heart failure

CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 70 NUMBER 2 FEBRUARY 2003 141

Improving care of chronic heart failure:Advances from drugs to devices

RANDALL C. STARLING, MD, MPH*Section of Heart Failure and Cardiac Transplant Medicine, Kaufman Centerfor Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic

ABSTRACTThe right combination of drugs andsurgical treatment can improve systolicfunction and prevent, attenuate, orreverse heart failure. Patient educationand disease management programs canreduce hospitalizations. Optimaltreatment for each patient is guided by athorough evaluation and use of functionalclassification and disease staging systems.

48-YEAR-OLD WOMAN is referred to uswith dyspnea on exertion after climbing

one flight of stairs. More than a year earlier,she had been treated in a hospital emergencydepartment and found to have an ejectionfraction of 15% to 20% and 4+ mitral regurgi-tation. After a catheterization found her coro-nary arteries to be normal, she was placed onquinapril and a diuretic.

As we began treating her, she was referredfor evaluation for transplantation and consid-eration for biventricular pacing or mitralvalve repair. However, she was not taking abeta-blocker, so we started her on a low dose(3.125 mg) of carvedilol. We also referred herto a nurse practitionerheart failure specialistfor education, disease management, and titra-tion of the carvedilol.

Six months later, she had reached her tar-get dose of carvedilol of 25 mg twice daily. Sheremained on quinapril and the diuretic, andhad also started spironolactone. She requiredneither a transplant nor mitral repair.

In fact, her ejection fraction hadimproved to 50%, and the dimension of herleft ventricle had decreased, from 6.3 cm to4.7 cm. The mitral regurgitation had van-ished.

PROGRESS IN HEART FAILURE

The marked improvement in this womansheart failure is not an isolated case. We seethis often in patients who are treated aggres-sively with medical therapy.

Medical therapy, notably the use of beta-blockers, has revolutionized the care of heartfailure patients. In addition, patient educationand disease management programs can helpreduce the frequent and expensive hospital-izations of heart failure patients.

Even those patients with more advancedheart failure have a variety of surgical and deviceoptions that were not available in the past.

Still, all these new options raise a numberof difficult issues. Given the growingpolypharmacy, what is the optimal drug ther-apy for which patients? How can the growinghealthcare costs be controlled? And how willthe many new devices fit into the therapeuticoptions for patients?

DRUG THERAPY IS GUIDEDBY FUNCTIONAL CLASS

The choice of drugs in the treatment of heartfailure can be guided by the New York HeartAssociation (NYHA) functional class (TABLE1).1 Recently, the American College of

A

MEDICAL GRAND ROUNDS TAKE-HOMEPOINTS FROM

LECTURES BY

CLEVELAND CLINIC

AND VISITING

FACULTY

*The author has indicated that he has received grant or research supportfrom Acorn Cardiovascular corporation, and is a consultant for Novartis.This paper discusses therapies that are experimental or not approved bythe US Food and Drug Administration for the use under discussion.Medical Grand Rounds articles are based on edited transcripts fromDivision of Medicine Grand Rounds presentations at The Cleveland Clinic.They are approved by the authors but are not peer-reviewed.

Beta-blockershaverevolutionizedheart failuretreatment

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Cleveland Clinic Journal of Medicine

142 CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 70 NUMBER 2 FEBRUARY 2003

Cardiology (ACC) devised another classifica-tion system, also with four stages, to emphasizethe idea of considering heart failure before itoccurs in patients with hypertension, diabetes,and coronary artery disease. (TABLE 2).2

Most patients with heart failure receive anangiotensin-converting enzyme (ACE)inhibitor, a beta-blocker, a diuretic, and digox-in. Evidence suggests that angiotensin IIreceptor blockers (ARBs) convey no survivalbenefit over ACE inhibitors. Therefore, ARBsare recommended for use only in patients whocannot tolerate ACE inhibitors because ofangioedema or intractable cough.3,4

Give ACE inhibitors almost always:High or low dose is the questionAs demonstrated in more than 7,000 patientsin more than 30 placebo-controlled trials,ACE inhibitors alleviate symptoms, improvefunctional class, and decrease risk of death and

the combined risk of death or hospitalization.These drugs are now recommended forpatients in all functional classes of heart fail-ure unless the patient cannot tolerate them orthis class of drugs is otherwise contraindicated.

The Studies of Left VentricularDysfunction (SOLVD) prevention trial5showed that ACE inhibitors may prevent dis-ease progression. They should be used even inpatients with structural heart disease but nosymptoms; patients with symptoms shouldcontinue to take ACE inhibitors even if theydo not achieve complete relief.

