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opulations for CRT devicesmaar Ujeyl, MD, Lynne Warner Stevenson, MD*

rom II. Medizinische Abteilung, Asklepios Klinik St. Georg, Hamburg, Germany, and *Advanced Heart Disease

rogram, Brigham and Women’s Hospital, Boston Massachusetts.

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pidemiology of heart failurehe increasing prevalence of chronic heart failure reflects

he improved survival after acute myocardial infarction, thempact of recommended heart failure therapies to decreasearly mortality, and the growing elderly population. Heartailure currently affects 2% to 2.5% of adults in the Unitedtates, the United Kingdom, and Western countries. In thenited States, approximately two thirds of patients witheart failure are older than 65 years, accounting for 13% ofll Medicare beneficiaries, 24% of all Medicare hospitalischarges, and 37% of all Medicare spending in 2005.

Regardless of left ventricular ejection fraction, the clin-cal syndrome of heart failure typically is characterized byhronic exertional intolerance punctuated by episodic fluidetention. During episodes of decompensation, symptomsan include immediate dyspnea with light exertion, orthop-ea, peripheral edema, and gastrointestinal discomfort. Al-hough the focus often has been on decreased contractility ineart failure, it is increasingly recognized that half of heartailure hospitalizations for this syndrome occur in patientsith higher ejection fraction, variably defined as greater

han 40% or, in some cases, greater than 50% to 55%Figure 1). Such patients often are older women with arequent history of hypertension, diabetes, and obesity.eart failure with ejection fraction greater than 40% haseen called heart failure with preserved ejection fractionnd “diastolic dysfunction,” although the necessary andufficient echocardiographic criteria for the latter remainomewhat controversial, in part because they frequentlyccompany heart failure with reduced ejection fraction.

Most therapies for heart failure, including approved de-ices, have been designed and investigated for heart failureith low left ventricular ejection fraction, defined as less

han 30% to 40%. The most commonly identified cause ofeduced ejection fraction is coronary artery disease, with aide spectrum of other causes including genetic (“familial”)

EYWORDS Heart failure; Cardiac resynchronization therapy (Hearthythm 2009;6:1373–1377)

Dr. Stevenson is a consultant for and receives research support fromedtronic, Inc., and CardioMEMS. Address reprint requests and cor-

espondence: Dr. Amaar Ujeyl, Asklepios Klinik St. Georg, II. Mediz-nische Abteilung, Lohmohlenstrasse 5, 20099 Hamburg, Germany. E-mail

tddress: amaar_ujeyl@web.de.

547-5271/$ -see front matter © 2009 Heart Rhythm Society. All rights reserved

ardiomyopathy, primary valve disease, alcohol or otheroxic exposure, presumed previous myocarditis, and thearge residual category of “idiopathic.” Multiple levels ofathophysiology have been implicated in the progression ofeart failure with reduced ejection fraction. The renin-an-iotensin-aldosterone axis and components of the adrener-ic nervous system are activated both locally within theeart and systemically. Molecular responses to initial andngoing stresses within the heart trigger and are triggeredy structural “remodeling.” Abnormal calcium movementnd sequestration within the cell impair contraction/relax-tion and facilitate spontaneous afterdepolarizations. Fibro-is and altered collagen scaffolding affect compliance, con-ribute to regional excitation–contraction heterogeneity, andreate pathways for reentrant arrhythmias. As the left ven-ricle dilates with decreased contractility, dynamic mitralegurgitation develops, left atrial and pulmonary venousressures increase, and secondary right ventricular failureith tricuspid regurgitation limits exercise, nutrition, and

enal function.

tages versus symptom classes of heartailurehe four stages of heart failure progression linked to goalsf therapy have been defined largely in terms of heart failureith reduced ejection fraction. Progression in stages occurs

n only one direction, regardless of possible improvement inymptoms. Stage A is the presence of risk factors such asypertension, diabetes, or previous chemotherapy, withoutetectable cardiovascular disease. Stage B is objective evi-ence of abnormal cardiac structure/function, most often arevious myocardial infarction or decreased left ventricularjection fraction, without apparent heart failure symptoms.n this stage, the focus of therapy is on prevention of diseaserogression by interrupting molecular and structuralhanges that lead to further ventricular dilation and dys-unction, and the prevention of unexpected fatal tachyar-hythmias in patients who have substantial risk of suddeneath despite absence of symptoms.

