Cardiac drugs 1e (2013) PDF UnitedVRG

CARDIAC
DRUGS



CARDIAC
DRUGS

Editors
Kanu Chatterjee MBBS FRCP (London) FRCP (Edin)
FCCP FACC MACP

Clinical Professor of Medicine
Division of Cardiology
The Carver College of Medicine
University of Iowa
Iowa City, Iowa, USA
Emeritus Professor of Medicine
University of California
San Francisco, California, USA
Eric J Topol MD FACC
Director, Scripps Translational Science Institute
Chief Academic Officer, Scripps Health
Vice Chairman, West Wireless Health Institute
The Gary and Mary West Chair of Innovative Medicine
Professor of Translational Genomics
The Scripps Research Institute
La Jolla, California, USA

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or application of any of the contents of this work. If not specifically stated,
all figures and tables are courtesy of the contributors. Where appropriate,
the readers should consult with a specialist or contact the manufacturer of
the drug or device.
Cardiac Drugs/Editors Kanu Chatterjee, Eric J Topol
First Edition: 2013
ISBN 978-93-5025-879-8
Printed at:


Dedicated to
Our wives
Docey Chatterjee and Susan Topol



CONTENTS

Contributorsix
Prefacexi
Acknowledgmentsxiii

CHAPTER 1

Angiotensin, Aldosterone, and Renin Inhibition in
Cardiovascular Disease

1

Abdallah Kamouh, Gary S Francis, Kanu Chatterjee
CHAPTER 2

Positive Inotropic Drugs: A Limited but Important Role

34

Carl V Leier, Garrie J Haas, Philip F Binkley
CHAPTER 3

Antihypertensive Drugs

72

William J Lawton, Kanu Chatterjee
CHAPTER 4

Diuretics158
Michael E Ernst
CHAPTER 5

Drugs for Dyslipidemias

184

Byron Vandenberg
CHAPTER 6

Drugs for Diabetes and Cardiodysmetabolic Syndrome

242

Prakash Deedwania, Sundararajan Srikanth
CHAPTER 7

Drugs for Acute Coronary Syndromes

267

Stephen W Waldo, Yerem Yeghiazarians, Kanu Chatterjee
CHAPTER 8

Drugs for Dysrhythmia

326

Rakesh Gopinathannair, Brian Olshansky
vii


CARDIAC DRUGS

CHAPTER 9

Drugs for Heart Failure

389

Kanu Chatterjee
CHAPTER 10

Drugs for Stable Angina

424

Kanu Chatterjee, Wassef Karrowni
CHAPTER 11

Drugs for Pulmonary Hypertension

454

Ravinder Kumar, Sif Hansdottir
CHAPTER 12

Cardiac Drugs in Pregnancy and Lactation

485

Wassef Karrowni, Kanu Chatterjee
CHAPTER 13

Future Directions: Role of Genetics in Drug Therapy

506

Eric J Topol

Index509

viii


CONTRIBUTORS

EDITORS
Kanu Chatterjee MBBS FRCP (London) FRCP (Edin) FCCP FACC MACP
Clinical Professor of Medicine
Division of Cardiology
The Carver College of Medicine
University of Iowa
Iowa City, Iowa, USA
Emeritus Professor of Medicine
University of California, San Francisco, California, USA
Eric J Topol MD FACC
Director, Scripps Translational Science Institute
Chief Academic Officer, Scripps Health
Vice-Chairman, West Wireless Health Institute
The Gary and Mary West Chair of Innovative Medicine
Professor of Translational Genomics
The Scripps Research Institute
La Jolla, California, USA
CONTRIBUTING AUTHORS
Philip F Binkley MD MPH

Wilson Professor of Medicine
College of Medicine, The Ohio
State University
Professor of Epidemiology
College of Public Health, The
Ohio State University
Vice Chairman for Academic Affairs
Department of Internal Medicine,
The Ohio State University
Director, Center for FAME
Associate Dean for Faculty Affairs
College of Medicine, The Ohio
State University
Columbus, Ohio, USA

