Heart Failure 2007

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Heart FailureDiagnosis page ITC12-2

Treatment page ITC12-6

Practice Improvement page ITC12-14

Patient Information page ITC12-15

CME Questions page ITC12-16

Section EditorsChristine Laine, MD, MPHDavid Goldmann, MD

Science WriterJennifer F. Wilson

The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), includingPIER (Physicians’ Information and Education Resource) and MKSAP (MedicalKnowledge and Self-Assessment Program). Annals of Internal Medicineeditors develop In the Clinic from these primary sources in collaboration withthe ACP’s Medical Education and Publishing Division and with the assistance of science writers and physician writers. Editorial consultants from PIER andMKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://pier.acponline.org and otherresources referenced in each issue of In the Clinic.

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© 2007 American College of Physicians

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What patients should cliniciansconsider to be at risk for heartfailure?Elderly persons are at highest risk.The overall prevalence of heart fail-ure in persons over 80 years of ageis approximately 10% comparedwith just 1% among persons underage 50 (2). African Americans alsoface an increased risk for heart fail-ure. African Americansbetween 45 and 64years of age are 2.5times more likely to diefrom heart failure thanCaucasians in the sameage range (3). Menhave a higher rate ofheart failure thanwomen, although thisdifference narrows aswomen get older.

Certain conditions and behaviorsalso increase the risk for heart fail-ure, and these conditions should be treated to reduce the risk (seeBox). In addition to these, epi-demiologic study has linked in-creased risk for heart failure tophysical inactivity, obesity, and lower levels of education (4).

HypertensionLongstanding untreated hyperten-sion is associated with the develop-ment of both systolic and diastolicheart failure as well as an inde-pendent risk for coronary arterydisease (CAD). Clinical trials haveshown that a reduction in systolic

or diastolic blood pressure can re-duce the subsequent risk for devel-oping heart failure (5). Even mod-est decreases in systolic bloodpressure reduce mortality and therisk for heart failure (6).

DiabetesDiabetes markedly increases therisk for heart failure and is an inde-

pendent risk factor forCAD.

The HOPE (Heart Out-comes Prevention Evalu-taion) trial found thatamong patients at least 55years of age with eitheratherosclerosis or diabetesand at least 1 other risk factor but without a historyof heart failure, the angiotensin- conver tingenzyme (ACE) inhibitor

ramipril reduced the risk for stroke, my-ocardial infarction (MI), and death fromcardiovascular disease by 22% while alsosignificantly reducing heart failure (6).

Cardiotoxic Substance UseAlcohol is a direct myocardial toxinand can be the primary cause ofheart failure. Abstinence from alco-hol may reverse left ventricular dys-function. Tobacco and cocaine usesignificantly increase the risk forCAD, which in turn can lead toheart failure. Cocaine also has direct effects on the myocardium.Chemotherapeutic agents, such asanthracycline and trastuzumab,can also exert toxic effects on themyocardium.

© 2007 American College of Physicians ITC12-2 In the Clinic Annals of Internal Medicine 4 December 2007

Approximately 5 million people in the United States have heart failure,and the number is on the rise, according to the National Heart Lungand Blood Institute. Heart failure is the most frequent cause of hos-

pitalization in U.S. patients older than 65 years, and the disease leads toabout 300 000 deaths per year (1). Heart failure is a significant problemthroughout the rest of the world as well, but few accurate data are available.The most common cause of heart failure in industrialized countries is is-chemic cardiomyopathy, whereas other causes, such as infectious diseases,assume a larger role in underdeveloped countries. Despite recent advances inthe management of patients with heart failure, morbidity and mortality ratesremain high. The estimated 5-year mortality rate is 50%.

Diagnosis

1. Finn P. AmericanHeart Association—scientific sessions2005. 13-16 Novem-ber 2005, Dallas, TX,USA. IDrugs.2006;9:13-5.[PMID: 16374724]

2. Kannel WB. Currentstatus of the epi-demiology of heartfailure. Curr CardiolRep. 1999;1:11-9.[PMID: 10980814]

3. Centers for DiseaseControl and Preven-tion (CDC). Mortalityfrom congestiveheart failure—UnitedStates, 1980-1990.MMWR Morb MortalWkly Rep. 1994;43:77-81. [PMID: 8295629]

4. He J, Ogden LG, Baz-zano LA, et al. Riskfactors for congestiveheart failure in USmen and women:NHANES I epidemio-logic follow-up study.Arch Intern Med.2001;161:996-1002.[PMID: 11295963]

5. The sixth report ofthe Joint NationalCommittee on pre-vention, detection,evaluation, and treat-ment of high bloodpressure. Arch InternMed. 1997;157:2413-46. [PMID: 9385294]

6. HOPE Investigators.Effects of ramipril oncoronary events inhigh-risk persons: re-sults of the HeartOutcomes PreventionEvaluation Study. Cir-culation.2001;104:522-6.[PMID: 11479247]

Common Conditions andBehaviors that Increasethe Risk for Heart Failure• Hypertension• Diabetes• Cardiotoxic substance use• Hyperlipidemia• Thyroid disorders• Tachycardia• Coronary artery disease


7. Sacks FM, Pfeffer MA,Moye LA, et al. Theeffect of pravastatinon coronary eventsafter myocardial in-farction in patientswith average choles-terol levels. Choles-terol and RecurrentEvents Trial investiga-tors. N Engl J Med.1996;335:1001-9.[PMID: 8801446]

8. Klein I, Ojamaa K. Thy-roid hormone andthe cardiovascularsystem. N Engl J Med.2001;344:501-9.[PMID: 11172193]

9. Fadel BM, Ellahham S,Ringel MD, et al. Hy-perthyroid heart dis-ease. Clin Cardiol.2000;23:402-8.[PMID: 10875028]

10. Coleman HN III, Tay-lor RR, Pool PE, et al.Congestive heartfailure followingchronic tachycardia.Am Heart J.1971;81:790-8.[PMID: 5088355]

11. Peters KG, KienzleMG. Severe car-diomyopathy due tochronic rapidly con-ducted atrial fibrilla-tion: complete re-covery afterrestoration of sinusrhythm. Am J Med.1988;85:242-4.[PMID: 3400701]

12. Grogan M, SmithHC, Gersh BJ, WoodDL. Left ventriculardysfunction due toatrial fibrillation inpatients initially be-lieved to have idio-pathic dilated car-diomyopathy. Am JCardiol.1992;69:1570-3.[PMID: 1598871]

13. Dargie HJ. Effect ofcarvedilol on out-come after myocar-dial infarction in pa-tients withleft-ventricular dys-function: the CAPRI-CORN randomisedtrial. Lancet.2001;357:1385-90.[PMID: 11356434]

© 2007 American College of PhysiciansITC12-3In the ClinicAnnals of Internal Medicine4 December 2007

HyperlipidemiaHyperlipidemia is strongly associ-ated with CAD, which may ulti-mately lead to heart failure. Large-scale clinical trials have shown thebenefit of lipid lowering for pri-mary and secondary prevention ofcardiovascular events.

The CARE (Cholesterol and RecurrentEvents) trial found that pravastatin treat-ment significantly reduced mortality as wellas subsequent cardiovascular events andreduced the incidence of heart failure (7).

Thyroid DisordersBoth hyperthyroidism and hypo-thyroidism are associated withheart failure, and correction to aeuthyroid state can potentially return ventricular function to nor-mal (8, 9). Hyperthyroidism is associated with atrial fibrillationand tachycardia, which may com-plicate or worsen heart failure.

TachycardiaStudies have shown that rapid pro-longed ventricular rates can lead tocardiomyopathy. Restoration ofnormal rhythm or rate control inpatients with poorly controlled atrial fibrillation and othersupraventricular tachycardias canimprove function and potentiallyprevent left ventricular dysfunction(10–12).

Coronary Artery DiseaseAggressive risk-factor modificationwith cholesterol-lowering drugsand aspirin, ACE inhibitors, and β-blockers can significantly reducemortality and the risk for futurecardiovascular complications, in-cluding heart failure.

The CAPRICORN (Carvedilol Post-InfarctSurvival Control in Left Ventricular Dys-function) trial demonstrated that the β-blocker carvedilol significantly benefitedmortality in patients with left ventriculardysfunction with or without heart failureafter MI in the setting of background ther-apy with ACE inhibitors, revascularization,and aspirin (13).