Stage C includes most patients who have been diagnosedith heart failure. There is no returning back to stage B oncepatient has ever had clinical symptoms of heart failure,hich can encompass New York Heart Association class I

o IV symptom severity at any given time. For stage C

. doi:10.1016/j.hrthm.2009.04.011

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1374 Heart Rhythm, Vol 6, No 9, September 2009

atients who responded to therapy and currently have fewymptoms, the focus is on stabilization and prevention ofisease progression and sudden death, as for stage B. Fortage C patients who have more advanced heart failureymptoms that limit daily life (class III or IV), a major focuss on relieving symptoms and increasing daily activity.tage D defines patients with refractory or frequently recur-ent class IV symptoms despite repeated attempts to adjustecommended therapies. Even within this group there arearying degrees of severity. “Ambulatory” patients withecurrent but not persistent symptoms may benefit fromnterventions that not only relieve symptoms but can stillmpact on disease progression.

Prognosis is likely to be poor regardless of choice ofherapy for patients who continue to have symptoms at rest,ho demonstrate deteriorating renal function or symptom-

tic hypotension, who are no longer able to tolerate neuro-ormonal antagonist therapy, or who require frequent intra-enous therapy for hemodynamic support.1 Right ventricularysfunction, which worsens with disease progression, predictsorse prognosis overall and has been associated with aecreased chance of clinical benefit with cardiac resynchro-ization therapy (CRT). After referring a small minority foronsideration of cardiac transplantation or mechanical cir-ulatory support, management of Stage D patients shouldocus on determining patient priorities and preferences toaximize the value of a limited remaining survival time.

enefit of CRTn the background of recommended medical therapies,enefit from CRT to improve symptoms and objective func-ional capacity is anticipated in 64% with prolonged QRSnd heart failure symptoms limiting daily life (average Min-esota Living with Heart Failure score 59 [from MIRACLEMulticenter InSync Randomized Clinical Evaluation)]).2

he clinical impact on hospitalizations was suggested by thenitial trials and confirmed by the larger COMPANIONComparison of Medical Therapy, Pacing and Defibrillationn Chronic Heart Failure) trial, with 19% reduction.3 The

igure 1 Epidemiology of heart failure. Distribution of left ventricularjection fraction (LVEF) and proportions of functional class in patientsith heart failure diagnosis. NYHA � New York Heart Association.

rend for prolonged survival from CRT in these trials was d

ubsequently proven in the patients carefully selected forhe CARE-HF (Cardiac Resynchronization-Heart Failure)rial.4

The initial clinical benefits have been demonstrated inatients with class III or ambulatory class IV symptoms.nlike most therapies for heart failure, the rapidity andagnitude of improvement of CRT often is clearly evident

o the patient and family within the first weeks after therocedure, although full measured improvement may takeonths. An early clinical sign of improvement often is an

ncrease in systolic blood pressure, which allows intensifi-ation of therapy with neurohormonal antagonists. Diureticoses frequently can be decreased. Improved functionalapacity is generally accompanied by reductions in leftentricular size and mitral regurgitation and by increases ineft ventricular ejection fraction.

The duration of benefit after the first 2 years has not beenystematically reported. Some late failures result from leadislodgment. Clinical experience encompasses patientshose benefit persists for 5 years or longer. Some of theost dramatic cases are ambulatory transplant candidatesith remarkable improvements in ejection fraction and clin-

cal function who have left the transplant waiting list andtill have good quality of life with their native hearts.

More recent data from the REVERSE (REsynchroniza-ion reVErses Remodeling in Systolic left vEntricular dys-unction)-HF5 trial indicate that patients who currently haveew or no current symptoms can experience longer-termRT benefits of reduction in left ventricular dilation and

mproved ejection fraction. For these patients in earliertages of disease, hospitalization rates are low and the fullmpact of CRT may not be evident until longer follow-up.

opulations to consider for CRTRS duration remains the primary descriptor of patients

onsidered for CRT. The length of the QRS increases withisease severity and predicts higher mortality, more com-only from pump failure than sudden death. QRS duration

oes not correlate reliably with echocardiographic measuresf dyssynchrony, and QRS shortening does not correlateeliably with clinical improvement after CRT. However,ther measures of dyssynchrony that appeared promisinghen performed meticulously in single centers have not

hus far proven useful in trial populations.The standard for consideration of CRT is QRS dura-

ion �120 ms, but enthusiasm is higher for patients withRS �150 ms.6 Although most trials have included as the

ower limit a QRS of 120 to 130 ms, the majority of patientsntered in all major trials had QRS duration �150 ms.linical benefit has been highest in groups with the highestaseline QRS duration and has generally not been shown forroups of patients with QRS �150 ms. Although theARE-HF trial targeted patients with either QRS �150 msr QRS 120 to 150 ms with echocardiographic dyssyn-hrony, only 11% of subjects actually enrolled had QRS

uration �150 ms.

