Cardiovascular Disease: Update on Management of Heart Failure, Acute Myocardial Infarction, and Cardiac Arrhythmias Monograph No. 1, 1998 Learning Objectives American Family Physician monographs are designed to provide family physi- cians with high-quality continuing medical education that reflects the spectrum of family practice. After reading this monograph, physicians should be able to: 1.Understand the actions of the various pharmacologic agents used in the treatment of acute and chronic heart failure. 2.Differentiate heart failure due to diastolic versus systolic dysfunction and discuss the drugs most suitable for each. 3.Describe the therapeutic stages in the management of acute myocardial infarction (MI). 4.State current recommendations for the management of patients following acute MI, as well as recommendations for reducing coronary artery disease risk. 5.Review the treatment approaches to the arrhythmias most often seen in clinical practice. 6.Describe the three main steps involved in managing the patient with atrial fibrillation. This American Family Physician monograph is made possible by an education- al grant from the following companies: Bristol-Myers Squibb Company, Hoechst Marion Roussel, Novartis Pharmaceutical Corporation, Knoll Phar- maceutical Company and Wyeth-Ayerst Laboratories. The information pre- sented and opinions expressed herein are those of the authors and do not necessarily represent the views of the sponsors, American Family Physician or its publisher, the American Academy of Family Physicians. Any recommen- dation made by the authors must be weighed against the physician(cid:213)s own clinical judgment, based on but not limited to such factors as the patient(cid:213)s condition, benefits versus risks of suggested treatments and comparisons with recommendations of pharmaceutical compendia and other authorities. The American Academy of Family Physicians (AAFP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to spon- sor continuing medical education for physicians. This program has been reviewed and is acceptable for up to 2 Prescribed credit hours by the Ameri- can Academy of Family Physicians. Term of approval is one year from the distribution date of February 28, 1998. The AAFP designates this program for 2 credit hours in Category 1 of the American Medical Association(cid:213)s Physi- cian(cid:213)s Recognition Award (AMA PRA). Copyright ' 1998 American Academy of Family Physicians 8880 Ward Parkway Kansas City, Missouri 64114 Printed in U.S.A. This American Family Physician monograph was developed in cooperation with the American Heart Association as part of the 1997-1998 American Acad- emy of Family Physicians(cid:213) Annual Clinical Focus, (cid:210)Prevention and Manage- ment of Cardiovascular Disease(cid:211) and is supported by the following companies: Bristol-Myers Squibb Company, Hoechst Marion Roussel, Novar- tis Pharmaceutical Corporation, Knoll Pharmaceutical Company and Wyeth- Ayerst Laboratories. Cardiovascular Disease: Update on Management of Heart Failure, Acute Myocardial Infarction, and Cardiac Arrhythmias An American Family Physician Monograph Prepared by Health Science Communications, Inc., in consultation with: KEN GRAUER, M.D. University of Florida School of Medicine Gainesville, Florida DANIEL S. CLARK, M.D. UCLA School of Medicine Los Angeles, California GARY E. RUOFF, M.D. Michigan State University College of Medicine Kalamazoo, Michigan KENGRAUER, M.D., is professor and assistant director of the Family Practice Residen- cy Program, Department of Community Health and Family Medicine, School of Med- icine, University of Florida, Gainesville. After receiving his medical degree from the State University of New York at Syracuse, he completed residency training in family practice at St. Margaret Memorial Hospital, Pittsburgh, Pennsylvania. DANIEL S. CLARK, M.D., is assistant clinical professor of medicine (cardiology) at UCLA School of Medicine, Los Angeles, and director of the Critical Care Unit, Ven- tura County Medical Center, Ventura, California. He received his medical degree from Tufts University School of Medicine, Boston, Massachusetts, and completed an internship/residency in medicine