Cardiac drugs 1e (2013) PDF UnitedVRG

Director-ANGIOTENSIN CONVERTING ENZYME INHIBITORS Introduction Angiotensin converting enzyme inhibitors ACEIs have emerged as one of the most important and high impact classes of drugs d

DRUGS

Editors

Kanu Chatterjee MBBS FRCP (London) FRCP (Edin)

FCCP FACC MACPClinical Professor of Medicine

Division of CardiologyThe Carver College of Medicine

University of IowaIowa City, Iowa, USAEmeritus Professor of Medicine

University of California San Francisco, California, USA

Eric J Topol MD FACCDirector, Scripps Translational Science InstituteChief Academic Officer, Scripps Health

Vice Chairman, West Wireless Health InstituteThe Gary and Mary West Chair of Innovative Medicine

Professor of Translational Genomics

The Scripps Research Institute

La Jolla, California, USA

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by the contributors contained herein are original, and is intended for educational purposes only While every effort is made to ensure the accuracy of information, the publisher and the editors specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use

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

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Contributors ix Preface xi Acknowledgments xiii

Positive Inotropic Drugs: A Limited but Important Role 34

Carl V Leier, Garrie J Haas, Philip F Binkley

Drugs for Diabetes and Cardiodysmetabolic Syndrome 242

Prakash Deedwania, Sundararajan Srikanth

CHAPTER 7

Stephen W Waldo, Yerem Yeghiazarians, Kanu Chatterjee

CHAPTER 8

Rakesh Gopinathannair, Brian Olshansky

Drugs for Heart Failure 389

Kanu Chatterjee

CHAPTER 10

Kanu Chatterjee, Wassef Karrowni

CHAPTER 11

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

Index 509

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

Prakash Deedwania MD FACC

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

Michael E Ernst Pharm DProfessor (Clinical)Department of Pharmacy Practice and ScienceCollege of PharmacyDepartment of Family MedicineCarver College of MedicineThe University of IowaIowa City, Iowa, USA

Gary S Francis MDProfessor of MedicineCardiovascular DivisionUniversity of MinnesotaMinneapolis, Minnesota, USA

Rakesh Gopinathannair MD MADirector

Cardiac ElectrophysiologyUniversity of Louisville HospitalAssistant Professor of MedicineDivision of Cardiology University of LouisvilleLouisville, Kentucky, USA

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

EDITORS

CONTRIBUTING AUTHORS

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

Division of Cardiovascular Diseases

The Carver College of Medicine

University of Iowa Hospitals and

Associate Professor Emeritus

Department of Internal Medicine

Nephrology-Hypertension Division

Carver College of Medicine

University of Iowa Hospitals and

Clinics

Iowa City, Iowa, USA

Overstreet Professor of Medicine and Pharmacology, Division of Cardiovascular Medicine, Davis Heart Lung Research InstituteThe Ohio State University of Medicine and Public HealthColumbus, Ohio, USA

Brian Olshansky MD FACC FAHA FHRS

Professor, Division of Cardiovascular MedicineUniversity of Iowa HospitalsIowa City, Iowa, USA

Sundararajan Srikanth MDCardiology Fellow, Department

of MedicineUCSF Program at FresnoSan Francisco, California, USA

Byron Vandenberg MDAssociate Professor, Division of Cardiovascular Medicine Department of Internal MedicineUniversity of Iowa Hospitals and Clinics

Iowa City, Iowa, USA

Stephen W Waldo MDFellow in CardiologyDepartment of MedicineUniversity of California San Francisco, California, USA

Yerem Yeghiazarians MDAssociate Professor of MedicineUniversity of California San Francisco, California, USA

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

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 Publishing), 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

(Director-ANGIOTENSIN CONVERTING

ENZYME INHIBITORS

Introduction

Angiotensin converting enzyme inhibitors (ACEIs) have emerged

as one of the most important and high impact classes of drugs

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

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

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

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

Abdallah Kamouh, Gary S Francis, Kanu Chatterjee

Angiotensin, Aldosterone,

and Renin Inhibition in

Cardiovascular Disease

1

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)

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

AVP, arginine vasopressin; NE, norepinephrine.

