Advances in Mechanical Circulatory...

Advances in Mechanical Circulatory Support

Mechanical Circulatory Support for AdvancedHeart Failure

Patients and Technology in Evolution

Garrick C. Stewart, MD; Michael M. Givertz, MD

After nearly 50 years of clinical development, durablemechanical circulatory support (MCS) devices are

widely available for patients with advanced heart failure. Thefield of circulatory support has matured dramatically in recentyears, thanks to the advent of smaller, rotary pumps. Theresulting transition away from older pulsatile devices hasbeen swift. Accelerated use of continuous-flow left ventric-ular assist devices (LVADs) for long-term support haschanged the face of advanced heart failure care. MCScandidate selection, risk stratification, and management strat-egies are evolving in tandem with new pump technology,producing a shift in the profiles of patients being consideredfor MCS. Timely referral for MCS evaluation and appropriateimplantation now depends on familiarity with recent ad-vances in pump design and clinical outcomes. This review,the first in a series on Advances in Mechanical CirculatorySupport, will focus on durable intracorporeal LVADs used inadults with advanced heart failure, and highlight the evolutionin both patients and technology.

History of Mechanical CirculationThe modern era of cardiac surgery began in 1953 with thefirst clinical use of cardiopulmonary bypass, allowing in-creasingly complex operations and laying the foundation forcirculatory assist devices.1 Shortly after its invention, theheart-lung machine began to be used to support patients withpostcardiotomy cardiogenic shock to facilitate recovery afterfailed operations. By the 1960s, simple cardiac assist devicesbegan to replace cardiopulmonary bypass for the treatment ofpostcardiotomy shock (Figure 1). The first clinical use of animplantable artificial ventricle was reported by Liotta et al2 in1963. This primitive ventricular assist device (VAD) con-sisted of a pneumatically driven, tubular displacement pumpwith a valved conduit connecting the left atrium to thedescending thoracic aorta. The pump provided partial leftventricular bypass for 4 days after postoperative cardiacarrest before the patient died of multiorgan failure. Inspiredby this pioneering work in cardiac surgery and encouraged byresults from large animal experiments, the National Institutesof Health (NIH) established the Artificial Heart Program in1964,3 and 6 companies were contracted to assess the

engineering feasibility of such a device. By 1966, the firstsuccessful pneumatic LVAD had been used by Debakey tosupport a patient for 10 days after complex cardiac surgery.4

Shortly after the first human heart transplant by Barnard in1967, artificial ventricle technology began being used as amechanical bridge to support patients with postcardiotomyshock until a donor organ could be identified. Cooley et al5

reported the first use of a total artificial heart as a bridge totransplant (BTT) in 1969. Ever since, the fields of mechanicalcirculation and cardiac transplantation have evolved in coun-terpoint to each other. Despite the early promise of humanheart transplantation, in the 1970s, high mortality rates earlyposttransplant attributable to inadequate immunosuppressionfurther spurred on the development of MCS. However, thefirst generation of extracorporeal pneumatic LVADs of the1970s could only be in place for a matter of days. Thesepumps had a traumatic blood interface leading to hemolysisand thrombosis, as well as inadequate power supply, faultycontrol mechanisms, and prohibitive cost. These limitationsprompted the NIH to issue another series of initiatives in thelate 1970s to develop component technology for deploymentin durable implantable assist devices intended for use inchronic heart failure.

The apogee of popular interest in mechanical circulatoryreplacement came in 1982 after Barney Clark, a Seattledentist, received the Jarvik-7 total artificial heart (TAH). Thiswas the first device intended for permanent circulatorysupport and allowed the recipient to survive 112 days beforedying of sepsis.6 TAH development eventually stalled be-cause of high rates of infection, pump thrombosis, and stroke.Meanwhile, the MCS community redoubled efforts to designsimpler, single-chamber pumps that could act as assist de-vices in series with the native ventricle. In addition, cardiactransplantation experienced a renaissance after the US Foodand Drug Administration (FDA) approved cyclosporine in1983. Improved immunosuppression featuring a calcineurininhibitor contributed to a sharp increase in graft survival anda rapid expansion in the number of heart transplant programsin the United States.7 Hopes for artificial circulation persistedthanks to the collaborative efforts of intrepid surgeons,innovative engineers, and courageous patients. The NIH-

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.Correspondence to Michael M. Givertz, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail

[email protected](Circulation. 2012;125:1304-1315.)© 2012 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.060830

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sponsored programs for long-term support bore fruit in 1984with successful deployment of the electric, pulsatile NovacorLVAD as a BTT.8 That same year the Centers for Medicareand Medicaid Services codified distinct strategies for me-chanical support to guide device development and regulatoryapproval (Table 1). By the mid-1990s, FDA had approvedmultiple pulsatile platforms allowing patients to recover frompostcardiotomy shock or bridge to cardiac transplant.8

The expansion of durable LVAD options for patients withadvanced heart failure came just as the significant shortage ofdonor hearts was becoming apparent. The advanced heartfailure epidemic in the United States has been estimated toinclude 100 000 to 250 000 patients with refractory NewYork Heart Association (NYHA) class IIIB or IV symptoms.9

Yet �2300 donor hearts are available and reserved for highlyselected, younger candidates with limited comorbidities.10

Figure 1. Historical perspective on mechanical circulatory support. This timeline marks the seminal events in mechanical circulatorysupport over the previous 5 decades, from the first reported use of an artificial ventricle in 1963 to the current generation ofcontinuous-flow pumps. ADVANCE indicates Evaluation of the HeartWare Ventricular Assist Device for the Treatment of AdvancedHeart Failure; CMS, Centers for Medicare and Medicaid Services; FDA, Food and Drug Administration; INTERMACS, Interagency Reg-istry for Mechanically Assisted Circulatory Support; NHLBI, National Heart, Lung and Blood Institute; NIH, National Institutes of Health;NYHA, New York Heart Association; REVIVE-IT, Randomized Evaluation of Ventricular Assist Device Intervention before InotropeDependence; TAH, total artificial heart; and VAD, ventricular assist device.

