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Advances in Mechanical Circulatory Support
Mechanical Circulatory Support for Advanced
Heart Failure
Patients and Technology in Evolution
Garrick C. Stewart, MD; Michael M. Givertz, MD
A
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fter nearly 50 years of clinical development, durable
mechanical circulatory support (MCS) devices are
widely available for patients with advanced heart failure. The
field of circulatory support has matured dramatically in recent
years, thanks to the advent of smaller, rotary pumps. The
resulting transition away from older pulsatile devices has
been swift. Accelerated use of continuous-flow left ventricular assist devices (LVADs) for long-term support has
changed the face of advanced heart failure care. MCS
candidate selection, risk stratification, and management strategies are evolving in tandem with new pump technology,
producing a shift in the profiles of patients being considered
for MCS. Timely referral for MCS evaluation and appropriate
implantation now depends on familiarity with recent advances in pump design and clinical outcomes. This review,
the first in a series on Advances in Mechanical Circulatory
Support, will focus on durable intracorporeal LVADs used in
adults with advanced heart failure, and highlight the evolution
in both patients and technology.
engineering feasibility of such a device. By 1966, the first
successful pneumatic LVAD had been used by Debakey to
support a patient for 10 days after complex cardiac surgery.4
Shortly after the first human heart transplant by Barnard in
1967, artificial ventricle technology began being used as a
mechanical bridge to support patients with postcardiotomy
shock until a donor organ could be identified. Cooley et al5
reported the first use of a total artificial heart as a bridge to
transplant (BTT) in 1969. Ever since, the fields of mechanical
circulation and cardiac transplantation have evolved in counterpoint to each other. Despite the early promise of human
heart transplantation, in the 1970s, high mortality rates early
posttransplant attributable to inadequate immunosuppression
further spurred on the development of MCS. However, the
first generation of extracorporeal pneumatic LVADs of the
1970s could only be in place for a matter of days. These
pumps had a traumatic blood interface leading to hemolysis
and thrombosis, as well as inadequate power supply, faulty
control mechanisms, and prohibitive cost. These limitations
prompted the NIH to issue another series of initiatives in the
late 1970s to develop component technology for deployment
in durable implantable assist devices intended for use in
chronic heart failure.
The apogee of popular interest in mechanical circulatory
replacement came in 1982 after Barney Clark, a Seattle
dentist, received the Jarvik-7 total artificial heart (TAH). This
was the first device intended for permanent circulatory
support and allowed the recipient to survive 112 days before
dying of sepsis.6 TAH development eventually stalled because of high rates of infection, pump thrombosis, and stroke.
Meanwhile, the MCS community redoubled efforts to design
simpler, single-chamber pumps that could act as assist devices in series with the native ventricle. In addition, cardiac
transplantation experienced a renaissance after the US Food
and Drug Administration (FDA) approved cyclosporine in
1983. Improved immunosuppression featuring a calcineurin
inhibitor contributed to a sharp increase in graft survival and
a rapid expansion in the number of heart transplant programs
in the United States.7 Hopes for artificial circulation persisted
thanks to the collaborative efforts of intrepid surgeons,
innovative engineers, and courageous patients. The NIH-
History of Mechanical Circulation
The modern era of cardiac surgery began in 1953 with the
first clinical use of cardiopulmonary bypass, allowing increasingly complex operations and laying the foundation for
circulatory assist devices.1 Shortly after its invention, the
heart-lung machine began to be used to support patients with
postcardiotomy cardiogenic shock to facilitate recovery after
failed operations. By the 1960s, simple cardiac assist devices
began to replace cardiopulmonary bypass for the treatment of
postcardiotomy shock (Figure 1). The first clinical use of an
implantable artificial ventricle was reported by Liotta et al2 in
1963. This primitive ventricular assist device (VAD) consisted of a pneumatically driven, tubular displacement pump
with a valved conduit connecting the left atrium to the
descending thoracic aorta. The pump provided partial left
ventricular bypass for 4 days after postoperative cardiac
arrest before the patient died of multiorgan failure. Inspired
by this pioneering work in cardiac surgery and encouraged by
results from large animal experiments, the National Institutes
of Health (NIH) established the Artificial Heart Program in
1964,3 and 6 companies were contracted to assess the
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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Stewart and Givertz
Mechanical Circulatory Support in Evolution
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Figure 1. Historical perspective on mechanical circulatory support. This timeline marks the seminal events in mechanical circulatory
support over the previous 5 decades, from the first reported use of an artificial ventricle in 1963 to the current generation of
continuous-flow pumps. ADVANCE indicates Evaluation of the HeartWare Ventricular Assist Device for the Treatment of Advanced
Heart Failure; CMS, Centers for Medicare and Medicaid Services; FDA, Food and Drug Administration; INTERMACS, Interagency Registry 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 Inotrope
Dependence; TAH, total artificial heart; and VAD, ventricular assist device.