The optimal dosage remains contentious.The Assessment of Treatment with Lisinopriland Survival (ATLAS) trial6 showed that,compared with low doses, high doses of thesedrugs do not reduce the mortality rate but aremore effective at reducing hospitalizations andslowing progression of heart failure. However,common sense suggests that modest doses may

HEART FAILURE STARLING

ARBs have notprovensuperiorto ACEinhibitors

General guidelines for use of drugsin each New York Heart Association functional class

Class I Angiotensin-converting enzyme (ACE) inhibitor

Class II ACE inhibitor, beta-blocker, diuretic

Class III ACE inhibitor, beta-blocker, spironolactone,* digoxin, diuretic

Class IV ACE inhibitor, beta-blocker, spironolactone,* digoxin, diuretic

*Spironolactone should be reserved for those with severe heart failure who remain symptomaticdespite standard therapy with an ACE inhibitor, a beta-blocker, digoxin, and a diuretic, or those withhypokalemia and an intolerance for potassium supplements.

T A B L E 1

T A B L E 2


be appropriate in patients who are receivingincreasing doses of additional important med-ications (eg, beta-blockers) that can haveantihypertensive effects.

ACE inhibitors plus spironolactonein severe heart failureThe Randomized Aldactone Evaluation Study(RALES)7 fueled interest in using the combi-nation of an ACE inhibitor and spironolac-tone. In this study of 1,663 patients, the addi-tion of spironolactone reduced the mortalityrate by 30%. However, it is important toobserve several points: Enrollment in the study was completedbefore beta-blockers were in common use forheart failure; only 18% of the patients in thestudy were receiving them. The study included patients with severeheart failure; 72% were in NYHA class III and27% were in NYHA class IV. Patients with elevated levels of creatinineand potassium were excluded. The target dose of spironolactone was low.This dose was derived from a pilot study,which determined that only a low dose wasneeded to achieve an advantageous sodiumbalance.

This study generated no evidence thatspironolactone is advantageous in patientswith NYHA class I or II heart failure. Thus,spironolactone should be reserved for thosewith severe heart failure who still have symp-toms despite standard therapy with an ACEinhibitor, a beta-blocker, digoxin, and adiuretic, or those with hypokalemia who can-not tolerate potassium supplements.

ACE inhibitor plus an ARB?The Valsartan in Heart Failure (Val-HeFT)study,8 in 5,010 patients with moderate tosevere heart failure, showed that the additionof the ARB valsartan to standard therapyreduced the combined end point of all-causemortality, hospitalizations for heart failure,cardiac arrest or resuscitation, or intravenousinotropic or vasodilator therapy by 13.3%.Furthermore, treatment with valsartan alsoresulted in improvement in NYHA functionalclass, ejection fraction, and quality of life.

However, valsartan did not decrease themortality rate, and post hoc analysis showed

that valsartan had an adverse effect in thosereceiving both an ACE inhibitor and a beta-blocker.

This finding has led to the consensus thatthe combination of an ACE inhibitor, an ARB,and a beta-blocker should not be used becauseit produces too much neurohormonal blockade.It also led the Cardiorenal Advisory Board ofthe US Food and Drug Administration (FDA)to require a warning on valsartan packagingthat, while it is approved for treatment of heartfailure in patients who cannot tolerate ACEinhibitors, it should not be used in combinationwith both ACE inhibitors and beta-blockers.

Other studies now in progress areexpected to yield more information on usinga combination of these drugs and on theireffect on remodeling after myocardial infarc-tion (MI).

Beta-blockers:A true revolution in heart failure careBeta-blockers have revolutionized the care ofpatients with heart failure and represent oneof the most exciting advances in the last 15years. They reduce total mortality and slowleft ventricular remodeling, improve ejectionfractions by 8 to 10 units, and reduce the sizeof the heart. Studies of more than 10,000patients in more than 20 placebo-controlledtrials strongly support the use of carvedilol,bisoprolol, or metoprolol in nearly all patientswith NYHA class II or III heart failure.

What about class IV? Although currentguidelines suggest that patients with NYHAclass IV failure should not receive a beta-blocker, the Carvedilol Prospective Random-ized Cumulative Survival (COPERNICUS)study,9 with 2,289 patients, showed thatcarvedilol reduced the mortality rate by 35%compared with placebo, even in patients withsevere heart failure.

The only patients in whom beta-blockershave not been studied are those with NYHAclass I failure; a large trial is planned to addressthat group.

