JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
5, 2019
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VOL. 74, NO.
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
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JACC FOCUS SEMINAR: PHARMACOLOGICAL AGENTS FOR CV CARE
JACC STATE-OF-THE-ART REVIEW
From ACE Inhibitors/ARBs to ARNIs in
Coronary Artery Disease and
Heart Failure (Part 2/5)
Darryl P. Leong, MBBS, MPH, MBIOSTAT, PHD,a John J.V. McMurray, MD,b Philip G. Joseph, MD,a
Salim Yusuf, MBBS, DPHILa
ABSTRACT
The pharmacological inhibition of the renin-angiotensin-aldosterone system as a therapeutic strategy is one of the
most significant advances in the treatment and prevention of cardiovascular disease in heart failure with reduced
ejection fraction and in coronary artery disease. Recently, the addition of neprilysin inhibition to angiotensin receptor
blockade has been shown to be even more effective than angiotensin-converting enzyme inhibition alone in heart
failure with reduced ejection fraction, marking an important new milestone in heart failure treatment. This review
summarizes the major trials that have informed the clinical role of inhibition of the renin-angiotensin-aldosterone
and neprilysin pathways, as well as the limitations of these strategies. (J Am Coll Cardiol 2019;74:683–98)
© 2019 by the American College of Cardiology Foundation.
T he objectives of this paper are to provide
guidance on the use of drugs that act on
the renin-angiotensin-aldosterone
(RAAS) and the natriuretic peptide pathways in coro-
system
infarction (MI); plasminogen activator inhibitor C-1 is
an important inhibitor of tissue-type plasminogen
activator, thus blocking endogenous fibrinolysis.
Aldosterone, whose release is triggered in part by
nary artery disease and in heart failure (HF) (Central angiotensin II, has several effects that may be delete-
Illustration), and to highlight the remaining areas of rious, including enhancing fibrosis through both in-
uncertainty in this field. Braunwald (1) elegantly flammatory and noninflammatory pathways and
described how the physiological role of the RAAS promoting hypertrophy in the heart and in blood
was discovered at the beginning of the twentieth cen- vessels (4,5).
tury. Subsequently, we have come to understand that In the latter half of the twentieth century, atrial
the major physiological role of activation of the RAAS natriuretic peptides (ANPs) were described following
(i.e., preventing hypotension by enhancing vascular the observation in rats of a relationship between so-
smooth muscle contraction and promoting sodium dium loading and the histological finding of “gran-
reabsorption in the proximal renal tubules) is ulti- ules” within their atrial tissue (6). These granules
mately maladaptive if allowed to persist. Chronic were presumed to contain secretory molecules
elevation of angiotensin II stimulates myocardial hy- related to sodium and water homeostasis. This hy-
pertrophy and promotes oxidative stress. Angiotensin pothesis was supported by the finding that when
II also induces the synthesis of plasminogen activator atrial tissue extracts were injected intravenously in
inhibitor C-1 (2,3), which is a risk factor for myocardial rats, significant natriuresis occurred (7). Since then,
From aThe Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada;
and the bBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. All authors
have reported that their respective institutions have received research support from granting agencies and pharmaceutical
companies that manufacture products described in this paper. Dr. Leong is funded by the Heart and Stroke Foundation of Canada.
Dr. Yusuf is funded by the Marion Burke Chair of the Heart and Stroke Foundation of Canada.
Manuscript received February 18, 2019; revised manuscript received April 17, 2019, accepted April 17, 2019.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.04.068
684 Leong et al. JACC VOL. 74, NO. 5, 2019

ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease AUGUST 6, 2019:683–98

ABBREVIATIONS several classes of natriuretic peptide have

AND ACRONYMS HIGHLIGHTS
been recognized, including ANP, B-type
natriuretic peptide (BNP), C-type natriuretic  CVD is the leading cause of death
ACE = angiotensin converting
enzyme
peptide, dendroaspis natriuretic peptide, and globally.
urodilatin (8). These peptides are expressed
ANP = atrial natriuretic peptide  Inhibition of the RAS reduces mortality by
in diverse tissues, including cardiovascular
ARB = angiotensin receptor 11% in individuals with atherosclerotic
blocker (CV), brain, and renal, and are released as
vascular disease.
ARNI = angiotensin receptor-
pro-hormones in response to stimuli
neprilysin inhibitor including myocardial distension (ANP and  In individuals with HF and reduced LVEF,
BNP = brain natriuretic peptide BNP) and vascular shear stress (C-type inhibition of the RAS and blockade of
HF = heart failure natriuretic peptide) (9). They are cleaved to mineralocorticoid receptors reduce mor-
HFpEF = heart failure with
yield active molecules that stimulate vaso- tality by 19%, and the combination of
preserved ejection fraction dilatation (by stimulating cyclic GMP syn- valsartan-sacubitril reduced mortality
HFrEF = heart failure with thesis), natriuresis, and diuresis (by beyond enalapril by a further 16% in the
reduced ejection fraction increasing renal blood flow and by inhibiting PARADIGM-HF trial.
LVEF = left ventricular ejection sodium reabsorption from the proximal and
fraction  Further research is needed to identify
distal tubules), and inhibit renin and aldo-
MI = myocardial infarction strategies to improve clinical outcomes
sterone release and myocardial hypertrophy
for individuals with HF and preserved or
MRA = mineralocorticoid and fibrosis. The finding that natriuretic
receptor antagonist midrange ejection fraction.
peptides are removed from the circulation in
NT-proBNP = amino-terminal
part by a peptidase, variously named nepri-
pro-brain natriuretic peptide up-titration to 50 mg twice daily) or placebo was
lysin or neutral endopeptidase, led to the
RAAS = renin-angiotensin- given to participants within 24 h of suspected MI (12).
aldosterone system
development of neprilysin inhibitors that
A total of 70% of participants received fibrinolytic
promote natriuresis and diuresis through
RAS = renin-angiotensin
therapy. Patients in cardiogenic shock or with
system augmentation of natriuretic peptides while
persistent, severe hypotension were not included in
simultaneously inhibiting the RAAS. Impor-
the trial. In those randomized to captopril, the 5-week
tantly, neprilysin also degrades angiotensin II, so that
mortality rate was 7.19%, which was significantly
its chronic inhibition leads to increased angiotensin II
lower than in the placebo group (7.69% 5-week mor-
concentrations (10), which could offset some of its
tality; p ¼ 0.02). In the Chinese Cardiac Study, 13,634
salutary effects when unaccompanied by inhibition of
patients presenting to 650 Chinese hospitals within
the RAAS.
36 h of onset of a suspected MI who had systolic blood
Over the last 3 decades, angiotensin-converting
pressure $90 mm Hg were randomized to receive
enzyme (ACE) inhibitors, angiotensin receptor
captopril at doses that were titrated up to 12.5 mg 3
blockers (ARBs), mineralocorticoid receptor antago-
times daily or placebo (13). At 4 weeks’ follow-up,
nists (MRAs), and now, more recently, angiotensin
9.1% of captopril recipients died compared with
receptor-neprilysin inhibitors (ARNIs) have been
9.6% of placebo recipients. In a pooled analysis of
proven to reduce mortality and morbidity in a range
trials comparing ACE inhibitors with a control group
of cardiovascular disease (CVD) conditions. In the
in patients within 36 h of the onset of symptoms of a
following text, we will describe the results of the
MI, the 30-day mortality rate was 7.11% among 49,214
major clinical trials in several CV conditions.
participants allocated to ACE inhibitor and was 7.59%
ACUTE CORONARY SYNDROMES: among 49,269 control participants (14). Thus, ACE
EARLY, SHORT-TERM TREATMENT inhibitor leads to a 7% (95% CI: 2% to 11%) reduction
OF UNSELECTED PATIENTS in the risk of 30-day death when initiated within 36 h
of the onset of MI. Therefore, in patients without
In the GISSI-3 (Gruppo Italiano per lo Studio severe hypotension, an ACE inhibitor should be
della Sopravvivenza nell’infarto Miocardico-3) trial initiated during the index hospitalization for a MI.
(Figure 1), 19,394 patients were randomized to receive
lisinopril versus control within 24 h of the onset of ACUTE CORONARY SYNDROMES:
symptoms of an acute MI (11). At 6 weeks, mortality LONG-TERM TREATMENT OF
was significantly reduced by lisinopril, with an odds SELECTED HIGH-RISK PATIENTS
ratio: 0.88 (95% confidence interval [CI]: 0.84
to 0.98). In the ISIS-4 (Fourth International Study In the SAVE (Survival and Ventricular Enlargement)
of Infarct Survival), captopril (with rapid-dose trial (Figure 1), 2,231 patients with left ventricular
JACC VOL. 74, NO. 5, 2019 Leong et al. 685
AUGUST 6, 2019:683–98 ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease

C ENTR AL I LL U STRA T I O N Evidence to Support the Use of Angiotensin-Converting Enzyme Inhibitor,

Angiotensin Receptor Blocker, Mineralocorticoid Receptor Antagonist, and Angiotensin Receptor-Neprilysin Inhibitors in
Coronary Artery Disease and Heart Failure

Atherosclerotic Coronary Heart Failure - Increasing Left

Disease – Increasing Risk Ventricular Ejection Fraction

High-Risk Heart Failure Heart Failure Heart Failure

Stable Acute Post- With With With
Post-
Atherosclerotic Myocardial Reduced Midrange Preserved
Myocardial
Vascular Disease Infarction Ejection Ejection Ejection
Infarction Fraction Fraction Fraction
Angiotensin-Converting + + + + ? –
Enzyme Inhibitor

Angiotensin Receptor + + + + ? –
Blockers

Mineralocorticoid ? + + + ? (+)
Receptor Antagonists

Angiotensin Receptor- ? To Be To Be + To Be To Be
Neprilysin Inhibitors Determined Determined Determined Determined

Leong, D.P. et al. J Am Coll Cardiol. 2019;74(5):683–98.

D ¼ the presence of clinical trial evidence to support use; (þ) ¼ weak clinical trial evidence to support use;  ¼ neutral clinical trials; ? ¼ a lack of evidence to support
use.

ejection fraction (LVEF) #40% but no HF or ischemic from 23% to 17%; the risk reduction was 27%
symptoms 3 to 16 days following MI were randomized (95% CI: 11% to 40%). A meta-analysis of SAVE,
to receive captopril or placebo (Table 1) (15). After an TRACE, and AIRE found that in patients with left
average follow-up of 3.5 years, 25% of the placebo ventricular dysfunction or HF within 3 to 16 days after
group and 20% of the captopril group died. Captopril an acute MI, the use of ACE inhibitor led to a 23.4%
led to a 19% (95% CI: 3% to 32%) reduction in mor- mortality rate at 31 months compared with a 29.1%
tality. In the TRACE (Trandolapril Cardiac Evaluation) mortality rate among placebo recipients; odds ratio
trial, 1,749 patients with left ventricular systolic 0.74 (95% CI: 0.66 to 0.83) (18).
dysfunction (equivalent to LVEF #35%) 3 to 7 days ANGIOTENSIN RECEPTOR BLOCKERS VERSUS ACE
after MI were randomized to receive trandolapril or INHIBITORS. The VALIANT (Valsartan in Acute
placebo (16). Follow-up ranged from 24 to 50 months. Myocardial Infarction) trial compared the ARB val-
Trandolapril led to a reduction in mortality from as sartan with the ACE inhibitor captopril in patients up
early as 1 month after randomization. During follow- to 10 days following MI who had clinical or radiolog-
up, 34.7% of the trandolapril group died as ical signs of HF, moderate-severe systolic LV
compared with 42.3% of the placebo group; the dysfunction, or both (19). This study demonstrated
overall relative risk of death was 0.78 (95% CI: 0.67 to the noninferiority of valsartan at a noninferiority
0.91). In the AIRE (Acute Infarction Ramipril Efficacy) margin for death of 1.13. The 1-year mortality rates
study, patients with clinical evidence of HF, irre- were 12.5% in the valsartan group and 13.3% in the
spective of left ventricular systolic function, 3 to captopril group, and the rates of hospitalization for
10 days following an acute coronary syndrome were MI or HF were 18.7% in the valsartan group and 19.3%
randomized to receive ramipril or placebo (17). During in the captopril group during a median follow-up of
an average 15 months of follow-up, 17% of the ram- 25 months. Therefore, in high-risk individuals
ipril group died compared with 23% of the placebo following a MI, an ARB is an acceptable alternative to
group. Ramipril use led to a reduction in mortality an ACE inhibitor.
686 Leong et al. JACC VOL. 74, NO. 5, 2019

ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease AUGUST 6, 2019:683–98

F I G U R E 1 Chronology of Landmark Trials Involving RAAS/ACE inhibitors in HFrEF and CAD

HFrEF Coronary Artery Disease

Timeline

1987 - CONSENSUS: 1st trial to demonstrate

mortality reduction using an ACE inhibitor in heart
failure

1990

1992 - SOLVD-P: 1st trial to show that ACE inhibitors
reduce death or heart failure in
asymptomatic systolic LV dysfunction
1999 - RALES: 1st trial to demonstrate
mortality reduction using MRA in addition
to ACE inhibitor
1992 - SAVE: 1st trial to show that ACE inhibitors reduce
long-term mortality post-MI with LV dysfunction
1994 - GISSI-3: 1st trial to show that ACE inhibitors reduce
short-term mortality post-MI
2000 2000 - HOPE: 1st trial to show that ACE inhibitors reduce
CV events in high-CV risk adults without HF

2003 - EUROPA: confirmed the efficacy of ACE inhibitors in

adults with stable coronary artery disease

2010

2014 - PARADIGM-HF: 1st trial to

demonstrate mortality reduction using
ARNI instead of ACE inhibitor

During the past 30 years, trials in heart failure with reduced ejection fraction (HFrEF) have demonstrated additive benefit of inhibition of the renin-angiotensin-
aldosterone axis (RAAS) and neprilysin, as well as the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients both with manifest coronary
artery disease (CAD) and at high risk of developing coronary disease. ARNI ¼ angiotensin receptor-neprilysin inhibitor; CONSENSUS ¼ Cooperative North Scandinavian
Enalapril Survival Study; CV ¼ cardiovascular; EUROPA ¼ EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease;
HOPE ¼ Heart Outcomes Prevention Evaluation; GISSI-3 ¼ Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico-3; LV ¼ left ventricular;
MI ¼ myocardial infarction; MRA ¼ mineralocorticoid receptor antagonist; PARADIGM-HF ¼ Prospective Comparison of ARNI with ACE-I to Determine Impact on Global
Mortality and Morbidity in Heart Failure; RALES ¼ Randomized Aldactone Evaluation Study; SOLVD-P ¼ Studies of Left Ventricular Dysfunction-Prevention.