What symptoms and signs shouldprompt clinicians to consider thediagnosis of heart failure?Patients with underlying risk fac-tors, including CAD, valvular heartdisease, and longstanding hyperten-sion, may be asymptomatic, andclinicians should not wait forsymptoms to develop before evalu-ating and treating them for earlyleft ventricular dysfunction. Oncestructural or functional heart dis-ease affects the ability of the my-ocardium to fill and pump bloodnormally, patients may develop dyspnea, fatigue, exercise intoler-ance, and fluid retention manifest-ed by pulmonary congestion andedema. Sometimes the breathingdifficulties and cough of heart fail-ure are initially misdiagnosed asbronchitis, pneumonia, or asthma,especially in young patients. Physi-cal signs of heart failure may reflectthe underlying cause, as shown byelevated blood pressure or an abnor-mal cardiac murmur, or the result-ing fluid retention, as shown by elevated jugular venous pressure,pulmonary crackles, a third heartsound, and lower extremity edema.

What tests should cliniciansconsider in the evaluation ofpatients with suspected heartfailure?ElectrocardiographyThe American College of Cardiol-ogy (ACC)/American Heart Asso-ciation (AHA) recommends elec-trocardiography (ECG) in anypatient at risk for or with a historyof cardiac disease, including new-onset or exacerbated heart failure.If possible, the tracing should becompared with a previous baselinetracing. Results can help documentthe presence of ventricular hyper-trophy, atrial abnormality, arrhyth-mias, conduction abnormalities,prior MI, and evidence of active is-chemia.

EchocardiographyTwo-dimensional echocardiographywith Doppler should be performed


in all patients with suspected heartfailure. It is a key study for deter-mining left ventricular cavity sizeand function, identifying wall mo-tion abnormalities, measuring leftand right ventricular ejection frac-tions, documenting the presence ofvalvular abnormalities, and differ-entiating between systolic and dias-tolic heart failure. In diastolic heartfailure, the ejection fraction is nor-mal (>50%), and there is evidenceof ventricular hypertrophy. In sys-tolic dysfunction, the ejection frac-tion is <50%, and there is left ven-tricular dilatation. The degrees ofleft ventricular systolic and diastolicdysfunction are important in pre-dicting prognosis, and the treat-ment of systolic and diastolic heartfailure may differ.

Exercise TestingA traditional exercise stress test or apharmacologic stress test usingdipyridamole, dobutamine, oradenosine for patients who are un-able to exercise can be used to lookfor ischemia and quantitate func-tional capacity in patients withheart failure. Metabolic stress test-ing with respiratory gas analysiscan determine the extent of disabil-ity, differentiate between cardiac orpulmonary limitation to exercise,and determine functional class inpatients who are candidates for car-diac transplantation (14).

Cardiac Catheterization andEndomyocardial BiopsyCardiac catheterization should beconsidered in patients with heartfailure when echocardiography isinsufficient in defining severity ofvalvular heart disease and whenknown or suspected ischemic heartdisease is being evaluated. Endomy-ocardial biopsy should not be donein most patients with suspectedmyocarditis unless giant cell my-ocarditis is being considered. Evenwhen systemic diseases, such ashemochromatosis, sarcoidosis, or

amyloidosis, are thought to be thecause of infiltrative disease in theheart, the diagnosis can usually bemade without endomyocardialbiopsy.

B-Type Natriuretic PeptideB-type natriuretic peptide (BNP) isa sensitive marker of ventricularpressure and volume overload andcan be useful in determining thecause of dyspnea when the clinical presentation and physical examina-tion are equivocal in the acute set-ting (15). However, BNP levels canalso be elevated in women, olderpatients, persons with renal disease,and in patients with acute MI andsome noncardiac conditions.

Other Laboratory StudiesConsider obtaining serum thyroid-stimulating hormone levels in allpatients with new-onset heart fail-ure to rule out occult thyroid dis-ease. Anemia, renal insufficiency,infection, and concurrent pul-monary disease can exacerbateheart failure, and the clinical situation should dictate the needfor additional tests, including complete blood cell count, electro-lytes, blood urea nitrogen, creati-nine, chest X-ray, pulmonary function studies, or appropriate cultures to guide therapy.

What are the types of heartfailure, and how should cliniciansgo about differentiating them?There are multiple causes of heartfailure, and it is sometimes usefulto divide them into dilated, hyper-trophic, and restrictive types (Table1). Most causes of heart failurelead to cardiac dilatation. Hyper-trophic cardiomyopathy is due togenetic abnormalities or hyperten-sion. Restrictive heart failure isusually due to systemic infiltrativediseases.

More important is the functionaldistinction between systolic and diastolic heart failure. In systolic

14. Myers J, MadhavanR. Exercise testingwith gas exchangeanalysis. Cardiol Clin.2001;19:433-45.[PMID: 11570115]

15. Morrison LK, Harri-son A, Krish-naswamy P, et al.Utility of a rapid B-natriuretic peptideassay in differentiat-ing congestive heartfailure from lung dis-ease in patients pre-senting with dysp-nea. J Am CollCardiol. 2002;39:202-9. [PMID: 11788208]

16. Owan TE, HodgeDO, Herges RM, et al.Trends in prevalenceand outcome ofheart failure withpreserved ejectionfraction. N Engl JMed.2006;355(3):251-9.[PMID: 16855265]



heart failure, the heart is dilatedwith an ejection fraction below50%, whereas in diastolic heart fail-ure, which occurs more often inelderly patients with hypertension,there is less dilatation and a normal

ejection fraction. Among patientswith heart failure, those with preserved ejection fraction repre-sent a significant proportion andhave a similar survival rate to thosewith systolic heart failure (16, 17)

17. Bhatia RS, Tu JV, LeeDS, et al. Outcomeof heart failure withpreserved ejectionfraction in a popula-tion-based study. NEngl J Med.2006;355(3):260-9.[PMID: 16855266]


Table 1. Underlying Causes of Heart Failure*Causes Characteristics

Dilated cardiomyopathies

Ischemic heart disease Occurs in people with a history of MI, presence of infarction pattern on ECG, or risk factors for coronary disease.

Hypertension Presents in people with a history of poorly controlled blood pressure, presence of an S4 on physicalexamination, or left ventricular hypertrophy on echocardiogram or ECG. Hypertension can also causehypertrophic as well as dilated caridomyopathy.

Valvular heart disease Mitral regurgitation: ejection murmur at apex, dyspnea on exertion, atrial fibrillation. Aortic stenosis:dyspnea with exertion, ejection murmur at base that radiates to carotid arteries, decreased carotidupstroke, syncope, angina.

Bacterial myocarditis Fever, exposure to known agent, or positive blood cultures. Includes Borrelia burgdorferi (Lyme disease), diphtheria, rickettsia, streptococci, and staphylococci.

Parasitic myocarditis Travel history to endemic areas, fever, or peripheral stigmata of infection. Rare in United States. Includes Trypanosoma cruzi (Chagas disease), leishmaniasis, and toxoplasmosis.

Giant cell myocarditis Intractable ventricular or supraventricular arrhythmias with rapidly progressive left ventricular dysfunction: Endomyocardial biopsy specimen may be used to confirm the diagnosis. Effective immunotherapy may be available, but prognosis is poor without ventricular assist device or transplantation.

Familial dilated cardiomyopathies Family history of heart failure or sudden cardiac death in blood relatives.

Toxic cardiomyopathies History of exposure to toxic agents, such as alcohol, anthracycline, radiation, cocaine, or catecholamines.

Collagen vascular disease History, positive serology results, or other stigmata of a collagen vascular disease, including systemiclupus erythematosus, polyarteritis nodosa, scleroderma, or dermatomyositis.

Granulomatous disease, such Atrial and ventricular arrhythmias that are difficult to control, rapidly progressive left as sarcoidosis ventricular dysfunction, heart block.

Endocrinologic or metabolic disorders Clinical history of hyperthyroidism, acromegaly, hypothyroidism, uremia, pheochromocytoma, diabetesmellitus, thiamine deficiency, selenium deficiency, carnitine deficiency, kwashiorkor, carcinoid tumor,or obesity; serum test for endocrine abnormality; long-term resident of a developing country or anarea with endemic nutritional deficiency. Nutritional deficiencies are rare in the United States.

Peripartum cardiomyopathy Heart failure symptoms with left ventricular dysfunction within 6 months of a pregnancy.

Neuromuscular disorders Clinical history of Becker muscular dystrophy, myotonic dystrophy, Friedreich ataxia, limb-girdle muscular dystrophy, or Duchenne muscular dystrophy. Physical examination findings depend on theunderlying disease.