Michael E Ernst Pharm D
Professor (Clinical)
Department of Pharmacy
Practice and Science
College of Pharmacy
Department of Family Medicine
Carver College of Medicine
The University of Iowa
Iowa City, Iowa, USA

Prakash Deedwania MD FACC

Rakesh Gopinathannair MD MA
Director
Cardiac Electrophysiology

University of Louisville Hospital
Assistant Professor of Medicine
Division of Cardiology
University of Louisville
Louisville, Kentucky, USA

FACP FAHA

Chief of Cardiology Division
VACCHCS/UMC, UCSF Program
at Fresno, Fresno, California, USA
Professor of Medicine
UCSF School of Medicine
San Francisco, California, USA

Gary S Francis MD
Professor of Medicine
Cardiovascular Division
University of Minnesota
Minneapolis, Minnesota, USA

ix


CARDIAC DRUGS

Garrie J Haas MD FACC
Professor of Medicine
Division of Cardiovascular
Medicine

Davis Heart and Lung Research
Institute
The Ohio State University of
Medicine and Public Health
Columbus, Ohio, USA

Carl V Leier MD
Overstreet Professor of Medicine
and Pharmacology, Division of
Cardiovascular Medicine, Davis
Heart Lung Research Institute
The Ohio State University of
Medicine and Public Health
Columbus, Ohio, USA

Sif Hansdottir MD PhD
Assistant Professor of Medicine
Division of Pulmonary and
Critical Care
The Carver College of Medicine
University of Iowa Hospitals and
Clinics
Iowa City, Iowa, USA

FHRS

Abdallah Kamouh MD
Fellow, Advanced Heart Failure
and Transplantation
Cardiovascular Division

University of Minnesota Medical
Center
Minneapolis, Minnesota, USA
Wassef Karrowni MD
Division of Cardiovascular Diseases
The Carver College of Medicine
University of Iowa Hospitals and
Clinics
Iowa City, Iowa, USA
Ravinder Kumar MD
Fellow, Cardiovascular Medicine
Pulmonary Division
University of Iowa Hospitals and
Clinics
Iowa City, Iowa, USA
William J Lawton MD
Associate Professor Emeritus
Department of Internal Medicine
Nephrology-Hypertension Division
Carver College of Medicine
University of Iowa Hospitals and
Clinics
Iowa City, Iowa, USA

x

Brian Olshansky MD FACC FAHA
Professor, Division of
Cardiovascular Medicine
University of Iowa Hospitals

Iowa City, Iowa, USA
Sundararajan Srikanth MD
Cardiology Fellow, Department
of Medicine
UCSF Program at Fresno
San Francisco, California, USA
Byron Vandenberg MD
Associate Professor, Division of
Cardiovascular Medicine
Department of Internal Medicine
University of Iowa Hospitals and
Clinics
Iowa City, Iowa, USA
Stephen W Waldo MD
Fellow in Cardiology
Department of Medicine
University of California
San Francisco, California, USA
Yerem Yeghiazarians MD
Associate Professor of Medicine
University of California
San Francisco, California, USA


PREFACE

The book Cardiac Drugs presents an evidence-based approach
towards the pharmacologic agents that are used in various clinical
conditions in cardiovascular medicine.
The classes of drugs, such as renin-angiotensin-aldosterone

blocking drugs, positive inotropic drugs, diuretics, and anti‑
hypertensive drugs are discussed in great details with their
pharmacokinetics, pharmacodynamics, indications, contra‑
indications, and doses. Drugs for heart failure, acute coronary
syndromes, and pulmonary hypertension are also discussed
similarly. Pharmacologic agents, which are in development for
various clinical syndromes are also discussed. The unique feature
of this book is the detailed discussion on the guidelines of the
American College of Cardiology/American Heart Association for
the use of pharmacologic agents in various clinical conditions.
Kanu Chatterjee
Eric J Topol

xi



ACKNOWLEDGMENTS

We are very grateful to all the contributing authors. Their
expertise is very much appreciated. We also acknowledge the
help of our all administrative assistants and colleagues.
We sincerely thank to Shri Jitendar P Vij (Group Chairman),
Mr Ankit Vij (Managing Director), Mr Tarun Duneja (DirectorPublishing), Dr Neeraj Choudhary, Ms Shaila Prashar, and the
expert team of M/s Jaypee Brothers Medical Publishers (P) Ltd.,
New Delhi, India for their concerted efforts. Without their hard
work, this book could not have been published.