MINERALOCORTICOID RECEPTOR ANTAGONISTS. after acute MI were randomized to eplerenone or

Eplerenone blocks the mineralocorticoid receptor
(and not glucocorticoid, progesterone, or androgen
receptors) more selectively than spironolactone. In
EPHESUS (Eplerenone Post-Acute Myocardial Infarc-
tion Heart Failure Efficacy and Survival Study), pa-
tients who had an LVEF #40% and clinical or
radiographic signs of HF (or diabetes) 3 to 14 days
placebo (20). In this trial, 87% of participants were
taking an ACE inhibitor or ARB at baseline (and 75% a
beta-blocker). During a mean follow-up of 16 months,
14.4% of the eplerenone group died compared with
16.7% of the placebo group, with relative risk: 0.85
(p ¼ 0.008). Eplerenone also reduced the number
of HF hospitalizations, with relative risk: 0.77
JACC VOL. 74, NO. 5, 2019 Leong et al. 687
AUGUST 6, 2019:683–98 ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease

T A B L E 1 Achieved Drug Doses in Positive Renin-Angiotensin-Aldosterone Inhibitor/Angiotensin Receptor-Neprilysin Inhibitor Trials

Heart Failure With Reduced Ejection Fraction Coronary Artery Disease

Trial Finding Daily Dose Achieved Trial Finding Daily Dose Achieved

CONSENSUS Enalapril reduced 6-month mortality in 18.4 mg SAVE Captopril reduced mortality from 25% 79% achieved 150 mg daily
patients with severe heart failure to 20% at 3.5 yrs after MI with
from 44% to 26% reduced LVEF
SOLVD-T Enalapril reduced 41-month mortality 11.2 mg ISIS-4 Captopril reduced 5-week mortality Target daily dose 100 mg
in patients with heart failure and from 7.69% to 7.19% following
LVEF #35% from 39.5% to 35.2% acute MI
SOLVD-P Enalapril reduced death or heart failure 16.7 mg EUROPA Perindopril reduced CV mortality, MI, 81% adherence at 3 yrs, of
in asymptomatic patients with and resuscitated cardiac arrest whom 93% were taking
LVEF #35% from 39% to 30% at from 10% to 8% at 4.2 yrs in 8 mg and 7% were
3 yrs patients with stable coronary taking 4 mg
artery disease
RALES Spironolactone reduced 2-yr mortality 26 mg HOPE Ramipril reduced 5-yr mortality from 10 mg taken by 83% at 1 yr
from 46% to 35% in patients with 12.2% to 10.4% in patients with and 62% at 4 yrs
severe HFrEF vascular disease or diabetes and 1
cardiovascular risk factor
EMPHASIS-HF Eplerenone reduced 21-month 39 mg
mortality from 15.5% to 12.5% in
patients with NYHA functional
class II heart failure and
LVEF #35%
PARADIGM-HF Valsartan/sacubitril reduced mortality 300 mg valsartan
at 27 months from 20% to 17% equivalent
compared with enalapril in patients
with symptomatic HFrEF

CONSENSUS ¼ Cooperative North Scandinavian Enalapril Survival Study; CV ¼ cardiovascular; EMPHASIS-HF ¼ Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure;
EUROPA ¼ EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease; HFrEF ¼ heart failure with reduced ejection fraction; HOPE ¼ Heart Outcomes Prevention
Evaluation; ISIS-4 ¼ Fourth International Study of Infarct Survival; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NYHA ¼ New York Heart Association; PARADIGM-HF ¼ Prospective
Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure; RALES ¼ Randomized Aldactone Evaluation Study; SAVE ¼ Survival and Ventricular Enlargement;
SOLVD-P ¼ Studies of Left Ventricular Dysfunction-Prevention; SOLVD-T ¼ Studies of Left Ventricular Dysfunction-Treatment.

(p ¼ 0.002). Therefore, in patients experiencing HF Angiotensin Converting Enzyme Inhibition). The