Table 1. Implant Strategies and Target Populations for Mechanical Circulatory Support

Strategy Definition Target Population

Bridge to transplant (BTT) For patients actively listed for transplant thatwould not survive or would develop

progressive end-organ dysfunction from lowcardiac output before an organ becomes

available.

Patients with progressive end-organ dysfunctionor refractory congestion, those anticipated to

have a long waitlist time (eg, highly sensitized,blood group O), or who desire improved quality

of life while waiting.

Bridge to candidacy (BTC) For patients not currently listed fortransplant, but who do not have an absoluteor permanent contraindication to solid-organtransplant. This includes patients in whom

potential for recovery remains unclear.

Patients who might be eligible for transplantafter a period of circulatory support that allowsfor improved end-organ function, unloading (eg,pulmonary vasodilation) or nutrition, resolutionof a comorbid condition (eg, cancer treatment)or institution of lifestyle changes (eg, weight

loss, smoking cessation).

Destination therapy (DT) For patients who need long-term support,but are not eligible for transplant because of

one or more relative or absolutecontraindications.

Older patients (eg, �70 y) or those withmultiple comorbidities anticipated to require

only left ventricular support.

Bridge to recovery (BTR) For patients who require temporarycirculatory support, during which time theheart is expected to recover from an acute

injury, and mechanical support is thenremoved without need for transplant.

Patients with reversible cardiac insults such aspost–myocardial infarction or post–cardiotomy

shock, fulminant myocarditis, or peripartumcardiomyopathy.

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Although LVAD technology was pioneered in the bridgesetting where transplant offered a bailout for device failure, asdevices matured, development began to be targeted towarddevices capable of long-term or permanent circulatorysupport.11

Over the past 2 decades, a series of revolutions in pumpdesign and pivotal clinical trials have changed the face ofadvanced heart disease care (Table 2). The landmark FDAapproval of the HM XVE for permanent destination therapy(DT) in 2003 uncoupled access to durable MCS from trans-plant eligibility. As VAD therapy entered the mainstream, thecollaborative Interagency Registry of Mechanically AssistedCirculatory Support (INTERMACS) was established in 2006to map the evolution of durable MCS. Since the approval ofthe continuous-flow HeartMate (HM) II for DT in 2010, therehas been a 10-fold increase in approved LVADs implantedfor lifelong support in transplant-ineligible patients.12,13 With1-year survival now �80% with the approved continuous-flow LVAD, the promise of half a century’s work has beenrealized, and “the decade of the ventricular assist device”14

has arrived.

Pumps in EvolutionEvolving Flow ProfileIn the field of assisted circulation, evolving pump design hasdriven clinical progress (Table 3). After the invention of a

smaller high-speed, rotary impeller pump with a singlemoving part, continuous-flow VADs with enhanced durabil-ity and near-silent operation became available. The transitionfrom pulsatile technology toward continuous flow has beenremarkably swift. Before 2008, all VADs implanted in theUnited States outside the clinical trial setting deliveredpulsatile flow via an electrically (Novacor, HeartMate XVE)or pneumatically (HeartMate IP, Thoratec IVAD/PVAD)driven volume displacement pump. However, after FDAapproval of the HM II for BTT and then DT, by the first halfof 2010 �98% of all LVADs implanted in the United Stateswere continuous flow.13

The rapid rise of continuous-flow pumps has been pro-pelled by their significant survival and performance advan-tage over older, pulsatile devices. The randomized HM II DTstudy enrolled NYHA class IV patients ineligible for trans-plant and directly compared flow profiles. Superior survivalwas seen with the continuous in comparison with pulsatile(HM XVE) VAD at both 1 year (68% versus 55%) and 2years (55% versus 24%) (Table 2).15 The INTERMACSregistry confirmed the superior survival with continuousversus pulsatile flow LVADs at 1 year (83% versus 67%) and2 years (75% versus 45%), with an overall P�0.0001.13

Although continuous-flow pumps increase the probability ofsurvival to transplant, once a patient receives a transplant,survival is similar regardless of whether a pulsatile or

Table 2. Landmark Trials in Mechanical Circulatory Support

Study (Year) Strategy Device Flow Profile Population Design (n) Primary End Point(s) Outcomes

REMATCH (2001) DT ThoratecHeartMate XVE

Pulsatile NYHA class IV; LVEF�0.25 with VO2 �12mL � kg�1 � min�1 orinotrope dependent;

ineligible for transplant

Randomly assigned 1:1to HeartMate XVE (68)

vs optimal medicalmanagement (61)

Death from any cause 48% reduction in deathwith LVAD vs medical

therapy (P�0.001)Overall survival at 1 y

52% with LVAD vs25% with medicaltherapy (P�0.002)

Total artificial heart (2004) BTT SynCardiaCardioWest

TAH-t

Pulsatile Transplant eligible; risk ofdeath from biventricular

failure

Nonrandomized TAH at5 centers (81) vs

historical controls (35)

Survival until transplant;overall survival

Survival to transplant79% with TAH-t vs

46% controls(P�0.001); overall

survival at 1 y 70%with TAH vs 31%

controls (P�0.001)

HeartMate II BTT (2007) BTT ThoratecHeartMate II

Continuous (axial) NYHA class IV; listed fortransplant UNOS status

1A or 1B

Nonrandomized (133),without controls orcomparison group

Proportion transplanted,listed or eligible to belisted, or recovery with

explant by 180 d

75% met primary endpoint (42%

transplanted, 32% alivewith ongoing device

support, 1% recovered)