Cardiac transplant rejection History of cardiac transplant, medication noncompliance, shortness of breath, atrial or ventricular arrhythmias, or tachycardia, summation gallop on examination.

Hypertrophic cardiomyopathies

Hypertrophic obstructive History or family history of hypertrophic cardiomyopathy, echocardiographic and ECG findings of cardiomyopathy hypertrophy. Screen for outflow tract gradient by physical examination, echocardiography, or cardiac

catheterization. Significant hypertrophy can also be seen in hypertension.

Restrictive cardiomyopathies

Infiltrative diseases affecting History of amyloidosis, sarcoidosis, hemochromatosis, Fabry disease, glycogen storage diseases, the myocardium Gaucher disease, mucopolysaccharidosis, endomyocardial fibrosis, or hypereosinophilic syndrome;

thickening of the myocardium on echocardiogram, suggesting an infiltrative process; cardiac MRIshowing infiltration; family history of an inborn error of metabolism or amyloidosis; presence of S

4on examination; right-sided heart failure more severe than left-sided failure; other organs

involved in underlying disease process.

* ECG = electrocardiography; MI = myocardial infarction; MRI = magnetic resonance imaging.



18. Sullivan MJ, CobbFR. The anaerobicthreshold in chronicheart failure. Rela-tion to blood lactate,ventilatory basis, re-producibility, and re-sponse to exercisetraining. Circulation.1990;81:II47-58.[PMID: 2295152]

19. Myers J, Gianrossi R,Schwitter J, et al. Ef-fect of exercise train-ing on postexerciseoxygen uptake ki-netics in patientswith reduced ven-tricular function.Chest.2001;120:1206-11.[PMID: 11591562]

20. Sullivan MJ, CobbFR. Central hemody-namic response toexercise in patientswith chronic heartfailure. Chest.1992;101:340S-346S.[PMID: 1576862]

How should clinicians evaluatefunctional capacity in patientswith suspected heart failure todetermine treatment?Clinicians should determine func-tional capacity by using the NewYork Heart Association (NYHA)classification system (see Box).Tracking changesin clinicalNYHA class atevery visit mayidentify patientswith progressiveheart failure whomay eventuallybenefit from spe-cialized care orcardiac trans-plantation.

Additional func-tional capacitytests that can befollowed overtime include the6-minute walk test (see Box) andformal exercise or pharmacologicstress testing. Measuring peak oxy-gen consumption (VO

2) at the time

of exercise testing can be useful indetermining prognosis.

What is the role of diet in themanagement heart failure?Despite a paucity of definitive evidence, ACC/AHA and otherguidelines recommend sodium re-striction in patients with sympto-matic heart failure as well as avoid-ance of salt-retaining medications,

such as nonsteroidal anti-inflam-matory drugs. Some clinicians rec-ommend that patients with moreadvanced heart failure limit intaketo 2 grams of sodium and 2 quartsof fluid per day to increase the ef-fectiveness of diuretic therapy.Limitation of salt and fluid intake

results in fewer hos-pitalizations for decompensated heartfailure. Patients whohave cardiovascularrisk factors, such ashyperlipidemia, obe-sity, or diabetes,should also be encouraged to followdietary recommenda-tions specific to these underlyingconditions.

What shouldclinicians advisepatients about

exercise? Do formal exerciseprograms provide benefit?Exercise improves physical and psy-chological well-being. In patientswith heart failure, it improves peakVO

2(18, 19) as well as metabolic

and hemodynamic indices and de-lays the onset of anaerobic thresh-old (18, 20). Clinicians should en-roll patients with medically stableNYHA class II, III, and perhapsclass IV heart failure in a long-termaerobic exercise program tailored tothe patient’s functional capacity. Astructured cardiac rehabilitationprogram may be particularly

Diagnosis... Be alert for the development of heart failure in older persons; AfricanAmericans; men; and in patients with hypertension, hyperlipidemia and diabetes,and those who smoke, drink alcohol, or use illicit drugs. Dyspnea and fatigue arethe primary symptoms of heart failure. In addition to history and physical exami-nation, use 2-dimensional Doppler echocardiography to assess left ventricularfunction along with ECG and additional studies to determine the cause of theheart failure and to identify exacerbating factors.

CLINICAL BOTTOM LINE

How to Perform the 6-minuteWalk TestAsk the patient to walk for 6 minutes in a straight line back andforth between 2 points separated by60 feet. Allow the patient to stopand rest or even sit, if necessary. Ateither end of the course, placechairs that can quickly be moved ifthe patient needs to sit. Note thetotal distance walked in 6 minutes,which correlates well with othermeasures of functional capacity.Gender-specific equations havebeen developed using age, height,and weight to calculate predicteddistance for healthy adults.

New York Heart Association(NYHA) Classification System:• NYHA class I (mild): Patient has

asymptomatic left ventricular dys-function. Normal physical activitydoes not cause undue fatigue, pal-pitation, or shortness of breath.

• NYHA class II (mild): Patient has fa-tigue, palpitation, or shortness ofbreath with normal physical activity.

• NYHA class III (moderate): Patienthas shortness of breath with mini-mal activity, including usual activi-ties of daily living.

• NYHA class IV (severe): Patient hasshortness of breath at rest and isunable to carry out any physical activity without discomfort. Physicalactivity of any kind increases discomfort.

Treatment



21. The CONSENSUS Tri-al Study Group. Ef-fects of enalapril onmortality in severecongestive heart fail-ure. Results of theCooperative NorthScandinavianEnalapril SurvivalStudy (CONSENSUS).N Engl J Med.1987;316:1429-35.[PMID: 2883575]

22. The SOLVD Investi-gators. Effect ofenalapril on survivalin patients with re-duced left ventricu-lar ejection fractionsand congestiveheart failure. N EnglJ Med. 1991;325:293-302. [PMID: 2057034]

23. The SOLVD Investi-gators. Effect ofenalapril on mortali-ty and the develop-ment of heart failurein asymptomatic pa-tients with reducedleft ventricular ejec-tion fractions. N EnglJ Med. 1992;327:685-91. [PMID: 1463530]

24. Pitt B, Segal R, Mar-tinez FA, et al. Ran-domised trial oflosartan versus cap-topril in patientsover 65 with heartfailure (Evaluation ofLosartan in the El-derly Study, ELITE).Lancet.1997;349:747-52.[PMID: 9074572]

25. Pitt B, Poole-WilsonPA, Segal R, et al. Ef-fect of losartan com-pared with captoprilon mortality in pa-tients with sympto-matic heart failure:randomised trial—the Losartan HeartFailure SurvivalStudy ELITE II.Lancet.2000;355:1582-7.[PMID: 10821361]

26. Cohn JN, Tognoni G.A randomized trialof the angiotensin-receptor blocker val-sartan in chronicheart failure. N EnglJ Med.2001;345:1667-75.[PMID: 11759645]

27. Maggioni AP, AnandI, Gottlieb SO, et al.;Val-HeFT Investiga-tors (Valsartan HeartFailure Trial). Effectsof valsartan on mor-bidity and mortalityin patients withheart failure not re-ceiving angiotensin-converting enzymeinhibitors. J Am CollCardiol.2002;40:1414-21.[PMID: 12392830]

effective because it can provide supervised exercise as well as sup-port in making lifestyle modifica-tions. Exercise should be stoppedtemporarily in patients with wors-ening heart failure until symptomsare stabilized. In addition, if pa-tients show evidence of exercise-induced ischemia, exercise shouldbe stopped until further evaluationand therapy are initiated.

When should clinicians beginfirst-line drug therapy with ACEinhibitors or angiotensin-receptorblockers? What are thealternatives for patients whocannot tolerate these drugs?ACE InhibitorsACE inhibitors should be used byall patients with heart failure re-gardless of functional class exceptthose with intolerance or a contra-indication, such as angioedema.These vasodilators alter the naturalhistory of the disease and improvesurvival and quality of life. Numer-ous randomized, placebo-controlledclinical trials have demonstratedthat ACE inhibitors reduce mortal-ity in patients with left ventriculardysfunction, even in those withoutsymptoms.

The CONSENSUS (Cooperative North Scan-dinavian Enalapril Survival Study) trialevaluated 253 patients with NYHA class Ito IV heart failure who were randomly as-signed to enalapril or placebo in a blindedstudy. All patients were also receiving di-uretics, and 93% received digitalis glyco-sides. The mortality rate was reduced by27% (P < 0.001) in the patients receivingenalapril compared with placebo (21).

