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STATE-OF-THE-ART PAPER

Advanced Heart FailureEpidemiology, Diagnosis, and Therapeutic Approaches

Lauren K. Truby, MD, Joseph G. Rogers, MD

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HIGHLIGHTS

� The prevalence of heart failure is increasing as the population ages. As a result of advancesin medical therapy for heart failure, more patients are living longer and with more end-stage disease.

� The current review focuses on the diagnosis and management of advanced heart failure,including cardiogenic shock, temporary mechanical circulatory support, durable heartfailure therapies including left ventricular assist devices and heart transplantation, andpalliative care.

� Future directions discussed include translational research efforts in myocardial recovery,emerging left ventricular assist device technology, and innovative approaches to post-heart transplant care.

ABSTRACT

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In broad terms, “advanced” heart failure describes a clinical syndrome characterized by persistent or progressive

symptoms and ventricular dysfunction despite guideline-directed medical therapy. Clinically the definition is often

dependent upon iterative and integrated clinical assessments to identify patients with worsening status and reliance on

specific therapies. This review examines current consensus definitions, highlights strategies for risk stratification and

prognostication, and examines short- and long-term treatment strategies. Lastly, this paper explores future directions of

research and development for the field. (J Am Coll Cardiol HF 2020;-:-–-) © 2020 by the American College of Car-

diology Foundation.

EPIDEMIOLOGY OF

ADVANCED HEART FAILURE

Heart failure (HF) affects 6.2 million American adults,with an incidence approaching 21 per 1.000 popula-tion after the age of 65 years (1). Projections estimatethat by 2030, more than 8 million people over the ageof 18 years will be affected by HF (2,3). Estimating the

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titutions and Food and Drug Administration guidelines, including patien

it the JACC: Heart Failure author instructions page.

nuscript received October 7, 2019; revised manuscript received January 1

prevalence of advanced HF remains an epidemiolog-ical challenge as a result of the relatively low inci-dence of the condition and the dependence of thedefinition on an evolving series of therapies. Over adecade ago, a population-based, cross-sectionalanalysis of Olmstead County, Minnesota, suggestedadvanced HF affected 0.2% of the population(w13,000 patients), whereas data from the ADHERE

https://doi.org/10.1016/j.jchf.2020.01.014

edical Center, Durham, North Carolina. Both authors

is paper to disclose.

es and animal welfare regulations of the authors’

t consent where appropriate. For more information,

7, 2020, accepted January 28, 2020.


http://heartfailure.onlinejacc.org/content/instructions-authors1

ABBR EV I A T I ON S

AND ACRONYMS

CAV = cardiac allograft

vasculopathy

CS = cardiogenic shock

DCD = donation after

circulatory death

DT = destination therapy

HF = heart failure

INTERMACS = Interagency

Registry for Mechanically

Assisted Circulation

ISHLT = International Society

for Heart and Lung Transplant

LV = left ventricular

LVAD = left ventricular assist

device

NYHA = New York Heart

Association

PGD = primary graft

dysfunction

RV = right ventricular

VA-ECMO = venoarterial

extracorporeal membrane

oxygenation

Truby and Rogers J A C C : H E A R T F A I L U R E V O L . - , N O . - , 2 0 2 0

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(Acute Decompensated Heart Failure) na-tional registry suggested a prevalence ofcloser to 5% among hospitalized patients(w23,000 patients) (4,5). With the globalburden of HF increasing, however, advanceddisease will undoubtedly increase in tandem.Last year alone, more than 3,000 patientswere treated with a left ventricular assistdevice (LVAD), and more than 3,000 patientsreceived heart transplants in the UnitedStates, with an additional 3,500 patientsawaiting transplantation (6,7).

DEFINING ADVANCED HF

Multiple classification systems have beendeveloped to characterize patients with HFand define those with advanced disease(Central Illustration). For example, New YorkHeart Association (NYHA) functional class IVdefines those with symptoms at rest andwith any physical activity. In 2001, theAmerican College of Cardiology and theAmerican Heart Association developed anew construct for defining HF, describing

Stage D patients as those who require specializedinterventions due to refractory symptoms despitemaximal medical therapy (8). The Interagency Reg-istry for Mechanically Assisted Circulation (INTER-MACS) classification system was developed to riskstratify patients with advanced HF to better defineprognosis and urgency of intervention (9). These 3classification systems may be used in parallel inorder to more precisely define where an individualpatient lies on the spectrum of this progressivedisease. Professional societies have also publishedconsensus definitions to improve the early identifi-cation and treatment of patients that rely on com-binations of symptoms, objective data, andtherapeutic interventions (Figure 1) (10,Supplemental Refs. 11,12).