HeartMate II DT (2009) DT ThoratecHeartMate II andHeartMate XVE

Continuous (axial)and Pulsatile

NYHA class IIIB or IV;LVEF �0.25 with VO2

�14 mL � kg�1 � min�1

or �50% predicted;ineligible for transplant

Randomized 2:1 toHeartMate II (134) vsHeartMate XVE (66)

Survival at 2 y free ofdisabling stroke or

reoperation for devicerepair or replacement

Composite end point in46% with HeartMate IIvs 11% with HeartMate

XVE (P�0.001)Actuarial survival at 2 y

58% vs 24%,respectively

ADVANCE (2010) BTT HeartWare HVAD Continuous(centrifugal)

NYHA class IV; listed fortransplant UNOS status

1A or 1B

Nonrandomized HVAD(137) vs contemporaryLVAD registry controls

(499)

Proportion alive ortransplanted at 180 d

compared with registrycontrols (propensity

score adjusted)

Alive or transplanted:92% of HVAD vs 90%of controls (P�0.001

for noninferiority)

ADVANCE indicates Evaluation of the HeartWare Ventricular Assist Device for the Treatment of Advanced Heart Failure; BTT, bridge to transplant; DT, destinationtherapy; HVAD, HeartWare ventricular assist device; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association;REMATCH, Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure; TAH-t, temporary total artificial heart; UNOS, UnitedNetwork of Organ Sharing; and VO2, peak oxygen consumption.

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continuous-flow LVAD is used as a bridge.16,17 Furthermore,although older data have shown impaired posttransplantsurvival in patients bridging with LVADs,18 a new Interna-tional Society for Heart and Lung Transplantation reportshows similar outcomes in comparison with patients who donot require pretransplant LVAD support.17

Interestingly, both REMATCH and the HM II DT trialshowed similar 50% to 60% 1-year survival with the XVEdevice despite nearly a decade of intervening clinical expe-rience, suggesting a limit to further long-term progress withapproved pulsatile LVAD technology.19 In contrast, there hasbeen a notable temporal improvement in survival to trans-plant with the HM II in recent years. In the extendedenrollment phase of the pivotal trial, 1-year survival increasedfrom 68% to 74% in comparison with the original cohort,then increased further to 85% in the postapproval setting.20,21

The apparent learning curve after adoption of continuous-flow technology may be attributed to improved patientselection, surgical experience, and postoperative medicalcare. Management suggestions have been published for in-hospital and longitudinal management of LVADs, althoughthe brisk pace of change in the field has precluded develop-ment of consensus guidelines.22–24

Smaller rotary pumps like the HM II have some uniquebenefits beyond improved survival. The lower pump profileallows preperitoneal abdominal implantation in somewhatsmaller patients, including women and adolescents. Beforethe HM II, patients with small body surface area wererelegated to an extracorporeal pump as a BTT and had noapproved DT option that could safely fit in their abdomen.Smaller pump profiles also have been linked to earlierpostoperative recovery and enhanced comfort due to lesscrowding. The newer HeartWare VAD (HVAD) and Jarvik-2000, which are still under investigation, are small enough toallow intrapericardial implantation, which may further en-hance comfort.25,26 The near-silent operation of nonpulsatiletechnology also makes these pumps less intrusive for patientsand their caregivers, particularly in quiet public places.

Evolving Pump ComplicationsAll MCS devices are subject to complications resulting fromthe complex interplay between pump and patient. Althoughdevice durability has been dramatically enhanced withcontinuous-flow pumps, stroke and infection remain substan-

tial risks, and unanticipated hazards specific to rotary VADshave been recognized. The greatest recent impact of pumpdesign on reducing adverse events is the extended durabilityof continuous-flow rotary pumps. Mechanical failure offirst-generation electric and pneumatically driven pulsatilepumps frequently resulted in reoperation for device exchangeor even death. In REMATCH, 35% of HM XVE recipientsexperienced component failure within 24 months.27 Similarly,in the HM II DT study, 20 of 59 patients randomly assignedto HM XVE required 21 device replacements and 2 deviceexplants because of bearing wear and valve dysfunction.15 Bycontrast, current continuous-flow LVADs like the HM II aredesigned with only a single, nearly frictionless moving part(the impeller) and do not have a pusher plate or artificialvalves. In the pivotal HM II DT trial, the rate of pumpreplacement was only 0.06/patient-year for HM II in compar-ison with 0.51/patient-year for HM XVE (P�0.001). Reop-eration to repair or replace the pump, a key secondary endpoint in the HM II DT trial, was significantly lower for therotary pump (hazard ratio 0.18, P�0.001).15 Continuous rotoractivity ensures unidirectional blood flow and obviates theneed for valved conduits, which were subject to structuralvalve deterioration. Primary pump failure remains exceed-ingly rare with the HM II, but device exchange may still berequired for pump thrombosis, cannula malposition, or deepinfection. In the HM II BTT experience of 133 implants, 1device-related death and 5 pump replacements (VAD throm-bosis in 2 patients, surgical complications in 3) were ob-served.28 Third-generation pumps currently under develop-ment operate without bearings by use of eitherhydrodynamically (eg, HVAD) or magnetically (DuraHeartLVAD, HeartMate III) levitated rotors, which may alloweven greater pump longevity.29

Although LVAD durability has been greatly extended, theinherent risks of bleeding, stroke, and infection remain.Debilitating stroke is the most dreaded complication of MCSand is equally common with continuous-flow pumps andpulsatile devices. In the postmarketing BTT HM II study,stroke rate was 0.08 events/patient-year for HM II and 0.11events/patient-year for the contemporaneous pulsatile de-vices, including HM XVE and Thoratec IVAD (P�0.38).21

Embolic strokes appear more common than hemorrhagicstrokes with all device designs,21 and may arise not only fromin situ clot formation on a pump component, but also from

Table 3. Implantable LVADs in Evolution

HeartMate XVE Thoratec IVAD* HeartMate II HeartWare HVAD Jarvik 2000

Manufacturer Thoratec Thoratec Thoratec HeartWare Jarvik Heart

Flow profile Pulsatile Pulsatile Continuous (axial) Continuous (centrifugal) Continuous (axial)

Implant site Abdomen Abdomen Abdomen Pericardium Pericardium

Driver Electric Pneumatic Electric Electric Electric

Weight 1150 g 339 g 290 g 160 g 90 g

Displacement 400 mL 252 mL 63 mL 50 mL 25 mL

FDA approval BTT, DT BTT BTT, DT IDE IDE

BTT indicates bridge to transplant; DT, destination therapy; FDA, Food and Drug Administration; HVAD, HeartWare ventricular assistdevice; IDE, investigational device exemption; and IVAD, implantable ventricular assist device.