at Greenwich Hospital, Greenwich, Connecticut, and a clinical fellowship in cardiology at the University of Miami School of Medi- cine, Miami, Florida. GARYE. RUOFF, M.D., is clinical professor of family practice at Michigan State Univer- sity College of Medicine, and director of clinical research at Westside Family Medical Center where he has a full-time medical practice, all in Kalamazoo. After receiving his medical degree from Stritch School of Medicine/Loyola University, Chicago, Illi- nois, he completed an internship at Borgess Hospital, Kalamazoo, Michigan. Prepared by Health Science Communications, Inc., New York, N.Y., based on interviews with Ken Grauer, M.D., Daniel S. Clark, M.D., and Gary E. Ruoff, M.D. Author disclosure policy: We believe that readers need to be aware of any affiliation or finan- cial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We therefore make every reasonable effort to obtain a completed disclosure form from every author, and we inform the reader of any pertinent relationships disclosed. Ray Jarris, M.D. Medical Editor Contents Leigh McKinney Special Projects Department Manager 3 Introduction Michele Webb 3 Heart Failure Special Projects Editor 12 Acute Myocardial Infarction Brian Torrey Special Projects Editor 22 Cardiac Arrhythmias Dana Guthrie Editorial Assistant 28 References Joetta Melton 30 Monograph Quiz Publisher and Project Coordinator 6 Table 1. Etiology of Heart Failure (HF) Robert L. Edsall Editorial Director 8 Table 2. Effects of ACE Inhibitors in Heart Disease Kathy Mayfield 9 Table 3. Pharmacokinetics and Dosing of ACE Inhibitors in Heart Failure Production Manager 13 Table 4. Differential Diagnosis of Chest Pain Julia Nothnagel Assistant Production 16 Table 5. Contraindications to Thrombolytic Therapy Manager 17 Table 6. Comparison of Selected Thrombolytic Agents John Allison Art Director 20 Table 7. Recommendations for Reducing Coronary Risk Factors in Patients Stacey Herrmann After Acute MI Graphic Associate 23 Table 8. Underlying or Precipitating Causes of Atrial Fibrillation Clayton Raker Hasser Group Publisher and 27 Table 9. Extracardiac Factors and Exacerbating Causes of Ventricular Arrhythmias Vice President for Publications and Communications 3 Figure 1. Schematic illustration of selected types of hypertrophic responses. Robert Graham, M.D. 19 Figure 2. Algorithm for a suggested approach to cost-effective risk stratification acute Executive Vice President and after management myocardial infarction. 21 Figure 3. Algorithm for office staff response to patients with symptoms of acute MI. Cover illustration by William B. Westwood Albany, New York 2 Cardiovascular Disease Introduction THEFAMILYPHYSICIANISOFTENCALLEDUPONTO infarction (MI), and cardiac arrhythmias. This diagnose and manage major causes of cardio- monograph provides an overview of these vascular morbidity and mortality, which conditions and addresses their causes and include heart failure (HF), acute myocardial management. Heart Failure Epidemiology easily recognized on echocardiography as a HEARTFAILURE, DEFINEDASANIMPAIRMENTTHAT (cid:210)big, baggy heart.(cid:211) prevents the heart from adequately perfusing In HF due to diastolic dysfunction, cardiac body tissues to meet metabolic demands,1is a contractility is preserved or even increased major health problem that affects between 2 (Figure 1C). The thickened and stiffened ven- and 3 million Americans.2 With 400,000 new tricle limits the amount of blood that can enter cases of HF diagnosed annually, the cost to the the heart, resulting in decreased ventricular U.S. health care system is considerable, since filling during diastole. Ventricular dysfunction HF is the primary reason for an estimated 1 million hospitalizations per year. In 1990, HF was responsible for approximately $10 billion Figure 1 in direct (e.g., hospitalization) and indirect (e.g., prolonged nursing home stays) costs.2 Schematic illustration of selected types of hypertrophic responses. In A, the HF has a poor prognosis. After the left ventricular dimensions are normal. With end-stage systolic dysfunction onset of symptoms, the five-year mortality (B), cardiac chamber wall thickness remains the same or