Heart failure and cardiac hypertrophy

Heart failure, with an incidence of over 500,000 and a prevalence of 5 million, is the most frequent cause of hos-pital admissions in the United States in individuals over the age of 65 years. Systemic hypertension is a major cause of congestive heart failure (CHF) and is antecedent in 91% of cases. Despite its importance in the development of heart failure, the progression of hypertensive left ventricular (LV) remodeling and the mechanisms that impact the transition of systemic hypertension to LV failure are not well under-stood in humans. The prevailing paradigm of hypertensive heart disease—systemic afterload causing left ventricular hypertrophy (LVH) followed by LV dilatation and LV failure with systolic dysfunction—has been a recurrent observation in animal models of systemic hypertension and pressure overload [1–3]. In human hypertension the picture is more complex, with significant variability in the hypertrophic response to systemic afterload and the pro-gression to heart failure [4•,5]. Furthermore, heart failure with preserved left ventricular ejection fraction (LVEF; with or without LV diastolic impairment) is commonly associ-ated with concentric LVH, especially in elderly women with increased vascular stiffness [6–8].

Myocardial hypertrophy is an essential adaptive response of the heart to stress and injury. Paradoxically, LVH is associated with cardiovascular morbidity and

mortality. The mechanisms that distinguish pathologic from physiologic hypertrophy are yet to be elucidated; nevertheless, the incidence of cardiovascular events associated with LVH, including stroke and heart failure, is continuing to rise, prompting clinician-scientists to revisit current management strategies aimed at prevent-ing or regressing LVH. A distinct clinical entity, hyper-trophic cardiomyopathy secondary to sarcomeric gene mutations is pathologic and often associated with exten-sive myocardial fibrosis leading to diastolic LV failure and increased risk of sudden cardiac death.

Several investigations suggest that regression of hypertensive LVH is associated with improved prognosis with respect to cardiovascular outcomes [9–12]. Because obesity is an independent risk factor for the development of LVH, lifestyle interventions that successfully result in weight loss as well as proven surgical therapies such as Roux-en-Y gastric bypass have been demonstrated to regress LV mass by decreasing LV wall thickness.

Current pharmacologic treatment options are focused on therapies that reduce LV afterload by achiev-ing control in systemic blood pressure because treat-ment of hypertension has been consistently shown to attenuate the development of LVH and heart failure. In a meta-analysis of major hypertension trials, heart failure

Heart Failure and Cardiac HypertrophyHeart Failure and Cardiac HypertrophyJ. Eduardo Rame, MD, MPhilDaniel L. Dries, MD, MPHCorresponding authorJ. Eduardo Rame, MD, MPhilDivision of Cardiology, University of California San Francisco, 505 Par-nassus Avenue, Box 0124 M1177C, San Francisco, CA 94143-0124, USA.E-mail: [email protected]

Current Treatment Options in Cardiovascular Medicine 2007, 9:289–301Current Medicine Group LLC ISSN 1092-8464Copyright © 2007 by Current Medicine Group LLC

Opinion statementLeft ventricular failure is the final common pathway for a wide spectrum of myo-cardial insults, including systemic hypertension and myocardial infarction. Al-though left ventricular hypertrophy is an adaptive response to pressure and vol-ume overload, this process becomes maladaptive if left untreated and pathologic cardiac hypertrophy then becomes an important and independent risk factor for the development of heart failure. Despite its importance, the transition from hy-pertrophy to heart failure in humans is poorly understood. The focus of treatment should be prevention of heart failure and other cardiovascular events, such as stroke and atrial fibrillation. When heart failure is present, treatment with medical and device therapy is then focused on improving functional capacity, increasing survival, and preventing progression to end-stage heart failure.

Introduction

290 Heart Failure

TreatmentTreatmentDiet and lifestyle

• Obesity, independent of hypertension or diabetes, is associated with LVH and is a known risk factor for CHF. Several studies have demon-strated that along with improvements in metabolic parameters such as insulin resistance, weight loss is accompanied by reduction in LV mass [17–19]. Surgical treatment with gastric bypass, an effective approach to weight reduction in morbidly obese individuals, has been associated with a decrease in LV mass resulting from decreased LV wall thickness and improvement in aortic compliance and LV diastolic function [20••].

Pharmacologic treatment• As in the treatment of subclinical hypertension, the focus of therapy in a

patient with electrocardiographic or echocardiographic LVH should be prevention of clinically relevant end points (including stroke, heart failure, symptomatic atrial fibrillation, and sudden cardiac death). Although blood pressure reduction is a desired outcome in hypertensive patients with concentric myocardial hypertrophy, not all antihypertensive therapies are considered equivalent in this regard. Vasodilator therapies such as minoxi-dil and doxazosin may result in volume retention and increase susceptibil-ity to CHF, especially in patients with myocardial hypertrophy. In meta-analyses of studies comparing hypertensive therapies, ACE inhibitors and angiotensin II receptor blockers (AT1 receptor blockers) were identified as the most effective class of antihypertensives in regressing LV mass [21,22].