complicating acute MI, an MRA should be initiated, in
addition to an ACE inhibitor/ARB,
LVEF is #40%.
ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS. No
large trial of ARNI has been completed in patients
with an acute coronary syndrome. In the ongoing
PARADISE-MI (Prospective ARNI vs ACE Inhibitor
Trial to Determine Superiority in
Heart Failure Events after MI), patients will be ran-
domized to receive sacubitril-valsartan or ramipril
12 h to 7 days after an MI if they exhibit clinical HF or
LVEF #40% (NCT02924727). The results from this
trial, which are expected in 2020, will inform whether
ARNI confer additional benefit to ACE inhibitor in
patients with an acute coronary syndrome and
reduced LVEF or HF.
STABLE CORONARY DISEASE
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS.
Three large randomized trials have evaluated the role
of ACE inhibitor in stable coronary disease: HOPE
(Heart Outcomes Prevention Evaluation)
EUROPA (EURopean trial On reduction of cardiac
events with Perindopril in stable coronary Artery
disease) (22), and PEACE (Prevention of Events with
HOPE study (Figure 1) included 9,297 adults $55 years
if the of age with either vascular disease or diabetes plus 1
CVD risk factor. Individuals with known LV
dysfunction were excluded. Participants were ran-
domized to receive ramipril or placebo and were fol-
lowed for a mean of 5 years. Ramipril led to a
significant reduction in the primary outcome of MI,
Reducing stroke, or CVD death, with relative risk: 0.78 (95% CI:
0.70 to 0.86), with significant reductions in each
component (CV deaths, strokes, and MIs). The mor-
tality rate in the ramipril group was 10.4% compared
with 12.2% in the placebo group. In EUROPA, adults
with stable coronary disease were randomly allocated
to receive perindopril or placebo (22). The mean
follow-up was 4.2 years, during which 9.9% of the
placebo group experienced the primary endpoint of
CV death, MI, or cardiac arrest. Perindopril reduced
the risk of the primary endpoint with a relative risk
reduction of 20% (95% CI: 9% to 29%). The PEACE
trial evaluated the role of ACE inhibitor in lower-risk
patients with stable coronary disease, and normal or
slightly reduced LV function (23). Adults age $50
(21), years were eligible if they had any coronary disease
and LVEF >40%. The mortality rate in the placebo
group was 8.1% compared with 7.2% in the trando-
lapril group, with hazard ratio (HR): 0.89 (95% CI:
688 Leong et al.
ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease
0.76 to 1.04). The primary endpoint of CV death, MI,
or coronary revascularization occurred in 22.5% of the
placebo group and in 21.9% of the trandolapril group
over a median follow-up of 4.8 years; HR: 0.96
(95% CI: 0.88 to 1.06). This finding was less promising
than the HR observed for all-cause mortality, perhaps
because revascularization rates depend on local
practice, and the threshold for percutaneous coronary
intervention is relatively low in the United States.
Dagenais et al. (24) performed a pooled analysis of
HOPE, EUROPA, and PEACE. Over 4 to 5 years,
compared with placebo, ACE inhibitor led to a clear
reduction in overall mortality (7.8% vs. 8.9%;
p ¼ 0.0004), nonfatal MI (5.3% vs. 6.4%; p ¼ 0.0001),
stroke (2.2% vs. 2.8%; p ¼ 0.0004), and HF (2.1% vs.
2.7%; p ¼ 0.0007). A systematic review identified 6
trials in which patients with coronary disease and
preserved LVEF were randomized to ACE inhibitor or
placebo (25). The pooled relative risk of death in the
ACE inhibitor group was 0.87 (95% CI: 0.81 to 0.94).
PROGRESS (Perindopril protection against recurrent
stroke study) was a study conducted in patients with
a stable cerebrovascular disease (stroke or transient
ischemic attack) in which participants were randomly
allocated to receive perindopril 4 mg daily or placebo
(26). Perindopril reduced stroke risk with relative risk
reduction 28% (95% CI: 17% to 38%) and the risk of
any major CV event with relative risk reduction 26%
(95% CI: 16% to 34%), with similar risk reductions
observed among both non-hypertensives and hyper-
tensives. Thus, the findings from PROGRESS support
those from the trials conducted in stable coronary
artery disease. Overall, the evidence clearly suggests
that adults with stable coronary disease benefit from
ACE inhibitor, even in the absence of HF or systolic
left ventricular dysfunction. ACE inhibitors should be
avoided in patients with clear contraindications, such
as symptomatic low blood pressure or potassium
concentration >5.5 mmol/l (22). These data comple-
ment the data in patients with HF and suggest that
ACE inhibitors should be considered in most patients
with vascular disease.
ANGIOTENSIN RECEPTOR BLOCKERS. The TRAN-
SCEND (Telmisartan Randomised Assessment Study
in ACE-I Intolerant Subjects with Cardiovascular
Disease) evaluated the role of an ARB in those with
vascular disease or diabetes with end-organ damage,
who were intolerant of ACE inhibitor (27). The median
duration of follow-up was 56 months, during which
12.3% of the telmisartan group died, compared with
11.7% of the placebo group. Compared with placebo,
telmisartan reduced the outcome of CV death, MI or
stroke, with HR: 0.87 (95% CI: 0.76 to 1.00); however,
JACC VOL. 74, NO. 5, 2019
AUGUST 6, 2019:683–98
the primary outcome of CV death, MI, stroke, or HF
hospitalization only showed a nonsignificant trend to
benefit, with HR: 0.92 (95% CI: 0.81 to 1.05). In the
ONTARGET (Ongoing Telmisartan Alone and in
Combination with Ramipril Global End-point Trial),
25,620 patients with known vascular disease or dia-
betes with end-organ damage were randomized to
receive telmisartan, ramipril, or both (28). During a
median 56 months of follow-up, mortality rates in the
ramipril, telmisartan, and combination therapy
groups were 11.8%, 11.6%, and 12.5%, respectively.
Telmisartan was equally as effective as ramipril for
the prevention of MI, stroke, CVD death, or HF hos-
pitalization, with relative risk: 1.01 (95% CI: 0.94 to
1.09). The combination of ramipril and telmisartan
did not reduce the primary outcome event rate
compared with ramipril alone, but led to an increase
in hypotension (4.8% vs. 1.7%). In the VALIANT trial,
the combination of valsartan and captopril was
compared with valsartan alone and with captopril
alone in patients randomized within 10 days of MI.
During a median follow-up of 24.7 months, respective
mortality rates in the valsartan, combination, and
captopril groups were 19.9%, 19.3%, and 19.5%. The
combination of valsartan and captopril did not reduce
the risk of all-cause mortality, CV death, or CV
morbidity beyond captopril alone (19). Therefore,
ARB is an acceptable alternative to ACE inhibitor in
individuals with known stable vascular disease for
the prevention of CVD events.
ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR.
There are few data on the role of neprilysin inhibition
in the management of stable coronary artery disease.
In a post hoc analysis of the PARADIGM-HF (Pro-
spective Comparison of ARNI with ACE-I to Deter-
mine Impact on Global Mortality and Morbidity in
Heart Failure) trial, there was no evidence to suggest
that sacubitril-valsartan reduced the risk of ischemic
events compared with enalapril (29). Ongoing trials,
such as PARADISE-MI, will provide more information
on the efficacy of ARNI in the treatment of coronary
artery disease.
HF WITH REDUCED EJECTION FRACTION
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS.
In CONSENSUS (Cooperative North Scandinavian
Enalapril Survival Study) (Figure 1), patients with New
York Heart Failure functional class IV HF and car-
diomegaly (LVEF was not an eligibility criterion) were
randomized to receive enalapril or placebo (30).
During an average follow-up of 188 days, 44% of the
placebo group died compared with 26% of the ena-
lapril group (p ¼ 0.002). In the SOLVD-Treatment
JACC VOL. 74, NO. 5, 2019
AUGUST 6, 2019:683–98
trial, 2,569 patients with HF and LVEF #35% were
randomized to placebo or enalapril (31). During an
average 41 months of follow-up, 40% of the placebo
group had died. Enalapril reduced the risk of death by
16% (95% CI: 5% to 26%). The SOLVD-Prevention trial
also demonstrated that in asymptomatic individuals
with LVEF #35% who were followed for an average
37.4 months, enalapril reduced the risk of HF or death
beyond placebo, with a risk reduction of 29% (95% CI:
21% to 36%) (32). During this time, 15.8% of the pla-
cebo group died compared with 14.8% of the enalapril
group. At 12-year follow-up, the beneficial effects of
enalapril persisted. In a meta-analysis of 32 HF trials
including 7,105 participants randomized to receive an
ACE inhibitor or placebo, the use of an ACE inhibitor
led to a significant reduction in the risk of death, with
odds ratio: 0.77 (95% CI: 0.67 to 0.88) (33), and of HF
hospitalization, with odds ratio: 0.65 (95% CI: 0.57
to 0.74).
ANGIOTENSIN RECEPTOR BLOCKERS. A Cochrane
systematic review identified 22 trials (17,900 partici-
pants) comparing an ARB against placebo in in-
dividuals with heart failure with reduced ejection
fraction (HFrEF) (defined as symptomatic HF with
LVEF #40%) (34). They found nonsignificant trends
toward reduction in mortality, with relative risk: 0.87
(95% CI: 0.76 to 1.00), and hospitalizations, with
relative risk: 0.94 (95% CI: 0.88 to 1.01) compared
with placebo. In the ELITE II (Losartan Heart Failure
Survival Study), 3,152 patients with symptomatic HF
and LVEF #40% were randomly allocated to receive
losartan 50 mg daily or captopril 50 mg 3 times daily
(35). After a median 1.5 years, there were 530 deaths,
with a nonsignificant trend toward more deaths in the
losartan group; HR: 1.13 (95% CI: 0.95 to 1.35). There
was no difference in hospitalizations between the