decreases in associa- tion with generalized dilatation of several cardiac chambers. Contractile rate in patients with HF(cid:209)based on data from activity is globally reduced. In lesser degrees of systolic dysfunction, contrac- the Framingham Heart Study(cid:209)is 62 percent tility is reduced, but cardiac chambers do not necessarily demonstrate in men and 42 percent in women,3 with marked dilatation. In pure diastolic dysfunction (C), symmetric thickening of 200,000 deaths attributable to HF each year in the IVS and LVFW occurs at the expense of left ventricular cavitary volume. the United States alone. Cardiac contractility is typically preserved, if not increased, resulting in cor- responding preservation (or increase) in ejection fraction. However, overall Pathophysiology cardiac output is reduced because the ventricle never completely fills. Traditionally, HF has been thought to be a result of an impairment of systolic (inotropic) IVS = interventricular septum; function, which is a reflection of decreased A LA = left atrium; LV = left ventricle; LA contractility of myocardial cells, most common L LVFW = left ventricular free wall; V RA = right atrium; RV = right in the left ventricle. More recently, impaired F left ventricular (LV) filling, or diastolic dys- RA W ventricle. function, has also been recognized as a signifi- I LV V cant contributor to the development of HF and S RV B is a reflection of reduced ventricular compli- ance related to scar tissue, ischemia, or hyper- trophy of normal myocardial cells. Many cases of HF have components of both systolic and diastolic dysfunction. C In HF due to systolic dysfunction, the left ventricle is enlarged and overstretched (i.e., thinned) (Figure 1B; Figure 1Acorresponds to a normal heart). Systolic dysfunction is the result of decreased cardiac contractility, which causes low cardiac output. Common causes of systolic dysfunction include scarring due to mycardial infarction and viral cardiomyopathy. The heart in end-stage HF due to systolic dysfunction is 3 is often mixed, however, and has elements of system, increases release of atrial natriuretic both systolic and diastolic dysfunction. peptide (ANP), may increase the secretion of Unfortunately, the physical examination antidiuretic hormone (ADH) and renal will usually not allow the physician to reliably prostaglandins, and has long-term pathologic distinguish between systolic and diastolic consequences.6 dysfunction. Sometimes, a laterally displaced, Early in the course of HF, neurohormon- dilated point of maximum impulse (PMI) al responses to hypovolemia lead to plasma may suggest that HF has a component of sys- expansion and selective vasoconstriction. The tolic dysfunction. On the other hand, in pure cardiovascular system compensates for the diastolic dysfunction, the PMI is not typically functional decrease in circulatory volume by displaced or dilated, albeit the impulse may shunting blood away from nonvital organ sys- be abnormally sustained in duration. tems (e.g., kidneys, gastrointestinal tract), and It is important to recognize that diastolic by increasing cardiac contractility. Long-term and systolic dysfunction often overlap and neurohormonal adaptation to decreased per- may occur in the same patient. As an exam- fusion results in desensitization of the heart to ple, hypertensive patients commonly devel- sympathetic stimulation, increased impedence op concentric hypertrophy with diastolic to LV outflow, dysfunctional vascular dysfunction as a result of the increase in after- endothelium, impaired glycolysis in fast- load associated with persistent hypertension. twitch muscles, physical deconditioning, and If the hypertension is not controlled, LV func- muscle deterioration. tion eventually deteriorates, and systolic dys- In HF, norepinephrine is chronically ele- function becomes superimposed on the vated due to an increase in release and initially hypertrophied left ventricle. Eventu- spillover from the adrenal gland, decreased ally, the left ventricle dilates and the diastolic plasma clearance, and decreased neuronal and dysfunction present in the early HF of hyper- non-neuronal reuptake. Norepinephrine tension evolves to dilated