• In patients with clinically apparent heart failure and LV systolic dys-function, neurohormonal antagonism with ACE inhibitors, angiotensin II receptor blockers, -adrenergic receptor blockers, and aldosterone blockers has been demonstrated to decrease progression of heart failure

may be reduced by one-half [13], a treatment effect that is likely an underestimate given the increased aggres-siveness of blood pressure control advocated by cur-rent guidelines such as the Seventh Report of the Joint National Committee (JNC 7) [14]. Neurohormonal blockade of the renin-angiotensin system with angioten-sin-converting enzyme (ACE) inhibitors or angiotensin receptor II blockers has been demonstrated to regress LVH, especially when systemic hypertension is present. The landmark LIFE (Losartan Intervention for End-point Reduction in Hypertension) trial is the first ran-domized study in patients with LVH to investigate not only regression of LVH but also determine the efficacy of distinct antihypertensive drug therapies on clinically relevant outcomes [15]. The LIFE trial demonstrated that, despite equivalent blood pressure reduction, ran-domization to losartan versus atenolol was associated with a reduction in the composite primary end point of cardiovascular death, myocardial infarction (MI), or stroke, with this difference being primarily driven by a 25% reduction in stroke. Importantly, a greater reduc-tion in echocardiographic LV mass was identified in the losartan group and regression of LVH correlated with improvement in cardiovascular outcomes [16••].

INDICATIONS FOR HOSPITALIZATIONHospitalization is indicated for patients with acute decom-pensated heart failure, especially those who have failed intensification of outpatient heart failure therapies. In patients with newly diagnosed heart failure presenting with new-onset cardiomyopathy syndrome, admission to the hospital should be strongly considered because acute myocarditis needs to be evaluated and closely followed up in this patient population and other “reversible” causes of LV failure (eg, metabolic, nutritional, and so forth) need to be excluded. In patients with acute or chronic heart failure, certain clinical markers of increased risk have been identi-fied and should be used in deciding the need for inpatient hospitalization. These include low systemic blood pressure, renal failure or diuretic resistance, and hyponatremia.

In the absence of clinically overt heart failure, hospitalization may be indicated in patients with electrocardiographic or echocardiographic evidence of LVH in the setting of acute atrial or ventricular arrhythmias, especially when there is hemodynamic intolerance. In this case, an inpatient workup may be indicated to investigate the presence of infiltrative myocardial disease such as cardiac amyloidosis, sar-coidosis, or acute myocarditis.

Heart Failure and Cardiac Hypertrophy Rame and Dries 291

and mortality (on average by 30%) in large randomized placebo-con-trolled trials. Careful uptitration of neurohormonal blockers (especially -adrenergic blockade) is indicated because the benefit is observed

chronically and no proven benefit has been demonstrated of aggressive uptitration in the setting of acute decompensated heart failure.

• In patients with heart failure, LVH, and preserved LVEF, evidence-based strategies have not been demonstrated as in the case of heart failure with LV systolic dysfunction. Current opinion recommends vigilant volume management with diuretic therapy and tight control of systemic hypertension with neurohormonal blockers of the renin-angiotensin-al-dosterone axis, especially in the setting of other compelling indications such as diabetes and renal failure. More evidence of renin-angiotensin system blockade is forthcoming from the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) trial, which is attempt-ing to demonstrate efficacy with respect to mortality and cardiovascular hospitalization in older patients (age > 60 years) with heart failure and LVEF greater than 45% [23]. The currently enrolling TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Frac-tion Congestive Heart) study is attempting to demonstrate a treatment effect (morbidity and mortality) for Aldactone (Pfizer U.S. Pharmaceuti-cals, New York, NY) in patients with nonsystolic heart failure.

• If restrictive physiology is demonstrated or there is clinical suspicion for restrictive cardiomyopathy on the basis of biatrial enlargement, a work-up for infiltrative cardiac disease is indicated and may include noninva-sive diagnostics, such as MRI with delayed gadolinium enhancement, or invasive methods, such as endomyocardial biopsy. Medical therapy for restrictive cardiomyopathy is tailored to etiologic substrate (eg, sarcoid, amyloid, and so forth), but again careful management of volume status is indicated. Hypertension is often not a feature of severe restrictive car-diomyopathy and patients often have very limited stroke volume reserve, so that initiation of any vasodilator or negatively chronotropic agent (eg, blocker, calcium channel blocker) must be followed.

Angiotensin II receptor blockersLosartan

Standard dosage Adults: 25 to 50 mg once daily; can be administered once or twice daily with total daily doses ranging from 25 to 100 mg. Usual initial doses in patients receiving diuretics: 25 mg. Nephropathy in patients with type 2 diabetes and hypertension: Initial dose (oral) is 50 mg once daily; can be increased to 100 mg once daily based on blood pressure response. Stroke reduction (hypertension with LVH): Oral dose is 50 mg once daily (maximum daily dose: 100 mg); may be used in combination with a thiazide diuretic.

Contraindications Hypersensitivity to losartan or any component of the formulation; hypersensitivity to other angiotensin II receptor antagonists; bilateral renal artery stenosis; pregnancy (1st, 2nd, and 3rd trimesters).

Main drug interactions Fluconazole: Increases plasma levels of losartan via 2C8/9 inhibition (decreases the plasma levels of the active metabolite). Monitor for increased losartan efficacy. Lithium: Risk of toxicity may be increased by losartan; monitor lithium levels. Nonsteroidal anti-inflammatory drugs (NSAIDs): May decrease angiotensin II antagonist efficacy; effect has been seen with losartan, but may occur with other medications in this class; monitor blood pressure. Potassium-sparing diuretics (eg, amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Main side effects Side effects that are greater than 10% include the following systems: Cardiovascular—chest pain (12% diabetic nephropathy); Central nervous

292 Heart Failure

system—fatigue (14% diabetic nephropathy); Endocrine—hypoglycemia (14% diabetic nephropathy); Gastrointestinal—diarrhea (2% hypertension to 15% diabetic nephropathy); Genitourinary—urinary tract infection (13% diabetic nephropathy); Hematologic—anemia (14% diabetic nephrop-athy); Neuromuscular and skeletal—weakness (14% diabetic nephropathy), back pain (2% hypertension to 12% diabetic nephropathy); and Respira-tory—cough (3% to 11%; similar to placebo; incidence higher in patients with previous cough related to ACE inhibitor therapy).