Which beta-blocker to use remains con-troversial.10 Metoprolol and carvedilol are theonly ones approved for this indication, andcarvedilol is thought to be ideal because it is anonselective vasodilator with antioxidant andantiendothelin properties.

An ARBshould notbe added toan ACE inhibitorplus a beta-blocker

The best candidates for beta-blockers arestable with mild to moderate heart failureand optimal fluid status. It is important thatthe drugs be initiated at a low dose and slow-ly and carefully adjusted upward every 2 to 4weeks.

SURGICAL AND MECHANICALINTERVENTIONS

Beta-blockers and biventricular pacing werenot part of our routine clinical armamentari-um until recently. Many patients with heartfailure had no options beyond cardiac trans-plantation. And the waiting list for cardiactransplantation is expanding, while the num-ber of heart transplants performed in theUnited States has plateaued.

Experience with partial left ventriculec-tomy (the Batista procedure) spawnedtremendous interest in new surgical proce-dures for the treatment of heart failure.11 Inaddition, the recognition that wall stress andsphericity could be altered surgically andwould impact future structural and biologicalchanges generated further interest and thedevelopment of therapies. A growing body ofevidence in both animals and humans indi-cates that surgically deployed devices canchange the structure and the biology of theventricle.

Contemporary medical therapy is highlyeffective and must be given before and aftersurgical treatments. Beta-blockers and ACEinhibitors can independently promotereverse remodeling (improved ejection frac-tion and reduced chamber dimensions).Also, new-onset cardiomyopathy should beeffectively treated medically and the patientobserved before surgical therapy is consid-ered, as marked improvement in ventricularperformance and anatomy often canoccur.12

The goal today is to avoid or delay cardiactransplantation whenever feasible, as its limi-tations are well recognized. If a surgical proce-dure can improve quality of life and delay theneed for cardiac transplantation, it should beundertaken. Patients can live many years withabnormal ventricles after surgical optimizationin conjunction with contemporary medicaland device therapy.

Biventricular pacingBiventricular pacing is a good option forpatients who are receiving optimal drug ther-apy but remain symptomatically impaired withleft bundle branch block. This method,approved by the FDA in 2001, is safe and welltolerated. It also improves quality of life, func-tional class, exercise capacity, and structureand function of the heart.13

This technique is meant to correct inter-ventricular conduction delays in patients withleft bundle branch block that lead to abnor-mal filling patterns of both ventricles.Resynchronization of the filling of both ven-tricles shortens the QRS duration.

The procedure consists of placing a stan-dard pacemaker with an additional third pace-maker lead via the coronary sinus to the later-al wall of the left ventricle to control when itis activated and bring the other side of the leftventricle into synchrony.

The Cleveland Clinic has been veryinvolved in clinical trials of this technology.The 6-month Multicenter InSync RandomizedClinical Evaluation (MIRACLE) trial14recruited patients with advanced heart failure,a widened QRS complex, reduced ejectionfraction, and cardiomegaly. Patients in thisstudy had been receiving stable medical thera-py and a beta-blocker for more than 3 monthsbefore they were randomly assigned to thetherapy or the control group; this precautionruled out any improvement due to medicaltherapy.

The 6-minute walk time, oxygen con-sumption, and total exercise timeimproved in patients who received biven-tricular pacing, as did the quality of life asassessed by the Minnesota Living withHeart Failure Questionnaire. NYHA func-tional class also improved; 90% of thepatients had been in class III at the begin-ning of the study, and 52% were reassignedto class II at the end.

Data also suggested a tendency towardreduction of the size of the left ventricle anddiastolic diameter. An increase in the ejectionfraction was observed, although it was not sta-tistically significant.14

More trials are examining pairing biven-tricular pacing with an implantable cardiacdefibrillator.


Beta-blockershave not yetbeen testedin class Iheart failure


Left ventricular assist devicesLeft ventricular assist devices (LVADs)achieved favorable results in the RandomizedEvaluation of Mechanical Assistance for theTreatment of Congestive Heart Failure(REMATCH).15 The patients, most of whomrequired inotropic therapy and were not can-didates for cardiac transplantation, were giveneither a LVAD or medical therapy and fol-lowed for 2 years.

The LVAD reduced death from any causeby 48%. The survival rate at 1 year was 52%with the LVAD vs 25% with medical therapy;at 2 years, it was 23% vs 8%. This statistictranslates into 270 deaths prevented per 1,000patients; in contrast, about 70 lives per 1,000are saved each year with ACE inhibitors orbeta-blockers.