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

Renin is a proteolytic enzyme released primarily by the kidneys This release is stimulated by decrease in kidney perfusion, decrease in

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

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;

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

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;

inhibitor; tPA, tissue plasminogen activator; PGs, prostaglandins; TIMP, tissue inhibitor of metalloproteinase.

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

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

to be as high as 15%, but the need to withdraw the drug because of

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

infarction after acute myocardial infarction

systolic heart failure

nephropathy

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

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, asympto-matic 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

to tolerate an ACEI due to symptomatic hypotension are powerful

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

Side Effects of Angiotensin Converting Enzyme Inhibitors

High risk in patients with:

Allergic skin rash Reported more with captopril (rare)

dysfunction and connective tissue disorders

risk of dying or being hospitalized independent of other baseline

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

inhibition of aldosterone formation, which normally promotes urinary potassium excretion The overall incidence of hyper-

or ARB in carefully conducted clinical trials is approximately

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 anti-

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

TABLE 3

Contraindications of Angiotensin Converting Enzyme Inhibitors

converting enzyme inhibitor

converting enzyme inhibitors, especially in patients with collagen vascular disease

artery stenosis or in patient with oliguric acute renal failure

Angioedema

Therapy with ACEIs is rarely associated with the occurrence

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 African-Americans 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

Contraindications

Pregnancy

ACEIs and ARBs are contraindicated during each trimester of

does not employ ACEI therapy in women of childbearing age unless there are unusual circumstances Other contraindications

of ACEIs are discussed in table 3

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 cons-tellation 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

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

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

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

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.

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

causes in patients at high risk (>55 years with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes).

HTN, hypertension; HF, heart failure; CV, cardiovascular; OD, once a day;

BD, twice a day; TID, thrice a day.

recommended by the pharmaceutical manufactures (Table 4) This titration period typically occurs over 1–3 weeks, but there are no data to support how one should precisely titrate these drugs In general, the dose-response curve to ACEIs is rather flat.Although the optimal doses of ACEIs in patients with systolic

HF have not always been clearly established by clinical trials, several studies have examined this question In a study comparing enalapril 10 mg twice a day to 60 mg once a day, there was no benefit

in terms of mortality or changes in hemodynamic status with the

low or high-dose lisinopril Although this study demonstrated no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% in patients receiving high-dose lisinopril compared with low-dose (p < 0.001) A reduction

of 24% was observed in HF hospitalization (p  =  0.002) with the higher dose The survival benefits and the significant reduction

in cardiovascular morbidity related to treatment with ACEIs are best achieved by uptitrating the dose of ACEIs to the target dose achieved in clinical trials In routine practice, these doses are

physicians or nurses regarding hypotension Clinical endpoints including New York Heart Association (NYHA) class and HF-related hospitalizations have been reduced by higher doses, but

Angiotensin Converting Enzyme

Inhibitors and Hyponatremia

Hyponatremia can be a marker of intense activation of the RAAS and marked hyperreninemia This may occur following substantial diuresis Such patients are notoriously sensitive to ACEIs and may develop precipitous, symptomatic hypotension If over-diuresis with volume depletion is clinically suspected and serum sodium

is low, small doses of short-acting captopril may be safer to use than the long-acting ACEIs

Angiotensin Converting Enzyme Inhibitors and

Heart Failure with Preserved Ejection Fraction

There are no survival benefit data to support the use of ACEIs or any other neurohormonal blocking agents for the treatment of

randomized trials of RAAS blocking agents in HF with preserved

LV function—Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in

demonstrated no clear benefit with regard to all-cause mortality and HF-related hospitalizations However, RAAS inhibition continues to be valuable in the management of hypertension commonly found in this patient population Patients with this form of HF continue to be a source of intensive investigations; however, no specific therapy has emerged as consistently successful Blood pressure control and diuretics continue to be the mainstay of therapy