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1375Ujeyl and Stevenson Populations for CRT Devices

Patients undergoing implantation of defibrillator/pacingevices who are likely to require chronic ventricular pacingay be considered for CRT in the absence of prolonged

ative QRS. This may be particularly important for patientsndergoing AV nodal ablation for rate control of atrialbrillation.

Etiology of left ventricular dysfunction can influence theecision for CRT. The largest improvements in ejectionraction continue to be seen in patients without coronaryrtery disease, whether spontaneously, while taking on betalockers, or with CRT. Patients with coronary artery diseaseonetheless frequently have improvement that is clinicallyvident. This would seem most likely without lateral wallnfarction but has not been easy to predict based on imagingtudies. Information is not sufficient to predict benefit withess common etiologies of heart failure, but the presence ofarked left ventricular dilation and mitral regurgitation

eem to provide better substrates for CRT improvement.ardiomyopathies with smaller ventricular size may be ac-ompanied by a component of fibrosis that restricts im-rovement. The growing population of patients with car-iomyopathy related to chemotherapy with doxorubicinAdriamycin), trastuzumab (Herceptin), and newer small-olecule inhibitors have not been studied with CRT, but

entricular size and QRS duration are less distorted than inther low ejection fraction cardiomyopathies.

Clinical severity of heart failure is a key determinant ofoth procedural risk and early outcomes. In advanced heartailure, CRT should be considered an elective procedure tomprove the level of chronic compensation, not a rescueherapy from acute decompensation. Patients whose symp-oms relate only to exertional intolerance are most likely tomprove. Although patients designated as class IV haveeen included in trials of both medical therapy and pacingevices, these patients were ambulatory without restingemodynamic compromise and were not typical of class IVatients who frequently require hospitalization. Patientsith evidence of clinical congestion at rest, particularly as

ndicated by orthopnea or immediate dyspnea with lightxertion, should undergo vigorous therapy to reestablishptimal volume status prior to the procedure, both to makehe procedure safer and to enhance the likelihood of symp-omatic improvement. This sometimes requires days of super-ised diuresis in hospital. When diuresis is limited by severeenal dysfunction or requires intravenous inotropic support, theisk is high for early heart failure events, with or without CRT.ccasional cases of CRT response in such individuals do notarrant routine device implantation when the initiation of

nd-of-life discussions may be more appropriate.The distinction between class I to II symptoms and class

II symptoms is relatively clear for active patients but be-omes problematic for sedentary patients. This distinctionecomes less crucial now that the remodeling benefit haseen shown even for patients with class I to II symptoms.s for improvement in symptomatic patients, the impact of

everse remodeling in early disease is seen more often in o

atients without coronary artery disease. Although the cur-ent guidelines do not encourage consideration of CRT foratients without major symptoms, growing experience sug-ests that patients undergoing device implantation for pri-ary prevention be considered for CRT when the nativeRS is prolonged into the range where benefit has beenroven. It is also reasonable when continuous ventricularacing is anticipated, such as for patients with sick sinusyndrome or AV nodal ablation. However, current dosingatterns of beta-adrenergic blocking agents may suppressntrinsic heart rate down below usual backup rates and mayead to ventricular pacing in the absence of conductionystem disease. We have not determined how to balance theenefits of beta-blockade with the potential depression ofntrinsic heart rate and heart rate reserve during exercise.

onresponderseported nonresponse rates of 20% to 30% of symptomaticatients continue to challenge clinicians in the selection ofoth patients and left ventricular pacing lead positions.chocardiographic parameters of dyssynchrony, including

issue Doppler imaging technique, lack sufficient predictivealue to reliably distinguish responders from nonre-ponders. Myocardial viability may also be a crucial deter-inant of CRT effectiveness, as suggested by contrast-

nhanced magnetic resonance imaging (MRI).7 MRI-guidedead placement and integration of three dimensional echo-ardiography-based visualization of dyssynchrony warranturther exploration. However, acute effects on ventricularolume and ejection fraction do not necessarily predictelayed reverse remodeling, particularly in earlier stages ofisease. Whether echocardiographic guidance helps to op-imize pacing algorithms during later patient follow-up iseing addressed in ongoing trials.

he right therapy for each patienthe search for regulatory and reimbursement approval has

ocused attention on selecting from among a population theatients most likely to show benefit from the therapy. How-ver, care of each patient focuses on selecting the therapyost likely to provide benefit to that individual. Individuals

lace different priorities on these outcomes of symptomatictatus and activity, on overall survival, and on the antici-ated mode of death.8