cardiomyopathy, so increases afterload, causes cardiac arrhythmias, that the component of diastolic dysfunction and has a direct toxic effect on the myocardi- may no longer be recognized. um. There is a direct correlation between nor- Myocardial function is controlled by epinephrine levels and both the hemodynamic preload (Frank-Starling curve), afterload, severity and the poor prognosis of HF.6 ventricular contractility, heart rate, and heart Decreased cardiac output, characteristic rhythm. In HF, impaired heart function of HF, results in constriction of the kidney(cid:213)s results in hemodynamic stress in the form of efferent arterioles, which maintain the glomeru- falling cardiac output. This stress unleashes a lar filtration rate (GFR). As HF progresses, a series of interdependent acute and chronic point is reached at which further constriction compensatory events, all of which are intend- is impossible, and the GFR becomes flow- ed to maintain perfusion to vital organs. dependent and decreases in tandem with Myocardial cell hypertrophy and additional decreases in cardiac output. increased LV wall thickness resulting from When the GFR falls, sodium is reab- HF are accompanied by decreased ventricu- sorbed by the renal tubules, which activates lar compliance (increased ventricular stiff- the RAA system. The RAA system plays a key ness), and, in the elderly, increased vascular role in regulating blood pressure and vascular resistance.4 The ensuing structural deteriora- tone, and maintaining salt and water homeo- tion transforms the left ventricle from its nor- stasis. Renin, a proteolytic enzyme stored in mal elliptical shape to a rounded shape(cid:209)a the juxtaglomerular complex, cleaves angio- process known as remodeling. The rounded, tensinogen (a glycoprotein formed in the liver) or globoid, heart of late-stage HF may be to form angiotensin I. Angiotensin I is split by accompanied by functional mitral regurgita- angiotensin-converting enzyme into angio- tion, ventricular dilatation, and thinning of tensin II, a potent vasoconstrictor that also the ventricular wall.5 stimulates the synthesis and secretion of aldos- terone, which leads to sodium retention. Acti- Neurohormonal Activation vation of the RAA system in HF is thought to The functional decrease in cardiac output and occur in steps, as it normalizes in early-stage, atrial hypertension results in arterial hypo- compensated HF. As HF worsens, the RAA volemia that characterizes HF. HF activates system is reactivated, and is a major contribu- the adrenergic (sympathetic) nervous system tor to the relatively intense edema and vaso- and the renin-angiotensin-aldosterone (RAA) constriction typical of decompensated HF. 4 Cardiovascular Disease ADH is produced in the posterior pitu- cardiac index and oxygen saturation, and lac- itary and promotes renal tubular reabsorp- tic acidosis. Low-output HF may be (cid:210)for- tion of water by the kidneys in response to ward,(cid:211) in which oxygenated blood does not decreased plasma volume, as occurs in HF. reach peripheral tissues, or (cid:210)backward,(cid:211) in Although ADH is often increased in HF, its which blood backs up in the lungs. contribution to the vascular dynamics of HF The symptoms of low-output forward is unclear. HF include weakness, fatigue, lethargy, light- ANP is produced in atrial tissue of the headedness, and confusion. In decompensated heart in response to atrial stretch from HF, cardiac cachexia, which is characterized increased blood volume. This causes natriuresis by generalized exhaustion and loss of lean and vasodilation, and counteracts the water- muscle mass, ensues. The symptoms of low- retaining effect of the adrenergic and RAA sys- output backward, or congestive, HF reflect tems. In early-stage HF, the vasodilatory pulmonary edema, in which fluids accumulate response of peripheral arteries to ANP is pre- in the lungs and result in dyspnea, initially served, but it becomes blunted as the HF enters only on exertion. Decompensated low-output a decompensation phase, an effect attributed to backward failure is characterized by orthop- the down-regulation of ANP receptors.6 nea and paroxysmal nocturnal dyspnea. One of