The highly unpredictable clinical course of HF canchallenge even the most experienced clinician tocorrectly identify the optimal timing of referral to aHF specialist. Whereas some HF cases are abrupt andobvious, others are related to progressive diseasesthat evolve subtly over time. The addition of objec-tive measures of exercise performance, quality of life,cardiac structure and function, biomarkers and labo-ratory assessments, and arrhythmia burden are usefulin the ongoing evaluation of patients with chronic HFand may serve as important adjuncts to obviate thesense of clinical stability. One particularly helpfulmnemonic that may help identify patients in need of

referral to a HF specialist is “INEEDHELP,” whichintegrates clinical history, hospitalizations, medica-tion intolerance, in addition to symptoms and end-organ dysfunction (Supplemental Figure 1)(Supplemental Refs. 13,14). Consensus supports theconcept of early referral to avoid the debilitation andend-organ dysfunction that accompanies prolongedadvanced HF and may preclude candidacy foradvanced therapies (Figure 2) (SupplementalRefs. 11,15,16).

CLINICAL APPROACH TO THE PATIENT WITH

ADVANCED CHRONIC HF

Patients should have a thorough evaluation toexclude reversible causes of HF and ensure treatmentwith maximally tolerated guideline-directed medicaltherapy (8). Testing for ischemia in selected patients,surgical or percutaneous management of valvulardisease, treatment of atrial and ventricular arrhyth-mias (including high premature ventricular contrac-tion burden), evaluation for other systemicconditions such as thyroid disease and sarcoidosis,and a trial of abstinence from substance abuse mayidentify patients whose native cardiac function willsufficiently improve. In addition to renin-angiotensinantagonists, beta-blockers, and aldosterone antago-nists, angiotensin receptor-neprilysin inhibitors arenow routinely recommended in patients with chronicNYHA functional class II/III HF symptoms andadequate blood pressure, although their efficacy andsafety have not yet been evaluated in patients withadvanced HF (Supplemental Ref. 17). Cardiacresynchronization therapy can also improve symp-toms, exercise capacity, reverse remodeling, andejection fraction in appropriately selected patients(Supplemental Ref. 18). For those with moderate-to-severe secondary mitral regurgitation, transcathetermitral valve repair appears to improve survival andfreedom from HF hospitalizations (SupplementalRef. 19). Consideration of candidacy for advancedHF therapies is appropriate for those with residualventricular dysfunction and limiting symptomsdespite aggressive attempts at medical, electric, andmechanical optimization. In the absence of obviouscontraindications to advanced therapies, the patientshould undergo assessment of clinical and hemody-namic stability, systemic perfusion, and end-organfunction. Evidence of shock or rapidly progressiverenal/hepatic dysfunction should prompt urgentreferral to a specialized HF center (Figure 3).

Cardiopulmonary exercise testing may be the sin-gular most important risk stratification test in pa-tients with advanced HF (Supplemental Ref. 20). The











CENTRAL ILLUSTRATION Heart Failure Stages and Symptoms Across Multiple Classification Schemes

ACC Stages

A: Patient is at high risk for developingheart failure but has no functional orstructural heart disorder

B: Structural heart disorder withoutsymptoms

C: Past or current symptoms or heartfailure associated with structural disorder

D: Advanced heart disease requiringhospital-based support, transplant,or palliative care.

A B C D

7 6 5 4 3 2 1

2 3 41

NYHA Classes

I: No limitation in normal physical activity

II: Mild symptoms with normal activity

III: Markedly symptomatic during dailyactivities, asymptomatic only at rest

IV: Severe limitations, symptoms evenat rest

INTERMACS Profiles

Profile 1: Critical Cardiogenic Shock

Profile 2: Progressive Decline

Profile 3: Stable. But Inotrope Dependent

Profile 4: Resting Symptoms

Profile 5: Exertion Intolerant

Profile 6: Exertion Limited

Profile 7: Advanced NYHA Class III

ACC Stages

NYHA Classes

INTERMACS Profiles

Truby, L.K. et al. J Am Coll Cardiol HF. 2020;-(-):-–-.

Stages of heart failure as described by American College of Cardiology (ACC) and New York Heart Association (NYHA) stages as well as Interagency Registry for

Mechanically Assisted Circulation (INTERMACS) profiles (8,9).

J A C C : H E A R T F A I L U R E V O L . - , N O . - , 2 0 2 0 Truby and Rogers- 2 0 2 0 :- –- Advanced Heart Failure

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International Society for Heart and Lung Transplant(ISHLT) guidelines support transplant evaluation inthose with a peak VO2 < 12 ml/kg/min (or <14 ml/kg/min if beta-blocker intolerant) or <50% predictedvalue (Supplemental Refs. 21,22). In addition to peakVO2, patients with a ventilatory equivalent of carbondioxide (VE/VCO2) >35 have a poor prognosis andshould be considered for advanced therapies(Supplemental Ref. 22). Another commonly usedmetric is the 6-min walk distance: a measure offunctional capacity reflective of exercise performanceand the patient’s ability to perform the activities ofdaily living. The distance walked in 6 min is highlycorrelated with peak VO2 and its impact on survival(Supplemental Refs. 23,24).

