence is lacking on the efficacy of ACE inhibitor therapy

for HFrEF in patients with severe renal dysfunction (stage 4 and 5 CKD;
eGFR <30 mL/min/1.73 m2). We avoid ACE inhibitor therapy in nondialysis
patients with serum creatinine >3.5 mg/dL (310 micromol/L) or eGFR
<20 mL/min/1.73 m2 [21,28]. Patients treated with dialysis can be treated
with ACE inhibitors, with careful monitoring to avoid hyperkalemia.
(See "Therapy of heart failure in hemodialysis patients", section on
'Pharmacologic therapy for systolic dysfunction'.)

Of note, short-term worsening of renal function in response to an ACE

inhibitor does not necessarily indicate long-term intolerance to
angiotensin inhibition or lack of benefit from therapy, as illustrated by the
following observations.

●In the CONSENSUS trial, the rise in serum creatinine following

initiation of enalapril therapy occurred within the first three weeks
and then remained stable to the end of follow-up at six months [29].
Although most patients assigned to ACE inhibitor therapy in this trial
experienced an increase in serum creatinine, mortality at one year
was reduced by 31 percent with ACE inhibitor therapy compared with
placebo [1].
●An analysis of data on 6337 subjects enrolled in the SOLVD trial
showed that early worsening renal function (decrease in eGFR by at
least 20 percent at 14 days) was not associated with increased
mortality in the enalapril group but was associated with increased
mortality in the placebo group [47]. A significant survival benefit from
 enalapril therapy was observed in patients who continued enalapril
despite early worsening renal function.

Elderly patients — All of the major randomized trials included many

elderly patients. However, some elderly patients with comorbidities
would likely have been excluded from these trials. Despite this concern,
community-based observational studies support a benefit from ACE
inhibitors in elderly patients with HF that is similar in magnitude to that
seen in younger patients [48,49]. Long-term benefit is seen even in those
who have a perceived contraindication to ACE inhibitors (systolic
pressure ≤90 mmHg, serum creatinine
≥2.5 mg/dL [221 micromol/L], serum potassium ≥5.5 meq/L, and severe
aortic stenosis) [50,51].

Influence of gender — ACE inhibitors should be used in women (as well

as men) with HFrEF, although the available data are not definitive [52], as
illustrated by the following studies:

●A meta-analysis of ACE inhibitor trials suggested that the benefit

from these drugs might not apply to women [53]. A total of 3492 men
and 1079 women from three trials were included. The relative
mortality risk with ACE inhibitor therapy was significantly reduced in
men at 0.80 (95% CI 0.68-0.93) but showed only a trend toward
significance in women at 0.90 (95% CI 0.78-1.05). However, the
difference in effect between men and women did not reach statistical
significance (p = 0.07).
●An observational study of 27,837 patients with a discharge diagnosis
of HF suggested that ACE inhibitors improve survival in women and
men although the estimated effect was larger in men (adjusted HR
women 0.80, 95% CI 0.76-0.85; adjusted HR men 0.71, 95% CI 0.67-
0.75) [54].

Influence of race — There are conflicting data as to whether blacks have

a lesser response to ACE inhibition than whites. Given the available
evidence, ACE inhibitor therapy recommendations are the same for
blacks as for whites [52].

A post-hoc analysis of data from the V-HeFT trials and a matched cohort
study of the SOLVD trials suggested that there may be differences
between blacks and whites in their responses to ACE inhibitors
[41,55,56]. Two major findings were noted:

●In both studies, black and white patients randomly assigned to

placebo had similar rates of hospitalization for HF and mortality
[41,56].
●In the SOLVD matched cohort study, enalapril compared with
placebo was associated with a 44 percent reduction in hospitalization
in whites; by contrast, there was no significant reduction among
blacks (figure 6) [56].