Infection and device mechanical failurewere major factors in the poor 2-year survivalrate. The rate of neurologic events was 4.35times as great in the LVAD group, but 76% ofpatients were free of serious neurologic eventswithout routine anticoagulation.

In November 2002, the FDA approvedthe use of the Thoratec HeartMate LVAD forpatients with severe end-stage heart failue(NYHA class IV/ACC stage D) who are onoptimized medical therapy, are not eligiblefor heart transplantation, and have an antic-ipated life expectancy of less than 2 years.The Novacor LVAD, the AbioCor total artifi-cial heart, and the Jarvik 2000 are currentlyundergoing clinical trials.

Cardiac support deviceThe Acorn Cardiac Support Device, a meshdevice sewn on the surface of the heart, hasbeen shown in animal and human studies toprovide diastolic support, reduce wall stress,and allow recovery of ventricular function,leading to higher ejection fractions and aslight reduction in the size of the heart.16NYHA functional class improves. The devicecan adhere to the surface of the heart withoutcausing fibrosis.

The Cleveland Clinic is involved in a mul-ticenter randomized study to determine the effi-cacy of this device in patients with advancedheart failure that is symptomatic despite excel-lent medical treatment. Recruitment for thissurgical trial is expected to end in early 2003.

MyosplintThe Myocor Myosplint changes the shape ofthe left ventricle, leading to improved ven-tricular function. It has been shown in animalstudies to improve the structure of the heartand to reduce wall stress.17 Clinical trials ofthis device are under way in the United Statesand Europe.

Dor procedureAfter an MI, regions of the heart not involvedin the MI become dysfunctional due tochanges in the chamber dimensions, resultingin increased wall stress. Vincent Dor, a cardio-vascular surgeon, showed that removal of thescarred regions improved the areas of theheart that were not involved in the MI.

Endoventricular patch plasty, alsoknown as ventricular restoration and the Dorprocedure, has been performed at TheCleveland Clinic in more than 250 patientswith anterior MI and adverse remodeling.Performed during a bypass procedure, the Dorprocedure consists of suturing the areabetween normal muscle and scar tissue toexclude the area of dysfunctional chamber(infarct exclusion surgery) where blood hadbeen merely swirling around.18 The result is amore muscular cavity without the bulgingarea of scar tissue.

The Dor procedure appears to alter thenatural history of readmissions for heart fail-ure, improve functional class, and result inlong-lasting improved structure of the heart.The National Institutes of Health has justapproved the $40 million Surgical Treatmentfor Ischemic Heart Failure (STITCH) study,which will be conducted at centers around thecountry and is designed to determine theadded benefit of ventricular restoration vscoronary artery bypass alone.

KEEPING PATIENTSOUT OF THE HOSPITAL

The hospital readmission rate for patientswith heart failure is dismal, with 30% to 40%of patients returning to the hospital within 90days. Patient education and disease manage-ment programs can reduce that readmissionrate and improve patients quality of life.Studies have shown that patients who were


Mechanical andsurgicaltreatments canimprove thestructure andbiology of theventricle

REFERENCES1. The Task Force on Heart Failure of the European

Society of Cardiology. Guidelines for the diagnosis ofheart failure. Eur Heart J 1995; 16:741751.

2. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guide-lines for the evaluation and management of chronicheart failure in the adult: executive summary. A reportof the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines(Committee to revise the 1995 Guidelines for theEvaluation and Management of Heart Failure). J AmColl Cardiol 2001; 38:21012113.

3. Heart Failure Society of America (HFSA) practice guide-lines. HFSA guidelines for management of patientswith heart failure caused by left ventricular systolic dys-functionpharmacological approaches. J Card Fail1999; 5:357382.

4. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losar-tan compared with captopril on mortality in patientswith symptomatic heart failure: randomized trialtheLosartan Heart Failure Survival Study ELITE II. Lancet2000; 355:15821587.

5. Konstam MA, Kronenberg MW, Rousseau MF, et al.Effects of the angiotensin-converting enzyme inhibitorenalapril on the long-term progression of left ventricu-lar dilatation in patients with asymptomatic systolicdysfunction. SOLVD (Studies of Left VentricularDysfunction) Investigators. Circulation 1993;88:22772283.

6. Sculpher MJ, Poole L, Cleland J, et al. Low doses vs.high doses of the angiotensin-converting inhibitorlisinopril in chronic heart failure: a cost-effectivenessanalysis based on the Assessment of Treatment withLisinopril and Survival (ATLAS) study. The ATLAS StudyGroup. Eur J Heart Fail 2000; 4:447454.