groups. The losartan dose used in ELITE II may have
been suboptimal, however. In the HEAAL
(Heart Failure Endpoint Evaluation of Angiotensin II
Antagonist Losartan) trial, 3,846 patients with
symptomatic HF and LVEF #40% were randomly
allocated to receive losartan 150 mg daily or losartan
50 mg daily (36). During 4.7 years follow-up, losartan
150 mg daily reduced the primary outcome of death or
HF hospitalization as compared with losartan 50 mg
daily (HR: 0.90; 95% CI: 0.82 to 0.99). Therefore,
while head-to-head evidence is limited, the available
data suggest that ACE inhibitor should in general be
preferred over ARB in patients with HFrEF, unless
patients are intolerant to ACE inhibitor (most
commonly because of cough), when an ARB is a
reasonable alternative.
Leong et al. 689
ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease
COMBINATION OF ACE INHIBITOR AND ARB. Two
large trials compared ACE inhibitor and ARB with ACE
inhibitor alone for HFrEF. In CHARM Added, 2,548
patients with symptomatic HF and LVEF #40% who
were taking an ACE inhibitor were randomized to
candesartan or placebo (37). Only 55% of participants
were also treated with beta-blocker and 17% spi-
ronolactone. Participants were followed for a median
of 41 months. The addition of candesartan to ACE
inhibitor led to a reduction in the primary outcome of
CV death or HF hospitalization, with HR: 0.85
(95% CI: 0.75 to 0.96). In total, 30% of the candesartan
group died compared with 32% of the placebo group,
with HR: 0.89 (95% CI: 0.77 to 1.02). However, the
incidence of hyperkalemia was increased from 0.7%
to 3.4% by the addition of candesartan. In Val-HeFT,
5,010 patients with symptomatic HF and
LVEF <40% with left ventricular dilatation were
randomized to receive valsartan or placebo (38).
Participants were to continue their baseline HF ther-
apies, which included ACE inhibitors in 93% and beta-
blockers in 35%. During a mean follow-up of
23 months, valsartan led to a 13% (95% CI: 3% to 23%)
reduction in the primary outcome of mortality or
cardiac morbidity (cardiac arrest, HF hospitalization,
or need for intravenous HF therapy). This benefit was
driven by nonfatal outcomes, as there was no differ-
ence in mortality between the groups; 19.7% of the
valsartan group died compared with 19.4% of the
placebo group, with relative risk: 1.02 (95% CI: 0.88 to
1.18). Furthermore, the positive findings in these tri-
als may be due in part to the dose of ACE inhibitor
used, which may have been suboptimal in the control
arms. In CHARM Added, the mean daily doses of
enalapril (17.2 mg), lisinopril (17.7 mg), captopril
(82.7 mg), and ramipril (7.3 mg) in the placebo arm,
and in Val-HEFT, the mean daily doses of enalapril
(17 mg), lisinopril (19 mg), captopril (80 mg), and
ramipril (6 mg) were less than the optimal daily doses
(40, 40, 150, and 10 mg, respectively). Thus, it is
unclear whether the addition of an ARB to an
optimally-dosed ACE inhibitor confers additional
benefit in HFrEF.
MINERALOCORTICOID RECEPTOR ANTAGONISTS.
In the RALES (Randomized Aldactone Evaluation
Study) (Figure 1), the role of spironolactone in pa-
tients with New York Heart Association functional
class III or IV HF, LVEF #35%, serum
creatinine #221 mmol/l, and potassium #5 mmol/l was
evaluated (39). Nearly all (95%) were treated with
ACE inhibitors, and 11% were treated with beta-
blockers. The mean follow-up was 24 months.
690 Leong et al.
ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease
Compared with placebo, spironolactone reduced the
primary outcome of mortality from 46% in the pla-
cebo group to 35% in the spironolactone group, with
HR: 0.70 (95% CI: 0.60 to 0.82). In the EMPHASIS-HF
(Eplerenone in Mild Patients Hospitalization And
SurvIval Study in Heart Failure) trial, patients with
mild (New York Heart Association functional class
II) HF symptoms and LVEF #35% who were on
optimally-dosed ACE inhibitor/ARB and beta-
blocker were randomized to receive eplerenone
or placebo (40). Patients were ineligible if the
estimated glomerular filtration rate was <30 ml/
min/1.73 m2 body surface area or the serum potassium
concentration was >5 mmol/l. At a median 21 months
of follow-up, the primary outcome of CV death or HF
hospitalization was reduced by eplerenone, with HR:
0.63 (95% CI: 0.54 to 0.74), as was the secondary
outcome of mortality from 15.5% to 12.5%, with HR:
0.76 (95% CI: 0.62 to 0.93). Therefore, an MRA is
indicated in patients with HFrEF in the absence of
severe kidney disease if the serum potassium con-
centration is #5 mmol/l.
ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS.
When the ARB valsartan is combined with the nepri-
lysin inhibitor sacubitril, outcomes in HFrEF are
improved over ACE inhibitor. In the PARADIGM-HF
trial (Figure 1), patients with symptomatic HF and
LVEF #40%, accompanied by 1 additional risk marker
(elevated BNP or HF hospitalization), were randomly
allocated to enalapril or sacubitril-valsartan, and were
followed for a median of 27 months (41). Approxi-
mately one-half of participants were taking an MRA;
there was no evidence to suggest that the benefits with
valsartan-sacubitril were attenuated by MRA use. The
primary outcome of CV death or HF hospitalization
was significantly reduced by sacubitril-valsartan, with
HR: 0.80 (95% CI: 0.73 to 0.87), as was the secondary
outcome of mortality, from 19.8% to 17.0%; HR: 0.80
(95% CI: 0.71 to 0.89) (41).
The findings from PARADIGM-HF confirm the
importance of the natriuretic peptide pathway in
HFrEF—a new paradigm in HFrEF therapy. A subse-
quent meta-analysis that included PARADIGM-HF, as
well as trials of the neprilysin inhibitor omapatrilat
(which is not in clinical use owing to an excess of
angioedema), demonstrated that compared with ACE
inhibitor, a strategy including neprilysin inhibition
led to a consistent reduction in mortality, with a
pooled HR of 0.88 (95% CI: 0.80 to 0.98) and the
composite of death or HF hospitalization, with a
pooled HR of 0.86 (95% CI: 0.76 to 0.97) (42). In the
PIONEER-HF (Comparison of Sacubitril-Valsartan
versus Enalapril on Effect on NT-proBNP in
JACC VOL. 74, NO. 5, 2019
AUGUST 6, 2019:683–98
Patients Stabilized from an Acute Heart Failure
Episode) trial, patients hospitalized for HF with
LVEF #40% and an amino-terminal pro-brain natri-
uretic peptide (NT-proBNP) concentration $1,600
pg/ml or a BNP concentration $400 pg/ml were
randomly allocated to receive sacubitril-valsartan or
enalapril while still in hospital (43). Patients were
eligible only if their systolic blood pressure was at
least 100 mm Hg for 6 h with no increase in their
requirements for intravenous diuretic or intravenous
vasodilator for 24 h. Sacubitril-valsartan led to a
larger reduction in NT-proBNP concentration than
enalapril. There was no difference between
sacubitril-valsartan and enalapril with respect to
safety outcomes, including renal function, symp-
tomatic hypotension, and angioedema. The findings
from PIONEER-HF therefore support the use of
sacubitril-valsartan in the setting of acute stabilized
HF.
Should all patients with HFrEF then be treated
with ARNI, rather than an ACE inhibitor? The bene-
ficial effects of ARNI over ACE inhibitor were consis-
tent among participants with and without an
implantable cardioverter-defibrillator, among those
taking and not taking a MRA, and among those taking
higher and lower doses of beta-blocker (44), sug-
gesting that ARNI are efficacious even in patients who
are treated optimally for HFrEF. Only patients with
systolic blood pressure $95 mm Hg were eligible for
randomization in PARADIGM-HF. Sacubitril-valsartan
led to more symptomatic hypotension (2.7% of re-
cipients) than enalapril (1.4% of recipients). However,
sacubitril-valsartan recipients were less likely to
experience cough or severe hyperkalemia. Therefore,
except for patients with symptomatic hypotension,
we conclude that sacubitril-valsartan is the preferred
treatment over ACE inhibitor (or ARB alone) for
HFrEF.
At present, cost is likely to be an important
obstacle to widespread uptake of sacubitril-valsartan.
Cost-effectiveness analyses are country-specific
because drug costs and willingness-to-pay thresh-
olds vary by country. In two U.S. cost-effectiveness
analyses, the cost per quality-adjusted life-year
gained was estimated at 2015 US$45,017 and $50,959,
respectively, over a lifetime (45,46). This suggests
that in the United States context, sacubitril-valsartan
is likely to be cost-effective at current willingness-to-
pay thresholds of $50,000 to $100,000 per quality-
adjusted life-year gained. However, the perspectives
from payors may be different in other countries,
especially in low- and middle-income countries, un-
less the costs are made more affordable.
JACC VOL. 74, NO. 5, 2019
AUGUST 6, 2019:683–98
HF WITH PRESERVED EJECTION FRACTION
Although there is convincing evidence to support the
role of renin-angiotensin system (RAS) blockade for
the treatment of HFrEF, there is a lack of evidence to
indicate that RAS inhibition is an effective strategy
for heart failure with preserved ejection fraction
(HFpEF). In the CHARM Preserved trial, patients with
symptomatic HF, a CV hospitalization, and LVEF
>40% were randomized to candesartan (target dose
32 mg daily, which was achieved in 58% of partici-
pants) or placebo (47). Approximately one-third of
patients had LVEF <50%, and HF was considered due
to hypertensive heart disease in one-quarter of cases.
Candesartan did not reduce the occurrence of the
primary composite outcome of CV death or HF hos-
pitalization (HR: 0.89; 95% CI: 0.77 to 1.03); however,
this study was only powered to detect an 18% relative
reduction in the primary outcome, so a smaller effect