Phosphodiesterase-5 inhibition has been reported to exert beneficial effects in patients with HF with preserved ejection

and mixed type of pulmonary hypertension with increased pulmonary capillary wedge pressures as well as increased pulmonary vascular resistance The patients were randomized

to receive either sildenafil (50 mg thrice a day) or placebo The long-term treatment with sildenafil was associated with a significant reduction in pulmonary capillary wedge pressure, pulmonary artery pressure, and pulmonary vascular resistance There was a substantial reduction in right atrial pressure and

an improvement in right ventricular systolic function There was also a substantial reduction in the lung water content due

to treatment with sildenafil Systemic vascular resistance and arterial pressure, however, remained unchanged, indicating that there was no systemic vasodilatation with sildenafil.The hemodynamic improvement was associated with clinical improvement and improved exercise tolerance

Angiotensin Converting Enzyme Inhibitors and

Hypertension

Under normal circumstances, the blood pressure is maintained through a variety of mechanisms, including the activation of RAAS When there is sodium restriction or diuretic use, the RAAS can be further activated This is especially true of patients with renal artery stenosis, hyponatremia, or volume depletion ACEIs lower blood pressure through a variety of mechanisms, including vasodilation, reduced aldosterone production, release

of bradykinin, and attenuation of SNS activity They appear to be more effective in Caucasian than black patients, but, when used with diuretics, ACEIs are also quite effective in black patients

In elderly patients, they may control blood pressure better than

ARB, actually lowers serum uric acid levels

Angiotensin Converting Enzyme Inhibitors for

Early-phase Acute Myocardial Infarction or

Postinfarct Left Ventricular Dysfunction

ACEIs or ARBs are uniformly recommended for the treatment

of LV dysfunction when patients are hemodynamically stable following MI In general, the patients with the most advanced HF probably derive the most benefit from ACEIs Such patients would include those with diabetes mellitus, anterior MI, persistent

choose to withhold ACEIs during the first 24 hours following

MI until the patient is hemodynamically stable Several large clinical trials, including GISSI-3 (Gruppo Italiano per lo Studio

ACEIs reduce mortality at 6 weeks, particularly, in patients with diabetes mellitus The effectiveness of ACEIs in patients with MI

is not off-set by the use of aspirin Likewise, β-blockers are given concomitantly with ACEIs under most circumstances

At least 3 major trials have demonstrated that mortality reduction occurs when ACEIs are used in patients with postinfarct

contributes importantly to improved survival This benefit is

ACEIs are prescribed long-term for patients who have sustained

LV dysfunction following MI

Angiotensin Converting Enzyme Inhibitors and

Long-term Cardiovascular Protection

ACEIs protect against the development of coronary artery disease (CAD) This protection extends even to low risk patients These trials found an 18% reduction in the odds ratio for the combined outcomes of cardiovascular death, nonfatal MI, or stroke, which is highly significant In the Prevention of Events with ACE inhibition (PEACE) trial, trandolapril reduced total mortality in patients with CAD, a preserved ejection fraction,

anti-ischemic agents, they seem to reduce ischemic events by indirectly reducing myocardial oxygen demand, SNS activity, and improving endothelial function

Angiotensin Converting Enzyme Inhibitors and

Renal Protection

It is now apparent that patients with diabetes mellitus benefit greatly from blood pressure control Patients with type 1 diabetes and renal insufficiency also demonstrate less proteinuria and reduced further loss of renal function when

decline in proteinuria When microalbuminuria is observed, ACE inhibition is indicated In fact, ACE inhibition can delay

role in progressive impairment of renal function, ACEIs may delay the development of end-stage renal failure, in part, by

of decline in glomerular filtration rate (GFR) more than that

high level of serum creatinine may not be a contraindication of ACEIs in patients with renal disease, although it remains a point

of controversy and uncertainty among physicians Of interest, African-Americans with renal insufficiency treated with ACEIs

