Heart Failure: Update on Therapeutic OptionsPublished on Physicians Practice (http://www.physicianspractice.com)

Heart Failure: Update on Therapeutic OptionsDecember 31, 2006By David T. Nash, MD [1]

Heart failure statistics are daunting: 550,000 new cases each year, a 1-year mortality rate of nearly20%, and annual direct and indirect costs that total $24.3 billion.1 The diverse etiology of heartfailure and the complex, progressive course of the disease can make treatment decisions dauntingas well.

Heart failure statistics are daunting: 550,000 new cases each year, a 1-year mortality rate of nearly20%, and annual direct and indirect costs that total $24.3 billion.1 The diverse etiology of heartfailure and the complex, progressive course of the disease can make treatment decisions dauntingas well. Here I discuss current recommendations for heart failure management, as well as the clinicalimplications of the results of recent studies. RISK FACTORSAmong the 5143 participants in the original Framingham Heart and Offspring studies, the mostcommon risk factor for heart failure was hypertension. Of those study participants in whom heartfailure developed, 91% were hypertensive.2 Among hypertensive men and women in these studies,myocardial infarction (MI), diabetes, left ventricular hypertrophy, and valvular heart disease werecofactors that were associated with an increased risk of heart failure. MI was a particularly commoncofactor in this group; 52% of the men with heart failure and 34% of the women had a history ofMI.2PATHOPHYSIOLOGYThe pathophysiology of heart failure involves both hemodynamic and neurohormonal abnormalities,although the interactions between them are incompletely understood. Survival benefits that resultfrom drug-induced decreases in neurohormonal activity underscore the role of increasedneurohormonal activity in chronic heart failure. Impaired left ventricular function activatesneuroendocrine compensatory mechanisms, both vasoconstrictive and vasodilative. The primaryvasoconstrictive systems are the sympathetic nervous system and the reninangiotensin system.Increased plasma levels of norepinephrine, which reflect sympathetic nervous system activity, havebeen correlated directly with disease severity and mortality in heart failure.3 Activation of therenin-angiotensin system increases systemic vascular resistance and has also been correlated withdisease progression. DIAGNOSISThe history and physical findings often point to heart failure. Common presenting symptoms inpatients with left ventricular dysfunction are:

Decreased exercise tolerance (manifested by dyspnea).Fluid retention (manifested by swollen feet).

According to the latest American College of Cardiology and American Heart Association (ACC/AHA)guidelines, the most useful diagnostic test is the 2-dimensional echocardiogram, performed inconjunction with Doppler flow studies (Table 1).3 Much interest has recently focused on brainnatriuretic peptide (BNP) as a prognostic indicator or surrogate marker.4-6 This neurohormone issecreted mainly in the cardiac ventricles. Volume expansion of the ventricles and increasedintraventricular pressure raise circulating BNP levels, which rise in proportion to disease severity.The significance of this elevation depends on the patient profile (which includes systolic function andsex); thus, assessment of left ventricular function is also required.7 In a study of 78 ambulatorypatients with heart failure, plasma BNP levels provided prognostic information as accurate as thatderived from the commonly used multifactorial heart failure survival score.4 BNP levels were the onlyindependent predictor of sudden death in another study population. 5 A more recent study found notonly that elevated BNP values correlated with first morbid event and mortality but also thatpercentage reduction in BNP during treatment predicted decreased risk of first morbid event andmortality.6 When performed in conjunction with echocardiography, measurement of plasma BNPconcentrations may serve as a useful screening tool and thus may reduce the need for moreexpensive and invasive tests.4,5,7THERAPEUTIC APPROACHESNonpharmacologic measures. Whether heart failure is diastolic or systolic, management always

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Heart Failure: Update on Therapeutic OptionsPublished on Physicians Practice (http://www.physicianspractice.com)