7. Pitt B, Zannad F, Remme WJ, et al. The effect ofspironolactone on morbidity and mortality in patientswith severe heart failure. Randomized AldactoneEvaluation Study Investigators. N Engl J Med 1999;341:709717.

8. Cohn JN, Tognoni G. A randomized trial of theangiotensin-receptor blocker valsartan in chronic heartfailure. N Engl J Med 2001; 345:16671675.

9. Packer M, Coats AJS, Fowler MB, et al for theCarvedilol Prospective Randomized CumulativeSurvival Study Group. Effect of carvedilol on survival insevere chronic heart failure. N Engl J Med 2001;344:16511658.

10. Kukin ML. Are all -blockers the same for heart failure?Congest Heart Fail 2000; 6:153157.

11. Starling RC, McCarthy PM, Buda T, et al. Results of par-tial left ventriculectomy for dilated cardiomyopathy:

hemodynamic, clinical and echocardiographic observa-tions. J Am Coll Cardiol 2000; 36:20982103.

12. McNamara DM, Holubkov R, Starling RC, et al.Controlled trial of intravenous immune globulin inrecent-onset dilated cardiomyopathy. Circulation 2001;103:22542259.

13. Cazeau S, LeClercq C, Lavergne T, et al. Effects of multi-site biventricular pacing in patients with heart failureand intraventricular conduction delay. N Engl J Med2001; 344:873880.

14. Abraham WT, Fisher WG, Smith AL, et al for the MIRA-CLE Study Group. Cardiac resynchronization in chronicheart failure. N Engl J Med 2002; 346:18451853.

15. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-termmechanical left ventricular assistance for end-stageheart failure. N Engl J Med 2001; 345:14351443.

16. Konertz WF, Shapland JE, Hotz H, et al. Passive contain-ment and reverse remodeling by a novel textile cardiacsupport device. Circulation 2001; 104(suppl 1):I-270I-275.

17. McCarthy PM, Takagaki M, Ochiai Y, et al. Device-basedchange in left ventricular shape: a new concept for thetreatment of dilated cardiomyopathy. J ThoracCardiovasc Surg 2001; 122:483490.

18. Athanasuleas CL, Stanley AW Jr, Buckberg GD, et al.Surgical anterior ventricular endocardial restoration(SAVER) in the dilated remodeled ventricle after anteri-or myocardial infarction. RESTORE group.Reconstructive Endoventricular Surgery returningTorsion Original Radius Elliptical Shape to the LV. J AmColl Cardiol 2001; 37:11991209.

19. Rich MW, Beckham V, Wittenberg C, Leven CL,Freedland KE, Carney RM. A multidisciplinary interven-tion to prevent the readmission of elderly patients withcongestive heart failure. N Engl J Med 1995;333:11901195.

20. West JA, Miller NH, Parker KM, et al. A comprehensivemanagement system for heart failure improves clinicaloutcomes and reduces medical resource utilization. AmJ Cardiol 1997; 79:5863.

21. Fonarow GC, Stevenson LW, Walden J, et al. Impact ofa comprehensive heart failure management programon hospital readmission and functional status ofpatients with advanced heart failure. J Am Coll Cardiol1997; 30:725732.

22. Krumholz HM, Amatruda J, Smith GL, et al.Randomized trial of an education and support inter-vention to prevent readmission of patients with heartfailure. J Am Coll Cardiol 2002; 39:8389.

ADDRESS: Randall C. Starling, MD, MPH, Department ofCardiovascular Medicine, F25, The Cleveland ClinicFoundation, 9500 Euclid Avenue, Cleveland, OH 44195.


educated about their condition and givenrapid access to a health care provider if theirsymptoms changed were 60% to 80% less like-ly to go back into the hospital.1922

In such programs, typically run by nurseclinicians, patients are instructed how tomaintain fluid balance by restricting sodium,weighing themselves daily, and adjustingdiuretic doses. They are also educated aboutthe symptoms and signs of heart failure pro-gression and the need to continue medica-tion even when they have no symptoms. An

education program recently was started at TheCleveland Clinic; although no data have beenpublished, initial results have been encourag-ing.

In conclusion, successful treatment ofheart failure requires specialized expertise indiagnosis and management and a multidisci-plinary approach to patient education and fol-low-up. Utilization of the latest heart failureguidelines results in improved quality of lifeand survival that was unobtainable just a fewyears ago.


Patienteducation anddiseasemanagementcan reducehospitalreadmissionrates

heart failure

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