sponsored programs for long-term support bore fruit in 1984
with successful deployment of the electric, pulsatile Novacor
LVAD as a BTT.8 That same year the Centers for Medicare
and Medicaid Services codified distinct strategies for mechanical support to guide device development and regulatory
approval (Table 1). By the mid-1990s, FDA had approved
multiple pulsatile platforms allowing patients to recover from
postcardiotomy shock or bridge to cardiac transplant.8
Table 1.
The expansion of durable LVAD options for patients with
advanced heart failure came just as the significant shortage of
donor hearts was becoming apparent. The advanced heart
failure epidemic in the United States has been estimated to
include 100 000 to 250 000 patients with refractory New
York Heart Association (NYHA) class IIIB or IV symptoms.9
Yet ⬍2300 donor hearts are available and reserved for highly
selected, younger candidates with limited comorbidities.10
Implant Strategies and Target Populations for Mechanical Circulatory Support
Strategy
Definition
Target Population
Bridge to transplant (BTT)
For patients actively listed for transplant that
would not survive or would develop
progressive end-organ dysfunction from low
cardiac output before an organ becomes
available.
Patients with progressive end-organ dysfunction
or 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 for
transplant, but who do not have an absolute
or permanent contraindication to solid-organ
transplant. This includes patients in whom
potential for recovery remains unclear.
Patients who might be eligible for transplant
after a period of circulatory support that allows
for improved end-organ function, unloading (eg,
pulmonary vasodilation) or nutrition, resolution
of 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 absolute
contraindications.
Older patients (eg, ⬎70 y) or those with
multiple comorbidities anticipated to require
only left ventricular support.
Bridge to recovery (BTR)
For patients who require temporary
circulatory support, during which time the
heart is expected to recover from an acute
injury, and mechanical support is then
removed without need for transplant.
Patients with reversible cardiac insults such as
post–myocardial infarction or post–cardiotomy
shock, fulminant myocarditis, or peripartum
cardiomyopathy.
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Circulation
Table 2.
Landmark Trials in Mechanical Circulatory Support
Study (Year)
March 13, 2012
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Strategy
Device
Flow Profile
Population
Design (n)
Primary End Point(s)
Outcomes
REMATCH (2001)
DT
Thoratec
HeartMate XVE
Pulsatile
NYHA class IV; LVEF
ⱕ0.25 with VO2 ⱕ12
mL 䡠 kg⫺1 䡠 min⫺1 or
inotrope dependent;
ineligible for transplant
Randomly assigned 1:1
to HeartMate XVE (68)
vs optimal medical
management (61)
Death from any cause
48% reduction in death
with LVAD vs medical
therapy (P⫽0.001)
Overall survival at 1 y
52% with LVAD vs
25% with medical
therapy (P⫽0.002)
Total artificial heart (2004)
BTT
SynCardia
CardioWest
TAH-t
Pulsatile
Transplant eligible; risk of
death from biventricular
failure
Nonrandomized TAH at
5 centers (81) vs
historical controls (35)
Survival until transplant;
overall survival
Survival to transplant
79% 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
Thoratec
HeartMate II
Continuous (axial)
NYHA class IV; listed for
transplant UNOS status
1A or 1B
Nonrandomized (133),
without controls or
comparison group
Proportion transplanted,
listed or eligible to be
listed, or recovery with
explant by 180 d
75% met primary end
point (42%
transplanted, 32% alive
with ongoing device
support, 1% recovered)
HeartMate II DT (2009)
DT
Thoratec
HeartMate II and
HeartMate XVE
Continuous (axial)
and Pulsatile
NYHA class IIIB or IV;
LVEF ⱕ0.25 with VO2
ⱕ14 mL 䡠 kg⫺1 䡠 min⫺1
or ⬍50% predicted;
ineligible for transplant
Randomized 2:1 to
HeartMate II (134) vs
HeartMate XVE (66)
Survival at 2 y free of
disabling stroke or
reoperation for device
repair or replacement
Composite end point in
46% with HeartMate II
vs 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 for
transplant UNOS status
1A or 1B
Nonrandomized HVAD
(137) vs contemporary
LVAD registry controls
(499)
Proportion alive or
transplanted at 180 d
compared with registry
controls (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, destination
therapy; 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, United
Network of Organ Sharing; and VO2, peak oxygen consumption.