the compensatory responses to The clinical findings in HF include the chronic overstimulation of the sympathet- peripheral edema, rales, S3 gallop, sinus ic nervous system (SNS) and the RAA system tachycardia, hypotension, increased jugular is an increased release of prostaglandins, venous pressure, and hepatojugular reflux. resulting in peripheral vasodilation. Despite the presence of one or more of these signs, HF may be misdiagnosed in up to 40 Clinical Findings percent of patients.7 The severity of HF can It is essential to keep in mind that mild HF is also be evaluated with chest radiography. not necessarily the same as early-stage HF. Chest films may demonstrate cardiac Mild HF suggests that the patient(cid:213)s ability to enlargement, interstitial and alveolar edema, function is only (cid:210)mildly(cid:211) affected. Early- and pulmonary vascular redistribution in HF. stage HF, on the other hand, refers to the However, HF may also be misdiagnosed duration of pathogenic events that occur in using x-ray studies. Therefore, all patients the compensated phase of HF. suspected of having HF should be evaluated It is also important to emphasize that by two-dimensional echocardiography and LV dysfunction does not always progress in a Doppler studies to determine LV contractili- predictable fashion, nor is the degree of LV ty, ventricular compliance, hypertrophy, and dysfunction necessarily paralleled by the the presence or absence of other underlying clinical severity of symptoms. Some patients conditions, such as valve pathology. may present with significant symptoms of HF, yet only have minimal alteration of LV Management Strategies function. Other patients with only mild HF is a syndrome that consists of a constella- symptoms may come to medical attention in tion of symptoms evoked by a wide range of later stages of HF, which reflects the efficacy conditions and precipitating factors (Table 1). Its of the body(cid:213)s compensatory mechanisms. management hinges on correction (when possi- For practical purposes, HF may be ble) of precipitating factors, treatment of acute divided into high-output failure, which is symptoms, and compliance with long-term usually secondary to other, noncardiac condi- strategies that are intended to prolong survival. tions, and low-output failure, which is pri- marily due to cardiac pump failure. Management of Acute High-output HF is very unusual in clinical Precipitating Factors practice and may be due to a marked hyper- HF may be caused by noncardiac factors, dynamic circulation with minimal functional including alcohol and drug abuse, excess fluid myocardial abnormalities, in which the or sodium intake, fever, hyperthyroidism, demand outstrips the capacity, resulting in a hypothyroidism, anemia, hypoxia, infection, hyperkinetic state. renal insufficiency, and hypertension. Con- In low-output HF, the cardiac output trol of these factors may attenuate or even falls below the tissue requirements for oxygen. eliminate the signs and symptoms of HF. It is associated with increased vascular resis- Indeed, if these precipitating factors are not tance and oxygen consumption, decreased diagnosed and eliminated or treated, the 5 Table 1 cal ventilation to optimize oxygenation and gas exchange. An intravenous (IV) diuretic Etiology of Heart Failure (HF) should be administered to reduce preload, relieve pulmonary congestion, and improve Cardiac causes of HF Cardiomyopathy oxygenation. Furosemide (Lasix) is usually Dilated (congestive) cardiomyopathy given in doses of 20 to 40 mg IV, with the dose Infectious (e.g., viral, parasitic) doubled, as needed, every 30 minutes until a Toxic (e.g., alcohol abuse, doxorubicin hydrochloride maximum of 160 mg is reached. The initial [Adriamycin], cyclophosphamide [Cytoxan, Neosar]) dose depends on the severity of pulmonary Nutritional (e.g., l-carnitine, selenium, thiamine, or protein deficiency) congestion, duration of HF symptoms (time to Connective tissue disease allow compensatory fluid retention), renal Hypertrophic cardiomyopathy (concentric left ventricular dysfunction, and known responsiveness to hypertrophy) furosemide. Infiltrative cardiomyopathy Morphine sulfate remains an