Right heart catheterization is a critical componentof the assessment and management of patients incardiogenic shock (CS) and patients being evaluatedfor advanced therapies (Supplemental Refs. 25,26).Invasive hemodynamics can be particularly useful toinform decision-making regarding specific pharma-cotherapy and subsequent durable advanced heartfailure therapies by providing the clinician assess-ment of left- and right-sided cardiac filling pressure,presence of pulmonary hypertension, cardiac output,

and measures of right ventricular (RV) performance(Supplemental Refs. 27,28). The ability to optimizefilling pressures has been shown to be a powerfulpredictor of outcomes—even to a greater degreethan cardiac output alone (Supplemental Ref. 29).In a randomized, controlled trial of an implantable,ambulatory pulmonary artery pressure monitoringdevice that guided directed medical therapy inpatients with NYHA functional class III HF, patientstreated with hemodynamic monitoring experienced asignificant reduction in hospitalization for decom-pensated HF (hazard ratio: 0.72; p ¼ 0.002, numberneeded to treat ¼ 8) (Supplemental Ref. 30). Patientsin the treatment arm also had significantly lowerpulmonary artery pressures, more days outside thehospital, and improvements in quality of life ascompared with controls (Supplemental Ref. 31).

RV failure is common in advanced HF and is asso-ciated with increased mortality (SupplementalRef. 32). In particular, RV dysfunction associatedwith pulmonary hypertension carries a poor prog-nosis (Supplemental Ref. 33). For those beingconsidered for durable LVAD, pre-implantation RVdysfunction may represent a relative or absolutecontraindication, because early post-operative RV












FIGURE 1 Definitions Of Advanced HF Among Professional Societies

Similarities and differences among definitions of advanced heart failure from the American College of Cardiology, European Society of Cardiology, and Heart Failure

Society of America (10, Supplemental Refs. 11,12). 6MWT ¼ 6-min walk time; ADL ¼ activities of daily living; BNP ¼ B-type natriuretic peptide; GDMT ¼ guideline-

directed medical therapy; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York

Hospital Association; PCWP ¼ pulmonary capillary wedge pressure; RAP ¼ right atrial pressure; RV ¼ right ventricular; SBP ¼ systolic blood pressure.



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failure is associated with excessive morbidity andmortality (Supplemental Ref. 34). Optimization ofright-sided filling pressures and RV performance is ofparamount importance to successful LVAD outcomes.Pulmonary hypertension also represents a possiblebarrier to cardiac transplantation, with a pulmonaryvascular resistance of >3 to 4 Woods units beingassociated with increased risk of post-transplantmortality (Supplemental Ref. 35). If prohibitivepulmonary hypertension is present, LVAD treatmentas bridge to heart transplantation, in combinationwith pulmonary vasodilators, may normalizemedically refractory pulmonary hypertension and

appears to have acceptable post-transplant outcomes(Supplemental Ref. 36).

SHORT-TERM THERAPY FOR CS AND

DECOMPENSATED HF

Although disease-modifying medical therapiescontinue to be the cornerstone of HF treatment, pa-tients with advanced disease and CS may requireintravenous or mechanical therapies to stabilizeclinical condition and end-organ function. Advancedtherapies employed in these cases include vasoactivemedication such as inotropes, intravenous





FIGURE 2 Clinical Course of Advanced HF

Expected natural history of the course of advanced heart failure (HF) including advanced therapies and palliative care interventions. The usual medical care and

palliative care curves were adapted with permission from American Thoracic Society. Figure adapted with permission from Allen et al. (Supplemental Ref. 16).

LVAD ¼ left ventricular assist device.


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vasodilators, vasopressors, and temporary mechani-cal circulatory support. Decision making surroundingchoice and timing of these therapies often dependson resources available at a given center, patient can-didacy for durable support or transplantation, centerexperience, and patient preference. There has been arecent paradigm shift in the care of patients with CS,with an emphasis being placed on early and aggres-sive treatment. In an effort to streamline the rapiddeployment of the complex medical and surgical carethese patients require, many centers have createdmultidisciplinary “shock teams” to standardize ap-proaches to care in this patient population(Supplemental Refs. 37,38). The Society for Cardio-vascular Angiography and Interventions recently is-sued a consensus statement that outlines 5 stages ofCS varying from Stage A (“at risk”) to Stage E(“extremis”) as a tool to aid in the timely diagnosisand management of critically ill patients and tofacilitate a common language for physicians andsurgeons (Figure 4) (Supplemental Ref. 39).

Inotropic therapy and intravenous vasodilators,are mainstays of improving hemodynamics indecompensated HF, and have been studied exten-sively in clinical trials. Although routine use of ino-tropes is not recommended, experts agree thatinotropic therapy is appropriate and beneficial inselect patients with evidence of end-organ dysfunc-tion and as a bridge to advanced therapies(Supplemental Refs. 11,40–43). However, in manypatients, medical therapy alone is insufficient tooptimize hemodynamics and improve end-organfunction. A key role of the “shock team” is to iden-tify the appropriate patients and timing of escalationof support (Figure 5). In these cases, temporary me-chanical circulatory support devices may a play a roleas a bridge to recovery, bridge to decision, or bridgeto heart replacement therapy (Supplemental Ref. 44).The specific device chosen largely depends uponthe etiology of CS, the patient’s unique physiology,and the cardiac output augmentation required(Figure 6).