Although LVAD technology was pioneered in the bridge
setting where transplant offered a bailout for device failure, as
devices matured, development began to be targeted toward
devices capable of long-term or permanent circulatory
support.11
Over the past 2 decades, a series of revolutions in pump
design and pivotal clinical trials have changed the face of
advanced heart disease care (Table 2). The landmark FDA
approval of the HM XVE for permanent destination therapy
(DT) in 2003 uncoupled access to durable MCS from transplant eligibility. As VAD therapy entered the mainstream, the
collaborative Interagency Registry of Mechanically Assisted
Circulatory Support (INTERMACS) was established in 2006
to map the evolution of durable MCS. Since the approval of
the continuous-flow HeartMate (HM) II for DT in 2010, there
has been a 10-fold increase in approved LVADs implanted
for lifelong support in transplant-ineligible patients.12,13 With
1-year survival now ⬎80% with the approved continuousflow LVAD, the promise of half a century’s work has been
realized, and “the decade of the ventricular assist device”14
has arrived.
Pumps in Evolution
Evolving Flow Profile
In the field of assisted circulation, evolving pump design has
driven clinical progress (Table 3). After the invention of a
smaller high-speed, rotary impeller pump with a single
moving part, continuous-flow VADs with enhanced durability and near-silent operation became available. The transition
from pulsatile technology toward continuous flow has been
remarkably swift. Before 2008, all VADs implanted in the
United States outside the clinical trial setting delivered
pulsatile flow via an electrically (Novacor, HeartMate XVE)
or pneumatically (HeartMate IP, Thoratec IVAD/PVAD)
driven volume displacement pump. However, after FDA
approval of the HM II for BTT and then DT, by the first half
of 2010 ⬎98% of all LVADs implanted in the United States
were continuous flow.13
The rapid rise of continuous-flow pumps has been propelled by their significant survival and performance advantage over older, pulsatile devices. The randomized HM II DT
study enrolled NYHA class IV patients ineligible for transplant and directly compared flow profiles. Superior survival
was seen with the continuous in comparison with pulsatile
(HM XVE) VAD at both 1 year (68% versus 55%) and 2
years (55% versus 24%) (Table 2).15 The INTERMACS
registry confirmed the superior survival with continuous
versus pulsatile flow LVADs at 1 year (83% versus 67%) and
2 years (75% versus 45%), with an overall P⬍0.0001.13
Although continuous-flow pumps increase the probability of
survival to transplant, once a patient receives a transplant,
survival is similar regardless of whether a pulsatile or
Stewart and Givertz
Table 3.
Manufacturer
Mechanical Circulatory Support in Evolution
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Implantable LVADs in Evolution
HeartMate XVE
Thoratec IVAD*
HeartMate II
HeartWare HVAD
Jarvik 2000
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 assist
device; 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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continuous-flow LVAD is used as a bridge.16,17 Furthermore,
although older data have shown impaired posttransplant
survival in patients bridging with LVADs,18 a new International Society for Heart and Lung Transplantation report
shows similar outcomes in comparison with patients who do
not require pretransplant LVAD support.17
Interestingly, both REMATCH and the HM II DT trial
showed similar 50% to 60% 1-year survival with the XVE
device despite nearly a decade of intervening clinical experience, suggesting a limit to further long-term progress with
approved pulsatile LVAD technology.19 In contrast, there has
been a notable temporal improvement in survival to transplant with the HM II in recent years. In the extended
enrollment phase of the pivotal trial, 1-year survival increased
from 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 continuousflow technology may be attributed to improved patient
selection, surgical experience, and postoperative medical
care. Management suggestions have been published for inhospital and longitudinal management of LVADs, although
the brisk pace of change in the field has precluded development of consensus guidelines.22–24
Smaller rotary pumps like the HM II have some unique
benefits beyond improved survival. The lower pump profile
allows preperitoneal abdominal implantation in somewhat
smaller patients, including women and adolescents. Before
the HM II, patients with small body surface area were
relegated to an extracorporeal pump as a BTT and had no
approved DT option that could safely fit in their abdomen.