xiii

1

C

H

A

P

T

E

R

Angiotensin, Aldosterone,
and Renin Inhibition in
Cardiovascular Disease
Abdallah Kamouh,
Gary S Francis, Kanu Chatterjee

ANGIOTENSIN CONVERTING
ENZYME INHIBITORS
Introduction
Angiotensin converting enzyme inhibitors (ACEIs) have emerged
as one of the most important and high impact classes of drugs
used today in cardiovascular medicine.1 These agents were

developed for use in patients with hypertension, but their
penetration into cardiovascular medicine has been far beyond
the treatment of high blood pressure. ACEIs protect the heart
and prevent remodeling in acute myocardial infarction (MI),
prevent the development of left ventricular (LV) remodeling in
patients with progressive heart failure (HF), and reduce mortality
in patients with a variety of cardiovascular risk factors.2,3
Although the renin-angiotensin-aldosterone system (RAAS)
evolved over millions of years and affords a certain survival
advantage, there is an overarching hypothesis that its activation
in cardiovascular disease states may be maladaptive and may
drive much of the pathophysiology. Over the years, it has
become increasingly clear that the RAAS contributes importantly
to cardiovascular diseases, including hypertension, acute MI, and
HF.4 Drugs that block the RAAS, such as ACEIs and angiotensin
receptor blockers (ARBs) are associated with prevention of
cardiac remodeling, less progression of HF, and reduced
mortality.
The emergence of ARBs was important, because these agents
are very well tolerated and appear to provide benefits similar
to ACEIs in most clinical trials.5,6 In recent years, it has become
clearer that mineralocorticoid receptor (MR) blockers or
aldosterone antagonists are also helpful in most patients with
symptomatic HF. Direct renin inhibitors (DRIs) are emerging,
and it is expected that these agents will also be useful in the
treatment of selected patients with hypertension and possibly
other cardiovascular disorders.
1

CARDIAC DRUGS

In summary, drugs that inhibit the RAAS are a very important
form of therapy with a strong safety profile and a track record
of improved survival across a wide array of acute and chronic
cardiovascular disorders, especially hypertension, MI, and HF.
They have been successful beyond our expectations and now form
the cornerstone of treatment for many cardiovascular disorders.
The purpose of this chapter is to detail how these drugs, which
are designed to block the RAAS, are used to treat patients with
cardiovascular disease.

Mechanism of Action and Pharmacology
ACEIs provide both primary and secondary protection against
cardiovascular diseases. Their mechanism of action is related to
the reduction of the adverse effects of angiotensin II on multiple
organs (Figure 1). Angiotensin I, a decapeptide, is a precursor
of angiotensin II and is a product of the interaction between
renin [molecular weight (MW) = 40,000] and angiotensinogen
(MW = 60,000). Angiotensin I is cleaved by ACE to form the
highly active octapeptide, angiotensin II. Most of this conversion
takes place in the endothelial surface of the lung that is rich in
ACE (Figure 2).

AVP, arginine vasopressin; NE, norepinephrine.

FIGURE 1. The biologic activities of angiotensin II on different organs.
They include myocardial hypertrophy and remodeling, arteriolar
vasoconstriction, facilitation of NE release from sympathetic
neurons, release of AVP from the posterior pituitary gland, secretion

of aldosterone from the adrenal cortex, sodium retention, glomerular
fibrosis, mesangial contraction, and constriction of the renal efferent
arteriole.
2


Angiotensin, Aldosterone, and Renin Inhibition in CVD

ACE, angiotensin converting enzyme; DRIs, direct renin inhibitors; ACEIs,
angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers;
AT1, angiotensin receptor 1; MRBs, mineralocorticoid receptor blockers;
Na+, sodium.