A lack of response in blacks has some biologic plausibility since similar

findings have been noted in patients with hypertension. Blacks respond
less well to ACE inhibitors than to most other antihypertensive drugs
(figure 7) [57]. In the matched cohort study from SOLVD, there were
significant reductions in systolic and diastolic pressure with enalapril in
whites (5/3.6) but not blacks [56]. It is not known if higher doses of an
ACE inhibitor might be more effective, although such a relationship has
been noted in hypertensive patients [58]. (See "Treatment of
hypertension in blacks".)

On the other hand, other observations suggest that ACE inhibitors have
similar effects in blacks and whites:

●An analysis of mortality data from the SOLVD trials found no

significant difference in the relative risk (RR) reduction for blacks as
compared with whites (RR for blacks 0.89, 95% CI 0.74-1.06; RR for
whites 0.89, 95% CI 0.82-0.97) [53]. The RR was significant in whites
but not blacks, an observation that is likely to be explained by the
smaller number of blacks in the trials (800 versus 5718).
●In an analysis limited to the SOLVD prevention trial, enalapril was
largely as effective in blacks as whites in preventing progression from
asymptomatic LV dysfunction to symptomatic HF [59]. As in the
matched cohort study, a significant reduction in first hospitalization
for HF was seen only in whites (RR 0.64 versus 0.85 in blacks).
However, this end point was much less frequent than progression to
symptomatic HF, and it is therefore uncertain if the difference in
response was real. (See "Management and prognosis of
asymptomatic left ventricular systolic dysfunction".)
A separate issue is the relative effect of another type of vasodilating
therapy, hydralazine plus isosorbide dinitrate, on survival in blacks and
whites. This issue is discussed separately. (See "Hydralazine plus nitrate
therapy in patients with heart failure with reduced ejection fraction".)

Influence of diabetes — The above meta-analysis of ACE inhibitor trials

found that the beneficial effect of ACE inhibitors in HF was the same for
patients with and without diabetes [53]. (See "Heart failure in diabetes
mellitus".)

After myocardial infarction — ACE inhibitors improve the outcome in

patients with asymptomatic LV dysfunction or overt HF occurring after an
acute MI. Evidence confirming these benefits and recommendations for
use are described in detail elsewhere. (See "Angiotensin converting
enzyme inhibitors and receptor blockers in acute myocardial infarction:
Clinical trials" and "Angiotensin converting enzyme inhibitors and
receptor blockers in acute myocardial infarction: Recommendations for
use".)

After revascularization — Although the prognosis of patients with

coronary artery disease and reduced LV function is improved with
revascularization, their outcome is still worse than in those who have
normal LV function. Since ACE inhibitors improve the outcome of patients
with asymptomatic LV dysfunction, they may be of benefit after
revascularization (figure 8). The data supporting this association are
presented elsewhere. (See "Medical therapy to prevent complications
after coronary artery bypass graft surgery", section on 'Angiotensin
converting enzyme inhibitors'.)

Use with other drugs

Use with other standard HFrEF drugs — For patients with HFrEF, ACE
inhibitor therapy is one component of combination pharmacologic therapy
that improves symptoms and prolongs survival. In addition to ACE
inhibitors, other drugs, including beta blockers and mineralocorticoid
receptor antagonists have been shown to improve survival in patients
with HFrEF (see "Overview of the therapy of heart failure with reduced
ejection fraction"). Most patients in the major trials evaluating beta
blockers were also treated with an ACE inhibitor (as well as diuretics
and digoxin as necessary). These trials showed that combination
therapy with an ACE inhibitor and beta blocker was more effective than
an ACE inhibitor or beta blocker alone in both symptomatic HF and
asymptomatic LV dysfunction (figure 9A-B) [60]. (See "Use of beta
blockers in heart failure with reduced ejection fraction".)

There is also an additive survival benefit with ACE inhibitors and

mineralocorticoid receptor antagonists (spironolactone or eplerenone) in
appropriately monitored patients with HFrEF [61-63]. A potential concern
is that ACE inhibitors and aldosterone antagonists both tend to raise the
plasma potassium concentration with risk of potentially life-threatening
hyperkalemia. (See "Use of mineralocorticoid receptor antagonists in
heart failure with reduced ejection fraction".)

