Heart Failure: Update on Therapeutic Options

Heart failure statistics are daunting:550,000 new cases each year, a 1-yearmortality rate of nearly 20%, and annualdirect and indirect costs that total $24.3billion.¹ The diverse etiology of heartfailure and the complex, progressivecourse of the disease can make treatmentdecisions daunting as well.Here I discuss current recommendationsfor heart failure management,as well as the clinical implicationsof the results of recent studies.RISK FACTORS
Among the 5143 participants inthe original Framingham Heart andOffspring studies, the most commonrisk factor for heart failure was hypertension.Of those study participants inwhom heart failure developed, 91%were hypertensive.² Among hypertensivemen and women in these studies,myocardial infarction (MI), diabetes,left ventricular hypertrophy, and valvularheart disease were cofactors thatwere associated with an increased riskof heart failure. MI was a particularlycommon cofactor in this group; 52% ofthe men with heart failure and 34% ofthe women had a history of MI.²PATHOPHYSIOLOGY
The pathophysiology of heart failureinvolves both hemodynamic andneurohormonal abnormalities, althoughthe interactions between themare incompletely understood. Survivalbenefits that result from drug-induceddecreases in neurohormonal activityunderscore the role of increased neurohormonalactivity in chronic heartfailure.Impaired left ventricular functionactivates neuroendocrine compensatorymechanisms, both vasoconstrictiveand vasodilative. The primary vasoconstrictivesystems are the sympatheticnervous system and the reninangiotensinsystem. Increased plasmalevels of norepinephrine, which reflectsympathetic nervous system activity,have been correlated directly with diseaseseverity and mortality in heartfailure.³ Activation of the renin-angiotensinsystem increases systemicvascular resistance and has also beencorrelated with disease progression.DIAGNOSIS
The history and physical findingsoften point to heart failure. Commonpresenting symptoms in patients withleft ventricular dysfunction are:

• Decreased exercise tolerance (manifestedby dyspnea).
• Fluid retention (manifested by swollenfeet).

According to the latest AmericanCollege of Cardiology and AmericanHeart Association (ACC/AHA) guidelines,the most useful diagnostic testis the 2-dimensional echocardiogram,performed in conjunction with Dopplerflow studies (

Table 1

).

³

Much interest has recently focusedon brain natriuretic peptide(BNP) as a prognostic indicator or surrogatemarker.

^4-6

This neurohormoneis secreted mainly in the cardiac ventricles.Volume expansion of the ventriclesand increased intraventricularpressure raise circulating BNP levels,which rise in proportion to diseaseseverity. The significance of this elevationdepends on the patient profile(which includes systolic function andsex); thus, assessment of left ventricularfunction is also required.

⁷

In a study of 78 ambulatory patientswith heart failure, plasma BNPlevels provided prognostic informationas accurate as that derived from thecommonly used multifactorial heartfailure survival score.

⁴

BNP levelswere the only independent predictor ofsudden death in another study population.

⁵

A more recent study found notonly that elevated BNP values correlatedwith first morbid event and mortalitybut also that percentage reductionin BNP during treatment predicteddecreased risk of first morbid eventand mortality.

⁶

When performed in conjunctionwith echocardiography, measurementof plasma BNP concentrations mayserve as a useful screening tool andthus may reduce the need for more expensiveand invasive tests.

^4,5,7

THERAPEUTIC APPROACHES

Nonpharmacologic measures.

Whether heart failure is diastolic orsystolic, management always includesnonpharmacologic measures in additionto drug therapy. Discuss dietaryrestrictions and exercise recommendationswith patients, and advise themabout when to seek medical attention.Possibly the most effective andleast employed therapy is consistent attention.Follow-up and between-visitsupervision by a nurse or physician assistanthas yielded significant clinicalbenefits in symptomatic patients.

³

Unfounded criteria for drug selection.

The use of hemodynamic functionparameters as criteria for drug selectionin heart failure therapy has beenbased on the assumption that hemodynamicimprovement will translate intosymptom relief. This has proved to bean uncertain premise.