FIGURE 3 Diagnostic and Therapeutic Approach to the Patient With Advanced HF

For patients with chronic heart failure, initial investigation should involve identifying and treating reversible causes of cardiomyopathy. Once these have been excluded,

or there has been no clinical improvement despite correction of these processes, guideline-directed medical therapy and device therapy should be optimized. Should

worsening end-organ function or shock develop, patients should be transferred to a specialized center and evaluated for advanced therapies (Supplemental

Ref. 13,15,17–19). Palliative care should be involved with all patients ill enough to quality for advanced therapies whether or not they are a candidate for ventricular

assist device or transplant. ACEi ¼ angiotensin-converting enzyme inhibitor; ARNI ¼ angiotensin receptor-neprilysin inhibitor; CAD ¼ coronary artery disease;

CRT ¼ cardiac resynchronization therapy; HIV ¼ human immunodeficiency virus; HT ¼ heart transplantation; LBBB ¼ left bundle branch block; LHC ¼ left heart

catheterization; LVEF ¼ left ventricular ejection fraction; MCS ¼ mechanical circulatory support; MR ¼ mitral regurgitation; RHC ¼ right heart catheterization;

tMVR ¼ transcatheter mitral valve replacement.



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The intra-aortic balloon pump is a percutaneouslydeployed catheter-based balloon that inflates duringdiastole and deflates during systole, augmenting cor-onary perfusion and myocardial oxygen supply whilereducing left ventricular afterload (SupplementalRef. 45). Although its overall contribution to cardiacoutput is modest, case series and cohort studies sug-gest benefit in a broad range of clinical conditionsincluding myocardial infarction, post-cardiotomyshock, and decompensated chronic HF. As a result, it

continues to be a mainstay of therapy in CS(Supplemental Refs. 46–49). Novel technology andsurgical approaches have facilitated expansion ofaxillary insertion techniques both in hospitalized pa-tients and in the ambulatory setting as a bridge toheart transplantation (Supplemental Refs. 50,51).

The use of catheter-based ventricular assist de-vices has rapidly expanded as a therapeutic modal-ity in refractory CS. The Impella microaxial flowdevice (Abiomed, Danvers, Massachusetts) can be







FIGURE 4 SCAI Classification of CS

Society for Cardiovascular Angiography and Interventions (SCAI) classification of cardiogenic shock with associated exam findings, laboratory values, and hemodynamics

for each stage. Adapted with permission from Catheterization and Cardiovascular Interventions (Supplemental Ref. 39). AMS ¼ altered mental status; CI ¼ cardiac

index; CPO ¼ cardiac power output; CPR ¼ cardiopulmonary resuscitation; CS ¼ cardiogenic shock; CVP ¼ central venous pressure; HR ¼ heart rate; JVP ¼ jugular

venous pressure; LFT ¼ liver function test; MAP ¼ mean arterial pressure; PAPI ¼ pulmonary artery pulsatility index; PA Sat ¼ pulmonary artery oxygen saturation;

UOP ¼ urinary output; other abbreviations as in Figure 1.


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placed percutaneously via arterial vascular accessacross the aortic valve, where it draws blood fromthe left ventricular (LV) and ejects into theascending aorta. In doing so, the device decreasesLV preload and myocardial wall stress, reducesmyocardial oxygen demand, and increases cardiacoutput and coronary perfusion. Small, randomizedcontrol trials comparing Impella 2.5 to intra-aorticballoon pump support have failed to demonstrate asurvival benefit despite a more favorable hemody-namic profile (Supplemental Refs. 52,53). As a result,most clinicians use the Impella CP or Impella 5.0 forpatients requiring greater hemodynamic supportsuch as those with CS (Supplemental Ref. 44).Complications related to Impella include hemolysisand migration of the cannula resulting in damage tothe mitral or aortic valve.

TandemHeart (LivaNova, London, UnitedKingdom) consists of an inflow cannula inserted inthe femoral vein with access to the left atrium viatrans-septal puncture, an extracorporeal centrifugalflow pump, and an arterial outflow cannula insertedinto the femoral artery. In this configuration,

TandemHeart directly unloads the LV and provides acardiac output up to 4 l/min. Due to the technicalexpertise required to position the device, it cannot beeasily deployed at the bedside and carries increasedrisk of complications relating to cannula migration.Similar to other percutaneous devices, randomizedcontrolled trials have yet to demonstrate a survivalbenefit (Supplemental Ref. 54).

Venoarterial extracorporeal membrane oxygena-tion (VA-ECMO) is capable of providing full cardio-pulmonary support and has been increasingly usedin refractory CS as bridge to heart replacementtherapy, bridge to decision, or bridge to recovery(Supplemental Ref. 55). The general concept under-lying VA-ECMO is that venous blood is drained fromthe right heart, passed through an oxygenator, andreturned to the arterial circulation. In this way, boththe circulatory and respiratory systems are sup-ported. The 2 most commonly used cannulationstrategies are: 1) peripheral cannulation in which afemoral venous cannula is advanced into the rightatrium for drainage and a second cannula is insertedin the femoral artery; and 2) central cannulation in