FIGURE 2. Renin-angiotensin-aldosterone system and different inhibitors.
Renin is a proteolytic enzyme released primarily by the kidneys. This
release is stimulated by decrease in kidney perfusion, decrease in
Na+ delivery to the distal tubules, and increase in sympathetic nerve
activation. Renin acts upon its substrate angiotensinogen secreted by
the liver to form angiotensin I. Vascular endothelium, particularly in the
lungs, has ACE that cleaves off 2 amino acids to form the octapeptide
angiotensin II. Angiotensin II acts on its receptor AT1 to generate a
host of biological activities, including the release of aldosterone from
the adrenal gland.

Angiotensin II Effects on
Different Receptor Subtypes
Angiotensin II acts on its cognate receptor subtype 1 (AT1) to
generate a host of biological activities (Figure 1). Angiotensin II
releases aldosterone from the adrenal cortex, which regulates
salt and water metabolism, facilitates the release of locally

synthesized norepinephrine, causes direct vasoconstriction of
arteries and veins, has a proliferative effect on vascular smooth
vessel, promotes cardiac myocyte hypertrophy, and stimulates
fibroblasts to synthesize collagen leading to fibrosis of tissues
(Figure 1). Angiotensin II also acts directly on the central nervous
system to drive thirst, and on the renal tubules to promote salt
and water retention, that helps to regulate intravascular volume.
Angiotensin II is an important participant in wound healing, but
its long-term effects on myocardial “healing” can lead to changes
3


CARDIAC DRUGS

in cardiac geometry, including chamber enlargement and scar
formation, a process referred to as myocardial remodeling. In
contrast, angiotensin II receptor subtype 2 (AT2) has effects
that counter AT1 receptor activation, as AT2 receptor activation
subserves vasodilation, and is responsible for the antifibrotic and
anti-inflammatory effects. Selective blockade of AT1 receptors
with ARBs leaves the AT2 receptors open for stimulation by
angiotensin II. The role of AT2 receptors in human physiology is
less understood, whereas the role of AT1 receptors is more clearly
linked to clinically recognized events (Figure 3).
Alternate Pathways of
Angiotensin II Generation
Non-ACE pathways are also present in humans and involve
chymase-like serine proteases that increase the formation of
angiotensin II. Chymase inhibition like ACE inhibition prevents
cardiac fibrosis and improves diastolic function,7 but its quantitative

role in the pathophysiology of cardiovascular disease is less clear.
Angiotensin Converting Enzyme
Inhibitors and Bradykinin
ACEIs not only decrease the formation of angiotensin II, but
also increase bradykinin at local tissue sites. ACE is identical to

ACEIs, angiotensin converting enzyme inhibitors; AT, angiotensin receptor;
ET, endothelin; NO, nitric oxide; Na+, sodium; PAI, plasminogen activator
inhibitor; tPA, tissue plasminogen activator; PGs, prostaglandins; TIMP,
tissue inhibitor of metalloproteinase.

FIGURE 3. Angiotensin II receptor subtypes and their roles.
4


Angiotensin, Aldosterone, and Renin Inhibition in CVD

TABLE 1
Therapeutic Uses of Angiotensin Converting Enzyme Inhibitors
ƒƒ As antihypertensives
ƒƒ Prevention or reversal of left ventricular hypertrophy and
cardiac remodeling
ƒƒ Provide protection against sudden death and second myocardial
infarction after acute myocardial infarction
ƒƒ Improvement in survival and hemodynamic parameters in
systolic heart failure
ƒƒ Prevention or delay in progression of diabetic and nondiabetic
nephropathy

kininase II, an enzyme that inactivates bradykinin; therefore,

ACEIs lead to an increase in local tissue bradykinin. Bradykinin
acts on its receptors to release nitric oxide and prostaglandins,
both of which promote vasodilation and may be important in
preventing cardiac remodeling.8 It is possible that the blood
pressure lowering effect of ACEIs is in part through local nitric
oxide production, which tends to have a favorable effect on
the endothelium. The accumulation of bradykinin is perhaps
responsible in part for some of the side effects of ACEIs, such as
cough and angioedema.