⁸

Furthermore,the correlation between relief of symptomsand survival is also uncertain. Forexample, although it is well establishedthat diuretics reduce the need for hospitalization,these agents have no apparenteffect on survival. Thus, correctionof a patient's hemodynamic abnormalitiesmay not prevent heart failureprogression or death.

⁸

Current guidelines.

Despite theheterogeneous etiology and complexpathogenesis of heart failure, a consensusis evolving as to what constituteseffective--and ineffective--treatment.

^3,9

The ACC/AHA guidelinesclassify heart failure into 4 stages ofseverity and recommend therapy targetedto each stage (

Table 2

). (Notethat the ACC/AHA stages, whichrange from "at risk for heart failure" to"advanced heart failure," differ fromthe classes in the New York Heart Association[NYHA] grading system; thelatter are based on the functional capacityof patients with heart failure.)According to the ACC/ AHA andHeart Failure Society of America(HFSA) guidelines, 4 classes of drugsshould be given routinely to appropriatepatients with symptomatic left ventriculardysfunction: a diuretic, an angiotensin-converting enzyme (ACE)inhibitor, a β-blocker, and (usually)digoxin (

Table 3

).

^3,9

DRUG THERAPYFOR HEART FAILURE

Diuretics.

These are the mostcommonly prescribed agents for heartfailure. Diuretics are effective in patientswith diastolic or systolic dysfunction.

^3,9

They are indicated for reductionof the volume overload that is commonin congestive heart failure, particularlyin the early phase of treatment.

Digoxin.

This is the only agentthat can provide long-term inotropicsupport in men. However, digoxin significantlyincreases the risk of mortalityin women.

¹⁰

Bear in mind that the serumdigoxin concentration may not correlatewith the drug dosage in older personsor in patients with renal dysfunction.9 Moreover, upward titration ofdigoxin increases the risk of toxicity,and the beneficial effects of digoxinare not greatly enhanced at higherdosages. Additional rate control, whenneeded, can be provided by β-blockersor amiodarone.

⁹

β-Blockers.

The ability of β-blockersto improve left ventricular systolicfunction is perhaps the most compellingevidence that chronic adrenergicstimulation damages the failingheart.9 The recent Carvedilol ProspectiveRandomized Cumulative Survival(COPERNICUS) study reaffirms thevalue of this class of drugs in severeheart failure.11 Prescribe low dosagesof β-blockers initially and monitor patientsfor worsening heart failure. Aftera patient has been stable for 2 weekson a starting regimen, the dosage maybe titrated upward. These agentsshould not be abruptly withdrawn.9 Toensure safe and effective treatment,prescribe β-blockers only for patientswho:

• Are clinically stable.
• Have left ventricular systolicdysfunction.
• Have mild to moderate symptoms.
• Are receiving standard therapy.^3,9

ACE inhibitors.

Treatment withACE inhibitors was the first interventionthat was shown unequivocally toimprove symptoms and prolong lifein patients with left ventricular dysfunction.These agents counteractneurohormonal activation by lesseningthe deleterious effects of therenin-angiotensin system through inhibitionof ACE.

⁹

Evidence suggeststhat the long-term benefits of ACE in-hibitors stem mainly from their abilityto reverse some of the structuralabnormalities associated with heartfailure rather than from their hemodynamiceffects.

^3,9

Prescribe an ACEinhibitor, together with a β-blockerand a diuretic, for patients with symptomaticsystolic heart failure--unlessthese agents are contraindicated.

^3,9

Angiotensin II receptor blockers.

Data now indicate that angiotensinII type 1 receptor blockers(ARBs) may confer benefits similar tothose of ACE inhibitors in patientswith heart failure.

¹²

The hemodynamicactions of ARBs--eg, their reductionof systemic vascular resistance inheart failure--are comparable to thoseof ACE inhibitors.

^3,9

ARBs also improveexercise capacity and reducenorepinephrine levels in a manner similarto that of ACE inhibitors.