The SOLVD (Studies of Left Ventricular Dys-function) treatment trial randomly as-signed 2569 patients with NYHA class I toIV heart failure to enalapril vs. placebo. Inpatients with heart failure receivingenalapril compared with placebo, therewas a 16% (P < 0.005) reduction in mor-tality rate, a 30% (P < 0.0001) reduction inheart failure hospitalizations, a 7% (P <0.01) reduction in total hospitalizations, a44% (P < 0.01) reduction in worseningheart failure, and a 23% (P < 0.02) reduc-tion in MI (22).

The SOLVD prevention trial enrolled 4228patients with NYHA class I. These patientshad asymptomatic left ventricular dys-function and were randomly assigned toenalapril vs. placebo. There was an 8% re-duction in mortality rate, a 31% (P < 0.001)reduction in heart failure hospitalizations,a 50% (P < 0.01) reduction in episodes of worsening heart failure, and a 24% (P < 0.01) reduction in MI in patients re-ceiving enalapril vs. placebo (23).

Initiate enalapril, captopril, lisino-pril, or ramipril at low doses andtitrate upward while monitoringblood pressure. The end point forblood pressure can be as low as 80 to 90 mm Hg systolic as long as the patient is asymptomatic.Important side effects includecough, worsening renal insufficiency,and hyperkalemia.

Angiotensin-Receptor BlockersClinicians should consider usingangiotensin-receptor blockers(ARBs) in patients with intolerableside effects from ACE inhibitors,such as cough.

The ELITE I (Evaluation of Losartan in theElderly) trial compared captopril withlosartan in elderly patients with heart fail-ure and showed a decrease in all-causemortality (4.8% vs. 8.7%; risk reduction46%, P = 0.035) in the losartan group. Ad-missions with heart failure were the samein both groups (5.7%), as was improve-ment in NYHA functional class from base-line (24). The ELITE II trial also comparedcaptopril with losartan, but there were no significant differences in all-causemortality (11.7% vs. 10.4% average annualmortality rate) or sudden death or resusci-tated arrests (9.0% vs. 7.3%) between thegroups (hazard ratios, 1.13 [95.7% CI, 0.95to 1.35], P = 0.16, and 1.25 [CI, 0.98 to 1.60],P = 0.08) (25).

The Val-HeFT (Valsartan–Heart Failure Tri-al) randomly assigned patients with heartfailure to valsartan or placebo in additionto standard heart failure medications.There was no difference in mortality, butthe incidence of the combined end point ofmorbidity or mortality was 13.2% lowerwith valsartan than with placebo (relativerisk, 0.87 [CI, 0.77 to 0.97]; P = 0.009) (26). Ina subgroup analysis, those not receiving anACE inhibitor but who were randomized to



28. Granger CB, McMur-ray JJ, Yusuf S, et al.Effects of candesar-tan in patients withchronic heart failureand reduced left-ventricular systolicfunction intolerantto angiotensin-con-verting-enzyme in-hibitors: the CHARM-Alternative trial.Lancet.2003;362:772-6.[PMID: 13678870]

29. Opie LH. Cellular ba-sis for therapeuticchoices in heart fail-ure. Circulation.2004;110(17):2559-61. [PMID: 15505109]

30. Loeb HS, Johnson G,Henrick A, et al. Ef-fect of enalapril, hy-dralazine plus isosor-bide dinitrate, andprazosin on hospital-ization in patientswith chronic con-gestive heart failure.The V-HeFT VA Co-operative StudiesGroup. Circulation.1993;87:VI78-87.[PMID: 8500244]

31. Johnson G, Carson P,Francis GS, Cohn JN.Influence of preran-domization (base-line) variables onmortality and on thereduction of mortali-ty by enalapril. Veter-ans Affairs Coopera-tive Study onVasodilator Therapyof Heart Failure (V-HeFT II). V-HeFT VACooperative StudiesGroup. Circulation.1993;87:VI32-9.[PMID: 8500237]

32. African-AmericanHeart Failure Trial In-vestigators. Combi-nation of isosorbidedinitrate and hy-dralazine in blackswith heart failure. NEngl J Med.2004;351:2049-57.[PMID: 15533851]

33. Packer M, BristowMR, Cohn JN, et al.The effect ofcarvedilol on mor-bidity and mortalityin patients withchronic heart failure.U.S. Carvedilol HeartFailure Study Group.N Engl J Med.1996;334:1349-55.[PMID: 8614419]

34. CIBIS Investigatorsand Committees. Arandomized trial ofbeta-blockade inheart failure. TheCardiac InsufficiencyBisoprolol Study(CIBIS). Circulation.1994;90:1765-73.[PMID: 7923660]

receive valsartan had a 33% reduction inall-cause mortality. This result is similar tothe magnitude of mortality reduction withACE inhibitors (27).

Evidence from the randomized, placebo-controlled CHARM-Alternative (Candesar-tan Cilexitil [Atacand] in Heart Failure As-sessment of Reduction Mortality andMorbidity) trial showed that the ARB can-desartan decreased a combined end pointof death from cardiovascular causes orhospitalization due to heart failure whencompared with placebo in patients withleft ventricular dysfunction intolerant ofACE inhibitors (28).

There have been some studies sug-gesting that combining ACE in-hibitors and ARBs may be benefi-cial in reducing left ventricular size and decreasing hospitaliza-tions, with an equivocal effect on mortality (29).

Hydralazine and NitratesPatients who are intolerant of bothACE inhibitors and ARBs shouldreceive hydralazine and long-actingnitrates. Evidence has shown thatthis combination improves clinicaloutcomes and decreases mortalityin patients with heart failure anddepressed ejection fraction (30, 31).However, the combination does notseem to have as much effect onmortality rates as ACE inhibitors.Hydralazine plus nitrates shouldalso be considered in addition tostandard therapy, including anACE inhibitor or ARB, in African-American patients with symptomaticheart failure, because this combina-tion may favorably affect myo-cardial remodeling and mortality inthese patients.

The A-HeFT (African American Heart Fail-ure Trial), which compared isosorbide plushydralazine with placebo isordil in African-American patients with heart failure,showed that the addition of this therapyincreased survival among those who werealready taking other neurohormonalblockers, including ACE inhibitors and β-blockers (32).

When should clinicians add β-blockers, aldosteroneantagonists, and loop diuretics?β-Blockersβ-blockers should be used in allNYHA classes of heart failure ifthe patient is stable on ACE inhibitors or other vasodilators and are not volume overloaded.β-blockers can reduce heart failuresymptoms, improve clinical out-comes, improve ejection fraction,and decrease mortality rate. Pa-tients with less-severe heart failurehave the greatest long-term benefit,including those with left ventriculardysfunction but no symptoms. Var-ious studies testing carvedilol, biso-prolol, and long-acting metoprololsuccinate have all found that β-blockers reduced hospitalizations,sudden death, and overall mortalityin patients with heart failure.

The CAPRICORN trial randomized patientswith left ventricular dysfunction after MIwith or without heart failure to β-blockadewith carvedilol. There was a significant re-duction in mortality that was even moremarked in the group that never had symp-tomatic heart failure (13).

The U.S. carvedilol trial randomly assigned696 patients to the carvedilol group and398 to the placebo group. Patients wereclassified with NYHA class I to IV heart failure. A 65% (P < 0.0001) reduction inmortality was seen in the carvedilol group.Cardiovascular hospitalizations were reduced (33).

The CIBIS (Cardiac Insufficiency BisoprololStudy) I trial randomly assigned 320 pa-tients to bisoprolol, 5 mg/d, or placebo.There was a statistically insignificant 20%reduction in mortality and a significant re-duction in heart failure hospitalizations(34). The CIBIS II trial randomly assignedpatients with NYHA class III to IV heart fail-ure to bisoprolol, 5 mg/d, or placebo. A to-tal of 3.6% of patients in the bisoprololgroup had sudden cardiac death versus6.3% in the placebo group (P < 0.01) (35).

The MERIT-HF (Metoprolol CR/XL Random-ized Intervention Trial–Heart Failure) ran-domly assigned 3991 patients with NYHAclass II to IV heart failure to metoprololCR/XL (up to 200 mg/d) versus placebo.



There was a 34% reduction in all-causemortality (P < 0.001) and a 59% reductionin sudden death (P < 0.001) for patients re-ceiving metoprolol versus placebo (36).

The COPERNICUS (Carvedilol ProspectiveRandomized Cumulative Survival) trialrandomly assigned patients with NYHAclass IV heart failure to carvedilol or place-bo. There was a 24% decrease in the com-bined risk for death or hospitalization withcarvedilol (P < 0.001) (37).