cannot be excluded. In this trial there was clear
reduction in hospitalizations for HF, which is
consistent with some benefit from the use of an ARB
in this population, although the size of the benefit
may be modest. In I-PRESERVE (Irbesartan in Heart
Failure with Preserved Ejection Fraction) study, pa-
tients with HF symptoms, LVEF $45%, and either
recent hospitalization for HF or objective evidence of
structural or functional cardiac abnormality were
randomized to receive irbesartan (titrated to 300 mg
daily) or placebo (48). Irbesartan did not reduce
mortality or HF hospitalization, despite reducing
blood pressure (from a mean systolic value of
137 mm Hg at baseline).
The TOPCAT trial studied the effects of spi-
ronolactone in patients with HF and “relatively pre-
served” LVEF (49). Patients were eligible
randomization to spironolactone or placebo if $50
years of age with at least 1 symptom and 1 sign of HF,
and LVEF $45%. To avoid the enrollment of patients
incorrectly diagnosed with HF, additional eligibility
criteria included hospitalization within 12 months for
HF or an elevated BNP ($100 pg/ml)/NT-proBNP
($360 pg/ml). Among 3,445 participants, two-thirds
achieved a spironolactone dose of $30 mg daily.
Spironolactone did not reduce the risk of the primary
composite outcome of CV death, cardiac arrest, or HF
hospitalization (HR: 0.89; 95% CI: 0.77 to 1.04).
A Cochrane systematic review identified 12 trials of
MRA, 8 trials of ACE inhibitor, and 8 trials of ARB in
HFpEF (50). MRA led to a reduced risk of HF hospi-
talization with relative risk: 0.82 (95% CI: 0.69 to
0.98). There were no significant effects of ACE in-
hibitor or ARB on HF hospitalization, and none of
Leong et al. 691
ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease
MRA, ARB, or ACE inhibitor demonstrated a reduc-
tion in mortality. There were no completed trials of
ARNI in HFpEF; however, there are biological path-
ways that may be exploited by neprilysin inhibition
to alter the natural history of HFpEF. Natriuretic
peptides, whose concentrations are increased by
neprilysin inhibition, enhance cyclic GMP signaling,
which may increase phosphorylation of the stiff titin
isoform, potentially reducing myocardial stiffness
(51). In animal models, neprilysin inhibition
increased the vasodilator, natriuretic and diuretic
responses to adrenomedullin—a peptide expressed by
endothelium (52). Neprilysin inhibition may thus act
on other pathophysiological pathways in a manner
that is complementary to RAS inhibition.
There are several ongoing trials of ARNI in patients
with HFpEF. One such trial is PARAGON-HF (Efficacy
and Safety of LCZ696 Compared to Valsartan, on
Morbidity and Mortality in Heart Failure Patients with
Preserved Ejection Fraction) (53). Patients were
eligible for recruitment into PARAGON-HF if they had
LVEF $45% and symptomatic HF requiring a diuretic
agent, as well as both echocardiographic evidence of
structural cardiac disease (left atrial enlargement or
left ventricular hypertrophy) and elevation in natri-
uretic peptide concentrations. Participants who
tolerated valsartan 80 mg twice daily were randomly
allocated to receive sacubitril-valsartan (at a target
dose of 97/103 mg twice daily) or valsartan (at a target
dose of 160 mg twice daily). The primary outcome is
the total number of HF hospitalizations or CV death.
In the PARALLAX (Randomized, Double-Blind, Multi-
Center, Parallel Group, Active Controlled Study to
Evaluate the Effect of LCZ696 on NT-proBNP, Exer-
cise Capacity, Symptoms and Safety Compared to
for Individualized Medical Management of Comorbidities
in Patients With Heart Failure and Preserved Ejection
Fraction) trial, patients with HFpEF will be randomly
allocated to sacubitril-valsartan versus enalapril,
valsartan, or placebo to determine the effect of
sacubitril-valsartan on NT-proBNP concentrations
and 6-min walk distance (NCT03066804).
Current evidence suggests that MRA may be of
value in individuals with HFpEF (54), but ideally, new
large trials are needed. There are several reasons why
the effect of RAS and mineralocorticoid receptor
blockade may be smaller in HFpEF than in HFrEF.
First, the pathophysiological mechanisms frequently
differ between HFrEF and HFpEF. HFpEF may feature
predominantly an increase in LV stiffness, differences
in cardiac energetics, and additional mechanisms,
such as increased vascular stiffness, pulmonary hy-
pertension, and renal interactions. Second, 84% of
692 Leong et al.
ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease
TOPCAT participants and nearly one-fifth of CHARM
Preserved participants were taking ACE inhibitor or
ARB at enrollment, and 78% of TOPCAT participants
and 56% of CHARM Preserved participants were tak-
ing beta-blockers at enrollment. The mean baseline
blood pressure in CHARM Preserved was 136/
78 mm Hg and was 130/80 mm Hg in TOPCAT. These
data indicate that hypertension—a major causal factor
in HFpEF—was well-treated on entry into these trials,
attenuating any benefit that might be achieved by
(additional) RAAS inhibition. Third, trials of treat-
ments for HFpEF have been hampered by challenges
in implementing diagnostic or eligibility criteria uni-
formly. For example, in TOPCAT, there were signifi-
cant differences between participants recruited from
Russia and Georgia (which contributed nearly one-
half of the sample) compared with the Americas
(55). Only 11% of participants from Russia and Georgia
had elevated BNP as an inclusion criterion, and par-
ticipants from Russia and Georgia were significantly
younger with less atrial fibrillation and kidney dis-
ease but had a higher prevalence of prior MI.
HF WITH MIDRANGE EJECTION FRACTION
There are relatively few data on the role of RAS in-
hibition or mineralocorticoid receptor blockade in
midrange ejection fraction (i.e., LVEF 40% to 49%). In
a post hoc analysis of data from the CHARM studies,
candesartan led to a lower risk of the primary
outcome of CV death or HF hospitalization among
participants with HF with midrange ejection fraction,
with HR: 0.76 (95% CI: 0.61 to 0.96) (56). In the
TOPCAT trial, there was a significant interaction be-
tween treatment allocation and LVEF for the occur-
rence of the primary outcome of CV death, HF
hospitalization, or aborted cardiac arrest (p ¼ 0.046)
(57). The respective HRs for participants with LVEF
45% to <50%, 50% to <55%, 55% to <60%, and $60%
were 0.72 (95% CI: 0.50 to 1.05); 0.85 (95% CI: 0.61 to
1.18); 0.94 (95% CI: 0.68 to 1.29); and 0.97 (95% CI:
0.76 to 1.23), respectively. More research is needed to
determine the role of RAS inhibition and mineralo-
corticoid receptor blockade in the treatment of HF
with midrange ejection fraction.
POTENTIAL COMPLICATIONS OF RAS AND
MINERALOCORTICOID RECEPTOR
INHIBITION AND THEIR IMPLICATIONS
FOR IMPLEMENTATION
Intolerance of RAS inhibition or mineralocorticoid
receptor blockade among patients with HF is a marker
of more advanced disease and poorer outcomes (58).
JACC VOL. 74, NO. 5, 2019
AUGUST 6, 2019:683–98
The most serious reasons for intolerance of these
agents are renal impairment, hyperkalemia, hypo-
tension, and angioedema.
RENAL IMPAIRMENT. ACE inhibitor/ARB can cause
an initial elevation in serum creatinine concentra-
tions; however, in chronic kidney disease, it can help
to slow deterioration in renal function. In the SOLVD-
Treatment trial, in which the average baseline serum
creatinine concentration was 106 m mol/l, enalapril
use led to a larger rise in serum creatinine concen-
trations than placebo (31). The proportions of partic-
ipants whose creatinine concentrations increased to
>177 m mol/l were 10.7% and 7.7%, respectively, in the
enalapril and placebo groups. However, a review that
included 12 trials randomizing nonhypertensive in-
dividuals to ACE inhibitor versus a control arm that
measured renal disease progression found that
despite an initial increase in serum creatinine con-
centration after ACE inhibitor, their use slows later
deterioration in renal function (59). In the Irbesartan
Diabetic Nephropathy Trial, among hypertensive pa-
tients with diabetic nephropathy (mean baseline
serum creatinine concentration 148 m mol/l), irbe-
sartan significantly reduced the incidence of the
composite endpoint of doubling of serum creatinine
concentration, end-stage renal disease, or death by
23% (p ¼ 0.006) compared with amlodipine and by
20% (p ¼ 0.02) compared with placebo (60). In the
RENAAL (Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan) trial, 1,513 in-
dividuals with diabetic nephropathy (mean serum
creatinine concentration 1.9 mg/dl [168 m mol/l]) were
randomly allocated to receive losartan 50 to 100 mg
daily or placebo (61). Losartan reduced the risk of
long-term dialysis or need for renal transplantation
by 28%.
In clinical practice, if creatinine increases to levels
at which the clinician is uncomfortable, it is prefer-
able to initially reduce the dose of diuretic agents
rather than the dose of the RAAS blocker.
A systematic review of randomized trials studying
the effects of ACE inhibitor/ARB in patients on he-
modialysis identified 11 trials that included 1,856
participants, who developed 455 CV events (MI,
stroke, or HF) and 265 deaths (62). There was no
significant effect of ACE inhibitor/ARB use on CV
events, with HR: 0.92 (95% CI: 0.79 to 1.08) or death,
with HR: 0.94 (95% CI: 0.75 to 1.17).
Therefore, at serum creatinine concentrations up
to 265 mmol/l, the benefit of ACE inhibitor/ARB out-
weighs its risks. There is a paucity of evidence to
inform the risk-benefit ratio at eGFR <30 ml/min,
however (59).
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AUGUST 6, 2019:683–98 ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease

F I G U R E 2 The Effects of RAS Inhibition or Mineralocorticoid Receptor Blockade on Mortality in Individuals With Stable Vascular Disease or HFrEF

Mortality

Study ID OR (95% CI) % Weight

Atherosclerotic vascular disease

AIRE 0.70 (0.56, 0.87) 2.16
Chinese Captopril 0.94 (0.84, 1.05) 14.85
EUROPA 0.89 (0.77, 1.02) 13.30
GISSI-3 0.88 (0.79, 0.99) 20.57
HOPE 0.83 (0.73, 0.94) 10.12
PEACE 0.88 (0.75, 1.04) 9.03
PROGRESS 0.96 (0.81, 1.13) 6.65
SAVE 0.79 (0.64, 0.96) 2.43
TRACE 0.73 (0.60, 0.88) 1.90
TRANSCEND 1.06 (0.90, 1.24) 6.45
Subtotal (I-squared = 54.1%, p = 0.020) 0.89 (0.85, 0.94) 87.47

Heart failure with reduced EF

CONSENSUS 0.55 (0.34, 0.91) 0.28
RALES 0.56 (0.46, 0.68) 1.87
SOLVD-P 0.93 (0.79, 1.10) 4.60
SOLVD-T 0.82 (0.70, 0.97) 2.80
EMPHASIS-HF 0.78 (0.63, 0.97) 2.98
Subtotal (I-squared = 83.6%, p = 0.000) 0.81 (0.73, 0.89) 12.53

Overall (I-squared = 76.1%, p = 0.000) 0.88 (0.84, 0.92) 100.00

.4 .6 .8 1 1.2

In randomized trials, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers reduced mortality in individuals with atherosclerotic vascular disease by
11%. In randomized trials of patients with heart failure with reduced ejection fraction (HFrEF), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers
and mineralocorticoid receptor antagonists reduced mortality by 19%. AIRE ¼ Acute Infarction Ramipril Efficacy; CI ¼ confidence interval; EMPHASIS-HF ¼ Eplerenone
in Mild Patients Hospitalization And SurvIval Study in Heart Failure; OR ¼ odds ratio; PEACE ¼ Prevention of Events with Angiotensin Converting Enzyme Inhibition;
PROGRESS ¼ Perindopril protection against recurrent stroke study; SAVE ¼ Survival and Ventricular Enlargement; SOLVD-T ¼ Studies of Left Ventricular Dysfunction-
Treatment; TRACE ¼ Trandolapril Cardiac Evaluation; TRANSCEND ¼ Telmisartan Randomised Assessment Study in ACE-I Intolerant Subjects with Cardiovascular
Disease; other abbreviations as in Figure 1.

HYPERKALEMIA. Aldosterone promotes
retention and potassium wasting. Thus, a common
characteristic of inhibitors of the RAS or mineralo-
corticoid receptors, which improve outcomes in
HFrEF, is that they increase the risk of hyperkalemia.
Hyperkalemia is one of the major limitations to the
implementation of RAS inhibition and mineralocor-
ticoid receptor blockade and can be a life-threatening
complication. In a meta-analysis of trials comparing
sodium ARB with placebo, ARB use led to an increase in the
risk of hyperkalemia (relative risk: 3.37; 95% CI: 1.60
to 7.11) (63). In a meta-analysis of trials comparing
MRA with placebo (with participants generally taking
ACE inhibitor/ARB), MRA use doubled the risk of
hyperkalemia (64). When hyperkalemia develops,
clinicians should search for added causes, stop
nonsteroidal anti-inflammatory drugs and potassium
supplements, and reduce the dose of other drugs that
694 Leong et al. JACC VOL. 74, NO. 5, 2019

ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease AUGUST 6, 2019:683–98

F I G U R E 3 The Effects of RAS Inhibition on Myocardial Infarction in Individuals With Vascular Disease or HFrEF

Nonfatal Myocardial Infarction

Events, Events,
Study OR (95% CI) Treatment Control

Trials without LV dysfunction or HF

HOPE (n = 9297) 0.77 (0.66, 0.91) 273/9297 351/9297
EUROPA (m = 12,218) 0.78 (0.67, 0.90) 295/12218 378/12218
PEACE (n = 8290) 1.01 (0.84, 1.22) 222/8290 220/8290
Subtotal (I-squared = 64.6%, p = 0.059) 0.83 (0.75, 0.91) 790/29805 949/29805

Trials with LV dysfunction or HF

SAVE (n = 2231) 0.79 (0.60, 1.03) 101/2231 127/2231
AIRE (n = 1986) 0.96 (0.68, 1.34) 68/1986 71/1986
TRACE (n = 1749) 0.76 (0.55, 1.05) 66/1749 86/1749
SOLVD-P (n = 4228) 0.70 (0.54, 0.89) 103/4228 147/4228
SOLVD-T (n = 2569) 0.79 (0.57, 1.10) 66/2569 83/2569
Subtotal (I-squared = 0.0%, p = 0.695) 0.78 (0.68, 0.89) 404/12763 514/12763

Overall (I-squared = 16.6%, p = 0.299) 0.81 (0.75, 0.88) 1194/42568 1463/42568

.541 1 1.85

In randomized trials including both individuals with and without reduced ejection fraction, angiotensin-converting enzyme inhibitors reduce myocardial infarction by
19%. Abbreviations as in Figures 1 and 2.