Choice of Angiotensin

Converting Enzyme Inhibitors

Overall, there is a little reason to believe that there are specific advantages observed for one ACEI over another In general, clinicians should choose ACEIs that have been vigorously

tested in clinical trials Captopril, a very short-acting ACEI, has the disadvantage of requiring dosing thrice a day However, it has the advantage of being relatively short-acting; therefore,

it is preferable for hospitalized patients when hypotension is

a potential concern One of the unique side effects related to captopril is neutropenia, which is typically associated with high doses It usually occurs in patients with underlying renal dysfunction and in especially those with a collagen vascular disease Now that low doses of captopril are more commonly employed, neutropenia is much less common Ramipril has undergone extensive testing in early postinfarction HF, in renoprotection studies, and in prevention studies of patients with cardiovascular risk factors A disadvantage of ramipril is that the blood pressure lowering effect is not sustainable over

24 hours Lisinopril is inexpensive, has relatively straightforward pharmacokinetics, is water soluble, and does not require liver transformation; thereby, making it easy to use It has been widely studied in major clinical trials Perindopril was used in EUROPA (the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease), in patients with stable CAD, where it had a favorable effect on cardiovascular

patients with previous stroke and in those with transient ischemic attack in the PROGRESS (perindopril protection

and other oversees countries

ANGIOTENSIN II RECEPTOR BLOCKERS

Mechanism of Action and Pharmacology

ARBs block the AT1 receptors and attenuate the deleterious pharmacodynamics effects of angiotensin II, such as vaso-constriction, hypertension, myocyte hypertrophy, ventricular and atrial adverse remodeling, renal dysfunction, and promotion

of atherothrombosis AT1-blockade is also associated with upregulation of the AT2 receptors which has the potential to produce beneficial effects on cardiovascular dynamics

The first ARB to be marketed was losartan and it is now widely used for patients with HF and hypertension It is also used for the prevention of stroke and diabetic nephropathy Over time,

we have learned that ARBs are seemingly better tolerated than ACEIs They have a remarkable lack of side effects and are regarded as first line therapy by many experienced physicians The indications and contraindications of ARBs are essentially similar to ACEIs and include cardiogenic shock, pregnancy, and bilateral renal artery stenosis Although better tolerated, ARBs are generally more costly than generic ACEIs This is likely

to change, as more ARBs become generic Although ACEIs are generally preferred as first line therapy for HF, the well-known tolerability of ARBs is gradually allowing them to assume a primary choice of treatment by many cardiologists ARBs reduce mortality of patients with systolic HF (Figure 5)

Many large trials have shown that ACEIs and ARBs are generally equivalent when used for patients with chronic HF or postinfarct

to date, comparing an ACEIs and an ARB, provided additional evidence that ARBs are equal to ACEIs in the prevention of clinical end-points, such as cardiovascular mortality and morbidity,

placebo in patients with systolic heart failure in the Val-HeFT trial

Data from Cohn JN, Tognoni G; Valsartan Heart Failure Trial

Investigators A randomized trial of the angiotensin-receptor blocker

valsartan in chronic heart failure N Engl J Med 2001;345(23):1667-75.

Val-HeFT, valsartan heart failure trial; ACEI, angiotensin converting enzyme inhibitor; CV, cardiovascular

MI, and stroke This was also noted in the VALIANT (VALsartan

that valsartan is as effective as captopril for patients following

an acute MI with HF and/or LV systolic dysfunction, and may be used as an alternative treatment in ACEI-intolerant patients

Combination of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Both the ONTARGET and the VALIANT trials demonstrated

no survival benefit with the combination of an ACEI and

an ARB over either agent used alone On the other hand, both

(Candesartan in Heart failure: Assessment of Reduction in

inhibition with ACEI and ARBs (valsartan or candesartan) may reduce morbidity and mortality in certain patient subgroups with chronic HF Accumulating evidence also points to the benefits

of the combination therapy in individuals with proteinuric nephropathies Despite these observations, combining ARBs with ACEIs has also been associated with more adverse effects

in some studies, including hypotension, renal insufficiency, and hyperkalemia These adverse effects occurred without additional