β-blockers should be initiated atthe lowest dose and slowly titratedupward every 2 to 4 weeks to thehighest therapeutic dose tolerated,as limited by bradycardia, hypoten-sion, or side effects. Instruct pa-tients to check their body weightand watch for worsening heart fail-ure symptoms during initiation andupward titration of β-blockade.

Aldosterone AntagonistsIf patients continue to have NYHAclass III to IV symptoms despitetherapy with ACE inhibitors andβ-blockers, consider treatment withlow doses of an aldosterone antago-nist. Spironolactone has been stud-ied the most.

The RALES (Randomized Aldosterone Eval-uation Study), a large, randomized, place-bo-controlled trial involving 1663 patientswith NYHA class III to IV heart failure on ap-propriate therapy with or without spirono-lactone, was halted 18 months early by theData Safety Monitoring Board becausethere were significantly fewer deaths in thespironolactone group than in the placebogroup (284 vs. 386 deaths; 35% reduction,P < 0.0001) (38).

Eplenerone is a newer, more selec-tive aldosterone antagonist withfewer undesirable side effects andhas been shown to decrease all-cause mortality in patients with anejection fraction < 40% after acuteMI (39), but it has only been ap-proved for use in hypertension.

Higher rates of hyperkalemia havebeen documented in patients takingACE inhibitors and spironolactone,necessitating careful monitoring ofserum potassium levels (40). The

combination of ACE inhibitors,ARBs, and spironolactone shouldbe avoided because of a significant-ly increased risk for hyperkalemia.

DiureticsDiuretics, which is the only therapythat acutely produces symptomaticbenefits, can reduce pulmonarycapillary wedge pressure and edemaand improve exercise capacity. Noclinical trials have assessed theirlong-term safety or impact on mor-tality in heart failure.

A single trial comparing furosemide withtorsemide found that torsemide had thetheoretical benefit of improved oral ab-sorption, plus patients receiving torsemidewere less likely to be readmitted for heartfailure (41).

Loop diuretics should be used incombination with a low-sodiumdiet to control volume overload,maintain a stable weight, and im-prove the functional capacity of pa-tients with NYHA class II to IVheart failure. Diuretics should neverbe used alone to treat heart failurebecause they do not prevent theprogression of disease or maintainclinical stability over time.

For patients resistant to loop di-uretics, thiazide diuretics may beadded to augment diuresis. Fur-thermore, the use of a thiazide di-uretic in combination with a loopdiuretic can be part of an effective“sliding” diuretic regimen based ona patient’s daily weight and symp-toms. A second class of diureticmay act synergistically with thefirst by blocking the adaptiveprocesses that limit diuretic effec-tiveness. With all diuretics, clini-cians should frequently monitor pa-tient renal function and electrolytes,especially potassium levels.

What is the role of digoxin in thetreatment of heart failure?Digoxin can alleviate symptomsand decrease hospitalizations in pa-tients with heart failure; however, itshould be reserved specifically for

35. The Cardiac Insuffi-ciency BisoprololStudy II (CIBIS-II): arandomised trial.Lancet. 1999;353:9-13. [PMID: 10023943]

36. Effect of metoprololCR/XL in chronicheart failure: Meto-prolol CR/XL Ran-domised Interven-tion Trial inCongestive HeartFailure (MERIT-HF).Lancet.1999;353:2001-7.[PMID: 10376614]

37. Packer M, Coats AJ,Fowler MB, et al. Ef-fect of carvedilol onsurvival in severechronic heart failure.N Engl J Med.2001;344:1651-8.[PMID: 11386263]

38. Pitt B, Zannad F,Remme WJ, et al.The effect ofspironolactone onmorbidity and mor-tality in patientswith severe heartfailure. RandomizedAldactone Evalua-tion Study Investiga-tors. N Engl J Med.1999;341:709-17.[PMID: 10471456]

39. Eplerenone Post-Acute Myocardial In-farction Heart FailureEfficacy and SurvivalStudy Investigators.Eplerenone, a selec-tive aldosteroneblocker, in patientswith left ventriculardysfunction aftermyocardial infarc-tion. N Engl J Med.2003;348:1309-21.[PMID: 12668699]

40. Juurlink DN, Mam-dani MM, Lee DS, etal. Rates of hyper-kalemia after publi-cation of the Ran-domized AldactoneEvaluation Study. NEngl J Med.2004;351(6):543-51.[PMID: 15295047]

41. Murray MD, DeerMM, Ferguson JA, etal. Open-label ran-domized trial oftorsemide com-pared withfurosemide therapyfor patients withheart failure. Am JMed. 2001;111:513-20. [PMID: 11705426]


patients with symptomatic NYHAclass II to IV heart failure, becauseresearch indicates that it providesno survival difference comparedwith placebo (42). Furthermore,digoxin does not appear to be effective in rate control for patientswith atrial fibrillation, providingonly rate control at rest (43).

It is important to ensure that elec-trolytes and renal function are sta-ble before starting digoxin, andserum levels should be monitored,especially if renal function ischanging. Some controversy existsover the appropriate serum level ofdigoxin. A recent study suggestedthat lower serum levels of digoxinwere as efficacious as “therapeutic”levels, with a lower risk for side effects (44). In fact, in a post hocsubgroup analysis of 1 recent study,mortality rate was increased amongwomen on digoxin compared withmen, which may have been due tohigher serum digoxin levels (45).

What drug therapy is appropriatefor patients with diastolicdysfunction?The goals of treatment of diastolicheart failure are: 1) to control heartrate to allow for adequate filling ofthe ventricle; 2) to maintain normalsinus rhythm, if possible; 3) to con-trol volume status to decrease dias-tolic pressures; 4) to control bloodpressure or other stimuli to leftventricular hypertrophy; and 5) tominimize myocardial ischemia inthe setting of left ventricular hyper-trophy, even in the absence of epi-cardial coronary disease.

There have been few randomizedtrials of the treatment for diastolicheart failure, and recommendationsare based on investigations in smallgroups of patients or are based ontheoretical concepts. The publica-tion of consensus guidelines on thedefinition of diastolic heart failurehas allowed for the design of multi-center clinical trials (46), several of which are now underway and

involve use of calcium-channel an-tagonists, aldosterone antagonists,ARBs, and clonidine in patientswith and without hypertension.

ACC/AHA guidelines and otherssuggest that patients with diastolicdysfunction should be treated withdiuretics, β-blockers, ACE in-hibitors, ARBs, and nitrates. Calci-um-channel blockers, such as vera-pamil and diltiazem, may alsoalleviate symptoms and improve exercise capacity. It is important toavoid overdiuresis, because dehy-dration can lead to lightheadednessand syncope in patients with dias-tolic dysfunction.

When should clinicians considerplacement of an intracardiacdevice in patients with heartfailure?Patients with left ventricular dys-function with an ejection fraction < 30% in NYHA class I, II, or IIIand an overall life expectancy ofmore than 6 months should beconsidered for placement of an in-tracardiac device (ICD) to monitorheart rate and rhythm and correctarrhythmia when it occurs. Datasuggest that patients with class IVsymptoms do not benefit fromICD placement, but those in classII may benefit most. Studies showa clear decrease in sudden deathand overall mortality.

The DEFINITE (Defibrillators in Non-is-chemic Cardiomyopathy Treatment Evalu-ation) trial randomized 458 patients withdilated nonischemic cardiomyopathy andleft ventricular ejection fraction < 36% tostandard medical therapy or standardmedical therapy plus a single-chamberICD. Over a follow-up period of 29 months,28 deaths occurred in the ICD group com-pared with 40 in the standard medicaltherapy group. Although overall mortalitywas not significantly lower, there were 3sudden deaths in the ICD group vs. 14 inthe standard therapy group, P = 0.006 (47).