*Thoratec PVAD is the same pump placed in a paracorporeal position.



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ingested thrombus propelled through the device. In therandomized HM II DT trial, which enrolled sicker patients,disabling stroke was not statistically different between con-tinuous and pulsatile flow (11% versus 12%, P�0.56).15

Overall stroke rates were modestly lower with HM II com-pared to HM XVE (0.13 versus 0.22 events/patient-year,P�0.21), with patients at equivalent risk of ischemic andhemorrhagic stroke. The ischemic stroke rate for HM IIpatients may not be significantly different from patients withend-stage heart failure without device support, althoughcontrolled comparative data do not exist. Data from thenonrandomized HeartWare HVAD BTT experience revealedsimilar risk of stroke in comparison with other VADs, with0.10 ischemic and 0.05 hemorrhagic strokes/patient-year, andan overall risk of disabling stroke of 0.06 events/patient-year.30 Long-term stroke risk with the HVAD pump will beclarified with the extended enrollment phase of the Evalua-tion of the HeartWare Ventricular Assist Device for theTreatment of Advanced Heart Failure (ADVANCE) trial.Anticoagulation regimens may ultimately be device specific,and the relatively low-level anticoagulation recommended forthe HM II may be inadequate for the HVAD. Stroke risk withthe Jarvik 2000 has not been published.

The optimum level of antiplatelet and anticoagulant ther-apy to minimize both thromboembolic and hemorrhagicstroke is unknown, and few comparative data exist. The HMII has relatively low thrombotic risk provided patients are onan anticoagulation regimen that features an antiplatelet agentsuch as aspirin along with warfarin with an internationalnormalized ratio goal of 1.5 to 2.0.22,31 As LVAD useexpands into older patient populations, it must be remem-bered that advanced age remains the most potent risk factorfor stroke. Indeed, stroke has become such a crucial safetyend point that stroke-free survival will be used as the primaryendpoint for the Evaluation of the HeartWare VentricularAssist System for Destination Therapy of Advanced HeartFailure (ENDURANCE) clinical trial, the ongoing random-ized study of the HVAD compared with contemporarycontinuous-flow pumps for DT.32 Careful adjudication ofneurological events is now central to MCS trial design. Strokerisk may be particularly relevant for those patients intendedas BTT because disabling stroke may render them ineligiblefor transplant. Stroke risk should be part of counseling beforeelective MCS, particularly as extended or lifetime mechanicalsupport becomes increasingly common and stroke risk maynot abate with time.

Device-related infection also remains common with MCSand has been described as the Achilles heel of circulatoryassist.33 The majority of infections involve the percutaneousdriveline, pump pocket, or both. Rotary blood pumps withsmaller surface areas and thinner drivelines may be less proneto infection than pulsatile pumps. Pump design, patientselection, surgical technique, and driveline care appear to bethe primary determinants of infectious risk.34 Immobilizationof the driveline may help avoid torsion and breakdown of thecutaneous junction, the most common entry point for infec-tions. Transcutaneous energy transfer systems may one dayeliminate the need for a percutaneous driveline, althoughprogress has been hampered by high-power requirements that

outstrip current battery technology.35 Fortunately, infectioninvolving the blood surface interface of the pump, known aspump endocarditis, is rare. Pump infections have dire conse-quences because they are so difficult to eradicate. Device-related infection even allows upgrade to United Network forOrgan Sharing status IA. For those ineligible for transplant,device infection represents an incurable and often fatalcomplication of MCS.

Multiple distinct and largely unanticipated complicationsof continuous (or nonpulsatile) blood flow have emerged thatwere not experienced with pulsatile pumps. Continuous-flowVADs have been associated with bleeding from cerebral andgastrointestinal arteriovenous malformations.36,37 In additionto stimulating the formation of arteriovenous malformations,continuous axial flow produces high-shear stress that disruptscirculating high-molecular-weight multimers of von Wille-brand factor, leading to an acquired von Willebrand syn-drome with defective platelet aggregation.38,39 Mucosalbleeding risk is compounded by the requirement for antico-agulation. In addition, chronic aortic insufficiency may de-velop with prolonged continuous flow and can representeither an exacerbation of mild preexisting regurgitation or denovo insufficiency.23,40 Development of aortic insufficiencyhas been attributed to expansion of the aortic sinus, infrequentvalve opening, and greater aortic diastolic pressures, each ofwhich can contribute to leaflet fusion and valvular incompe-tence.41 The cumulative risk of stroke, infection, bleeding,and aortic insufficiency will shape the debate about theeventual cost-effectiveness of rotary LVADs for chronicheart failure.