Doses of Angiotensin Receptor Blockers

Although ARBs has been studied extensively in patients with hypertension and HF, the relation between dose and clinical outcomes has not been well studied The dose of ARBs is largely based on clinical trials, and one dose does not fit all patients (Table 5) The HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) study is one of the first studies done to assess the relation between the dose and the

indicated that losartan at 150 mg/day reduced the rate of death or admission to the hospital for HF more than the commonly used dose of losartan 50 mg/day This supports the value of uptitrating the ARBs dose to achieve clinical benefit, but it is unlikely that additional large clinical trials comparing dose strength will be performed

Choice of Angiotensin Receptor Blockers

Although different ARBs have different affinity for the AT1 receptors and may have different clinical effects, most ARBs studied in patients with systolic HF demonstrated a reduction

in mortality and hospitalization Various ARBs have not been

studied in a comparative manner; however, candesartan compared with losartan has higher binding affinity for the AT1

a registry study of hypertension, candesartan compared with

study of elderly patients with HF, losartan was associated with a

A recently published registry from Sweden suggests that the use

of candesartan compared to losartan is associated with a lower

reliable than large randomized trials Nonetheless, it would be a value to have more comparative data among the various ARBs This is not likely to happen in the current era of cost-containment

Angiotensin Receptor Blockers and

Atrial Fibrillation

Early observations suggested that ARBs prevented atrial fibrillation, but this has not been consistently confirmed in other large follow-up clinical trials In a meta-analysis of 11 trials with ACEIs or ARBs involving 56,308 patients, both ACEIs and ARBs were demonstrated to reduce the relative risk of atrial fibrillation

atrial fibrillation (ACEIs: 28%, p = 0.01; ARBs: 29%, p = 0.00002) were produced by both the group of drugs The effect was greatest in patients with LV dysfunction or LVH, in whom the risk reduction was 44% (95% CI, 15–63%; p = 0.007) This reduction

in atrial fibrillation with RAAS blockade could at least partly

Different Types of Angiotensin Receptor Blockers

Generic name Initial daily dose

account for the reduction in stroke that has consistently been observed in other large outcome trials However, the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention

did not reduce cardiovascular events in patients with atrial fibrillation Overall, ARBs may reduce the incidence of atrial fibrillation in patients with HF, but this observation has not been consistently reported

Angiotensin Receptor Blockers and

Risk of Cancer

Although no studies were designed to specifically address cancer risk in patients taking ARBs, a large meta-analysis suggested an

meta-analysis from 70 randomized trials of 325,000 patients failed

to confirm the findings of the previous study and demonstrated

the USFDA conducted a large meta-analysis from 31 trials and 156,000 patients, comparing outcomes in patients randomized

to an ARB or “non-ARB treatment” with an average follow-up of

patient’s risk of developing cancer while taking ARBs

Angiotensin Receptor Blockers and

Aortic Aneurysm

AT1 receptor blockade is potentially beneficial in preventing aortic

mechanism of this beneficial effect of AT1 receptors blockade has not been elucidated The beneficial effects have been observed with doses of AT1 receptors blockers that do not lower arterial pressure

Activation of transforming growth factor-β (TGF-β) has been implicated in the pathogenesis of aortic aneurysms Angiotensin II stimulates TGF-β signaling pathways The AT1 receptors blocking agents decrease expression of TGF-β in aortic walls

It should be appreciated that the mechanisms involved in the aneurysm formation vary according to the anatomic location In the tissues of the thoracic aortic aneurysms, high-grade inflammatory response is usually absent In the abdominal aortic aneurysms, however, infiltration of macrophages with inflammatory and atherothrombotic changes are common Angiotensin II promotes atherosclerosis and exerts proinflammatory responses in the aortic walls AT1 receptors blockade can attenuate atherothrombotic and inflammatory responses in aortic aneurysms and decrease the risk of aneurysm expansion In animal models of abdominal

and ACEIs decrease aortic dilatation.