Special points Losartan is the only angiotensin II receptor blocker with proven efficacy in a randomized clinical trial (LIFE) demonstrating both regression of LVH and reduction in cardiovascular outcomes, including stroke and heart failure. [16••,17].

Cost/cost-effectiveness Tablets (Cozaar; Merck & Co., Whitehouse Station, NJ): 25 mg (30) cost $58.42, 50 mg (30) cost $57.99, and 100 mg (30) cost $74.99.

Candesartan

Standard dosage Adults with hypertension: Oral dose of 4 to 32 mg once daily. Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. With CHF: Initial dose (oral) is 4 mg once daily; double the dose at 2-week intervals, as tolerated; target dose: 32 mg.

Contraindications Hypersensitivity to candesartan or any component of the formulation; hypersensitivity to other angiotensin II receptor antagonists; bilateral renal artery stenosis; pregnancy (1st, 2nd, and 3rd trimesters).

Special points Candesartan has proven efficacy in patients with systolic heart failure, especially those who are ACE intolerant. In CHARM-PRESERVED (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity), a trial for patients without LV dilatation and nonsystolic heart failure, this agent has been shown to reduce hospitalization for heart failure but did not significantly reduce the composite end point of cardiovascular death or heart failure hospitalization [24]. In hypertensive patients with nonsystolic heart failure, this agent may prove efficacious in the reduction of systemic blood pressure and should be considered for preservation of renal function in individuals with type 2 diabetes mellitus. The progression of renal disease in these patients will often worsen heart failure, which in turn leads to increased neurohormonal activation and worsening renal function (cardiorenal syndrome).

Cost/cost-effectiveness Tablets (Atacand; AstraZeneca Pharmaceuticals, LP, Westborough, MA): 4 mg (30) cost $50.75, 8 mg (30) cost $50.75, 16 mg (30) cost $49.99, and 32 mg (30) cost $65.99.

Valsartan

Standard dosage Adults with hypertension: Initial dose is 80 or 160 mg once daily (in patients who are not volume depleted); dose may be increased to achieve desired effect; maximum recommended dose: 320 mg/d. Heart failure: Initial dose is 40 mg twice daily; titrate dose to 80 to 160 mg twice daily, as tolerated; maximum daily dose: 320 mg. LV dysfunction after MI: Initial dose is 20 mg twice daily; titrate dose to target of 160 mg twice daily as tolerated; may initiate 12 hours following MI.

Contraindications Hypersensitivity to valsartan or any component of the formulation; hypersensitivity to other angiotensin II receptor antagonists; bilateral renal artery stenosis; pregnancy (1st, 2nd, and 3rd trimesters).

Special points In patients with severe or advanced heart failure, low-dose initiation is recommended (20-mg test dose) with careful monitoring of systemic blood pressure and renal function. As with ACE inhibitors, intolerance to angiotensin II receptor blockers with worsening renal function or wors-ening heart failure does imply a poor prognosis and may be an important signal of advanced heart failure.


Cost/cost-effectiveness Tablets (Diovan; Novartis Pharmaceuticals, East Hanover, NJ): 40 mg (30) cost $48.25, 80 mg (30) cost $59.99, 160 mg (30) cost $55.99, and320 mg (30) cost $77.99.

ACE inhibitorsCaptopril

Standard dosage Adults: Titrate dose according to patient’s response. Hypertension: Initial dose (oral) is 12.5 to 25 mg two to three times a day; may increase by 12.5 to 25 mg per dose at 1- to 2-week intervals up to 50 mg three times a day. Maximum: 150 mg three times a day. Add diuretic before further dosage increases. CHF: Initial dose (oral) is 6.25 to 12.5 mg three times a day in conjunction with cardiac glycoside and diuretic therapy. Initial dose depends upon patient’s fluid and electrolyte status. Target: 50 mg three times a day. Prevention of LV dysfunction following MI: Initial dose (oral) is 6.25 mg; followed by 12.5 mg three times a day; increase to 25 mg three times a day over the next few days; following by gradual increase to a goal of 50 mg three times a day. Diabetic nephropathy: Oral dose is 25 mg three times a day. May be taken with other antihyperten-sive therapy if required to further lower blood pressure. Hemodialysis effects: Moderately dialyzable (20% to 50%); administer dose after dialysis or administer 25% to 35% supplemental dose. Peritoneal dialy-sis: Supplemental dose is not necessary.

Contraindications Hypersensitivity to captopril or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; idio-pathic or hereditary angioedema; bilateral renal artery stenosis; preg-nancy (1st, 2nd, and 3rd trimesters).

Main drug interactions 1 Blockers: Hypotensive effect increased. Aspirin: The effects of ACE inhibitors may be blunted by aspirin administration, particularly at higher dosages and/or increase adverse renal effects. CYP2D6 inhibitors: May increase the levels/effects of captopril. Examples of these inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Diuretics: Hypo-volemia due to diuretics may precipitate acute hypotensive events or acute renal failure. Lithium: Risk of lithium toxicity may be increased; monitor lithium levels, especially the first 4 weeks of therapy. Mercapto-purine: Risk of neutropenia may be increased. NSAIDs: May attenuate hypertensive efficacy; effect has been seen with captopril and may occur with other ACE inhibitors; monitor blood pressure. May increase adverse renal effects. Potassium-sparing diuretics (eg, amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Special points In patients with heart failure, low cardiac output and increased systemic vascular resistance, captopril uptitration can achieve remarkable hemo-dynamic improvement. Careful monitoring of renal function, especially when intravenous (IV) diuretic therapy is also administered, must take place in this setting.