extremely Amyloid effective treatment for pulmonary edema and Hemochromatosis Sarcoidosis administration should be titrated in small Hypertensive heart disease aliquots (2 to 5 mg IV) to reduce preload and Myocardial ischemia or infarction accompanied by left ventricular improve cardiac performance by reducing dysfunction afterload. Morphine also alleviates the sensa- Valvular heart disease tion of air hunger, thereby indirectly reducing Cardiac arrhythmias (e.g., persistent tachycardia, atrial fibrillation) the level of circulating catecholamines released due to anxiety. Overadministration of Noncardiac causes of HF morphine is unusual in patients with pul- Albright(cid:213)s disease (polyostotic fibrous dysplasia) Anemia monary edema; if respiratory depression does Carcinoid syndrome occur, it can be easily reversed with IV nalox- Arteriovenous fistulas (e.g., trauma, Paget(cid:213)s disease of bone, one hydrochloride (Narcan). hemangiomatosis, glomerulonephritis, hemodialysis) Nitroglycerin acts by reducing both pre- Hepatic disease (e.g., alcohol-related thiamine deficiency) load and afterload, thereby improving cardiac Decreased peripheral arterial resistance performance. Sublingual (0.4 mg), cutaneous, Hyperkinetic heart syndrome or IV nitroglycerin may be used, depending Polycythemia vera on the patient(cid:213)s clinical condition. IV nitroglyc- Thyrotoxicosis erin has a greater effect on afterload, whereas Factors that may precipitate HF the sublingual and cutaneous forms reduce Alcohol preload to a greater extent. Nitroglycerin is Cor pulmonale also indicated if angina accompanies HF. Drug-related (e.g., inappropriate medications, noncompliance) Inotropic therapy with digoxin is gener- Excess fluid or sodium intake ally not indicated in the treatment of acute Fever pulmonary edema. Digoxin may be useful, Hypothyroidism however, as an antiarrhythmic agent to slow Hypoxia rapid atrial fibrillation or atrial flutter if these Infection conditions accompany the HF. Central moni- Obesity Pregnancy toring with a balloon flotation catheter occa- Pulmonary embolism sionally may be needed if questions remain Renal insufficiency regarding hemodynamics or additional data Uncontrolled hypertension are required to follow the patient(cid:213)s response to therapy. patient could receive unnecessary or inappro- Long-term Management priate treatment. Once HF develops, unless a correctable cause is noted, continuous therapy is required to Management of Acute Symptoms minimize morbidity and reduce mortality. It Acute HF with pulmonary edema is a medical is imperative that the precipitating factors be emergency that requires immediate reduction eliminated or treated and the underlying of intravascular volume and myocardial oxy- causes of the patient(cid:213)s heart failure be identi- gen demand. Such patients should be placed fied and treated as completely as possible. in an upright position and given supplemental Thus, in addition to treatment of under- oxygen. Some patients may require mechani- lying hypertension, arrhythmias, ischemia, or 6 Cardiovascular Disease valvular disease, long-term therapy for HF clearance ‡20 mL per minute). These diuretics should be initiated, including both nonphar- are ineffective with more severe degrees of macologic supportive measures and pharma- renal impairment. cologic therapy. Nonpharmacologic measures In moderate to severe HF, low doses of include salt restriction (aiming for less than 2 g loop diuretics, such as furosemide, may be sodium per day), smoking cessation, elimina- effective. Other loop diuretics include tion of alcohol intake, aerobic exercise as tol- bumetanide (Bumex), which has a more erated, and fluid restriction in patients with rapid onset but a shorter duration of action; impaired renal function, refractory HF, or ethacrynic acid (Edecrin), the most ototoxic of psychogenic polydipsia. Patients who are the loop diuretics; and torsemide (Demadex), prone to developing congestive symptoms the newest of these agents, which is as effec- should monitor their weight daily and report tive as furosemide but has a longer duration any rapid weight gain in excess of 3 to 5 lb. of action, allowing for less frequent