Future Prospects for Pulsatile Flow, BiventricularTherapies, and Partial SupportDespite the ascendancy of continuous-flow pumps, pulsatileplatforms still have an important role in the modern era. Inacute cardiogenic shock, pulsatile flow maximizes bothperfusion pressure and unloading of the pulmonary circuitand right heart.42 Pulsatile technology also has an exclusiverole in the BTT setting when biventricular support or replace-ment is required, either in the form of biventricular assistdevices or TAH. Pulsatile devices also allow for easierconversion from an LVAD to biventricular support with asingle platform should right ventricular failure develop.Nevertheless, continuous-flow configurations for biventricu-lar assist devices are being actively explored, and case reportsof successful biventricular HM II and HVAD support havebeen published.43,44

The TAH offers full circulatory replacement therapy forpatients with irreversible biventricular failure, although only2% to 3% of current MCS implants are TAHs.13 Thepneumatically driven SynCardia TAH was FDA approved forBTT in 2004, and received Centers for Medicare and Med-icaid Services coverage in 2008. It requires no surgicalpocket, can provide up to 10 L/min flow with physiologicalcontrol through both pulsatile pumping chambers, and has theshortest blood path of any circulatory device. However, theTAH requires adequate mediastinal space to accommodatethe dual-chambered pump, and its utility has been limited bya large controller requiring permanent hospitalization.45 Syn-



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Cardia’s next-generation portable pneumatic controller (Free-dom Driver) is small enough at 5.9 kg that patients can bedischarged from the hospital and remain relatively indepen-dent despite orthotopic mechanical replacement. The Free-dom Driver is undergoing investigational device exemptioninvestigation with the previously approved TAH as a BTT.46

Perhaps most importantly, the TAH is currently the onlyMCS option for transplant candidates with restrictive orinfiltrative cardiomyopathies with ventricular cavities toosmall to accommodate apical inflow cannulae. Such patientswere previously relegated to prolonged hospitalization oninotropes, and now they too have an MCS option that couldallow discharge from the hospital while awaiting transplant.Device malfunction, along with bleeding, stroke, and infec-tion, remain concerns with TAH technology.

Another important trend in pump development has beenminiaturization, even at the expense of flow rate. Implantableminiature pumps may be able to deliver long-term partialcirculatory support to allow recovery of ventricular functionafter an acute insult or provide durable assistance. TheCircuLite Synergy micropump, under investigation, can pro-vide up to 3 L/min of flow from the left atrium into thesubclavian artery and can be implanted without cardiopulmo-nary bypass via a minithoracotomy.47 Investigators have alsodescribed using the continuity between the posterior aorticwall and left atrium as another means of providing LVsupport without entering the ventricle.48 As surgery becomesless invasive and successful strategies for long-term percuta-neous support are realized, MCS implantation will likelybecome more proactive and move into less sick patients withearlier stage heart failure.

Changing Patient PopulationsAs pump design has evolved, so has the population of patientswith advanced heart failure receiving MCS. With the recentexpansion in use of the HM II for DT, there is now ameaningful cohort of patients receiving lifetime LVAD sup-port. The success of LVAD therapy has generated debateabout the degree of heart failure that should prompt implantand has altered decisions about listing for transplantation.Elements of the preimplant assessment have also been recon-sidered, such as right ventricular (RV) function, nutritionalstatus and age. LVAD programs have in turn evolved to meetthe needs of the ever-expanding and varying group of patientsliving with MCS.

Evolving Role for LVADs and TransplantationSince 1999, more than a third of all listed adult hearttransplant candidates and 75% of those initially listed asUnited Network for Organ Sharing status IA have receivedMCS.49 Implantation of an LVAD in status I patients allowsthem to undergo transplantation relieved of the burden ofchronic congestion, with improved end-organ function andnutritional status. Although United Network for Organ Shar-ing status I was originally conceived for patients with lessthan a week to live, the average waiting time in status I is now�6 months, during which patients with end-stage heartfailure are exposed to risks of infection, blood clots, andpressure ulcers, and experience exhaustion of family support.

In this era of prolonged waitlist times, LVAD therapy canallow patients to return home with an improved quality of lifewhile waiting for a donor organ to become available.50 Earlyreferral for device therapy may also be reasonable in patientslisted for transplant who are anticipated to have a longwaiting time because of blood type, large body size, or a highdegree of allosensitization.

For patients listed as United Network for Organ Sharing statusII, survival without transplant or LVAD has been improving,with 81% 1-year and 74% 2-year survival in the era between2000 and 2005.51 Improved outcomes while listed may reflectbetter medical therapies or earlier listing (eg, lead-time bias) andhave occurred despite older age and a greater burden of comor-bidities. Survival with heart failure while listed as status II issimilar to that with the current second-generation continuous-flow LVADs. However, mechanical support may offer im-proved functional capacity and quality of life in comparison withoptimal medical therapy, including home inotropes. With lim-ited donor organ availability, only 14% of all heart transplants in2009 occurred in status II patients, highlighting the potential forexpanded LVAD use.49 Because of the success of LVADtherapy, transplant without MCS may be best reserved forpatients with dominant RV dysfunction, structural obstacles toisolated left ventricular support, or unacceptably high risk forreoperation. With extended LVAD durability, the eventual goalmay be to avoid transplant and its attendant complications for aslong as possible. This will likely require a change in patient,family, and/or provider expectations before VAD implantation.

LVADs have also been deployed as a bridge to candidacyin patients with potentially reversible or relative contraindi-cations to transplant. Encouraging data exist for the reversalof secondary pulmonary hypertension in select patients,although, in many cases, RV dysfunction may persist evenwith LVAD support.52–55 If pulmonary vascular resistanceremains elevated, sildenafil may be considered.56 Other con-traindications to transplant such as severe chronic kidneydisease or morbid obesity seldom improve to a degree thatallows listing. Given the scarcity of donor organs andimproving outcomes with LVAD support, recipients who arenot transplant candidates at time of implant should beprepared for the possibility of lifetime mechanical support.