Cost/cost-effectiveness Tablets (Capoten; Par Pharmaceuticals, Spring Valley, NY): 100 mg (60) cost $211.99. Tablets (captopril): 12.5 mg (100) cost $12.99, 25 mg (100) cost $14.99, 50 mg (60) cost $12.99, and 100 mg (60) cost $16.99.

Enalapril

Standard dosage Adults: Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe CHF, decreased renal function, or in those receiving diuretics. Asymptomatic LV dysfunction: Oral dose is 2.5 mg twice daily, titrated as tolerated to 20 mg/d. Hypertension: Oral dose is 2.5 to 5 mg/d then increase as required, usually at 1- to 2-week intervals; usual dose range (JNC 7): 2.5 to 40 mg/d in one to two divided doses. Initiate with 2.5 mg if patient is taking a diuretic that cannot be discontinued. May

294 Heart Failure

add a diuretic if blood pressure cannot be controlled with enalapril alone. Heart failure: Initial dose (oral) is 2.5 mg once or twice daily (usual range: 5–40 mg/d in two divided doses). Titrate slowly at 1- to 2-week intervals. Target dose: 10 to 20 mg twice daily (American College of Cardiology [ACC]/American Heart Association [AHA] 2005 heart failure guidelines). IV: Avoid IV administration in patients with unstable heart failure or those suffering acute MI. Moderately dialyzable (20% to 50%). Administer dose after dialysis or administer 20% to 25% supplemental dose following dialysis. Peritoneal dialysis effects: Supplemental dose is not necessary, although some removal of drug occurs.

Contraindications Hypersensitivity to enalapril or enalaprilat; angioedema related to previous treatment with an ACE inhibitor; patients with idiopathic or hereditary angioedema; bilateral renal artery stenosis; pregnancy (1st, 2nd, and 3rd trimesters).

Main side effects Main side effects between 1% to 10% in the following systems: Car-diovascular—hypotension (0.9% to 6.7%), chest pain (2%), syncope (0.5% to 2%), orthostasis (2%), orthostatic hypotension (2%); Central nervous system—headache (2% to 5%), dizziness (4% to 8%), fatigue (2% to 3%); Dermatologic—rash (1.5%); Gastrointestinal—abnormaltaste, abdominal pain, vomiting, nausea, diarrhea, anorexia, constipa-tion; Neuromuscular and skeletal—weakness; Renal—serum creatinine increased (0.2% to 20%), worsening of renal function (in patients with bilateral renal artery stenosis or hypovolemia); and Respiratory (1% to 2%)—bronchitis, cough, dyspnea.

Special points Enalapril has proven efficacy in patients with asymptomatic LV systolic dysfunction (SOLVD-PREVENTION [Studies of Left Ventricular Dys-function Prevention]) and systolic heart failure (SOLVD-TREATMENT [Studies of Left Ventricular Dysfunction Treatment]).

Cost/cost-effectiveness Tablets (enalapril maleate): 2.5 mg (30) cost $10.99, and 5 mg (30) cost $10.99. Tablets (Vasotec; Merck & Co.): 10 mg (30) cost $40.99.

Diuretics• Patients with refractory hypertension can have a remarkable response

to diuretic therapy (both potassium-sparing or nonpotassium-sparing agents), especially when salt-sensitive physiology is suspected.

• In heart failure, especially with coexisting renal dysfunction, thiazide diuretics are less effective and loop diuretics such as furosemide must be used to manage hypervolemia, especially when pulmonary venous or systemic venous (hepatic, and so forth) congestive signs and symptoms are present. However, it is important to use these agents sparingly and optimize all other medical and device therapies to achieve the minimum required dose because the nonpotassium-sparing agents are known to increase neurohormonal activation.

Hydrochlorothiazide

Standard dosage Adults with edema (diuresis): Oral dose is 25 to 100 mg/d in one to two doses; maximum: 200 mg/d. Hypertension: Oral dose is 12.5 to 50 mg/d; minimal increase in response and more electrolyte disturbances are seen with doses greater than 50 mg/d. Renal impairment: creatine clearance (Clcr) less than 10 mL/min: Avoid use. Usually ineffective with glomeru-lar filtration rate (GFR) less than 30 mL/min. Effective at lower GFR in combination with a loop diuretic.

Contraindications Hypersensitivity to hydrochlorothiazide or any component of the formu-lation, thiazides, or sulfonamide-derived drugs; anuria; renal decompen-sation; pregnancy.

Main drug interactions ACE inhibitors: Increased hypotension if aggressively diuresed with a thiazide diuretic. Blockers increase hyperglycemic effects in type 2


diabetes mellitus (non–insulin-dependent diabetes mellitus [NIDDM]). Cholestyramine: Hydrochlorothiazide absorption may be decreased. Colestipol: Hydrochlorothiazide absorption may be decreased. Cyclospo-rine and thiazides can increase the risk of gout or renal toxicity; avoid concurrent use. Digoxin toxicity can be exacerbated if a thiazide induces hypokalemia or hypomagnesemia. Lithium toxicity can occur by reducing renal excretion of lithium; monitor lithium concentration and adjust as needed. Neuromuscular-blocking agents can prolong blockade; monitor serum potassium and neuromuscular status. NSAIDs can decrease the efficacy of thiazides reducing the diuretic and antihypertensive effects.