The range of patients likely to benefit from prevention ofudden death overlaps with the range of patients likely toenefit from cardiac resynchronization (Figure 2). The sizef the overlap depends on the contour of the target popula-ion for an implantable cardioverter-defibrillator (ICD),hich is shaped in part by national priorities for health care

esources. This varies from a broad mound of patients withmall absolute chance of sudden death or device benefitFigure 2A) to a steeper pinnacle when expensive technol-gy is reserved for those at highest risk for sudden death andighest benefit from prolongation of survival (Figure 2B).Patients with a history of ventricular tachyarrhythmias and

therwise well-compensated left ventricular dysfunction

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1376 Heart Rhythm, Vol 6, No 9, September 2009

ould contribute to the height of this pinnacle. For primaryrevention, the pinnacle of benefit nestles somewhere be-ween class II, suggested by models from MADIT-II (Mul-icenter Automatic Defibrillator Implantation Trial-II) asresenting too little risk, and class III, reported by SCD-eFT (Sudden Cardiac Death in Heart Failure Trial) aseriving no benefit.9,10 Early during disease progression, theurrent CRT curves exclude patients with ejection fractioness than 30% to 35% and wide QRS without heart failureymptoms, although that may change as information accu-ulates about the benefit of resynchronization in reducing

eft ventricular size and mitral regurgitation (indicated byashed line in Figure 2). At the other end, ambulatoryatients who have frequent class IV symptoms withoutequiring inotropic agents are more likely to benefit fromesynchronization than from the addition of a defibrillator.11

his may be particularly true for patients with heart failuren the community, for whom 1-year survival even if alludden deaths could be prevented has been less than 50%fter three heart failure hospitalizations, or after two heartailure hospitalizations in patients with estimated glomeru-ar filtration rate less than 60 cc/min.

CRT has been shown to reduce mortality in both theOMPANION and CARE-HF trials, with a hazard ratio of.64 whether with or without a defibrillator. In both popu-ations with CRT alone, sudden death accounted for onehird of the overall mortality, which is a higher proportionhan in patients randomized to no device. In the CARE-HFopulation, with median QRS 160 ms, the reduction in

igure 2 Potential populations of heart failure patients for device therapyardioverter-defibrillator (ICD) populations with relation to disease severityf sudden death risk and survival benefit for ICD. B: ICD population withrolongation from prevention of sudden death.

ortality with CRT alone was distributed equivalently be- q

ween heart failure death and sudden death, such that theroportion of deaths occurring suddenly did not change. Whenhe defibrillator feature was added to CRT in COMPANION,he proportion of sudden deaths declined overall from 37%o 17%. For ambulatory class IV patients receiving CRT-D,he proportion of overall deaths that occurred suddenly waseduced by the ICD to 11%, leaving 89% deaths to occurore slowly.The clinical trials of devices for resynchronization and

or defibrillators, both separately and in combination, stud-ed patients with a mean age in the 60s and excluded manyommon noncardiac comorbidities. The interpretation andpplication of these trial results to national practice variesidely. Currently in the United States, 3,000 to 4,000RT-D devices are inserted each month, compared to 6,000

o 7,000 ICDs without CRT and relatively few devices foresynchronization alone. In European countries, the ratio ofRT pacing alone to CRT with defibrillators ranges from.22 in Germany to 1.79 in Sweden.12 Half of patientseceiving devices are older than 68 years and 15% are ateast 80 years old. The likelihood of both functional limi-ation and death from noncardiac causes increases with agen the overall population.13 Although randomized trials willot be feasible in all of the important subgroups, continuedareful tracking of outcomes should better inform decisionsor national health resource utilization. Most importantly,uch information will facilitate discussions between indi-idual patients and physicians about how best to matchevice therapy with the patients’ own priorities for the

g intersection of cardiac resynchronization therapy (CRT) and implantablepopulation with broad mound of eligibility encompassing multiple levels

le of benefit in patients with high sudden death risk and greatest survival

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1377Ujeyl and Stevenson Populations for CRT Devices

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3. Bristow MR, Feldman AM, Saxon LA. Heart failure management using im-plantable devices for intraventricular resynchronization: comparison of medicaltherapy, pacing and defibrillation in chronic heart failure (COMPANION) trial.J Card Fail 2000;6:276–285.

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9. Bardy GH, Lee KL, Mark DB, et al. The Sudden Cardiac Death in Heart FailureTrial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237.

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2. Swedberg K, Cleland J, Cowie MR, et al. Successful treatment of heart failuredevices requires collaboration. Successful treatment of heart failure with devicesrequires collaboration. Eur J Heart Fail 2008;10:1229–1236.

3. Setoguchi S, Nohria A, Rassen J, Stevenson LW, Schneeweiss S. Maximumpotential benefit of implantable defibrillators in preventing sudden death afterhospital admission because of heart failure. CMAJ 2009;180:611–616.

4. Hammill SC, Kremers MS, Stevenson LW, et al. Review of the Registry’ssecond year, data collected, and plans to add lead and pediatric ICD procedures.

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