dosing. The pharmacologic management of HF In patients with HF that is refractory to may require the use of multiple agents, includ- attempts at diuresis with moderate to high ing diuretics, angiotensin-converting enzyme doses of a loop diuretic, the addition of 2.5 to (ACE) inhibitors, digoxin, nitrates, calcium- 5.0 mg of metolazone (Mykrox, Zaroxolyn) 30 channel blockers (CCBs), and beta-adrenergic to 60 minutes before giving the loop diuretic blockers. Treatment should be tailored to the may restore an effective diuretic response. underlying systolic or diastolic dysfunction. Potassium-sparing diuretics effect mild diuresis but have the advantage of conserv- Diuretics ing both potassium and magnesium, which Diuretics are a mainstay in the acute manage- may be more effective in maintaining elec- ment of HF, and are usually the first drugs trolyte balance than cation supplementation. administered to the patient with congestive Potassium-sparing diuretics include amiloride symptoms. They reduce the preload (venous (Midamor), triamterene (Dyrenium), a combi- return volume and ventricular filling pressure) nation of hydrochlorothiazide and triamterene and, by decreasing the effective circulating vol- (Dyazide, Maxzide), and spironolactone ume, relieve the symptoms of pulmonary con- (Aldactone). Careful monitoring of potassium gestion and peripheral edema. Although highly is required when these agents are added to a effective in the management of acute conges- regimen that contains either ACE inhibitors or tion, diuretics do not prevent disease progres- angiotensin II receptor antagonists (ARAs) sion and their long-term effect on mortality is due to an increased risk for hyperkalemia. unknown. Moreover, the use of diuretics may Because of their weak diuretic action, potassi- be associated with adverse effects on hemody- um-sparing diuretics are mainly used as namics, renal function, and serum electrolytes. adjuncts to other, more potent diuretics. For example, they may result in reflex tachy- Diuretics must be used carefully in cardia, activation of the SNS and RAA system, patients with diastolic dysfunction, because increased blood urea nitrogen (BUN) and they are highly volume-dependent. Excessive creatinine levels (from volume depletion), and volume depletion could exacerbate the prob- decreased potassium and magnesium levels. lem with ventricular filling. Once the patient is stabilized (euvolemic), Diuretic therapy requires careful moni- diuretics take on a lesser role in the manage- toring with long-term use, since these drugs ment of HF, and are used in combination with may cause hypokalemia and activate the other agents, particularly with ACE inhibitors. RAA system. Diuretic-induced activation of The selection of a diuretic is based on the the RAA system explains why diuretics severity of the HF and whether the HF is relat- should generally not be used on a long-term ed to systolic or diastolic dysfunction. Mild HF basis unless ACE inhibitors or ARAs, which often responds to thiazides, such as hydrochlo- block RAA activation, are added to the thera- rothiazide (Esidrix, HydroDIURIL, Oretic, etc.), peutic regimen. which require adequate renal function (creati- nine clearance ‡30 mL per minute). Peripheral ACE Inhibitors edema in mild HF also responds to the nonthi- ACE inhibitors block circulating and tissue azide diuretic indapamide (Lozol), which has RAA systems by inhibiting the production of fewer adverse electrolyte and metabolic effects angiotensin II. These agents are both cardio- than hydrochlorothiazide and can be used in protective and vasculoprotective (Table 2). The patients with moderate renal failure (creatinine cardioprotective effects include improved 7 hemodynamics and electrical stability, as well After initial patient stabilization, ACE as reduced SNS activity and reduced LV mass. inhibitor therapy may be started with a short- The vasculoprotective benefits include acting agent (e.g, captopril [Capoten]) before improved endothelial function, vascular com- switching to a long-acting drug (Table 3). Ini- pliance and tone, as well as direct antiprolifer- tial use of short-acting ACE inhibitors mini- ative and antiplatelet effects.8 