Main side effects Main side effects between 1% to 10% include the following systems: Cardiovascular—orthostatic hypotension, hypotension; Dermato-logic—photosensitivity; Endocrine and metabolic—hypokalemia; and Gastrointestinal—anorexia, epigastric distress.

Special points ACC/AHA 2005 heart failure guidelines suggest that thiazides lose their efficacy when Clcr is less than 40 mL/min. Loop diuretic therapy with furosemide, bumetanide, or torsemide is the mainstay of therapy for management of hypervolemia in chronic heart failure.

Cost/cost-effectiveness Capsules (Microzide; Watson Pharmaceuticals, Corona, CA): 12.5 mg (30) cost $30.85.

Furosemide

Standard dosage Edema, CHF, or hypertension (diuresis): Oral dose is 20 to 80 mg per dose initially increased in increments of 20 to 40 mg per dose at intervals of 6 to 8 hours; usual maintenance dose interval is twice daily. Usual dos-age range for hypertension (JNC 7): 20 to 80 mg/d in two divided doses. Intramuscular (IM), IV: 20 to 40 mg per dose, may be repeated in 1 to 2 hours as needed and increased by 20 mg per dose with each succeeding dose up to 1000 mg/d; usual dosing interval: 6 to 12 hours. ACC/AHA 2005 guidelines for chronic CHF recommend a maximum single dose of 160 to 200 mg. Continuous IV infusion: Initial IV bolus dose 20 to 40 mg, followed by continuous IV infusion doses of 10 to 40 mg/h. ACC/AHA 2005 guidelines for chronic CHF recommend 40-mg IV load, then 10- to 40-mg/h infusion. Not removed by hemo- or peritoneal dialy-sis; supplemental dose is not necessary. Hepatic impairment: Diminished natriuretic effect with increased sensitivity to hypokalemia and volume depletion in cirrhosis. Monitor effects, particularly with high doses.

Contraindications Hypersensitivity to furosemide, any component, or sulfonylureas; anuria; patients with hepatic coma or in states of severe electrolyte depletion until the condition improves or is corrected.

Main drug interactions ACE inhibitors: Hypotensive effects and/or renal effects are potenti-ated by hypovolemia. Antidiabetic agents: Glucose tolerance may be decreased. Antihypertensive agents: Hypotensive effects may be enhanced. Cephaloridine or cephalexin: Nephrotoxicity may occur. Cholestyramine or colestipol may reduce bioavailability of furosemide. Digoxin: Furose-mide-induced hypokalemia may predispose to digoxin toxicity. Monitor potassium. Fibric acid derivatives: Blood levels of furosemide and fibric acid derivatives (ie, clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documenta-tion; monitor for increased effect/toxicity. Lithium: Renal clearance may be reduced. Isolated reports of lithium toxicity have occurred; monitor lithium levels. Metformin may decrease furosemide concentrations. Metformin blood levels may be increased by furosemide. NSAIDs: Risk of renal impairment may increase when used in conjunction with furosemide. Ototoxic drugs (eg, aminoglycosides, cisplatinum): Concomitant use of furosemide may increase risk of ototoxicity, especially in patients with renal dysfunction. Peripheral adrenergic-blocking drugs or ganglionic blockers: Effects may be increased. Phenobarbital or phenytoin may reduce diuretic response to furosemide. Salicylates (high dose) with furosemide

296 Heart Failure

may predispose patients to salicylate toxicity due to reduced renal excre-tion or alter renal function. Succinylcholine: Action may be potentiated by furosemide. Thiazides: Synergistic diuretic effects occur.

Main side effects Side effects include the following systems: Central nervous system—blurred vision, dizziness, fever, headache, lightheadedness, restlessness, vertigo, xanthopsia; Dermatologic—cutaneous vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, pruritus, purpura, rash, urticaria; Endocrine and metabolic—gout, hyperglycemia, hyperuricemia, hypocal-cemia, hypochloremia, hypokalemia, hypomagnesemia, hyponatremia, metabolic alkalosis; Gastrointestinal—anorexia, constipation, cramping, diarrhea, intrahepatic cholestatic jaundice, ischemia hepatitis, nausea, oral and gastric irritation, pancreatitis, vomiting; Neuromuscular and skeletal—muscle spasm, paresthesia, weakness; Otic—hearing impairment (reversible or permanent with rapid IV or IM administration), reversible deafness (with rapid IV or IM administration), and tinnitus; Renal—allergic inter-stitial nephritis, fall in GFR and renal blood flow (due to overdiuresis), glycosuria, transient rise in blood urea nitrogen, and vasculitis.

Special points When decreased efficacy with increasing dosing of furosemide is pres-ent (diuretic resistance), this may be a sign of worsening heart failure with cardiorenal syndrome physiology. In the setting where significant right heart failure is present (hepatic congestion, ascites, lower extremity edema), consideration should be given to other loop diuretics such as torsemide (Demadex; Roche Laboratories, Nutley, NJ) demonstrated to have superior absorption and increased bioavailability.

Cost/cost-effectiveness Solution (furosemide): 10 mg/mL (10) cost $8.99, 10 mg/mL (60) cost $10.99, and 10 mg/mL (120) cost $13.99. Tablets (furosemide): 20 mg (100) cost $8.99, 40 mg (100) cost $8.99, and 80 mg (100) cost $10.99. Tablets (Lasix; Aventis Pharmaceuticals, Bridgewater, NJ): 20 mg (30) cost $12.46, 40 mg (30) cost $12.46, and 80 mg (30) cost $17.45.