^3,9

Blockadeof angiotensin II type 1 (AT1) receptorsprevents the effects of angiotensinII--including that producedby enzymes other than ACE--and allowscirculating angiotensin II to stimulateangiotensin II type 2 (AT2) receptors.Data suggest that some benefitsof ARBs may be mediated throughthe AT

₂

receptor.

¹³

The Valsartan Heart Failure Trial(Val-HeFT) compared the ARB valsartanwith placebo in 5010 patients withNYHA class II to IV heart failure whoalso received standard therapy withACE inhibitors and/or β-blockers fora mean follow-up of 23 months.

¹²

Althoughoverall mortality was similar,the combined end point of morbidityand mortality was 13.2% lower in thevalsartan-treated group. The reductionin this combined end point resultedprimarily from the 27.5% reduction inhospitalization for heart failure seenwith valsartan.In a subgroup (7% of study participants)who did not receive an ACE inhibitor,valsartan reduced all-causemortality by 41% and hospitalization forheart failure by 57%.

¹⁴

Echocardiographyshowed that valsartan also reversedcardiac remodeling.15 Moreover,valsartan reduced BNP levels--and demonstrated for the first timethat a reduction in BNP levels duringtreatment is associated with a decreasedrisk of mortality and first morbidevent.

⁶

The data from Val-HeFTsuggest that valsartan is a practical alternativeto ACE inhibitor therapy.

¹⁶

The Losartan Intervention forEndpoint Reduction in Hypertension(LIFE) study showed that ARBs helpreduce cardiovascular morbidity andmortality. The study compared theARB losartan (plus background therapy)with atenolol (plus backgroundtherapy) in 9193 patients who had hypertensionand left ventricular hypertrophybut who did not have heart failure.

¹⁷

Losartan was associated with a13% greater reduction than atenolol inthe combined end point of cardiovasculardisease mortality, myocardial infarction(MI), and stroke.The Candesartan in Heart FailureAssessment of Reduction in Mortalityand Morbidity (CHARM) study confirmedthe benefit of ARB therapy in7599 patients, who were stratified byejection fraction (either greater than40%, or 40% or less) and by whetherthey had previously used an ACE inhibitor.

¹⁸

At a median follow-up of 38months, the adjusted risk rate (comparedwith standard care) for the primaryend point of all-cause mortalitywas 0.90 for patients who receivedcandesartan.

Aldosterone antagonists

. Increasedrenin and angiotensin II levelsstimulate the production of aldosterone,which contributes to the pathophysiologyof heart failure. Elevatedaldosterone levels enhance sodium retention,increase sympathetic activationand parasympathetic inhibition, andpromote cardiac remodeling.

³

ACE inhibitorshave been assumed to suppressaldosterone production, but increasingevidence suggests that thissuppression is only transient in somepatients. The addition of an aldosteroneantagonist such as spironolactone oreplerenone to the regimen may behelpful in such patients.

Spironolactone.

In the RandomizedAldactone Evaluation Study(RALES), patients with advanced heartfailure, normal serum potassium levels,and normal or mildly elevatedserum creatinine levels (less than 2.5mg/dL) received low-dose spironolactone(mean daily dose, 26 mg).

¹⁹

All patientsreceived diuretics, 95% receivedlow-dose ACE inhibitors (mean dailydose: captopril, 63.4 mg, or lisinopril,15.5 mg), 75% received digoxin, and11% received β-blockers. After 24months, the trial was terminated earlybecause patients assigned to spironolactonehad a 30% reduction in allcausemortality.

¹⁹

The reduction in morbidity andmortality among patients who were alreadyreceiving an ACE inhibitor suggeststhat low-dose ACE inhibitiondoes not effectively suppress aldosteroneproduction. Consider low-dosespironolactone for patients with severeheart failure caused by left ventricularsystolic dysfunction who remain symptomaticdespite optimal therapy withACE inhibitors, β-blockers, digoxin,and diuretics.20 However, a recentanalysis warns against inappropriate,indiscriminate use of spironolactone.20The patient's heart failure classification,ejection fraction, and backgroundtreatment must be considered, and adequatefollow-up must be ensured.

Eplerenone.