Earlier Timing for Durable SupportThe INTERMACS profiles have been developed to defineclinically important differences in the severity of diseaseamong patients with advanced heart failure (Table 4).57

Nearly 70% of all registered VADs have been implanted inthe sickest subset of patients with heart failure, those withcritical cardiogenic shock (INTERMACS level 1) or pro-gressive end-organ dysfunction despite inotropic support(INTERMACS level 2). Worsening INTERMACS profile hasbeen consistently associated with higher perioperative mor-tality.58 In the past 2 years, the field has moved away fromimplanting primary LVADs in level 1 patients because ofpoor outcomes.59 Many are now receiving temporary percu-taneous circulatory support, sometimes referred to as bridgeto bridge, as a way to support circulation and triage thesickest patients for eventual durable LVAD. Waiting forend-organ failure or even more subtle signs of debilitation



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before moving to LVAD support is no longer acceptable.59

Similarly, destination LVAD should be considered an elec-tive procedure in medically stable candidates rather than abailout for the patient sliding into refractory low-output heartfailure despite inotropic or temporary circulatory support.Some patients may require an inpatient medical tune-up withvasoactive or diuretic therapy immediately before LVADsurgery.

Dependence on intravenous positive inotropes has tradi-tionally been considered the threshold that prompts consid-eration of advanced therapies. Patients with advanced systolicheart failure, however, are currently eligible for destinationLVAD coverage even if they are not dependent on inotropes,provided they have symptoms at rest and a peak oxygenconsumption �14 mL � kg�1 � min�1 on optimal oraltherapies (INTERMACS levels 4 and 5) (Table 5). Only 18%

of durable adult LVADs are currently implanted in patientsnot yet dependent on intravenous inotropes.13 Low implantrates in ambulatory heart failure may reflect reluctance ofboth physicians and patients. Ambulatory patients with ad-vanced heart failure should have ongoing discussions aboutthe trade-offs of living with heart failure in comparison withundergoing VAD operation to identify preferences andthresholds for considering elective LVAD therapy.60

Fortunately, the evidence base to guide LVAD use beforeinotrope dependence is growing. Equipoise now exists for thestudy of smaller, more reliable continuous-flow pumps forDT in “less sick” patient with advanced heart failure. TheNIH has sponsored the Randomized Evaluation of VADIntervention before Inotropic Therapy (REVIVE-IT) trial tostudy LVAD therapy in patients who have advanced heartfailure with significant functional impairment and who areineligible for transplant, but who have not yet manifestedserious consequences of end-stage heart failure, such assevere end-organ dysfunction, immobility, or cardiac ca-chexia.61 The REVIVE-IT pilot study is in the advancedplanning stages and will randomly assign 100 patients withmoderately advanced heart failure in a 1:1 ratio to theHeartWare HVAD, an intrapericardially implantedcontinuous-flow centrifugal pump, or optimal medical ther-apy.62 The upcoming industry-sponsored ROADMAP (RiskAssessment and Comparative Effectiveness of Left Ventric-ular Assist Device and Medical Management in AmbulatoryHeart Failure Patients) trial will be a prospective, nonran-domized observational study of NYHA IIIB/IV patients notyet on inotropes that will compare the postmarketing effec-tiveness of the HM II for DT on optimal medical therapy. Inaddition, as part of the ongoing INTERMACS effort aparallel registry of medically managed chronic systolic heartfailure patients with refractory NYHA class III or IV symp-toms is being assembled as part of the Medical Arm ofMechanically Assisted Circulatory Support (MEDAMACS)initiative. This prospective, observational medical registrywill have a particular focus on INTERMACS profiles 4 to 6to help define the natural history of ambulatory advancedheart failure and refine patient selection in this crucial

Table 4. INTERMACS Patient Profile Levels

Level Patient CharacteristicsImplants*

(1/2009–6/2010), %Inotrope

Dependent

Target forREVIVE-ITDT Study

1 Critical cardiogenic shock despite escalating support 17 �

2 Progressive decline despite inotropes 45 �

3 Clinically stable, but inotrope dependent 20 �

4 Recurrent, not refractory, advanced heart failure 12 �

5 Exertion intolerant, but comfortable at rest and ableto perform activities of daily living with slight

difficulty

3 �

6 Exertion limited; able to perform mild activity, butfatigued within a few minutes of exertion

2 �

7 Advanced NYHA class III 1 �

INTERMACS indicates Interagency Registry of Mechanically Assisted Circulatory Support; NYHA, New York Heart Association; andREVIVE-IT, Randomized Evaluation of VAD InterVEntion before Inotropic Therapy.

*Data from Kirklin et al.13

Table 5. Requirements for Destination Therapy Coverage

Characteristic Requirement

Device FDA-approved device for DT (HeartMate XVE, HeartMate II)

Patient Chronic NYHA class IV heart failure

Not a candidate for heart transplant

Did not respond to optimal medical management for 45 oflast 60 d (including �-blockers and ACE inhibitors iftolerated), or IABP for 7 d, or IV inotrope for 14 d

LVEF �25%, and severe functional limitation with peakVO2 �14 mL � kg�1 � min�1, unless on IABP orinotropes, or physically unable to complete test

Facility Experienced surgeon (�10 VAD/TAH implants in 36 mo)

Member of INTERMACS Registry

Joint Commission-certified VAD program

ACE indicates angiotensin-converting enzyme; DT, destination therapy; IABP,intra aortic balloon pump; INTERMACS, Interagency Registry for MechanicallyAssisted Circulatory Support; IV, intravenous; NYHA, New York Heart Associa-tion; TAH, total artificial heart; VAD, ventricular assist device; and VO2, oxygenconsumption.

Adapted from National Coverage Determination (NCD) for Artificial Hearts andRelated Devices (20.9). Publication No. 100-3, Version No. 5, Implementation Date:January 6, 2011. Available at: http://www.cms.gov/medicare-coverage-database.Accessed October 25, 2011.



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spectrum of disease where the greatest expansion in LVADuse is anticipated.