-Adrenergic receptor blockers

Metoprolol

Standard dosage Hypertension: Oral dose is 100 to 450 mg/d in two to three divided doses, begin with 50 mg twice daily and increase doses at weekly intervals to desired effect; usual dosage range (JNC 7): 50 to 100 mg/d. Extended release: Initial dose is 25 to 100 mg/d (maximum: 400 mg/d). CHF (extended release; Toprol XL; AstraZeneca Pharmaceuticals, LP): Initial (oral) dose is 25 mg once daily (reduce to 12.5 mg once daily in New York Heart Association (NYHA) class higher than class II); may double dosage every 2 weeks as tolerated, up to 200 mg/d. When switch-ing from immediate-release metoprolol to extended release, the same total daily dose of metoprolol should be used. Renal impairment with hemodialysis: Administer dose after hemodialysis or administer 50-mg supplemental dose. Supplemental dose is not necessary following perito-neal dialysis. Hepatic impairment: Reduced dose is probably necessary.

Contraindications Hypersensitivity to metoprolol or any component of the formulation; sick sinus syndrome; sinus bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; acute decompensated cardiac failure; severe peripheral arterial disease; pheo-chromocytoma (without blockade); pregnancy (2nd and 3rd trimesters).

Main drug interactions Acetylcholinesterase inhibitors (eg, donepezil, galantamine, and neostig-mine): May enhance the bradycardic effect of blockers. and Agonists: Blockers may enhance the vasopressor effect of and agonists

(direct acting). 1 Blockers (eg, prazosin, terazosin): Concurrent use of blockers may increase risk of orthostasis. 2 Agonists: Blockers may

enhance the rebound hypertensive effect of 2 agonists. This effect can occur when the 2 agonist is abruptly withdrawn. Amiodarone: May


enhance the bradycardic effect of blockers. Antipsychotic agents (phenothiazines): May enhance the hypotensive effect of blockers. Blockers may decrease the metabolism, via CYP isoenzymes, of anti-

psychotic agents (phenothiazines). Cardiac glycosides: Blockers may enhance the bradycardic effect of cardiac glycosides. CYP2D6 inhibitors: May increase the levels/effects of metoprolol. Examples of these inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Dipyridamole: May enhance the bradycardic effect of blockers. Disopyramide: May enhance the bradycardic effect of blockers. Insulin: Blockers may blunt the hypoglycemic effects of insulin therapy. Lidocaine: blockers may decrease the metabolism of lidocaine. NSAIDs: May diminish the antihypertensive effect of blockers. Propafenone: May decrease the metabolism, via CYP isoenzymes, of blockers. Propafenone possesses some independent -blocking activity. Propoxyphene: May decrease the metabolism, via CYP

isoenzymes, of blockers. Quinidine: May decrease the metabolism, via CYP isoenzymes, of blockers. Selective serotonin reuptake inhibitors (SSRIs): May enhance the bradycardic effect of blockers. Sulfonylureas: Blockers may mask the hypoglycemic symptoms from sulfonylureas.

Theophylline: Blockers ( 1 selective) may diminish the bronchodilatory effect of theophylline derivatives.

Main side effects Side effects include the following systems: Cardiovascular—bradycardia (2% to 16%), hypotension (1% to 2%), arterial insufficiency (usually Raynaud type; 1%), chest pain (1%), CHF (1%), edema (peripheral; 1%), palpitation (1%), syncope (1%), gangrene (rare); Central nervous system—dizziness (2% to 10%), fatigue (10%), depression (5%), confu-sion, headache, insomnia, memory loss (short-term), nightmares, som-nolence; Dermatology—pruritus (5%), rash (5%), psoriasis increased, alopecia (reversible; rare); Endocrine and metabolic—libido decreased, Peyronie’s disease (< 1%); and Gastrointestinal—diarrhea (5%), consti-pation (1%), flatulence (1%), gastrointestinal pain (1%), heartburn (1%), nausea (1%), xerostomia (1%).

Special points Extended-release metoprolol (Toprol XL) is the proven therapy in patients with CHF and depressed LVEF. In the MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure) trial, 64% of patients reached a target dose of 200 mg/d and the mean daily dose was 159 mg [25]. In patients with advanced heart failure, the initial dose used in the trial was 12.5 mg/d with uptitration every 2 weeks to achieve the desired target. Failure to tolerate initial or increased dosing at the low dose range is a sign of advanced heart failure and referral for advanced therapies must be considered in this case.

Cost/cost-effectiveness Tablets, 24-hour (Toprol XL, metoprolol succinate): 25 mg (30) cost $24.99, 50 mg (30) cost $27.99, 100 mg (30) cost $39.99, and 200 mg (30) cost $58.99. Tablets (Lopressor; Novartis Pharmaceuticals): 50 mg (60) cost $66.16, and 100 mg (60) cost $102.61. Tablets (metoprolol tartrate): 25 mg (30) cost $8.99, 50 mg (60) cost $12.09, and 100 mg (60) cost $13.99.