Major Indications
ACEIs are indicated for the treatment of hypertension, chronic
systolic HF, acute MI, chronic ischemic heart disease, and renal
diseases, such as diabetic and hypertensive nephropathies
(Table 1). These drugs also promote cardiovascular protection in
patients with risk factors for cardiovascular diseases.2

Side Effects
Side effects of ACEIs are discussed in table 2.
Cough
One of the most common side effects of ACEIs is dry,
nonproductive, and persistent cough. Patients with HF may also
cough because of pulmonary congestion; therefore, one cannot
assume that all cough in patients taking ACEIs is due to the drug.
The incidence of cough in patients taking ACEIs is being reported
to be as high as 15%, but the need to withdraw the drug because of
cough arises in about 5% of patients.2 The mechanism of the cough
is not entirely clear but is likely due to the increased sensitivity
of the cough reflex and to the formation of local bradykinin and
prostaglandin in the proximal airways. The usual strategy when

patient does not tolerate an ACEI is to change to an ARB.
5


CARDIAC DRUGS

TABLE 2
Side Effects of Angiotensin Converting Enzyme Inhibitors
Side effects

Comment

Cough

5–15% of patients

Angioedema

1–2% of patients

Hypotension

Only 1–2% patients need to discontinue the
drug

Hyperkalemia

More commonly seen in those with:
ƒƒ Renal dysfunction
ƒƒ Diabetics

ƒƒ Concomitant use of nonsteroidal antiinflammatory drugs
ƒƒ Aldosterone antagonists
ƒƒ Potassium supplementation

Worsening
renal function
and acute renal
failure

High risk in patients with:
ƒƒ Chronic kidney disease
ƒƒ Hypertensive nephrosclerosis
ƒƒ Diabetics

Allergic skin rash

Reported more with captopril (rare)

Neutropenia

ƒƒ Mainly with captopril.
ƒƒ High risk in patients with underlying renal
dysfunction and connective tissue disorders

Dysgeusia

Mainly with captopril (rare)

Teratogenicity

In all trimesters of pregnancy

Hypotension
Hypotension, which can be symptomatic or asymptomatic, is
a common consequence of ACEI therapy. In the ONTARGET
(ONgoing Telmisartan Alone and in combination with Ramipril
Global Endpoint Trial) trial,9 hypotensive symptoms sufficient
to discontinue the drug occurred in 1.7% of the patients who
received ramipril and/or telmisartan.
Low systolic blood pressure is perceived by many physicians
to be a contraindication to the use of ACEIs, particularly in the
setting of HF. However, in the absence of symptoms, asymptomatic low blood pressure is usually well tolerated and is typically
not a reason to withdraw the drug. ACEIs are at least as effective
in improving outcomes in patients with systolic blood pressure
less than 100 mmHg as in those with normal or high blood
pressure.10 In patients with HF, hypotension and/or the inability
to tolerate an ACEI due to symptomatic hypotension are powerful
predictors of a poor prognosis.10-12 Although patients with HF and
low systolic blood pressure have a greater risk for developing
symptoms, they also receive a similar benefit as patients without
low blood pressure. This is probably because vasodilator can
increase stroke volume, which then maintains or even increases
systolic blood pressure in some patients with HF. Those patients
with HF and the lowest systolic blood pressure are at the highest
6