ACE inhibitors mizes the frequency and duration of ACE also stimulate prostaglandin synthesis, reduce inhibitor-related hypotensive episodes, as it the size of myocardial infarcts, reduce reperfu- permits more rapid withdrawal of therapy. sion injury and complex ventricular arrhyth- Such treatment is often not needed in more mias, and have antiatherogenic activity in stable patients. Although there are differences cholesterol-, mechanical- and immune-mediat- among the ACE inhibitors in pharmacokinet- ed experimental models of atherosclerosis. ics and other properties, these differences are ACE inhibitors have emerged as the of relatively little clinical significance. Long- treatment of choice in HF with systolic dys- acting ACE inhibitors are generally preferred function because of their neurohormonal for long-term therapy because of their effects and their ability to reduce both preload decreased frequency of administration, which and afterload. The ACE inhibitor-induced translates into improved patient compliance. reduction of angiotensin II results in reduced ACE inhibitors are indicated for use in release of aldosterone, which in turn reduces virtually all patients with HF due to systolic sodium and water retention, and, by exten- dysfunction, unless there are specific con- sion, decreases preload. ACE inhibitors traindications to their use, such as hyper- improve the hemodynamics of HF by reduc- kalemia, pregnancy, clinically significant ing right atrial pressure, pulmonary capillary renal insufficiency, symptomatic hypoten- wedge pressure, arterial blood pressure, and sion, or a history of adverse reactions or intol- pulmonary and systemic vascular resistance. erance. Potential adverse effects of ACE These agents also increase both the cardiac inhibitors include hypotension, renal impair- and stroke indices and reduce the right ven- ment, hyperkalemia, cough, and angioneu- tricular end-diastolic volume, thereby result- rotic edema. In addition, idiopathic adverse ing in increased cardiac output, reduced effects, such as skin eruptions, disturbances cardiac load, and decreased myocardial oxy- in taste, and bone marrow suppression, have gen consumption. They also down-regulate been noted. the SNS, which, as discussed earlier, is inti- In patients who cannot tolerate ACE mately linked to the pathogenesis of HF. inhibitors because of cough or angioedema, The net effects of the reversal of the two alternative therapeutic regimens can be pathophysiologic cascade of HF by ACE used: either combination therapy with inhibitors include improvement in symp- hydralazine (Apresoline) and a nitrate, or toms, functional status, exercise tolerance, treatment with an ARA, such as losartan and quality of life plus prolonged survival. (Cozaar), valsartan (Diovan) or irbesartan (Avapro). Despite the ability of hydralazine and isosorbide dinitrate (Isordil, Sorbitrate) to Table 2 effectively reduce preload and afterload, this combination should be considered a second- Effects of ACE Inhibitors in Heart Disease line therapy for a number of reasons. The com- Cardioprotective effects bination is associated with a high incidence of ¥Restored balance between myocardial oxygen supply and demand adverse reactions, such as headache, heart pal- ¥Reduction in left ventricular preload and afterload pitations, and nasal congestion. It is also likely ¥Reduction in left ventricular mass to cause reflex tachycardia, which increases ¥Reduction in sympathetic stimulation oxygen consumption. Hydralazine is often associated with tachyphylaxis. It should be Vasculoprotective effects kept in mind that these agents are not ¥Antiproliferative and antimigratory effects on smooth muscle and inflammatory cells approved by the U.S. Food and Drug Admin- ¥Antiplatelet effects istration as therapy for HF. ¥Improved arterial compliance and tone ARAs act by a somewhat different mech- ¥Improved and/or restored endothelial function anism than do ACE inhibitors. Initial data sug- ¥Antihypertensive effects gest that they may be at least as effective as ¥Possible antiatherosclerotic effect and better tolerated than ACE inhibitors.9 Although both ACE inhibitors and ARAs act 8 Cardiovascular Disease