Carvedilol

Standard dosage Reduce dosage if heart rate drops to less than 55 bpm. Hypertension: Immediate-release (oral) dose is 6.25 mg twice daily; if tolerated, dose should be maintained for 1 to 2 weeks, then increased to 12.5 mg twice daily. Dosage may be increased to a maximum of 25 mg twice daily after 1 to 2 weeks; maximum dose: 50 mg/d. Extended release: Initial (oral) dose is 20 mg once daily, if tolerated, dose should be maintained for 1 to 2 weeks then increased to 40 mg once daily if necessary; maximum dose: 80 mg once daily. CHF: Immediate-release (oral) dose is 3.125 mg twice daily for 2 weeks; if this dose is tolerated, may increase to 6.25 mg twice daily. Double the dose every 2 weeks to the highest dose tolerated by patient. Maximum recommended dose: In those with mild-to-moderate heart failure, for patients who weigh less than 85 kg, 25 mg twice daily;

298 Heart Failure

for patients who weigh greater than 85 kg, 50 mg twice daily. Severe heart failure: 25 mg twice daily. Extended release: Initial dose is 10 mg once daily for 2 weeks; if the dose is tolerated, increase dose to 20, 40, and 80 mg over successive intervals of at least 2 weeks. Maintain on lower dose if higher dose is not tolerated. LV dysfunction following MI: Should be initi-ated only after patient is hemodynamically stable and fluid retention has been minimized. Immediate release: Initial dose is 3.125 to 6.25 mg twice daily; increase dosage incrementally (ie, from 6.25–12.5 mg twice daily) at intervals of 3 to 10 days, based on tolerance, to a target dose of 25 mg twice daily. Extended release: Initial dose is 20 mg once daily; increase dosage incrementally at intervals of 3 to 10 days. Target dose: 80 mg once daily. Renal impairment: None necessary. Hepatic impairment: Use is contraindicated in severe liver dysfunction.

Contraindications Hypersensitivity to carvedilol or any component of the formulation; decompensated cardiac failure requiring IV inotropic therapy; bronchial asthma or related bronchospastic conditions; second- or third-degree atrioventricular block, sick sinus syndrome, and severe bradycardia (except in patients with a functioning artificial pacemaker); cardiogenic shock; severe hepatic impairment; pregnancy (2nd and 3rd trimesters).

Main drug interactions Cimetidine: May increase carvedilol serum levels. CYP2C9 inducers: May decrease the levels/effects of carvedilol. Examples of these inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and seco-barbital. CYP2C9 inhibitors may increase the levels/effects of carvedilol. Examples of these inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, sulfonamides, and tolbutamide. CYP2D6 inhibitors: May increase the levels/effects of carvedilol. Examples of these inhibitors include chlorpromazine, delavirdine, fluoxetine, micon-azole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Disopyramide: May exacerbate heart failure or enhance bradycardic effect of blockers. Insulin and oral hypoglycemics: Carvedilol may mask symptoms of hypoglycemia. NSAIDs (eg, ibuprofen, indomethacin, naproxen, piroxicam) may reduce the antihypertensive effects of block-ers. Rifampin: May increase the metabolism of carvedilol. Salicylates: May reduce the antihypertensive effects of blockers. SSRIs: May decrease the metabolism of carvedilol. Sulfonylureas: Blockers may alter response to hypoglycemic agents. Ethanol: Coreg CR (GlaxoSmithKline, Uxbridge, Middlesex, UK). Avoid ethanol (including prescription and over-the-coun-ter medications containing ethanol). Ethanol may affect extended-release properties causing a faster release; separate by at least 2 hours.

Special points In patients with systolic heart failure and normal to low systemic blood pressure, tolerance of carvedilol at dosing greater than or equal to 6.25 mg orally twice a day has been associated with morbidity and mortal-ity reduction. Tolerance of higher carvedilol dosing is associated with improved prognosis in this patient population.

Cost/cost-effectiveness Tablets (Coreg; GlaxoSmithKline): 3.125 mg (60) cost $110.05, 6.25 mg (30) cost $59.43, 12.5 mg (60) cost $112.32, and 25 mg (60) cost $112.32.

Aldosterone inhibitorsAldactone

Standard dosage Hypertension (JNC 7): 25 to 50 mg/d in one to two divided doses. Diag-nosis of primary aldosteronism: 100 to 400 mg/d in one to two divided doses. CHF, severe (with ACE inhibitor and a loop diuretic ± digoxin): 12.5 to 25 mg/d; maximum daily dose: 50 mg (higher doses may occa-sionally be used). In the RALES (Randomized Aldactone Evaluation Study) trial, 25 mg every other day was the lowest maintenance dose possible. If potassium greater than 5.4 mEq/L, consider dosage reduction. Renal impairment: Clcr 10 to 50 mL/min: Administer every 12 to 24 hours. Clcr less than 10 mL/min: Avoid use.


Contraindications Hypersensitivity to spironolactone or any component of the formulation; anuria; acute renal insufficiency; significant impairment of renal excretory function; hyperkalemia; pregnancy (pregnancy-induced hypertension, per expert analysis).

Main drug interactions ACE inhibitors can cause hyperkalemia, especially in patients with renal impairment, potassium-rich diets, or on other drugs causing hyperkale-mia; avoid concurrent use or monitor closely. Cholestyramine can cause hyperchloremic acidosis in cirrhotic patients; avoid concurrent use. Potas-sium supplements may increase potassium retention and cause hyperkale-mia; avoid concurrent use. Salicylates and NSAIDs may interfere with the natriuretic action of spironolactone.

Main side effects Side effects include the following systems: Central nervous system—disorders (23%, placebo 21%), which may include drowsiness, lethargy, headache, mental confusion, drug fever, ataxia, fatigue; Dermatologic—maculopapular, erythematous cutaneous eruptions, urticaria, hirsutism, eosinophilia; and Endocrine and metabolic—gynecomastia (men 9%; placebo 1%), breast pain (men 2%; placebo 0.1%), serious hyperkalemia (2%, placebo 1%), hyponatremia, dehydration, hyperchloremic meta-bolic acidosis (in decompensated hepatic cirrhosis), impotence, menstrual irregularities, amenorrhea, postmenopausal bleeding.