Angiotensin, Aldosterone, and Renin Inhibition in CVD

risk of dying or being hospitalized independent of other baseline

characteristics.12 Patients with a marked hyperreninemic state,
such as following a substantial recent diuresis, are especially
prone to develop abrupt and sometimes severe symptomatic
hypotension following the use of ACEIs.
When abrupt reduction in blood pressure occurs following
the use of ACEIs, it may also be due to venous rather than arterial
vasodilation. Symptomatic hypotension due to ACEIs can be
minimized by beginning with the lowest dose of a short-acting
drug, such as captopril. It can be often quickly treated by having
the patient lie down and elevating the legs modestly.
In summary, asymptomatic low blood pressure should not
be necessarily viewed as a contraindication for the use of ACEIs.
However, if symptoms of low blood pressure persist, ACEIs may
have to be withdrawn.
Hyperkalemia
ACEIs increase the serum potassium (K+), mainly through the
inhibition of aldosterone formation, which normally promotes
urinary potassium excretion. The overall incidence of hyperkalemia (serum K+ >5.5 mEq/L) in patients treated with an ACEI
or ARB in carefully conducted clinical trials is approximately
3.3%.2,9 Hyperkalemia is always a risk when patients are taking
ACEIs, particularly, if there is associated impaired renal function,
volume depletion, diabetes, recent use of contrast medium, and
concomitant use of ARBs, MR blockers, or nonsteroidal antiinflammatory drugs. Follow-up monitoring of serum K+ is essential
when managing patients taking ACEIs.
Renal Insufficiency
It can occur in patients receiving ACEIs, but is typically modest
and reversible. It is believed that the transiently reduced renal
function from ACEIs is a consequence of efferent arteriolar
vasodilation. The efferent glomerular arterioles are normally
tightly vasoconstricted by excessive angiotensin II in HF, leading

to a helpful maintenance of intraglomerular hydraulic pressure
and preserved filtration. When an ACEI or ARB is introduced in
the setting of HF, there is dilation of efferent glomerular arterioles,
thus, leading to reduced intraglomerular hydraulic pressure and
reduced glomerular filtration. For example, it is not unusual to
observe a 20% increase in serum creatinine with the use of ACEIs,
but this is not usually a reason to reduce or stop the ACEI therapy.
Often, the rise in serum creatinine occurs a few days after the
institution of therapy; therefore, renal function should be checked
after initiation of ACEI therapy. Rarely, irreversible renal failure
7


CARDIAC DRUGS

can occur when ACEIs are used in patients with bilateral renal
artery stenosis or in patient with oliguric acute renal failure.
Angioedema
Therapy with ACEIs is rarely associated with the occurrence
of angioedema. It is estimated to occur from 0.1 to 2%.13,14 The
exact mechanism behind the development of angioedema
asso­
ciated with ACEIs therapy is unknown; however, various
theories have been proposed, including inhibition of bradykinin,
antigen-antibody interactions, deficiency of complement
1-esterase inactivator, or impaired breakdown of substance P.
The development of angioedema is more common in AfricanAmericans and usually occurs within days of initiating ACEI
therapy. However, it can take months or even years after initiating
treatment. Very rarely, angioedema can be fatal. Although
switching to ARB is the usual strategy, there have been rare, isolated

instances whereby ARBs have also caused angioedema.15,16

Contraindications
Pregnancy
ACEIs and ARBs are contraindicated during each trimester of
pregnancy, as they are known to be teratogenic.17 Typically, one
does not employ ACEI therapy in women of childbearing age
unless there are unusual circumstances. Other contraindications
of ACEIs are discussed in table 3.

Clinical Evidence
Angiotensin Converting Enzyme Inhibitors and
Heart Failure
It is well established that the RAAS is highly active in patients
with HF. The RAAS, like the sympathetic nervous system (SNS),
likely represents an ancient evolutionary advantage. Presum‑
TABLE 3
Contraindications of Angiotensin Converting Enzyme Inhibitors
ƒƒ Bilateral renal artery stenosis
ƒƒ Acute oliguric renal failure
ƒƒ Pregnancy (all trimesters)
ƒƒ History of angioedema or hypersensitivity to angiotensin
converting enzyme inhibitor
ƒƒ Cardiogenic shock
ƒƒ History of neutropenia due to previous use of angiotensin
converting enzyme inhibitors, especially in patients with collagen
vascular disease
8