Routine use of the combination of an ACE inhibitor and an angiotensin II

receptor blocker (ARB) is potentially harmful and should be avoided.
(See "Use of angiotensin II receptor blocker in heart failure with reduced
ejection fraction", section on 'Use MRA rather than ARB with ACE
inhibitor'.)

The use of an angiotensin receptor-neprilysin inhibitor (ARNI, sacubitril-

valsartan) as an alternative to an ACE inhibitor in patients with HFrEF is
discussed separately. (See "Use of angiotensin receptor-neprilysin
inhibitor in heart failure with reduced ejection fraction".)

No benefit from addition of aliskiren — In patients with chronic NYHA

class II to IV HFrEF, a randomized trial found that the addition of the renin
inhibitor aliskiren to the ACE inhibitor enalapril led to more adverse
events (symptomatic hypotension, serum creatinine level
≥2.5 mg/dL, and serum potassium level >5.5 mmol/L) without an
improvement in outcomes [64]. Outcomes with aliskiren (in place of
enalapril) were similar to those with enalapril, but the criterion for
noninferiority of aliskiren compared with enalapril was not met. Given
these results, a role for aliskiren in the treatment of HFrEF has not been
established.

Aspirin interaction probably not significant — Although aspirin may

attenuate some of the acute hemodynamic effects of ACE inhibitors [65],
most of the evidence does not support a clinically significant adverse
effect of aspirin on the long-term outcome benefits of ACE inhibitors in HF
[66]. In patients with HF who have an indication for aspirin (eg, coronary
artery disease), aspirin should be used. For patients with HF without an
indication for antithrombotic therapy, aspirin is not indicated.
(See "Drugs that should be avoided or used with caution in patients with
heart failure", section on 'Aspirin' and "Antithrombotic therapy in
patients with heart failure".)

Aspirin, which is commonly given to patients with HF for indications

including coronary heart disease, is a prostaglandin synthesis inhibitor
and therefore might interfere with the efficacy of ACE inhibitors [66]. ACE
inhibitors reduce kinin degradation. Increased kinin levels may contribute
to the observed benefit seen with these drugs, an effect that may be
mediated by enhanced release of vasodilator prostaglandins. Aspirin
attenuates the beneficial effect of enalapril on systemic vascular
resistance and cardiac output in patients with severe HF [65].

Systematic reviews and observational studies have not demonstrated a

significant effect of aspirin on the clinical efficacy of ACE inhibitors
[22,60,67,68]. In a meta-analysis of five trials (three post-MI and including
SOLVD) involving 12,763 patients with HF or LV dysfunction (as described
above), aspirin did not significantly affect the benefits of ACE inhibitors
on mortality or the composite endpoint of death, HF, or MI [22]. Similarly,
an analysis of data from the WARCEF trial in 2305 patients with HFrEF
(nearly all treated with ACE inhibitors) randomly assigned to receive
either warfarin or aspirin found no difference in risk of HF events
between aspirin and warfarin-treated patients [69]. Thus, although some
studies suggest that aspirin may offset some of the survival benefit
of enalapril [70-72], the preponderance of the evidence suggests that
aspirin does not significantly affect mortality and HF events in patients
with HFrEF treated with ACE inhibitors.

Utilization — Despite the proven benefit of ACE inhibitors for reducing

mortality in HFrEF, many patients are not treated [48,49,73-77], and
treated patients often receive a less-than-recommended dose [77,78].
Patients with HFrEF with renal dysfunction are less likely to be treated
with ACE inhibitors [49] and are more likely to receive lower than
generally recommended doses [77].