Triggers for Evaluation of MCS CandidacyThe clinical sign posts that mark a downward trajectory ofpatients with chronic heart failure, and that may serve astriggers for referral for MCS, are often missed or recognizedonly in retrospect (Table 6). Common indicators of increasedmortality in heart failure include two or more hospitalizationsfor acute decompensation in a 12-month period, developmentof a circulatory or renal limitation to angiotensin-convertingenzyme inhibitor therapy, hypotension in response to�-blocker therapy, a peak oxygen consumption �14 to 16mL � kg�1 � min�1 or �50% predicted, symptoms at rest(NYHA class IV) on most days, failure to respond to cardiacresynchronization therapy, or 6-minute walk distance �300m.63–65 Other high-risk clinical and laboratory features in-clude worsening right heart failure and secondary pulmonaryhypertension, diuretic refractoriness associated with worsen-ing renal function, persistent hyponatremia, hyperuricemia,

and cardiac cachexia. Ventricular tachycardia refractory tomedical and ablative therapies, even in the absence of severeheart failure, is also an indication for considering MCSsupport.

The Seattle Heart Failure Model has been applied broadlyto estimate mortality and anticipate benefits from medical ordevice therapies.66 This model also predicts mortality afterLVAD implant, although it may underestimate the risk ofVAD or urgent transplant listing among ambulatory pa-tients.67,68 Patients with anticipated mortality �15% at 1 yearor �20% at 2 years based on the Seattle Heart Failure Modelshould be considered high risk and evaluated for MCScandidacy. For patients not facing imminent death, but whohave severe symptom burden, the functional benefits alonemay justify referral for LVAD therapy. The HM II has beenshown to increase 6-minute walk distance �200 m, with mostpatients improving to NYHA class I or II.69 Patients ap-proaching any of these signposts should be considered forreferral to an advanced heart disease program to determinecandidacy for transplant, MCS, or both (Figure 2).

Evolving Preimplant ConsiderationsConsiderable effort has gone into developing risk scores topredict perioperative outcomes after LVAD implant. Riskfactors for perioperative mortality focus on indices of hepaticand renal dysfunction and poor nutrition, which may bemanifestations of right heart failure that are unaddressed byleft-sided support alone.70,71 Risk scores developed in thepulsatile flow era may be less discriminating when applied tocontinuous-flow devices, in part, because of improved out-comes.72 The latest HM II risk score showed that multivari-able preoperative predictors of mortality included older age,higher creatinine, low albumin, and implant center inexperi-ence.71 Right heart failure after LVAD implant results in upto a 6-fold increase risk of death and is a major contributingfactor in prolonged hospitalizations.73 Accurate assessment ofRV function is required before LVAD implant, particularlywhen transplant is not an option, because biventricularsupport is not yet feasible (or approved) for DT. RV dysfunc-

Table 6. Triggers for Referral for VAD Evaluation

Inability to wean inotropes or frequent inotrope use

Peak VO2 �14–16 mL � kg�1 � min�1 or �50% predicted

Two or more HF admissions in 12 mo

Worsening right heart failure and secondary pulmonary hypertension

Diuretic refractoriness associated with worsening renal function

Circulatory-renal limitation to ACE inhibition

Hypotension limiting �-blocker therapy

NYHA class IV symptoms at rest on most days

Seattle HF model66 score with anticipated mortality �15% at 1 y

Six-minute walk distance �300 m

Persistent hyponatremia (serum sodium �134 mEq/L)

Recurrent, refractory ventricular tachyarrhythmias

Cardiac cachexia

ACE indicates angiotensin-converting enzyme; HF, heart failure; NYHA, NewYork Heart Association; and VO2, oxygen consumption.

Figure 2. Decision tree for elective mechani-cal circulatory support in advanced heart fail-ure. This is a suggested algorithm for decisionmaking about elective mechanical circulatorysupport in advanced heart failure. Once atrigger for VAD evaluation has been identified,patients should be referred to an experiencedMCS center where all advanced therapies,including transplant and VAD, can be consid-ered. Decisions about MCS are contingent oneligibility for transplantation, and the likelihoodof RV failure after LVAD implant, as well.Patients ineligible for heart transplant withhigh VAD implant risk or RV failure risk afterLVAD have few MCS options. Unless the pre-operative risk is reversible (eg, infection),these patients are candidates for medicaltherapy alone and may benefit from earlyreferral to supportive cardiology. AKI indicatesacute kidney injury; BIVAD, biventricular assistdevice; BTT, bridge to transplant; DT, desti-nation therapy; LVAD, left ventricular assistdevice; MCS, mechanical circulatory support;RV, right ventricular; and TAH, total artificialheart.



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tion present with inotropic support before LVAD appears topersist after implant, with uncertain long-term conse-quences.55 In the meantime, multiple RV clinical risk scoreshave been developed to anticipate RV failure and plan forbiventricular support (Table 7).73–75 However, none of thesescores was derived in a DT cohort or with newer continuous-flow LVADs, which may be even more sensitive to RVfailure because of greater systemic venous return and exag-gerated interventricular dependence.

Proactive relief of congestion in the hospital, often guidedby a pulmonary artery catheter, is indicated to prepare thepatient for implant. Early postoperative use of inotropes orinhaled pulmonary vasodilators, or proactive right ventricularassist device placement may allow the best chance forrecovery of RV function.76 The ability to adjust continuouspump speed in real time under echocardiographic guidancemay also help optimize RV contractile geometry and mini-mize residual tricuspid regurgitation.22 Although some sur-geons advocate prophylactic tricuspid valvuloplasty, othersurgeons have shown no benefit.77,78 Selection of patients forisolated LVAD will also be informed by our improvedunderstanding of load-independent RV function (eg, RVstroke work index), pulmonary impedance, and RV contrac-tile reserve. The right heart is central to all decisionssurrounding LVAD therapy.