Angiotensin, Aldosterone, and Renin Inhibition in CVD

ably, the release of renin and the action of angiotensin II and
aldosterone have a temporary favorable effect on maintaining
blood pressure and intravascular volume in patients with low
cardiac output. These are recognized as favorable short-term
adaptations, as if the body is trying to maintain intravascular
volume and perfusion pressure to vital organs in the face of a
falling cardiac output and/or volume depletion. However, the
RAAS and the SNS can become persistently active and eventually
promote maladaptive effects on the heart and the vascular
system. For example, sodium and fluid retention ensues, and
heightened vascular tone contributes to higher impedance to LV
ejection, which further reduces cardiac output. Importantly, the
chronic effects of the RAAS and the SNS can be directly toxic to
the myocardium and are associated with myocyte hypertrophy
and the development of myocardial fibrosis. These changes are
recognized clinically by increased peripheral vasoconstriction,
tachycardia, LV remodeling, increased LV wall stress, release
of brain natriuretic peptide, fluid and sodium retention, tissue
congestion, dilutional hyponatremia, and anemia. This constellation of abnormalities represents the clinical syndrome of
congestive HF. It then stands to reason that drugs designed to
reduce excessive angiotensin II activity (ACEIs and ARBs),
aldosterone activity (spironolactone and eplerenone), and SNS
activity (β-blockers) should be highly effective in the treatment
of patients with HF. The first group of these drugs to be widely
used to treat HF was the ACEIs.
Beneficial effects of Angiotensin Converting Enzyme
Inhibitors in Heart Failure: Vasodilators or Antiremodeling
Agents

Although many believe that the acute vasodilator effects of
ACEIs and the subsequent increase in cardiac output and fall in
venous pressure represent the dominant mechanism of action, it
is more likely that the highly favorable long-term effects of ACEIs
are due to their ability to inhibit the consequences of excessive
angiotensin II on various organs, especially remodeling. They
also reduce SNS activity by desensitizing effectors organs to
norepinephrine and by vitiating its release from sympathetic
neurons. This inhibitory effect on the SNS might also be
contributing to an antiarrhythmic effect of ACEIs and possibly
to the reduction of sudden death observed in several HF trials.18
ACEIs should be considered more as antiremodeling agents
than as acute vasodilators or afterload reducing drugs. The
amount of vasodilation and improvement in cardiac output in
response to ACEIs are relatively modest. Although there is a
reduction in the vascular resistance, the direct antiremodeling
9


CARDIAC DRUGS

CHF, congestive heart failure; ACEI, angiotensin converting enzyme inhibitor.

FIGURE 4. Results of treatment with ACEIs in patients with systolic
heart failure are illustrated. The results of 32 randomized trials are
summarized. Angiotensin converting enzyme inhibitors were shown
to decrease mortality and morbidity of patients with systolic heart
failure. Data from Garg R, Yusuf S. Overview of randomized trials of
angiotensin-converting enzyme inhibitors on mortality and morbidity
in patients with heart failure. Collaborative Group on ACE Inhibitor

Trials. JAMA. 1995;273:1450-6.

effect on the heart is probably more important with regard to
patient survival over the long run. Other vasodilators that fail
to block the RAAS, such as amlodipine and prazosin, provide
no long-term survival benefits. The combination of hydralazine
and isosorbide dinitrate however does have long-term survival
benefits, possibly mediated by nitric oxide production.
ACEIs have become first line therapy for early HF. ACEIs
decrease mortality in patients with systolic HF (Figure 4). Based
on the SOLVD prevention (Studies Of Left Ventricular Dysfunction
prevention) trial,3 they are also beneficial in patients with stage
B HF (cardiac structural changes but without symptoms). ACEIs
are generally used in conjunction with diuretics and β-blockers
for the treatment of HF. ACEIs should be used very cautiously, if
at all, when the baseline serum creatinine exceeds 2.5–3.0 mg/dL
(220–264 mmol/L). The real possibility of ACEIs aggravating
baseline renal insufficiency must be balanced against the possible
benefits on the kidney and the heart along with other structural
attributes associated with their use. In general, the threshold to use
ACEIs in patients with cardiovascular disease should be quite low.
Optimal Doses of Angiotensin
Converting Enzyme Inhibitors in
Heart Failure
ACEIs are usually begun with small doses that are gradually
titrated (days to weeks) to the doses used in large clinical trials or
10