PREVENTION OF HF — The efficacy of ACE inhibitors in patients with

asymptomatic left ventricular (LV) dysfunction is discussed separately.
(See "Management and prognosis of asymptomatic left ventricular
systolic dysfunction".)
Data from a post-hoc analysis of the HOPE trial suggest that ACE inhibitor
therapy may reduce the risk of developing HF in high-risk patients without
LV dysfunction [79]. Two prospectively defined end points (HF death and
HF hospitalization) were combined with two post-hoc end points (HF
leading to open label ACE inhibitor use or development of signs and
symptoms of HF). Ramipril significantly reduced the event rate
compared with placebo (9.0 versus 11.5 percent, RR 0.77). However, it is
not clear whether this benefit was a specific effect of ACE inhibition or a
consequence of blood pressure reduction.

SOCIETY GUIDELINE LINKS — Links to society and government-

sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Heart failure
in adults".)

SUMMARY AND RECOMMENDATIONS

●For patients with heart failure with reduced ejection fraction (HFrEF;
with left ventricular ejection fraction [LVEF] ≤40 percent), we
recommend angiotensin converting enzyme (ACE) inhibitor therapy
(Grade 1A). (See 'Indications' above.)
●As discussed separately, we suggest use of an ACE inhibitor (or
single-agent angiotensin II receptor blocker [ARB] (see "Use of
angiotensin II receptor blocker in heart failure with reduced ejection
fraction")) rather than sacubitril-valsartan as a component of initial
medical therapy for HFrEF (algorithm 1). Some experts have instead
suggested use of sacubitril-valsartan as a component of initial
therapy for HFrEF. The use of sacubitril-valsartan as an alternative to
an ACE inhibitor in patients with HFrEF is discussed separately.
(See "Use of angiotensin receptor-neprilysin inhibitor in heart failure
with reduced ejection fraction".)
●Multiple large, prospective, randomized trials have consistently
demonstrated that ACE inhibitor therapy in patients with HFrEF (LVEF
≤40 percent) results in a significant reduction in mortality as well as
alleviation of symptoms and improvement in clinical status. Transition
to sacubitril-valsartan to improve outcomes is discussed separately.
(See 'General efficacy' above and "Use of angiotensin receptor-
neprilysin inhibitor in heart failure with reduced ejection fraction".)
●For patients with HFrEF, ACE inhibitor therapy is one component of
combination therapy (along with beta blocker therapy and, in selected
patients, mineralocorticoid receptor antagonist), which improves
symptoms and prolongs survival. ACE inhibitor therapy is generally
started at low doses (eg, 5 to 10 mg daily of lisinopril) to reduce the
likelihood of complications such as hypotension and azotemia. If
initial therapy is tolerated, the dose is then gradually increased to a
maintenance dose of up to 40 mg/day of lisinopril
or quinapril unless side effects occur. (See 'Dose initiation and
titration' above and "Overview of the therapy of heart failure with
reduced ejection fraction".)
●Side effects of ACE inhibitors include hypotension, worsening renal
function (discussed below), hyperkalemia, cough, and angioedema.
(See 'Side effects' above.)
●ACE inhibitor therapy has a variable effect on the glomerular
filtration rate (GFR) in patients with HF, as usually estimated from the
serum creatinine concentration. Worsening renal function as
evidenced by increases in serum creatinine is observed in
approximately 10 to 35 percent of patients with HFrEF after initiation
of an ACE inhibitor. However, some patients have no change in serum
creatinine, and approximately 10 to 25 percent have a reduction in
serum creatinine. (See 'Frequency' above.)
●Short-term worsening of renal function in response to an ACE
inhibitor does not necessarily indicate long-term intolerance to
angiotensin inhibition or lack of benefit but should prompt evaluation
of the diuretic regimen and other possible causes of worsening renal
function. (See 'Worsening renal function' above and 'Effect of renal
dysfunction' above.)
●The available data suggest that ACE inhibitor therapy for HFrEF is
beneficial across various patient subgroups including varying
functional classes of HF, elderly patients, patients with diabetes
mellitus, and after myocardial infarction. There are limited data
available on the efficacy of ACE inhibitor therapy among women with
HFrEF and black patients with HFrEF. Given the available evidence,
recommendations for ACE inhibitor therapy for HFrEF apply regardless
of patient gender or race. (See 'Use in subgroups' above.)