can raise potassium. To minimize the risk of hyper-
kalemia, the serum potassium concentration should
be measured 1 to 2 weeks after initiation of an ACE
inhibitor/ARB/MRA and then periodically there-
after (65).
HYPOTENSION WITH END-ORGAN COMPROMISE. A
common characteristic of drugs, including ACE in-
hibitor/ARB, that improve outcome in HF is their
blood pressure-lowering effects (63). This can place
significant limitations on therapeutic options in HF
patients with hypotension, which is itself an adverse
prognostic sign. The PARADIGM-HF study required
patients to have LVEF #40% and systolic blood
pressure $95 mm Hg. Potential participants under-
went a run-in phase first with enalapril 10 mg twice
daily then sacubitril-valsartan titrated to 97/103 mg
twice daily before being deemed
randomization. A total of 13% of
experienced hypotension during run-in or after
randomization (66). Hypotension was associated with
an increased risk of the primary outcome (HR: 2.63;
95% CI: 2.21 to 3.13). The beneficial effect of
sacubitril-valsartan over enalapril was consistent in
those who developed hypotension, however. Low
blood pressure should only necessitate reduction in
the dose of ACE inhibitor/ARB/MRA/ARNI if associ-
ated with clinical features of end-organ compromise,
such as syncope or recurrent pre-syncope.
ANGIOEDEMA. A systematic review of randomized
trials demonstrated that the risk of angioedema
among recipients of ACE inhibitor is 2.2 times higher
than among ARB recipients (95% CI: 1.5 to 3.3) (67).
The incidence of angioedema in these trials was 0.3%
among ACE inhibitor recipients compared with 0.11%
among ARB recipients (67). In contrast, the risk of
eligible for angioedema in those treated with ARB is no different
participants to the risk among placebo recipients, although a
modest positive relationship cannot be excluded due
JACC VOL. 74, NO. 5, 2019 Leong et al. 695
AUGUST 6, 2019:683–98 ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease

F I G U R E 4 The Effects of RAS inhibition on Stroke in Individuals With Vascular Disease or HFrEF

Stroke
Events, Events,
Study OR (95% CI) Treatment Control

Trials without LV dysfunction or HF

HOPE (n = 9297) 0.69 (0.56, 0.84) 156/9297 226/9297
EUROPA (m = 12,218) 0.96 (0.73, 1.27) 98/12218 102/12218
PEACE (n = 8290) 0.77 (0.57, 1.05) 71/8290 92/8290
Subtotal (I-squared = 44.6%, 0.77 (0.67, 0.89) 325/29805 420/29805
p = 0.164)

Trials with LV dysfunction or HF

SAVE (n = 2231) 1.05 (0.69, 1.60) 45/2231 43/2231
AIRE (n = 1986) 1.47 (0.80, 2.70) 25/1986 17/1986
TRACE (n = 1749) 1.02 (0.69, 1.52) 51/1749 50/1749
SOLVD-P (n = 4228) 0.90 (0.65, 1.24) 70/4228 78/4228
SOLVD-T (n = 2569) 0.78 (0.54, 1.15) 48/2569 61/2569
Subtotal (I-squared = 0.0%, p = 0.492) 0.96 (0.80, 1.15) 239/12763 249/12763

Overall (I-squared = 32.9%, p = 0.165) 0.84 (0.75, 0.94) 564/42568 669/42568

.37 1 2.7

In randomized trials including both individuals with and without reduced ejection fraction, angiotensin-converting enzyme inhibitors reduce stroke by 16%.
Abbreviations as in Figures 1 and 2.

to small number of angioedema events in placebo- circumstances should be individualized by discussing

controlled trials of ARB (63). The difference in the
risk of angioedema between ACE inhibitor and ARB is
likely related to differences in their effects on bra-
dykinin levels. Bradykinin, which binds the vascular
receptor, BK2, leads to vasodilation and increa-
sed vascular permeability. Angiotensin-converting
enzyme is 1 of 3 peptidases (along with aminopepti-
dase P and neutral endopeptidase) that degrades
bradykinin. Therefore, ACE inhibitor may predispose
to increased bradykinin and increased
angioedema (68). A systematic review evaluated the
risk of recurrent angioedema among those who
developed angioedema on an ACE inhibitor and who
were subsequently prescribed ARB (69). The inci-
dence of possible recurrent angioedema was esti-
mated at 9.4% (95% CI: 1.6% to 17%), and the
incidence of confirmed recurrent angioedema was
3.5% (95% CI: 0% to 9.2%). The decision about
whether to recommend an ARB under
the potential risks and benefits of this strategy.
As bradykinin may be degraded by neprilysin,
there is a theoretic concern that neprilysin inhibition
might increase the risk of angioedema. Data from the
trials in which participants were randomized to ACE
inhibitor or sacubitril-valsartan suggest that angioe-
dema rates between the 2 groups are similar, although
overall, the incidence of angioedema is rare, so more
data are needed to support these findings (70,71).
risk of
DISCONTINUING ACE INHIBITOR/ARB/
MRA/ARNI
In a trial of 224 patients with HF who were random-
ized after $10 weeks of single-blind quinapril to
either continue quinapril or change to placebo, the
cessation of quinapril led to worse exercise tolerance
and poorer quality of life (72). This finding was
these confirmed in a small trial that evaluated the safety of
696 Leong et al. JACC VOL. 74, NO. 5, 2019

ACE Inhibitors, ARBs, and ARNIs in HF and Coronary Artery Disease AUGUST 6, 2019:683–98

discontinuing HF medications in patients with non-
ischemic cardiomyopathy whose LVEF had improved
to $50% and who were asymptomatic with NT-
proBNP concentration <250 ng/l (73). During the
first 6 months, 44% of the 25 participants randomized
to the medication withdrawal group experienced
cardiomyopathy relapse (as defined by a composite of
clinical, NT-proBNP, and imaging endpoints) within
6 months; none of the medication continuation group
demonstrated cardiomyopathy relapse during this
time. Therefore, based on limited evidence, it is
advisable to continue ACE inhibitor/ARB/MRA/ARNI
indefinitely for HFrEF and likely for most patients if
tolerated.
(95% CI: 0.62 to 0.91). Future HF trials might include
the total number of HF hospitalizations as a key
outcome.
Future HF trials should also seek to address areas
of unmet need. Symptomatic hypotension, hyper-
kalemia, and renal dysfunction are major limitations
to the implementation of drugs that act on the RAS
and the neprilysin pathway. Compounds that permit
the safer inhibition of these pathogenic pathways
might allow a larger number of patients with HF to
benefit.
CONCLUSIONS

FUTURE DIRECTIONS FOR HF RESEARCH RAS inhibition has contributed to a transformation

The design of the PARAGON-HF trial features a count
of the total number of HF hospitalization events as
part of the primary efficacy outcome. A similar
approach was implemented in a post hoc analysis of
the CHARM-Preserved study (74). The rationale for
this analytic approach, in contrast to the traditional
time-to-first-event approach, is that it may charac-
terize the patient experience more completely.
Because HF is a chronic condition with acute exac-
erbations that frequently result in hospitalization, a
count of the number of HF hospitalizations may
provide a more fulsome assessment of the burden of
HF morbidity. In the primary analysis of the CHARM-
Preserved trial, candesartan did not reduce the in-
fluence the time to the composite outcome of CV
death or HF hospitalization, with HR: 0.89 (95% CI:
0.77 to 1.03). In the post hoc analysis that incorpo-
rated all hospitalizations, candesartan led to a sig-
nificant reduction in the composite of all HF
hospitalizations or CV death, with a rate ratio of 0.75
in the prognosis of patients with coronary disease or
HFrEF, in whom they reduced mortality, MI, and
stroke risk (Figures 2 to 4), and are recommended in
these individuals and as part of a strategy aiming
for a systolic blood pressure <130 mm Hg in those
with HFpEF. RAS inhibition and mineralocorticoid
receptor blockade in these circumstances are indi-
cated in the context of chronic kidney disease up to
a serum creatinine concentration 265 mmol/l (or
eGFR $30 ml/min). ARB is an acceptable alternative
when ACE inhibitor is not tolerated (principally due
to cough), and MRA should be added to the ACE
inhibitor/ARB. ARNI represents a new and more
effective alternative to ACE inhibitor for patients
with HFrEF.
ADDRESS FOR CORRESPONDENCE: Dr. Darryl Leong,
C2-238 David Braley Building, Hamilton General
Hospital, 237 Barton Street East, Hamilton, Ontario
L8L 2X2, Canada. E-mail: Darryl.Leong@phri.ca.
Twitter: @DarrylLeong.

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KEY WORDS ACE-I, ARB, ARNI, coronary
disease, heart failure