FIGURE 5 Temporary Mechanical Circulatory Support

Review of short-term mechanical circulatory support devices including intra-aortic balloon pump (IABP), Impella, TandemHeart, and venoarterial extracorporeal

membrane oxygenation (VA-ECMO). Presented are their expected augmentation of cardiac output, their advantages and disadvantages, contraindications and com-

plications (Supplemental Ref. 47,53,54,56). AAA ¼ abdominal aortic aneurysm; AI ¼ aortic insufficiency; CO ¼ cardiac output; LV ¼ left ventricular; LVEDP ¼ left

ventricular end-diastolic pressure; PAD ¼ peripheral artery disease; VSD ¼ ventricular septal defect; other abbreviations as in Figure 1



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which the venous and arterial cannulae are placeddirectly in the right atrium and ascending aorta,respectively (Supplemental Ref. 56). The hemody-namic improvements associated with VA-ECMOcommonly restore end-organ perfusion. However,VA-ECMO flow delivered retrograde to the aorta in-creases LV afterload. LV preload may also increaseas a result of incomplete capture of venous return.Clinically, this can result in LV distention whichmanifests as pulmonary edema with worseningoxygenation, increases the risk of LV thrombus for-mation as a result of stasis in the nonejecting LV,and is associated with lower rates of myocardialrecovery (Supplemental Ref. 57). Thus, some centers

attempt to use “partial flow” VA-ECMO, wherebyflow is minimized to sustain blood pressure andend-organ perfusion while inotropic agents areconcomitantly administered to ensure ejection ofblood from the LV (Supplemental Ref. 58). If LVdistention develops, the LV can be unloadedpercutaneously with the placement of an Impella orsurgically with placement of a vent (SupplementalRef. 59). Other common complications of VA-ECMOinclude acute limb ischemia (in the case of periph-eral cannulation), stroke, bleeding, and infection.

Once temporary mechanical circulatory supporthas been deployed, biventricular function should bereassessed with focused echocardiography and







FIGURE 6 Relative and Absolute Contraindications to Advanced HF Therapies

Review of the absolute and relative contraindications for heart transplantation and left ventricular assist device therapy (Supplemental Ref. 62,119,120). FEV1 ¼ 1-min

forced expiratory volume; HF ¼ hears failure; INR ¼ international normalized ratio; VAD ¼ ventricular assist device.


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frequent assessment of invasive hemodynamics inorder to determine which devices can be safelyweaned and which patients should be evaluated forescalation of support.

LONG-TERM MANAGEMENT OF ADVANCED

HF: HEART TRANSPLANTATION

Long-term advanced HF therapies should beconsidered for patients in whom guideline-directedmedical and device therapy has failed to result insufficient hemodynamic improvement to amelioratesymptoms or preserve end-organ function. For pa-tients without options for more durable treatments,long-term inotropic therapy may be administered toimprove quality of life and symptom burden(Supplemental Ref. 60). Although survival onchronic inotropic support remains poor, it doesappear to be improving in the current era with 1-year estimated survival now close to 40%(Supplemental Refs. 42,61).

Heart transplantation remains the gold standardtherapy for selected patients with demonstrable im-provements in quality of life, functional status, andlongevity when compared with conventional therapy(Supplemental Refs. 11,22). One-year survival

following cardiac transplantation is now >90% with amedian survival of 12.2 years, though patient selec-tion remains a critical component of achieving satis-factory post-transplant outcomes (Figure 7)(Supplemental Refs. 62–68). The United Network ofOrgan Sharing recently approved a major revision tothe heart allocation policy intended to decreasewaitlist mortality, particularly for the sickest candi-dates, and improve equitable distribution of donorhearts by introducing more granular stratification ofpatients, broader geographic sharing, mandatoryreassessment of high-priority patients, and stan-dardizing definitions (Supplemental Ref. 69)(Figure 8). Important features of the new allocationsystem include higher priority status for temporarymechanical circulatory support and deprioritizationof stable outpatients with durable LVADs. The newallocation system has not assigned higher priority topatients with nondilated myopathies includingrestrictive and hypertrophic cardiomyopathy despitesuggestion of increased waitlist mortality in thiscohort (Supplemental Ref. 70).

Organ scarcity continues to limit the number oftransplantations performed annually. In the UnitedStates, a recent increase in donor availability has beendriven by the opioid epidemic (Supplemental Ref. 71).









FIGURE 7 Evaluation of Heart Transplant Candidates

Components of the evaluation of candidates for heart transplantation as suggested by the International Society for Heart and Lung Transplant Guidelines

(Supplemental Refs. 62–67,121). CMV ¼ cytomegalovirus; ECG ¼ electrocardiogram; HIV ¼ human immunodeficiency virus; IgG ¼ immunoglobulin G;

IgM ¼ immunoglobulin M; RPR/VDRL ¼ rapid plasma reagin/venereal disease research laboratory.