includes nonpharmacologic measures in addition to drug therapy. Discuss dietary restrictions andexercise recommendations with patients, and advise them about when to seek medical attention.Possibly the most effective and least employed therapy is consistent attention. Follow-up andbetween-visit supervision by a nurse or physician assistant has yielded significant clinical benefits insymptomatic patients.3Unfounded criteria for drug selection. The use of hemodynamic functionparameters as criteria for drug selection in heart failure therapy has been based on the assumptionthat hemodynamic improvement will translate into symptom relief. This has proved to be anuncertain premise.8 Furthermore, the correlation between relief of symptoms and survival is alsouncertain. For example, although it is well established that diuretics reduce the need forhospitalization, these agents have no apparent effect on survival. Thus, correction of a patient'shemodynamic abnormalities may not prevent heart failure progression or death.8Currentguidelines. Despite the heterogeneous etiology and complex pathogenesis of heart failure, aconsensus is evolving as to what constitutes effective--and ineffective--treatment. 3,9 The ACC/AHAguidelines classify heart failure into 4 stages of severity and recommend therapy targeted to eachstage (Table 2). (Note that the ACC/AHA stages, which range from "at risk for heart failure" to"advanced heart failure," differ from the classes in the New York Heart Association [NYHA] gradingsystem; the latter are based on the functional capacity of patients with heart failure.) According tothe ACC/ AHA and Heart Failure Society of America (HFSA) guidelines, 4 classes of drugs should begiven routinely to appropriate patients with symptomatic left ventricular dysfunction: a diuretic, anangiotensin- converting enzyme (ACE) inhibitor, a β-blocker, and (usually) digoxin (Table 3).3,9DRUGTHERAPY FOR HEART FAILUREDiuretics. These are the most commonly prescribed agents for heart failure. Diuretics are effectivein patients with diastolic or systolic dysfunction. 3,9 They are indicated for reduction of the volumeoverload that is common in congestive heart failure, particularly in the early phase of treatment. Digoxin. This is the only agent that can provide long-term inotropic support in men. However,digoxin significantly increases the risk of mortality in women.10 Bear in mind that the serum digoxinconcentration may not correlate with the drug dosage in older persons or in patients with renaldysfunction. 9 Moreover, upward titration of digoxin increases the risk of toxicity, and the beneficialeffects of digoxin are not greatly enhanced at higher dosages. Additional rate control, when needed,can be provided by β-blockers or amiodarone.9β-Blockers.The ability of β-blockers to improve leftventricular systolic function is perhaps the most compelling evidence that chronic adrenergicstimulation damages the failing heart.9 The recent Carvedilol Prospective Randomized CumulativeSurvival (COPERNICUS) study reaffirms the value of this class of drugs in severe heart failure.11Prescribe low dosages of β-blockers initially and monitor patients for worsening heart failure. After apatient has been stable for 2 weeks on a starting regimen, the dosage may be titrated upward.These agents should not be abruptly withdrawn.9 To ensure safe and effective treatment, prescribeβ-blockers only for patients who:

Are clinically stable.Have left ventricular systolic dysfunction.Have mild to moderate symptoms.Are receiving standard therapy.3,9

ACE inhibitors. Treatment with ACE inhibitors was the first intervention that was shownunequivocally to improve symptoms and prolong life in patients with left ventricular dysfunction.These agents counteract neurohormonal activation by lessening the deleterious effects of therenin-angiotensin system through inhibition of ACE.9 Evidence suggests that the long-term benefitsof ACE in- hibitors stem mainly from their ability to reverse some of the structural abnormalitiesassociated with heart failure rather than from their hemodynamic effects.3,9 Prescribe an ACEinhibitor, together with a β-blocker and a diuretic, for patients with symptomatic systolic heartfailure--unless these agents are contraindicated.3,9Angiotensin II receptor blockers. Data nowindicate that angiotensin II type 1 receptor blockers (ARBs) may confer benefits similar to those ofACE inhibitors in patients with heart failure.12 The hemodynamic actions of ARBs--eg, their reductionof systemic vascular resistance in heart failure--are comparable to those of ACE inhibitors.3,9 ARBsalso improve exercise capacity and reduce norepinephrine levels in a manner similar to that of ACEinhibitors.3,9 Blockade of angiotensin II type 1 (AT1) receptors prevents the effects of angiotensinII--including that produced by enzymes other than ACE--and allows circulating angiotensin II tostimulate angiotensin II type 2 (AT2) receptors. Data suggest that some benefits of ARBs may bemediated through the AT2 receptor.13 The Valsartan Heart Failure Trial (Val-HeFT) compared the ARB

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Heart Failure: Update on Therapeutic OptionsPublished on Physicians Practice (http://www.physicianspractice.com)

valsartan with placebo in 5010 patients with NYHA class II to IV heart failure who also receivedstandard therapy with ACE inhibitors and/or β-blockers for a mean follow-up of 23 months.12