Special points The risk of hyperkalemia is the most important safety consideration in the use of this nonselective aldosterone inhibitor, especially in elderly patients and those with reduced GFR. Vigilance in patients with serum creatinine greater than 1.5 is indicated, with serial and frequent monitor-ing of potassium and creatinine levels.

Cost/cost-effectiveness Tablets (Aldactone): 25 mg (30) cost $24.23, 50 mg (30) cost $41.20, and100 mg (30) cost $61.69. Tablets (spironolactone): 25 mg (30) cost $12.99, 50 mg (30) cost $19.99, and 100 mg (30) cost $34.99.

Eplerenone

Standard dosage Hypertension: Initial (oral) dose is 50 mg once daily; may increase to 50 mg twice daily if response is not adequate; may take up to 4 weeks for full therapeutic response. Doses greater than 100 mg/d are associated with increased risk of hyperkalemia and no greater therapeutic effect. CHF (after MI): Initial (oral) dose is 25 mg once daily; dosage goal: titrate to 50 mg once daily within 4 weeks, as tolerated. Dosage adjustment per serum potassium concentrations and renal function for CHF. Renal impairment: Patients with hypertension with Clcr less than 50 mL/min or serum creatinine greater than 2.0 mg/dL in males or greater than 1.8 mg/dL in females: Use is contraindicated; risk of hyperkalemia increases with declining renal function. Hepatic impairment: No dosage adjustment needed for mild-to-moderate impairment. Safety and efficacy not established for severe impairment.

Contraindications Hypersensitivity to eplerenone or any component of the formulation; serum potassium greater than 5.5 mEq/L; Clcr 30 mL/min; concomitant use of strong CYP3A4 inhibitors (see Drug Interactions for details). The following additional contraindications apply to patients with hyperten-sion: Type 2 diabetes mellitus (NIDDM) with microalbuminuria; serum creatinine greater than 2.0 mg/dL in males or greater than 1.8 mg/dL in females; Clcr less than 50 mL/min; concomitant use with potassium supplements or potassium-sparing diuretics.

Main drug interactions ACE inhibitors: Concomitant use increases serum potassium, use of ACE inhibitors and another mineralocorticoid receptor blocker has led to clinically relevant hyperkalemia. Use with caution; monitoring of potassium levels recommended. Angiotensin II receptor antagonists: Concomitant use increases serum potassium, use of angiotensin II receptor antagonists and another mineralocorticoid receptor blocker has led to clinically relevant hyperkalemia. Use with caution; monitoring of potassium levels recommended. CYP3A4 inhibitors: May increase the levels/effects of eplerenone. Examples of these inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac,

300 Heart Failure

doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Potassium-sparing diuretics (eg, amiloride, spironolactone, triamterene): Increase risk of hyper-kalemia; concurrent use is contraindicated. Potassium supplements: Increase risk of hyperkalemia; concurrent use is contraindicated. Food: Grapefruit juice increases eplerenone area under the curve approximately 25%.

Special points In patients with systolic heart failure with side effects from the non-selective blockade of Aldactone (eg, breast tenderness, gynecomastia, decreased libido), eplerenone should be considered as a very viable substi-tute for aldosterone blockade. In patients who have sustained an MI and demonstrate CHF in the setting of depressed LV systolic dysfunction (or diabetes with asymptomatic LV systolic dysfunction), early initiation of eplerenone has been demonstrated to reduce mortality (including 30-day mortality reduction) [26]. As with Aldactone, careful monitoring of serum potassium and renal function is indicated.

Cost/cost-effectiveness Tablets (Inspra; Pfizer U.S. Pharmaceuticals): 25 mg (30) cost $104.97, and 50 mg (30) cost $104.99.

Interventional proceduresIn patients with heart failure and depressed LV systolic function (LVEF< 35%), consideration should be given to placement of an automatic implant-able cardioverter-defibrillator, which has been proven in randomized clinical trials to reduce mortality in comparison with optimal medical therapy.In patients with NYHA class III or IV heart failure (LV systolic dysfunc-tion) who have significant symptoms despite optimal medical therapy and who demonstrate evidence of mechanical dyssynchrony (often associated with widened QRS > 120 ms), consideration should be given to placement of biventricular pacing device (cardiac resynchronization therapy). Ran-domized clinical trials have demonstrated a reduction in hospitalization and mortality in patients who receive cardiac resynchronization therapy.

SurgeryIn patients with CHF with or without LV systolic dysfunction, con-sideration should be given to surgical therapies that relieve clinically significant (severe) aortic or mitral valvular obstruction because these therapies are well tolerated and often improve symptoms of heart failure in the patients who survive cardiac surgery.Surgical revascularization is indicated in patients with ischemic heart failure with or without LV systolic dysfunction, especially if angina pectoris is pres-ent. When angina is absent and myocardial viability has been demonstrated in patients with LV systolic dysfunction, current retrospective data indicate that revascularization is associated with improved prognosis. Results from the STICH (Surgical Treatment of Ischemic Heart Failure) trial are expected to expand our understanding of the risks and benefits of surgical revascu-larization in this patient population and also identify if any benefit exists to surgical ventricular restoration beyond revascularization.

• In patients with advanced (NYHA class IV) heart failure despite optimal medical, surgical, or device therapies, referral to an end-stage heart fail-ure program is indicated so the patient can be considered for orthotopic heart transplantation or mechanical circulatory support (as primary destination therapy or as bridge to cardiac transplantation). Recom-mendation for early referral cannot be overemphasized in patients with advanced heart failure because end-organ damage and nutritional com-promise will significantly impact survival before and after transplant.


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