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In multiple analyses, post-transplant outcomes ofthese higher-risk donors appear to be comparable tothose with other causes of death (SupplementalRef. 72). With the advent of direct-acting, curativeantiviral therapy, numerous transplant programshave also developed protocols to use hearts fromhepatitis C (HCV)-positive donors and have reportedexcellent post-transplant outcomes with eliminationof HCV viremia and presumed “cure” (SupplementalRefs. 73,74). Despite early enthusiasm for thisapproach, questions about cost-effectiveness andlong-term outcomes (including allograft vasculop-athy) remain (Supplemental Ref. 75). Another effortto increase the number of cardiac donors is expansionof organ donation after circulatory death (DCD). Theprinciples of DCD donation involve the declaration ofcirculatory death followed by a waiting perioddetermined legally and ethically by the country inwhich the donor is located—typically ranging from 2to 5 min (Supplemental Ref. 76). Since the first suc-cessful DCD heart transplant in 2014, internationalexperience suggests post-transplant outcomes arecomparable to traditional donors (SupplementalRefs. 77,78). Ex-vivo perfusion of donor hearts,which maintains the donor heart in a warm and con-tracting state during transport, has been pivotal inexpanding DCD donation and may facilitate safe useof organs that require extended travel times(Supplemental Refs. 79,80).

Although post-transplant survival remains excel-lent, the complex milieu of ischemia, host immu-nological recognition of the transplanted organ,systemic infections, medications, and traditional

risk factors for coronary disease limit the true po-tential of heart transplantation. Primary graftdysfunction (PGD)—acute failure of the allograft tosupport the circulation in the absence of rejection orother identifiable cause—continues to contribute toearly post-transplant mortality (SupplementalRef. 81). Management of PGD involves promptintraoperative identification, early institution of VA-ECMO support, and post-operative titration ofimmunosuppression, including avoidance of induc-tion therapy in the absence of sensitization, renalfailure, or other high-risk features (SupplementalRef. 81). The majority of PGD patients treated withVA-ECMO are weaned to recovery (SupplementalRef. 82).

Additional targets for improving post-transplantoutcomes include management of both cellular andhumoral rejection, personalized immunosuppression,and achieving an optimal balance between the two.Although endomyocardial biopsy remains the stan-dard for detecting rejection in the early post-transplant period, gene expression profiling withAllomap (CareDx, Brisbane, California) and measure-ment of donor-derived cell-free DNA are beingincreasingly used to facilitate non-invasive screeningfor rejection (Supplemental Refs. 83,84). CurrentISHLT guidelines support the use of gene expressiontesting for noninvasive monitoring of rejection forappropriate low-risk patients between 6 months and 5years after heart transplantation (SupplementalRef. 85).

Long-term graft survival is also limited by thedevelopment of cardiac allograft vasculopathy (CAV),




















FIGURE 8 Revised UNOS Heart Allocation System

The updated United Network of Organ Sharing (UNOS) Heart Allocation System, which went into effect in October of 2018 (Supplemental Ref. 69).

BIVAD ¼ biventricular assist device; RVAD ¼ right ventricular assist device; other abbreviations as in Figures 2 and 5.


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a disease of the coronary arteries characterized bywidespread fibrointimal hyperplasia affecting up to75% of patients 3 years post-transplant (SupplementalRef. 86). The use of intravascular ultrasound as partof routine coronary angiography has increased thesensitivity of screening, with CAV found in almostone-half of patients at 1 year using intravascular ul-trasound as compared with 10% to 20% using stan-dard coronary angiography alone (SupplementalRef. 87). After transplantation, aggressive lipid-lowering therapy should be prescribed, with pravas-tatin in particular shown to improve low-density li-poprotein cholesterol and triglyceride levels, increasehigh-density lipoprotein cholesterol, reduce intimalthickness and CAV, as well as improve survival(Supplemental Ref. 88). Newer antiproliferativeagents, mycophenolate mofetil, sirolimus, and ever-olimus, have also been shown to be more efficaciousin the prevention of CAV compared with azathioprine(Supplemental Refs. 89,90).

LONG-TERM MANAGEMENT OF ADVANCED

HEART FAILURE: MECHANICALLY

ASSISTED CIRCULATION

The REMATCH (Randomized Evaluation of Mechani-cal Assistance for the Treatment of Congestive HF)trial was the first randomized study to describe thebenefits of LVAD support compared with conven-tional medical therapy in patients with end-stage HFineligible for heart transplantation (SupplementalRef. 61). Since the REMATCH trial, LVAD therapyhas evolved rapidly, and with each subsequent gen-eration of devices has come improvements in dura-bility, device complications, and survival(Supplemental Ref. 91). As of 2017, over one-half ofheart transplant recipients reported in the ISHLTregistry had been supported with mechanicallyassisted circulation (Supplemental Ref. 92). TheINTERMACS registry reports that over 3,000 LVADsare implanted annually in the United States with












FIGURE 9 Personalized Approach To Addressing Patient Goals In Advanced HF

Evaluation of a patient with advanced heart failure should include an assessment of the

goals and outcomes most important to a given patient beyond clinical outcomes. These

include the costs and burden of care, expected quality of life, and end-of-life preferences

(Supplemental Ref. 115). HF ¼ heart failure.



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nearly one-half of those being for destination therapy(DT) (6).