In the MADIT II (Multicenter Automatic De-fibrillator Implantation Trial II), 1232 pa-tients with a previous MI and an ejectionfraction < 30% were randomly assigned (in

42. The Digitalis Investi-gation Group. Theeffect of digoxin onmortality and mor-bidity in patientswith heart failure. NEngl J Med.1997;336:525-33.[PMID: 9036306]

43. Khand AU, RankinAC, Kaye GC, ClelandJG. Systematic re-view of the manage-ment of atrial fibrilla-tion in patients withheart failure. EurHeart J. 2000;21:614-32. [PMID: 10731399]

44. Adams KF Jr, Gheo-rghiade M, UretskyBF, et al. Clinical ben-efits of low serumdigoxin concentra-tions in heart failure.J Am Coll Cardiol.2002;39:946-53.[PMID: 11897434]

45. Rathore SS, Wang Y,Krumholz HM. Sex-based differences inthe effect of digoxinfor the treatment ofheart failure. N EnglJ Med.2002;347:1403-11.[PMID: 12409542]

46. How to diagnose di-astolic heart failure.European StudyGroup on DiastolicHeart Failure. EurHeart J. 1998;19:990-1003.[PMID: 9717033]

47. Kadish A, Dyer A,Daubert JP, et al. Pro-phylactic defibrilla-tor implantation inpatients with nonis-chemic dilated car-diomyopathy. N EnglJ Med.2004;350:2151-8.[PMID: 15152060]

48. Moss AJ, Zareba W,Hall WJ, et al. Pro-phylactic implanta-tion of a defibrillatorin patients with my-ocardial infarctionand reduced ejec-tion fraction. N EnglJ Med. 2002;346:877-83. [PMID: 11907286]



49. Bardy GH, Lee KL,Mark DB, et al. Amio-darone or an im-plantable cardiovert-er-defibrillator forcongestive heart fail-ure. N Engl J Med.2005;352:225-37.[PMID: 15659722]

50. Young JB, AbrahamWT, Smith AL, et al.Combined cardiacresynchronizationand implantable car-dioversion defibrilla-tion in advancedchronic heart failure:the MIRACLE ICD Tri-al. Multicenter In-Sync ICD Random-ized ClinicalEvaluation (MIRACLEICD) Trial Investiga-tors. JAMA.2003;289:2685-94.[PMID: 12771115]

51. Cleland JG, DaubertJC, Erdmann E, et al.The effect of cardiacresynchronizationon morbidity andmortality in heartfailure. N Engl J Med.2005;352:1539-49.[PMID: 15753115]

52. Dunkman WB, John-son GR, Carson PE, etal. Incidence ofthromboembolicevents in congestiveheart failure. The V-HeFT VA CooperativeStudies Group. Cir-culation.1993;87:VI94-101.[PMID: 8500246]

53. Al-Khadra AS, SalemDN, Rand WM, et al.Warfarin anticoagu-lation and survival: acohort analysis fromthe Studies of LeftVentricular Dysfunc-tion. J Am Coll Cardi-ol. 1998;31:749-53.[PMID: 9525542]


the absence of electrophysiologic testingor other risk stratification) to ICD place-ment with conventional drug therapy orconventional drug therapy alone. The ICDgroup experienced a 28% reduction inmortality at 3 years (P = 0.007) (48).

The SCD-HeFT (Sudden Cardiac Death inHeart Failure trial) randomly assigned2521 patients with NYHA class II or III heartfailure and a left ventricular ejection frac-tion < 35% to conventional therapy forheart failure plus placebo; conventionaltherapy plus amiodarone; or conventionaltherapy plus a conservatively pro-grammed, shock-only, single-lead ICD.During a median follow-up of 45.5months, mortality was 29% in the placebogroup, 28% in the amiodarone group, and22% in the ICD group. The ICD therapy was associated with a 23% decreased risk for death (P = 0.007) compared withplacebo (49).

Placement of a biventricular pace-maker can improve quality of lifeand decrease hospitalizations in patients with heart failure, an ejec-tion fraction < 35%, a QRS interval > 130 msec on ECG, and symptomsdespite maximal medical therapy.

In the MIRACLE-ICD (Multicenter InSyncICD Randomized Clinical Evaluation) trial,369 patients with class III or IV heart failure,ejection fraction, and QRS interval < 130msec received an ICD with resynchroniza-tion device. Those in whom the latter de-vice was turned on demonstrated im-proved quality of life, functional status,and exercise capacity but no change inheart failure status, rates of hospitaliza-tion, or survival (50).

In the CARE-HF (Cardiac Resynchroniza-tion in Heart Failure) study, 813 patientswith NYHA class III or IV heart failure due toleft ventricular systolic dysfunction andcardiac dyssynchrony who were receivingstandardized drug therapy were randomlyassigned to receive medical therapy aloneor with cardiac resynchronization. Thestudy concluded that, in these patients,cardiac resynchronization improvedsymptoms and quality of life and reducedthe risk for death (51).

When should clinicians useinotropic agents in patients withheart failure?Inotropic agents, such as dobuta-mine and milrinone, can improvecardiac output in patients with lowcardiac output and decrease after-load in patients with severe heartfailure unresponsive to the tradi-tional heart failure medications.However, all inotropic agents withthe exception of digoxin have beenassociated with excess mortalityand should be reserved for patientsunresponsive to traditional oralheart failure medications. Becauseof the increased risk for suddencardiac death, they should only beused in a monitored setting or forpalliation of end-stage disease.

When should clinicians considerusing anticoagulants in patientswith heart failure?Dilated cardiomyopathy with de-pressed ejection fraction below35%, valvular lesions (especially mi-tral stenosis), and atrial fibrillationare all associated with embolicstroke. The incidence of throm-boembolic events was about 2.7 per100 patient-years in the 1 large tri-al database of patients with heartfailure (52). Although many expertsadvocate anticoagulation to reducethe risk for stroke for patients withheart failure and significantly de-pressed ejection fraction who haveno contraindications, anticoagula-tion remains controversial for pa-tients with an ejection fraction be-low 35% without atrial fibrillation,documented clot, or valvular heartdisease; and in another trial data-base, the use of warfarin in suchpatients was not associated with areduction in all-cause mortality(53). Therefore, it seems most ap-propriate to initiate anticoagulationwith warfarin in patients with doc-umented left ventricular clot onechocardiogram or ventriculogram,atrial fibrillation, or prior embolicevent and to use aspirin or clopi-dogrel in patients with coronary



Table 2. Drug Treatment for Heart Failure*Agent, Dosage Mechanism of Action Benefits Side Effects Notes

ACE inhibitors

Enalapril, 5–20 mg PO bid Inhibits angiotensin-converting Improves patient Cough, angioedema, Follow BUN, creatinine, and potassium enzyme; results in decreased exercise tolerance, renal insufficiency, levels; withdraw or decrease dose if renal

Captopril, 12.5–50.0 mg PO tid conversion of angiotensin I to hemodynamic status, hyperkalemia insufficiency exacerbated. For all classesangiotensin II and decreased survival; may halt of heart failure.

Lisinopril, 5–40 mg PO qd metabolism of bradykinin. The progression and cause or 5–20 mg PO bid latter produces prostaglandins regression of HF

and nitric oxide

Angiotensin-receptor antagonists

Losartan, 25–100 mg PO qd Inhibits renin–angiotensin system Improvement in hemo- Hyperkalemia, exacer- Follow BUN, creatinine, and potassium at angiotensin receptor level dynamics and symptoms. bation of renal in- levels. May use these agents in addition

Valsartan, 80–320 mg PO qd Should be used in patients sufficiency, hypotension to ACE inhibitors in patients with severe who cannot take ACE in- HF.

Candesartan, 16–32 mg PO qd hibitors. May be detrimental in patients already on ACE inhibitors and ß-blockers

ß-blockers

Carvedilol, 3.125–25.0 mg Inhibits adrenergic nervous Improves hemodynamic Bradycardia, depression, Avoid in patients with significant asthma, PO bid (50 mg PO bid system; improves survival and status, LVEF, survival; hypotension, diabetes, or high-grade conduction system disease for patients weighing LVEF in patients with HF; may halt progression exacerbation of asthma without pacemaker. For all classes of >85 kg) reduces sudden death risk and cause regression or COPD heart failure. Use with caution in patients

of HF with class IV heart failure.Carvedilol CR, 10–80 mg qd

Metoprolol XL/CR (succinate), 50–200 mg PO qd XL

Bisoprolol, 5 mg PO bid

Afterload reducersHydralazine, 25–100 mg PO Reduces afterload and preload Combination with nitrates Hypotension, lupus-like Combination with nitrates reserved forqid improves survival in patients syndrome (high doses patients intolerant to ACE inhibitors and ARBs

with HF; survival benefit of hydralazine)not as great as ACE inhibitors

Isosorbide dinitrate, 10–40 Reduces afterload and preload Combination with hydralazine Headache Combination with hydralazine reserved for mg PO tid improves survival in patients patients intolerant to ACE inhibitors and ARBs

with HF; survival benefit not as great as ACE inhibitors

Aldosterone antagonists

Spironolactone, 12.5–50.0 Inhibits aldosterone, which can Improves survival in Hyperkalemia, Follow potassium level, especially in mg PO qd escape ACE inhibition and has patients with NYHA gynecomastia patients taking ACE inhibitors. Aldosterone

Eplerenone, 25–50 mg numerous deleterious effects on stages III to IV HF. antagonists alone are not an adequate PO qd cardiovascular system in patients Improves survival after substitute for a loop diuretic in patients

with HF MI with LV dysfunction. who require diuretics. Eplerenone has fewer sex-hormone–related side effects. Avoid withcombination of ACE inhibitors and ARBs.