Adequate nutritional support reduces the risk of postoper-ative infection and improves functional recovery after LVADplacement. Yet patients with end-stage heart failure haveprofound metabolic imbalances, particularly when hepaticand gastrointestinal congestion is a prominent presentingfeature. Patients with cachexia and a low prealbumin and/orelevated C-reactive protein are at particularly high risk forperioperative death, often from infection.79 Other markers ofpoor nutritional status include reduced levels of serum albu-min, total protein, total cholesterol, and lymphocyte count.Aggressive nutritional support, including enteral feeding,should be considered in all LVAD candidates with any signof low nutritional reserve. In contrast to its role in transplantlisting, obesity is not a contraindication to LVAD implanta-tion, nor does it appear to increase the risk of drivelineinfection as previously feared.80 Low body mass index hasconsistently been shown to be a greater predictor of mortality

after LVAD than elevated body mass index. Whereas LVADtherapy has been proposed in BTC patients to facilitateweight reduction, there are few data to support a bridge toweight loss strategy,81 and such patients should be preparedfor the possibility of lifelong LVAD support.

Age is also one of the most commonly cited reasons fortransplant ineligibility, making older patients a target popu-lation for expanded LVAD use. Nearly 75% of patients withheart failure are �65 years of age, and the average age ofpatients hospitalized in the United States with low ejectionfraction heart failure is 75 years.82 The interaction betweenage and LVAD outcomes is evolving. In the INTERMACSregistry, age has been consistently associated with an in-creased hazard of early and late mortality, although the globalimprovements in results with continuous-flow pumps maydiminish the relative impact of age on outcomes.13,83 Indicesof frailty, which may be independent of age, may be evenmore potent predictors of outcome after cardiac surgery.84

Advancing age tracks with greater prevalence of comorbidi-ties such as chronic kidney disease, diabetes mellitus, andcerebrovascular disease, which may be greater drivers ofadverse outcomes. Improvement in survival and quality oflife after HM II therapy in select patients �70 years,including those self-referred from hospice, may not bedifferent from younger recipients, suggesting that age shouldnot be used as an independent contraindication to LVADtherapy at experienced centers.85

Evolution of MCS ProgramsUse of LVAD therapy is best accomplished within anintegrated program of advanced heart disease care. Successfulprograms emphasize teamwork and offer optimization ofmedical and device therapies, evaluation for transplant can-didacy and MCS, and, when appropriate, a focus on palliativecare and end-of-life choices.86 A full menu of MCS optionsshould be available, from temporary percutaneous support tothe latest durable LVAD or biventricular assist technology, sothat device selection can be tailored to patient circumstances.Center experience and procedural volume are of criticalimportance given the complexity of patient care withLVADs.87 Certification of a destination LVAD programrequires not only heart failure cardiologists and cardiac

Table 7. Predictors of Right Ventricular Failure after VAD Implantation

Matthews et al73 Fitzpatrick et al74 Drakos et al75

Definition of RV Failure RVAD or ECMO RVAD RVAD

Inhaled NO �48 h Inhaled NO �48 h

Inotrope �14 d Inotrope �14 d

Home inotrope

Predictors Vasopressor requirement Cardiac index �2.2 L � min�1 � m�2 Preoperative IABP

AST �80 U/mL RV stroke work index �0.25 Destination therapy

Total bilirubin �2 mg/dL Severe RV dysfunction on echo Elevated PVR

Creatinine �2.3 mg/dL Creatinine �1.9 mg/dL

Previous cardiac surgery

Systolic BP �96 mm Hg

AST indicates aspartate aminotransferase; BP, blood pressure; ECMO, extracorporeal membrane oxygenation; IABP, intraaorticballoon pump; NO, nitric oxide; PVR, pulmonary vascular resistance; RV, right ventricle; and RVAD, right ventricular assist device.



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surgeons, but also committed providers from cardiovascularimaging, nursing, psychiatry, social work, physical therapy,nutrition, and financial counseling.88 In addition, subspecial-ists in infectious disease, gastroenterology, and nephrologywith a focus on LVAD care are critical to anticipating andmanaging device-related complications. Quality assessmentand performance initiatives, along with frequent financialreview, further enhance program growth and development.

LVAD patients and their families require intensive educa-tion before implant and dedicated postoperative managementto prepare them for life outside the hospital.50 Patients andtheir caregivers must master device alarm troubleshooting,battery changes, and driveline care. In addition, local firstresponders must be trained and power companies notified toensure access to back-up generators. Committed LVAD caredoes not end with hospital discharge. Much of the responsi-bility for this rests on the shoulders of dedicated VADcoordinators, each of whom is responsible for 15 or moreoutpatients with LVADs.88 Routine outpatient encounterswith LVAD patients focus on blood pressure and volumecontrol, meticulous driveline care, anticoagulation adjust-ment, and counseling to facilitate reintegration into thecommunity and prevent caregiver burnout. Comprehensive,multidisciplinary outpatient MCS clinics have evolved toaddress these varied needs. Institutional commitment to MCSprogram excellence is required to sustain the promisingoutcomes achieved thus far with LVAD therapy.

ConclusionsThe rapid progress of MCS technology in recent years hasextended survival and improved quality of life for selectpatients with advanced heart failure. Indeed, mechanicalsupport has become central to the evidence-based care ofchronic, refractory heart failure. For the first time, there is ameaningful option for lifelong support even in patients whoare not candidates for transplantation. Novel pump design hasimproved clinical outcomes, altered the profile of MCScandidates, and changed the structure of advanced heartdisease programs. With these advances have come newchallenges and opportunities. This article represents the firstin a series of invited reviews on Advances in MechanicalCirculatory Support to appear in Circulation. Future articleswill address percutaneous circulatory support to treat cardio-genic shock, imaging of ventricular function and myocardialrecovery, bleeding and thrombosis risk with continuous flow,lessons from registry data, bridge to myocardial recovery,quality of life on MCS, and the cost-effectiveness of VADs inadvanced heart failure.

DisclosuresNone.

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KEY WORDS: cardiomyopathy � heart failure � ventricular assist device



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Garrick C. Stewart and Michael M. GivertzEvolution

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