The most recent device to gain Food and DrugAdministration approval for bridge to transplant andDT indications is the HeartMate 3 (Abbott, Chicago,Illinois). This fully magnetically levitated centrifugalpump was engineered to improve hemocompatibility,reduce stasis, and prolong durability. The pump isprogrammed to generate an artificial “pulse,” varyingspeeds from the set RPM by 2,000 every 2 s to pro-duce changes in flow and pressure in an effort toreduce the risk of pump thrombosis. The HeartMate 3was compared with the prior generation HeartMate IIaxial flow pump in the MOMENTUM 3 (MulticenterStudy of MagLev Technology in Patients UndergoingMechanical Circulatory Support Therapy with Heart-mate 3) study. When assessing the primary endpointof survival free from disabling stroke or the need toremove or replace the device, the HeartMate 3 wasshown to be noninferior to the HeartMate II, withsignificantly lower rates of device exchange resultingfrom pump thrombosis. When groups were comparedafter 2 years of support, 76.9% of patients supportedwith the HeartMate 3 achieved the primary endpointas compared with 64.8% of patients with the older-

generation axial flow pump (hazard ratio: 0.84, 95%confidence interval: 0.78 to 0.91; p < 0.001)(Supplemental Ref. 93). Freedom fromhemocompatibility-related events, includingnonsurgical bleeding, thromboembolic events, pumpthrombosis, and neurologic events, was also superiorin HeartMate 3 as compared with the HeartMate II: aresult that was particularly prominent in patients <65years of age at the time of implantation(Supplemental Ref. 94).

Adverse events remain the Achilles heel of LVADtechnology. In the MOMENTUM 3 trial, 10% of pa-tients supported with the HeartMate 3 experienced astroke (7% disabling), 43% experienced episodes ofnonsurgical bleeding, 24% experienced a drive-lineinfection, and 32% exhibited clinical signs of RVfailure. These device complications contribute tosignificant on-device morbidity and mortality, andmay necessitate re-evaluation of patients for trans-plant candidacy.

In patients ineligible for heart transplantation, useof LVAD as DT continues to grow (SupplementalRef. 95). In these patients, evaluation of INTER-MACS profiles can aid in identifying optimal timing ofdevice implantation. The prospective ROADMAP(Risk Assessment and Comparative Effectiveness ofLeft Ventricular Assist Device and Medical Manage-ment) study evaluated patients with advanced HFwho were not treated with inotropes (INTERMACSprofiles 4 to 7) and demonstrated superior survivaland functional status compared with those medicallymanaged, with the tradeoff of increased adverseevents and hospitalizations (SupplementalRefs. 96,97). It is important to remember, however,that no universal guideline exists to inform patientselection for LVAD therapy, and INTERMACS profilesare likely insufficient to quantify a patient’s riskalone. Other factors that must be taken into consid-eration include end-organ function, age, sex, frailty,and need for concomitant procedures (SupplementalRef. 98). In addition, a thorough and standardizedpsychosocial evaluation can help to ensure patientsatisfaction with LVAD therapy and decrease device-related complications (Supplemental Refs. 99,100).Low socioeconomic status alone, should not precludeLVAD candidacy (Supplemental Refs. 101).

Early data from LVAD studies suggest that somepatients are capable of achieving partial or completerecovery of LV function during LVAD support(Supplemental Ref. 102). Hypertrophy, beta-receptorsensitivity, collagen metabolism, and cytoskeletalstructure all improve with mechanical unloading(Supplemental Refs. 103–105). Despite these encour-aging molecular changes, contemporary studies















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suggest that <5% of patients with LVAD have theirdevice explanted for myocardial recovery(Supplemental Ref. 106). Multiple centers havedeveloped individualized recovery protocols toidentify patients most likely to benefit from aggres-sive LV unloading and neurohormonal blockade tofacilitate successful device explant. The weighted I-CARS score, which includes age <50 years, non-ischemic etiology, time from cardiac diagnosis <2years, absence of implantable cardioverter-defibrillator, creatinine <1.2 mg/dl, and LV end-diastolic dimension <6.5 cm has been shown toeffectively risk stratify patients for their probabilityof myocardial recovery (Supplemental Ref. 107).Ongoing translational research is focusing on thebiochemical and molecular pathways responsible forreverse remodeling in an effort to develop more tar-geted therapeutic agents to facilitate sustainedimprovement in LV function (Supplemental Ref. 108).

The future of LVAD therapy will likely see a shifttoward less invasive implantation strategies (i.e., vialateral thoracotomy approach) as well as adoption offully implantable devices (i.e., Leviticus FiVAD,Leviticus-Cardio, Petach Tikva, Israel) and remotemonitoring capabilities that may improve outcomes,particularly in high-risk individuals (SupplementalRefs. 109,110).