Loop diuretics

Furosemide, 10–160 mg PO Inhibits chloride uptake in the Palliative in patients Hypokalemia, hypo- Follow BUN, creatinine, potassium, qd bid loop of Henle; result is diuresis with congestive magnesemia, volume and magnesium levels and volume status.

Torsemide, 10–40 mg PO qd symptoms. No survival depletion, renal bid benefit. insufficiency

Bumetanide, 1–4 mg PO qd bid

Ethacrynic acid, 25–100 mg PO qd bid

Digitalis glycoside

Digoxin, 0.125–0.25 mg PO Positive inotropic agents. Improves exercise Arrhythmias, bradycardia Follow levels (aim for level <2.0). Follow qd Increased extracellular calcium, tolerance, reduces (exacerbated by potassium levels and avoid hypokalemia.

slow heart rate through vagal hospitalizations. Slows hypokalemia); visual Only positive inotropic agent not effects. heart rate. No survival changes. Low therapeutic associated with increased mortality. Use

benefit. index lower dose in elderly patients and patients with renal insufficiency.

Positive inotropic agents

Dobutamine, 2–10 µg/kg per Improves hemodynamics; Palliative in patients with Arrhythmogenic; no Cardiology consultation strongly encour-min IV arrhythmogenic severe HF in whom oral survival benefit aged before initiation. Should be reserved

Milrinone, 0.1–0.7 µg/kg per agents have failed to for patients awaiting transplantation min IV improve hemodynamics (ideally in monitored setting) or for

palliation of patients with severe, end-stage HF who are not transplant candidates.

* ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; bid = twice daily; BUN = blood urea nitrogen; HF = heart failure; COPD = chronic obstructive pulmonary disease; IV = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; PO = oral; qid = four times daily; qd = once daily; tid = three times daily.


54. American College ofCardiology/AmericanHeart Association TaskForce on PracticeGuidelines (Commit-tee to Revise the 1995Guidelines for theEvaluation and Man-agement of Heart Fail-ure). ACC/AHA Guide-lines for theEvaluation and Man-agement of ChronicHeart Failure in theAdult: Executive Sum-mary. Circulation.2001;104:2996-3007.[PMID: 11739319]


Treatment... Determine NYHA functional class to guide treatment in patients withheart failure. Limit salt and fluid intake in patients with symptomatic heart fail-ure, and recommend regular exercise as tolerated. Begin first-line drug therapywith ACE inhibitors or ARBs (or hydralazine and nitrates if these are not tolerated)as well as β-blockers in patients who are not volume overloaded. Add loop diureticsand digoxin in patients with NYHA classes II, III, and IV heart failure and aldos-terone antagonists in those with class III and IV and monitor potassium and renalfunction. Consult a cardiologist in patients with severe heart failure who may require hospitalization for inotropic agents; placement of ICD devices, pacemakers,or left ventricular assist devices; or cardiac transplantation. Recognize that anti-coagulation for patients with depressed ejection fractions remains controversial.Teach patients to participate in their own care by encouraging them to monitortheir diet, medical regimen, and weight.

CLINICAL BOTTOM LINE

disease, regardless of ejection fraction.

What should clinicians advisepatients to do to preventexacerbations of heart failure?Clinicians should advise patients toadhere to their fluid and salt re-striction and medical regimen,weigh themselves daily, and to re-port deviations from their “dryweight” before they become symp-tomatic. Some patients can learn touse a sliding dose of diuretic tomaintain their weight. Help fromnurses, dietitians, home health staff,and physical therapists can be in-valuable in helping patients preventexacerbations. Patients should re-ceive pneumococcal vaccine andannual influenza immunization.

Patients with established CADshould begin aggressive risk-factormodification, including attention todiet, exercise, weight control, andsmoking cessation. Behavior modi-fications should be prescribed aswell as pharmacologic therapy un-less contraindicated. Multiple stud-ies have shown that risk-factormodification with cholesterol-low-ering drugs and the use of aspirinor other antiplatelet drugs, ACEinhibitors, and β-blockers can sig-nificantly reduce the risk for futurecardiovascular events and reducemortality.

When should clinicians considerconsulting a cardiologist aboutmanagement of patients withheart failure?If symptoms worsen despite opti-mal medical therapy, consult a car-diologist for help in reviewing theneed for hospitalization for par-enteral inotropic drug treatment;catheterization; placement of anICD, biventricular pacemaker, orleft ventricular assist device; or car-diac transplantation. Consider ob-taining pulmonary consultationwhen primary lung disease, such aschronic obstructive pulmonary dis-ease or sleep apnea, is thought tobe contributing to the patient’ssymptoms.

When should clinicians hospitalizepatients with heart failure?Patients with severe NYHA classIV heart failure, characterized bydyspnea at rest, severe fatigue, orvolume overload unresponsive tooral diuretics or that requires inpa-tient evaluation and managementshould be hospitalized. This in-cludes patients with life-threaten-ing ventricular arrhythmias or atrialarrhythmias that worsen heart fail-ure symptoms or cause hypoten-sion. It also includes patients withsyncope, sudden cardiac death,and atrial arrhythmias with worsening clinical signs and symp-toms of heart failure who requireparenteral drug treatment or deviceplacement.



What do professionalorganizations recommend withregard to the care of patientswith heart failure?The ACC/AHA published guide-lines for the Evaluation and Man-agement of Chronic Heart Failure inthe Adult in 2001 (54), and thesewere updated in 2005 (55). Theguidelines contain extensive infor-mation on the characterization ofheart failure as a clinical syndrome,initial and serial clinical assessmentof patients, drug and device therapyfor patients with heart failure at vari-ous stages of the disease, treatmentof special populations, managing patients with heart failure and con-comitant disorders, end-of-life con-siderations, and issues involved inimplementation of the guidelines.The updated guidelines stress theimportance of early diagnosis to stopor slow disease progression andchanges in drug therapy based onseveral pivotal clinical trials.

In addition to the ACC/AHAguidelines, other significant guide-lines include the Heart Failure Soci-ety of America 2006 ComprehensiveHeart Failure Practice Guideline(56) and the Department of VeteransAffairs/Veterans Health Administra-tion 2003 guidelines relating to the

pharmacologic management ofchronic heart failure (57).

What measures do stakeholdersuse to evaluate the quality of carefor patients with heart failure?The Centers for Medicare andMedicaid (CMS) has started aPhysician Quality Reporting Initia-tive (PQRI) program, throughwhich clinicians can report a desig-nated set of quality measures onclaims for services provided duringthe period from 1 July through 31December 2007 and earn bonuspayments. Among the currentmeasures in the PQRI program, 2relate to heart failure. The first issimilar to the Ambulatory CareQuality Alliance measure relating touse of ACE inhibitors or ARBs,calling for use of these agents in patients over 18 years of age with adiagnosis of heart failure and leftventricular dysfunction. The secondmeasures use of β-blocker therapy inthe same population.

In addition, the Agency forHealthcare Research and Quality isusing quality indicators to measurethe hospital admission rate for heartfailure, and CMS has proposed thepublic reporting of hospital-level30-day mortality for patients withheart attack and heart failure.

Practice Improvement

55. American College ofCardiology.ACC/AHA 2005Guideline Update forthe Diagnosis andManagement ofChronic Heart Failurein the Adult: a reportof the American Col-lege of Cardiology/American Heart As-sociation Task Forceon Practice Guide-lines (Writing Com-mittee to Updatethe 2001 Guidelinesfor the Evaluationand Management ofHeart Failure): devel-oped in collabora-tion with the Ameri-can College of ChestPhysicians and theInternational Societyfor Heart and LungTransplantation: en-dorsed by the HeartRhythm Society.Circulation.2005;112:e154-235.[PMID: 16160202]

56. Heart Failure Societyof America. HFSA2006 Comprehen-sive Heart FailurePractice Guideline. JCard Fail. 2006;12:e1-2. [PMID: 16500560]

57. Pharmacy BenefitsManagement Strate-gic Healthcare Groupand the Medical Ad-visory Panel; Depart-ment of Veterans Af-fairs, Veterans HealthAdministration. ThePharmacologic Man-agement of ChronicHeart Failure. Ac-cessed at http://www.oqp.med.va.gov/cpg/CHF/CHF_Base.htm on 11 October2007.

inthe

c linicTool Kit

in the clinic

Heart Failure

PIER Moduleswww.pier.acponline.orgHeart failure and percutaneous coronary intervention modules with updated informationon current diagnosis and treatment of heart failure, designed for rapid access at the pointof care.