In the animal model of Marfan’s syndrome, angiotensin II causes progression of aortic aneurysm The selective AT1 receptors blockers attenuated progressive dilatation of the aneurysms

It was also observed that the presence of AT2 receptors provide better protection The activation of AT2 receptors decreases the deleterious effects of angiotensin II The ACEIs decrease the formation of angiotensin II and attenuate activation of both AT1 and AT2 receptors and, thus, are less effective than selective AT1 receptors blocker in preventing dilatation of the aortic aneurysms

In patients with Marfan’s syndrome with severe annuloaortic ectasia, angiotensin II concentrations in the tissues of the affected aorta are increased but remains normal in the tissues of the unaffected aorta This observation suggests that angiotensin II plays a role in the pathogenesis of aneurysms of ascending aorta

in Marfan’s syndrome and provides a rationale for the use of AT1 receptors blockers

Serial echocardiographic studies in patients with Marfan’s syndrome have revealed that treatment with AT1 receptors blockade is associated with a marked attenuation of the increase

in the size of the aortic aneurysm Based on these observations, the patients with Marfan’s syndrome are frequently treated with AT1 receptors blockers

In all aortic aneurysms, irrespective of location, there are changes in the extracellular matrix There is an imbalance between matrix collagen synthesis and breakdown Matrix degrading enzymes, matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are increased in thoracic and aortic aneurysms and have been suggested to be contributing factor in the pathogenesis

of aortic aneurysms In animal model, AT1 receptors blockade was associated with decreased expression of MMP-2 and MMP-9, which is another rationale for the use of AT1 receptors blocking agent for treatment of aortic aneurysms

FIGURE 6. Biological action of aldosterone that contribute to cardiovascular disease.

PAI-1, plasminogen activator inhibitor-1; LVH, left ventricular hypertrophy;

the Eplerenone Post-Acute Myocardial Infarction Heart Failure

in Mild Patients Hospitalization And SurvIval Study in Heart

aldosterone is highly important in the syndrome of systolic HF

water retention and remodeling of cardiac and vascular tissue The overly active RAAS is associated with higher mortality in patients with systolic HF Blocking aldosterone production (ACEIs) and inhibiting its receptor activity (spironolactone and eplerenone) have consistently improved survival in patients with systolic HF

In the RALES study, 1,663 patients with advanced chronic systolic heart failure were randomized to receive either spironolactone (25–50 mg/day) or placebo Spironolactone treatment was associated with a 31% reduction in cardiovascular death, a 36% reduction in death due to progressive heart failure, and a 29% reduction in sudden death Because chronic aldosterone inhibition by ACEIs may lead to “escape” of aldosterone production over time, it is believed that drugs, such as spironolactone and eplerenone, which directly block aldosterone receptors are associated with more durable antialdosterone pharmacologic effects over time compared to ACEIs or ARBs

After many years of study, it has become apparent that aldosterone blockade in patients with systolic HF reduces LV

reverse remodeling is illustrated After treatment with aldosterone antagonist spironolactone, there was a reduction in LVEDVI,

LVESVI, and LVMI Adapted from Tsutamoto T, Wada A, Maeda

K, Mabuchi N, Hayashi M, Tsutsui T, et al Effect of spironolactone

on plasma brain natriuretic peptide and left ventricular remodeling

in patients with congestive heart failure J Am Coll Cardiol 2001; 37:1228-33, with permission.

LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVMI, left ventricular mass index.

in LV end-diastolic and end-systolic volumes and LV mass after treatment with spironolactone Aldosterone blocking agent, spironolactone, reduces mortality of patients with systolic HF Aldosterone blockade is now an established therapeutic strategy for the treatment of systolic HF Unless contraindicated or not tolerated, aldosterone receptor blockers should be used virtually

in all patients with symptomatic HF in conjunction with a RAAS blocker and a β-adrenergic receptor blocker Selective aldosterone antagonist, eplerenone, decreases the mortality and morbidity of postinfarction patients with reduced LV ejection fraction In the EPHESUS study, 6,642 patients with left ventricular ejection fraction of 40% or less were randomized within 3–4 days

of incident infarction to receive either eplerenone (target dose

50 mg/day) or placebo Following treatment with eplerenone for

30 days, all cause mortality decreased by 31% (risk ratio 0.69); death from cardiovascular causes decreased by 32% (risk ratio 0.68) and sudden cardiac death decreased by 37% (risk ratio 0.63)