LIVING WITH ADVANCED HF

Although the aforementioned short- and long-termtreatment strategies are intended to increaselongevity, they do little to ameliorate the symptomburden and psychosocial distress that disproportion-ately affects patients dying from HF (SupplementalRef. 111). Patients often have limited insight into theseverity of their disease process and expected mor-tality—particularly those who are not candidates foradvanced therapies (Supplemental Refs. 112–114).Although most clinical trials have focused on mor-tality and rehospitalization, many patients valuequality of life and symptom relief over longevity(Figure 9) (Supplemental Ref. 115). As a result, palli-ative care—a multidisciplinary approach to assessingand improving quality of life and symptom manage-ment—is being increasingly integrated into standardmedical care to improve patient-centered outcomes.A randomized trial of palliative care in advanced HFrecently demonstrated significant improvements inquality-of-life metrics, anxiety, and depression ascompared with usual care alone (SupplementalRef. 116). As such, integration of palliative care withconventional medical therapy in patients with

advanced HF is recommended by multiple profes-sional societies. Importantly, palliative care andadvanced therapies are not mutually exclusive, butrather should be employed in concert to ensure thebest possible outcomes for patients and their families(Supplemental Ref. 117). Palliative care interventionbefore LVAD implantation or heart transplantation iscrucial in helping patients articulate their goals andhealth states they would find unacceptable. In thisway, patients and their families can feel empoweredto make difficult decisions to honor their wishes atthe end of life. Despite some progress in this area,there remains much work to be done, as only 34% ofpatients with HF are referred for palliative care intheir last month of life, and mean time from referralto death is <2 weeks (Supplemental Ref. 118).

FUTURE DIRECTIONS AND CONCLUSIONS

The syndrome of advanced HF remains an epidemi-ological, clinical, and financial challenge for patients,physicians, and policy makers. Recent improvementsin advanced therapies have helped more patients livelonger, but have substantially increased clinicalcomplexity and cost of care. Although temporarymechanical support has revolutionized the manage-ment of CS, the ongoing lack of prospective,randomized controlled trial data limits our under-standing of the risks and benefits of this technologyfor a given patient. As use of durable support in-creases, criteria and guidelines for patient selectionmust be standardized in order to curb costs of care andimprove post-implantation outcomes. In trans-plantation, work to expand the donor pool mustcontinue while we pursue basic and translationalresearch to understand how to improve allograftlongevity by preventing and treating PGD and CAV.Personalized approaches to immunosuppression arealso needed to maximize graft tolerance and minimizeinfectious risk. Ongoing research focusing onmyocardial recovery is desperately needed, becausebiochemical pathways capable of reversing, if notpreventing, HF would radically change our approachto care. Lastly, we must continue to integrate patient-centered, symptom-based palliative care into ouradvanced HF paradigm in an effort to help patientswith advanced HF not only live longer, but live better.

ADDRESS FOR CORRESPONDENCE: Dr. Joseph G.Rogers, Division of Cardiology, Department of Medi-cine, Duke University Medical Center, Durham, NorthCarolina. E-mail: [email protected].














mailto:[email protected]



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RE F E RENCE S

1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Amer-ican Heart Association Statistics Committee andStroke Statistics Subcommittee. Heart disease andstroke statistics-2017 update: a report from theAmerican Heart Association. Circulation 2017;135:e146–603.

2. Fang N, Jiang M, Fan Y. Ideal cardiovascularhealth metrics and risk of cardiovascular disease ormortality: a meta-analysis. Int J Cardiol 2016;214:279–83.

3. Kulshreshtha A, Vaccarino V, Judd SE, et al.Life’s Simple 7 and risk of incident stroke: thereasons for geographic and racial differences instroke study. Stroke 2013;44:1909–14.

4. Ammar KA, Jacobsen SJ, Mahoney DW, et al.Prevalence and prognostic significance of heartfailure stages: application of the American Collegeof Cardiology/American Heart Association heartfailure staging criteria in the community. Circula-tion 2007;115:1563–70.

5. Costanzo MR, Mills RM, Wynne J. Characteris-tics of “Stage D” heart failure: insights from theAcute Decompensated Heart Failure NationalRegistry Longitudinal Module (ADHERE LM). AmHeart J 2008;155:339–47.

6. Kirklin JK, Pagani FD, Kormos RL, et al. Eighthannual INTERMACS report: special focus onframing the impact of adverse events. J HeartLung Transplant 2017;36:1080–6.

7. Colvin M, Smith JM, Hadley N, et al. OPTN/SRTR2016 annual data report: heart. Am J Transplant2018;18 Suppl 1:291–362.

8. Yancy CW, Jessup M, Bozkurt B, et al. 2017ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart fail-ure: a report of the American College of Cardiol-ogy/American Heart Association Task Force onClinical Practice Guidelines and the Heart FailureSociety of America. J Am Coll Cardiol 2017;70:776–803.

9. Kirklin JK, Naftel DC, Stevenson LW, et al.INTERMACS database for durable devices for cir-culatory support: first annual report. J HeartTransplant 2008;27:1065–72.

10. Fang JC, Ewald GA, Allen LA, et al.Heart Failure Society of America GuidelinesCommittee. Advanced (stage D) heart failure: astatement from the Heart Failure Society ofAmerica Guidelines Committee. J Card Fail 2015;21:519–34.

KEY WORDS advanced heart failure,cardiogenic shock, heart transplantation, leftventricular assist device, mechanicalcirculatory support, palliative care

APPENDIX For a supplemental figure andexpanded reference list, please see the onlineversion of this paper.

http://refhub.elsevier.com/S2213-1779(20)30208-0/sref1


















































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