Although overall mortality was similar, the combined end point of morbidity and mortality was 13.2%lower in the valsartan-treated group. The reduction in this combined end point resulted primarilyfrom the 27.5% reduction in hospitalization for heart failure seen with valsartan. In a subgroup (7%of study participants) who did not receive an ACE inhibitor, valsartan reduced all-cause mortality by41% and hospitalization for heart failure by 57%.14 Echocardiography showed that valsartan alsoreversed cardiac remodeling.15 Moreover, valsartan reduced BNP levels-- and demonstrated for thefirst time that a reduction in BNP levels during treatment is associated with a decreased risk ofmortality and first morbid event.6 The data from Val-HeFT suggest that valsartan is a practicalalternative to ACE inhibitor therapy.16 The Losartan Intervention for Endpoint Reduction inHypertension (LIFE) study showed that ARBs help reduce cardiovascular morbidity and mortality. Thestudy compared the ARB losartan (plus background therapy) with atenolol (plus background therapy)in 9193 patients who had hypertension and left ventricular hypertrophy but who did not have heartfailure. 17 Losartan was associated with a 13% greater reduction than atenolol in the combined endpoint of cardiovascular disease mortality, myocardial infarction (MI), and stroke. The Candesartan inHeart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study confirmed thebenefit of ARB therapy in 7599 patients, who were stratified by ejection fraction (either greater than40%, or 40% or less) and by whether they had previously used an ACE inhibitor. 18 At a medianfollow-up of 38 months, the adjusted risk rate (compared with standard care) for the primary endpoint of all-cause mortality was 0.90 for patients who received candesartan. Aldosteroneantagonists. Increased renin and angiotensin II levels stimulate the production of aldosterone,which contributes to the pathophysiology of heart failure. Elevated aldosterone levels enhancesodium retention, increase sympathetic activation and parasympathetic inhibition, and promotecardiac remodeling.3 ACE inhibitors have been assumed to suppress aldosterone production, butincreasing evidence suggests that this suppression is only transient in some patients. The addition ofan aldosterone antagonist such as spironolactone or eplerenone to the regimen may be helpful insuch patients. Spironolactone. In the Randomized Aldactone Evaluation Study (RALES), patients withadvanced heart failure, normal serum potassium levels, and normal or mildly elevated serumcreatinine levels (less than 2.5 mg/dL) received low-dose spironolactone (mean daily dose, 26 mg).19

All patients received diuretics, 95% received low-dose ACE inhibitors (mean daily dose: captopril,63.4 mg, or lisinopril, 15.5 mg), 75% received digoxin, and 11% received β-blockers. After 24months, the trial was terminated early because patients assigned to spironolactone had a 30%reduction in allcause mortality.19 The reduction in morbidity and mortality among patients who werealready receiving an ACE inhibitor suggests that low-dose ACE inhibition does not effectivelysuppress aldosterone production. Consider low-dose spironolactone for patients with severe heartfailure caused by left ventricular systolic dysfunction who remain symptomatic despite optimaltherapy with ACE inhibitors, β-blockers, digoxin, and diuretics.20 However, a recent analysis warnsagainst inappropriate, indiscriminate use of spironolactone.20 The patient's heart failureclassification, ejection fraction, and background treatment must be considered, and adequatefollow-up must be ensured. Eplerenone. In the recently reported Eplerenone Post-Acute MI HeartFailure Efficacy and Survival Study (EPHESUS), patients with acute MI complicated by left ventriculardysfunction and heart failure were randomized within 3 to 14 days of hospitalization to additionaltherapy with eplerenone, 50 mg/d, or placebo.21 Patients with elevated serum creatinine clearance(greater than 2.5 mg/dL) or elevated serum potassium levels (greater than 5 mmol/L) were excludedfrom the study. The majority of patients were receiving standard therapy: ACE inhibitors or ARBs(87%), β-blockers (75%), aspirin (88%), and diuretics (60%). After a mean 16-month follow-up,all-cause mortality decreased by 15% in the eplerenone group. There was also a 13% reduction indeath or hospitalization caused by cardiovascular disease. The reduction in cardiovascular diseasemortality was in large part the result of a 21% reduction in the rate of sudden cardiac death.Because of an increased incidence of serious hyperkalemia in study participants (who had beenprescreened for elevated potassium levels), the investigators recommended monitoring serumpotassium levels in patients being treated with eplerenone.21HEART FAILURE THERAPY INSPECIAL POPULATIONSVery old patients. More than 80% of the 1 million patients hospitalized each year for heart failureare 65 years of age or older, and more than 50% are 75 years or older.22 Several studies have foundnearly half of their heart failure cohort are 80 years or older.22 Advanced age complicatestherapeutic decisions in several ways. First, clinical trial data in very old patients are lacking. Despitetheir heavy representation in the population with heart failure, older persons are underrepresented

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Heart Failure: Update on Therapeutic OptionsPublished on Physicians Practice (http://www.physicianspractice.com)

in clinical trials of new treatments; when included, these patients are likely to be lumped together ina homogeneous "over 65" group.23 This overly broad category is problematic because the commonmanifestations of heart failure vary with age and sex.3 For example, diastolic heart failure becomesincreasingly common with advanced age, particularly in women.3,22 Exclusion criteria used in clinicaltrials may further distort the study of therapy in older patients by eliminating characteristiccomorbidities. In a national sample of Medicare patients, more than 55% of those with heart failurehad a history of coronary disease, almost 40% had diabetes, and about 33% had chronic obstructivepulmonary disease; 10% had been admitted to the hospital from long-term care facilities.22