In the recently reportedEplerenone Post-Acute MIHeart Failure Efficacy and SurvivalStudy (EPHESUS), patients with acuteMI complicated by left ventricular dysfunctionand heart failure were randomizedwithin 3 to 14 days of hospitalizationto additional therapy witheplerenone, 50 mg/d, or placebo.21 Patientswith elevated serum creatinineclearance (greater than 2.5 mg/dL) orelevated serum potassium levels(greater than 5 mmol/L) were excludedfrom the study. The majority of patientswere receiving standard therapy:ACE inhibitors or ARBs (87%),β-blockers (75%), aspirin (88%), and diuretics(60%). After a mean 16-monthfollow-up, all-cause mortality decreasedby 15% in the eplerenonegroup. There was also a 13% reductionin death or hospitalization caused bycardiovascular disease. The reductionin cardiovascular disease mortality wasin large part the result of a 21% reductionin the rate of sudden cardiacdeath.Because of an increased incidenceof serious hyperkalemia in study participants(who had been prescreenedfor elevated potassium levels), the investigatorsrecommended monitoringserum potassium levels in patientsbeing treated with eplerenone.

²¹

HEART FAILURE THERAPYIN SPECIAL POPULATIONS

Very old patients.

More than 80%of the 1 million patients hospitalizedeach year for heart failure are 65 yearsof age or older, and more than 50% are75 years or older.

²²

Several studieshave found nearly half of their heartfailure cohort are 80 years or older.22Advanced age complicates therapeuticdecisions in several ways.First, clinical trial data in very oldpatients are lacking. Despite theirheavy representation in the populationwith heart failure, older persons areunderrepresented in clinical trials ofnew treatments; when included, thesepatients are likely to be lumped togetherin a homogeneous "over 65"group.

²³

This overly broad category isproblematic because the commonmanifestations of heart failure varywith age and sex.

³

For example, diastolicheart failure becomes increasinglycommon with advanced age, particularlyin women.

^3,22

Exclusion criteria used in clinicaltrials may further distort the study oftherapy in older patients by eliminatingcharacteristic comorbidities. In a nationalsample of Medicare patients,more than 55% of those with heart failurehad a history of coronary disease,almost 40% had diabetes, and about33% had chronic obstructive pulmonarydisease; 10% had been admittedto the hospital from long-term carefacilities.

²²

Furthermore, several normal aspectsof the aging process complicatemanagement. The glomerular filtrationrate declines with age and doesso more rapidly among patients withheart failure. Consequently, a creatininecutoff value that defines renal insufficiencyfor a specific medicationmay be inappropriately high for olderpersons. The effects of standard treatmentsat recommended dosages inolder patients may differ from their effectsin younger patients.Comorbid conditions can alsocomplicate heart failure therapy inolder patients. Conditions that requiremedication increase the potential foradverse drug interactions.

²²

Moreover,the additional medications may have anegative impact on a patient's heartfailure. Conversely, a comorbid conditionthat is not managed aggressivelyenough can also complicate heart failuretherapy.

Patients with diastolic dysfunction.

Among heart failure patients, 20%to 40% have preserved left ventricularfunction. For patients with systolic dysfunction,the value of various agentshas been established in large-scale clinicaltrials. However, for those with diastolicdysfunction, large-scale trial dataare lacking.

^3,24

Current pharmacologictreatment recommendations for patientswith diastolic dysfunction arebased on control of blood pressure andtachycardia, relief of myocardial ischemia,and blood-volume reduction.Treatment may include agents used forsystolic dysfunction as well as calciumchannel blockers and nitrates.

²⁴

References:

REFERENCES:

1.

American Heart Association. Heart Disease andStroke Statistics: 2003 Update. Dallas: American HeartAssociation; 2002.

2.

Levy D, Larson MG, Vasan RS, et al. The progressionfrom hypertension to congestive heart failure.JAMA. 1996;275:1557-1562.

3.

Hunt SA, Baker DW, Chin MH, et al. ACC/AHAguidelines 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 stratificationof patients with congestive heart failure. J Am CollCardiol. 2001;38:1934-1941.