Patient Informationwww.annals.org/intheclinicDownload copies of the Patient Information sheet that appears on the following page forduplication and distribution to your patients.

Quality Improvement Toolswww.ihi.org/ihi/search/searchresults.aspx?searchterm=heart+failure+tools&searchtype=basicLinks to a variety of helpful tools for managing various aspects of heart failure, compiledby the Institute for Healthcare Improvement.

www.gericareonline.net/tools/eng/heartfailure/index.htmlDownload a complete heart failure toolkit covering various topics in assessment,management, and follow-up with accompanying flowsheets from the Practicing Physicianin Education project, supported by the John A. Hartford Foundation.

www.cardiologyinoregon.org/information/information.html#toolkitResources from the Oregon Heart Failure GAP Toolkit, part of an American College ofCardiology project in 3 states to improve heart failure care.


THINGS PEOPLE SHOULD KNOWABOUT HEART FAILURE

In the ClinicAnnals of Internal Medicine

Web Sites with Good Information on Heart FailureAmerican College of Physicianswww.doctorsforadults.com/images/healthpdfs/heartfail.pdf

American Heart Associationwww.americanheart.org/presenter.jhtml?identifier=1486

National Heart, Lung, and Blood Institutewww.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html

• Heart failure, sometimes called congestive heart failure, is a condition in which theheart can’t pump as well as it should. Because the heart has a hard time getting bloodto the rest of the body, patients with heart failure can feel weak and tired.

• In some patients with heart failure, fluid (edema) builds up in the lungs and parts ofthe body, making it hard to breathe and causing swelling in the legs.

• Heart failure can result from many different conditions that directly or indirectly af-fect the heart. People with high blood pressure, diabetes, high cholesterol, and coro-nary artery disease can develop heart failure. Treating these conditions may preventheart failure.

• Treating heart failure means working together with your doctor to control salt in yourdiet, watching your weight, and taking all your medications every day. It’s importantto keep your regular doctor appointments.

• Heart failure affects nearly 5 million adults, and 550 000 new cases are diagnosedeach year. It is more common in older people but can occur at any age. Althoughthere is no cure yet, heart failure is very treatable and millions of Americans lead afull life by managing their condition through medications and by making healthychanges in their lifestyles.

Heart Failure Symptoms:

Breathlessness during activity, at rest, or while sleeping

Wheezing or coughing that may be dry or may produce white or pink blood-tinged phlegm

Swelling in the feet, ankles, legs or abdomen, or unexplained weight gain

A constant lack of energy and difficulty performing everyday activities

A sense of having a full or sick stomach

A feeling like the heart is racing or pounding

A feeling the heart is skipping beats or occasionally pounding very hard

Pati

ent

Info

rmat

ion



CME Questions

A 48-year-old woman with a history ofan ischemic cardiomyopathy and NewYork Heart Association class II heart fail-ure symptoms is seeking advice about hermedical therapy. She has no inducible ischemia on stress testing and her lastejection fraction by echocardiographywas estimated to be 35%. She was lasthospitalized for an exacerbation of heartfailure 1 year ago. She takes extended-release metoprolol, aspirin, lisinopril,digoxin, and furosemide. On physical examination, her heart rate is 62/min andblood pressure is 104/78 mm Hg. There isno jugular venous distention, and herchest is clear on auscultation. She has aregular rhythm without gallop or murmur.Her complete blood count and serumelectrolytes are normal.

Which one of the following changes inher medications should be made at thistime?

A. Add an angiotensin-receptorblocker.

B. Add nitroglycerin and hydralazine.C. Add spironolactone.D. Discontinue metoprolol.E. No changes at this time.

A 56-year-old woman who is new to yourpractice is evaluated for recent exacerba-tion of dyspnea and fatigue. She has idiopathic dilated cardiomyopathy andreceives a stable heart failure regimen,including lisinopril, 20 mg/d; digoxin, 125mg/d; furosemide, 40 mg/d; and meto-prolol XL, 50 mg/d. She also takes alen-dronate, hormone replacement therapy,glipizide, folic acid, and ibuprofen be-cause of rheumatoid arthritis. Thyroidhormone therapy with thyroxin was initi-ated because of the finding of an elevat-ed serum thyroid-stimulating hormonelevel 4 months earlier. The thyroid-stimulating hormone level returned tonormal after therapy.

On physical examination, blood pressureis 110/72 mm Hg, and heart rate is82/min. Jugular venous pressure is esti-mated at 10 cm H

2O. The lungs are clear.

Cardiac examination shows an S3

gallopand 2+ pitting edema.

Which of the following is most likely tobe exacerbating the heart failure in thispatient?

A. AlendronateB. GlipizideC. IbuprofenD. ThyroxinE. Estrogen

A 35-year-old man with a 2-year historyof dilated, nonischemic cardiomyopathyand New York Heart Association func-tional class III symptoms is admitted tothe hospital with worsening shortness ofbreath for the third time in 6 months. Hehas normal coronary arteries and an ejec-tion fraction of 25%. His current medica-tions include extended-release metopro-lol, lisinopril, furosemide, digoxin, andspironolactone. On physical examination,his blood pressure is 96/70 mm Hg, hispulse rate is 84/min, and his respirationrate is 22/min. He has crackles halfwayup his lung fields bilaterally, a displacedcardiac apex, and an S

3gallop. His electro–

cardiogram shows sinus rhythm with aleft bundle branch block and a QRS duration of 170 msec.

Which of the following outcomes canthis patient expect from a cardiac resynchronization procedure?

A. Decreased risk for all-causemortality

B. Decreased risk for cardiac deathC. Decreased risk for sudden cardiac

deathD. Improved heart failure symptoms

and exercise toleranceE. No benefit

A 65-year-old man who had an acutemyocardial infarction 10 years ago isreevaluated. Despite diet and exercisetherapy, he has had recurrent ischemicevents, and over the past 2 years, he hasbeen hospitalized several times for exacer-bations of heart failure. Six months ago,a dipyridamole thallium scan showed noischemia and echocardiogram showedanterior akinesia, global hypokinesia, and moderate to severe mitral regurgita-tion, with an ejection fraction of 28%.

Medications include ramipril, carvedilol,furosemide, aspirin, digoxin, and spirono-lactone. His condition is classified as New York Heart Association functionalclass III.

On physical examination, heart rate is62/min and blood pressure is 96/60 mm Hg.He has bibasilar crackles and jugular venous distention. A summation gallopand a 3/6 holosystolic murmur at theapex and radiating to the axilla are pres-ent. Electrocardiogram shows left bundlebranch block and first-degree atrial ven-tricular block.

Which of the following is the most appropriate next step in the managementof this patient?

A. Coronary artery bypass graftsurgery.

B. Left ventricular aneurysmectomy.C. Implantation of a cardiodefibrillator/

atrioventricular sequentialbiventricular pacemaker.

D. Mitral valve repair.E. Transmyocardial laser

revascularization.

A 72-year-old woman with a 2-year his-tory of ischemic heart disease and NYHAstage I heart failure seeks advice aboutimplantable defibrillators. One year ago, acardiac catheterization demonstratednonobstructive coronary artery diseaseand an ejection fraction of 55%. Herelectrocardiogram shows sinus rhythm at76/min with normal perfusion rate, quan-titative radioscintigraphy, and cardiacoutput intervals.

Which of the following outcomes canreasonably be expected with the use ofan implantable cardiac defibrillator inthis patient?

A. Fewer hospital admissions for heartfailure.

B. Decreased risk for acute coronarysyndrome.

C. Decreased risk for sudden cardiacdeath.

D. Decreased risk for cardiac death.E. No benefit.

Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP). Go to www.annals.org/intheclinic/ to obtain up to 1.5 CME credits, to view explanations for correct answers, or to purchase the complete MKSAP program.

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Heart Failure 2007

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