Furthermore, several normal aspects of the aging process complicate management. The glomerularfiltration rate declines with age and does so more rapidly among patients with heart failure.Consequently, a creatinine cutoff value that defines renal insufficiency for a specific medication maybe inappropriately high for older persons. The effects of standard treatments at recommendeddosages in older patients may differ from their effects in younger patients. Comorbid conditions canalso complicate heart failure therapy in older patients. Conditions that require medication increasethe potential for adverse drug interactions.22 Moreover, the additional medications may have anegative impact on a patient's heart failure. Conversely, a comorbid condition that is not managedaggressively enough can also complicate heart failure therapy. Patients with diastolicdysfunction. Among heart failure patients, 20% to 40% have preserved left ventricular function. Forpatients with systolic dysfunction, the value of various agents has been established in large-scaleclinical trials. However, for those with diastolic dysfunction, large-scale trial data are lacking.3,24

Current pharmacologic treatment recommendations for patients with diastolic dysfunction are basedon control of blood pressure and tachycardia, relief of myocardial ischemia, and blood-volumereduction. Treatment may include agents used for systolic dysfunction as well as calcium channelblockers and nitrates.24

References: REFERENCES:1. American Heart Association. Heart Disease and Stroke Statistics: 2003 Update. Dallas: AmericanHeart Association; 2002.2. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heartfailure. JAMA. 1996;275:1557-1562.3. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management ofchronic heart failure in the adult: executive summary. Circulation. 2001;104:2996-3007.4. Koglin J, Pehlivanli S, Schwaiblmair M, et al. Role of brain natriuretic peptide in risk stratification ofpatients with congestive heart failure. J Am Coll Cardiol. 2001;38:1934-1941.5. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death inpatients with chronic heart failure. Circulation. 2002;105: 2392-2397.6. Anand IS, Fisher LD, Chiang YT, et al, for the Val-HeFT Investigators. Changes in brain natriureticpeptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart FailureTrial (Val-HeFT). Circulation. 2003;107:1278-1283.7. Maisel AS, McCord J, Nowak RM, et al, for the Breathing Not Properly Multinational StudyInvestigators. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure withreduced or preserved ejection fraction. J Am Coll Cardiol. 2003;41:2010-2017.8. Anand IS, Florea VG, Fisher L. Surrogate end points in heart failure. J Am Coll Cardiol. 2002;39:1414-1421.9. Heart Failure Society of America (HFSA) Practice Guidelines. HFSA guidelines for management ofpatients with heart failure caused by left ventricular systolic dysfunction—pharmacologicalapproaches. Pharmacotherapy. 2000;20:495-522.10. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for thetreatment of heart failure. N Engl J Med. 2002;347:1403-1411.11. Krum H, Roecker EB, Mohacsa P, et al, Carvedilol Prospective Randomized Cumulative Survival(COPERNICUS) Study Group. Effects of initiating carvedilol in patients with severe chronic heart fail--ure: results from the COPERNICUS Study. JAMA. 2003;289:754-756.12. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of theangiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.13. de Gasparo M, Levens N. Does blockade of angiotensin II receptors offer clinical benefits overinhibition of angiotensin-converting enzyme? Pharmacol Toxicol. 1998;82:257-271.14. Diovan [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2002.15. Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in

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Heart Failure: Update on Therapeutic OptionsPublished on Physicians Practice (http://www.physicianspractice.com)

heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002;40:970-975.16. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality inpatients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol.2002;40: 1414-1421.17. Dahlof B, Devereau RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidityand mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): arandomised trial against atenolol. Lancet. 2002;359: 995-1003.18. Pfeffer MA, Swedberg K, Granger CB, et al, for the CHARM Investigators and Committees. Effectsof candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overallprogramme. Lancet. 2003;362:759-766.19. Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone Evaluation Study Investigators.The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl JMed. 1999;341:709-717.20. Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of spironolactone in heartfailure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol. 2003;41:211-214.21. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients withleft ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.22. Havranek EP, Masoudi FA, Westfall KA, et al. Spectrum of heart failure in older patients: resultsfrom the National Heart Failure project. Am Heart J. 2002;143:412-417.23. Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heartfailure clinical trials. Arch Intern Med. 2002;162: 1682-1688.24.Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, II: causalmechanisms and treatment. Circulation. 2002;105:1503-1508. Source URL: http://www.physicianspractice.com/articles/heart-failure-update-therapeutic-options

Links:[1] http://www.physicianspractice.com/authors/david-t-nash-md

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