5.

Berger R, Huelsman M, Strecker K, et al. B-typenatriuretic peptide predicts sudden death in patientswith chronic heart failure. Circulation. 2002;105:2392-2397.

6.

Anand IS, Fisher LD, Chiang YT, et al, for theVal-HeFT Investigators. Changes in brain natriureticpeptide and norepinephrine over time and mortalityand morbidity in the Valsartan Heart Failure Trial(Val-HeFT). Circulation. 2003;107:1278-1283.

7.

Maisel AS, McCord J, Nowak RM, et al, for theBreathing Not Properly Multinational Study Investigators.Bedside B-type natriuretic peptide in theemergency diagnosis of heart failure with reducedor preserved ejection fraction. J Am Coll Cardiol.2003;41:2010-2017.

8.

Anand IS, Florea VG, Fisher L. Surrogate endpoints in heart failure. J Am Coll Cardiol. 2002;39:1414-1421.

9.

Heart Failure Society of America (HFSA) PracticeGuidelines. HFSA guidelines for managementof patients with heart failure caused by left ventricularsystolic dysfunction-pharmacological approaches.Pharmacotherapy. 2000;20:495-522.

10.

Rathore SS, Wang Y, Krumholz HM. Sex-baseddifferences in the effect of digoxin for the treatmentof heart failure. N Engl J Med. 2002;347:1403-1411.

11.

Krum H, Roecker EB, Mohacsa P, et al, CarvedilolProspective Randomized Cumulative Survival(COPERNICUS) Study Group. Effects of initiatingcarvedilol 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 HeartFailure Trial Investigators. A randomized trial of theangiotensin-receptor blocker valsartan in chronicheart failure. N Engl J Med. 2001;345:1667-1675.

13.

de Gasparo M, Levens N. Does blockade of angiotensinII receptors offer clinical benefits over inhibitionof angiotensin-converting enzyme? PharmacolToxicol. 1998;82:257-271.

14.

Diovan [package insert]. East Hanover, NJ:Novartis Pharmaceuticals Corp; 2002.

15.

Wong M, Staszewsky L, Latini R, et al. Valsartanbenefits left ventricular structure and function inheart failure: Val-HeFT echocardiographic study.J Am Coll Cardiol. 2002;40:970-975.

16.

Maggioni AP, Anand I, Gottlieb SO, et al. Effectsof valsartan on morbidity and mortality in patientswith heart failure not receiving angiotensin-convertingenzyme inhibitors. J Am Coll Cardiol. 2002;40:1414-1421.

17.

Dahlof B, Devereau RB, Kjeldsen SE, et al, forthe LIFE Study Group. Cardiovascular morbidityand mortality in the Losartan Intervention For Endpointreduction in hypertension study (LIFE): a randomisedtrial against atenolol. Lancet. 2002;359:995-1003.

18.

Pfeffer MA, Swedberg K, Granger CB, et al, forthe CHARM Investigators and Committees. Effectsof candesartan on mortality and morbidity in patientswith chronic heart failure: the CHARM-Overallprogramme. Lancet. 2003;362:759-766.

19.

Pitt B, Zannad F, Remme WJ, et al, for the RandomizedAldactone Evaluation Study Investigators.The effect of spironolactone on morbidity and mortalityin patients with severe heart failure. N Engl JMed. 1999;341:709-717.

20.

Bozkurt B, Agoston I, Knowlton AA. Complicationsof inappropriate use of spironolactone in heartfailure: when an old medicine spirals out of newguidelines. J Am Coll Cardiol. 2003;41:211-214.

21.

Pitt B, Remme W, Zannad F, et al. Eplerenone,a selective aldosterone blocker, in patients with leftventricular 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. Representationof the elderly, women, and minorities in heartfailure clinical trials. Arch Intern Med. 2002;162:1682-1688.

24.

Zile MR, Brutsaert DL. New concepts in diastolicdysfunction and diastolic heart failure, II:causal mechanisms and treatment. Circulation.2002;105:1503-1508.