Mechanism of Action

Aldosterone levels increase in response to angiotensin II stimulation and hyperkalemia (Figure 8) It is now clear that therapy with MR blockers reduces LV remodeling, possibly by limiting the amount of myocyte hypertrophy, cardiac collagen

Excessive aldosterone has been shown to have a number of other adverse effects, including activation of other neurohumoral

release from the adrenal gland is directly stimulated by angiotensin II and hyperkalemia Aldosterone exerts multiple detrimental effects

on the heart, vasculature, and the kidneys

the NF-κβ and the activator protein 1 (AP-1) signaling pathways, vascular inflammation and fibrosis, myocardial hypertrophy,

It is also noted that spironolactone and eplerenone reduce the

favorable effects may be mediated in part by inhibition of cardiac norepinephrine release and/or concurrent relative hyperkalemia.Despite the benefits of MR blockade repeatedly demonstrated

in clinical trials, it has been difficult to determine the precise mechanism by which MR blockade translates into improved survival in patients with systolic HF The benefits are likely multifactorial

of spironolactone for the treatment of systolic HF is typically

<5 mEq/L The dose of spironolactone for resistant hypertension

is typically higher at 50–100 mg/day

Eplerenone received USFDA approval in 2002 and 2003 for the treatment of systolic HF and hypertension, respectively Eplerenone is metabolized by the hepatic cytochrome P450 system and may interact with multiple drugs No active metabolites

of eplerenone are known to exist The elimination half-life is 4–6 hours Steady-state is achieved within 2 days Blood levels are potentiated and increased with concomitant use of inhibitors

of the cytochrome P450 3A4 pathway (e.g., ketoconazole, saquinavir, and erythromycin) A major advantage of eplerenone over the more nonselective aldosterone receptor antagonist, spironolactone, is a lack of binding to pro gesterone and androgen receptors The usual dose of eplerenone in HF is 25–50 mg/day

Side Effects

Hyperkalemia

The main factor that limits the use of both eplerenone and spironolactone is the increased risk of hyperkalemia, which rarely

than placebo in RALES, EPHESUS, and the EMPHASIS trials,

respectively This frequency of increase in serum K >6 mEq/L was statistically significant except in the EMPHASIS trial (p = 0.29) Hyperkalemic events were most common during the first 30 days after introduction of the drug, coinciding with the period of drug titration, but occurred sporadically throughout the period of follow-up The predictors of hyperkalemia were reduced baseline

advanced age The highest reported rate of hyperkalemia was seen

in trials using doses in excess of 50 mg/day of either eplerenone

ACEIs and ARBs along with potassium chloride supplementation carry the highest risk of hyperkalemia, particularly, if there

is underlying diabetic nephropathy and concomitant use of anti-inflammatory drugs Hyperkalemia following aldosterone antagonists’ administration is usually managed by lowering the dose of these drugs or discontinuing therapy The frequency of hyperkalemia in the context of a controlled clinical trial may be less than expected in routine clinical practice These observations should increase the vigilance regarding hyperkalemia and

especially early after introducing the drug

Gynecomastia

Gynecomastia was reported in 4.3% of the

MR receptor, adverse effects, such as gynecomastia and vaginal bleeding, seem to be less likely in patients who take eplerenone than in those who take spironolactone

Contraindications

Aldosterone antagonists are contraindicated in patients with shock, oliguric renal failure, and/or hyperkalemia

Role of Aldosterone Inhibitors in

Heart Failure: Clinical Evidence

Spironolactone was used as an adjunctive diuretic agent for HF until 1999, when it jumped to the forefront of medical therapy for patients with advanced HF following the publication of

reduced mortality by 30% and HF hospitalizations by 35% in patients with severe HF on conventional medical therapy

Further proof of the importance of MR blockade for the

this study, eplerenone reduced the combined end-point of cardiovascular mortality and cardiovascular hospitalization by