Smaller pump profiles also have been linked to earlier
postoperative recovery and enhanced comfort due to less
crowding. The newer HeartWare VAD (HVAD) and Jarvik2000, which are still under investigation, are small enough to
allow intrapericardial implantation, which may further enhance comfort.25,26 The near-silent operation of nonpulsatile
technology also makes these pumps less intrusive for patients
and their caregivers, particularly in quiet public places.
Evolving Pump Complications
All MCS devices are subject to complications resulting from
the complex interplay between pump and patient. Although
device durability has been dramatically enhanced with
continuous-flow pumps, stroke and infection remain substan-
tial risks, and unanticipated hazards specific to rotary VADs
have been recognized. The greatest recent impact of pump
design on reducing adverse events is the extended durability
of continuous-flow rotary pumps. Mechanical failure of
first-generation electric and pneumatically driven pulsatile
pumps frequently resulted in reoperation for device exchange
or even death. In REMATCH, 35% of HM XVE recipients
experienced component failure within 24 months.27 Similarly,
in the HM II DT study, 20 of 59 patients randomly assigned
to HM XVE required 21 device replacements and 2 device
explants because of bearing wear and valve dysfunction.15 By
contrast, current continuous-flow LVADs like the HM II are
designed with only a single, nearly frictionless moving part
(the impeller) and do not have a pusher plate or artificial
valves. In the pivotal HM II DT trial, the rate of pump
replacement was only 0.06/patient-year for HM II in comparison with 0.51/patient-year for HM XVE (P⬍0.001). Reoperation to repair or replace the pump, a key secondary end
point in the HM II DT trial, was significantly lower for the
rotary pump (hazard ratio 0.18, P⬍0.001).15 Continuous rotor
activity ensures unidirectional blood flow and obviates the
need for valved conduits, which were subject to structural
valve deterioration. Primary pump failure remains exceedingly rare with the HM II, but device exchange may still be
required for pump thrombosis, cannula malposition, or deep
infection. In the HM II BTT experience of 133 implants, 1
device-related death and 5 pump replacements (VAD thrombosis in 2 patients, surgical complications in 3) were observed.28 Third-generation pumps currently under development operate without bearings by use of either
hydrodynamically (eg, HVAD) or magnetically (DuraHeart
LVAD, HeartMate III) levitated rotors, which may allow
even greater pump longevity.29
Although LVAD durability has been greatly extended, the
inherent risks of bleeding, stroke, and infection remain.
Debilitating stroke is the most dreaded complication of MCS
and is equally common with continuous-flow pumps and
pulsatile devices. In the postmarketing BTT HM II study,
stroke rate was 0.08 events/patient-year for HM II and 0.11
events/patient-year for the contemporaneous pulsatile devices, including HM XVE and Thoratec IVAD (P⫽0.38).21
Embolic strokes appear more common than hemorrhagic
strokes with all device designs,21 and may arise not only from
in situ clot formation on a pump component, but also from
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March 13, 2012
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ingested thrombus propelled through the device. In the
randomized HM II DT trial, which enrolled sicker patients,
disabling stroke was not statistically different between continuous and pulsatile flow (11% versus 12%, P⫽0.56).15
Overall stroke rates were modestly lower with HM II compared to HM XVE (0.13 versus 0.22 events/patient-year,
P⫽0.21), with patients at equivalent risk of ischemic and
hemorrhagic stroke. The ischemic stroke rate for HM II
patients may not be significantly different from patients with
end-stage heart failure without device support, although
controlled comparative data do not exist. Data from the
nonrandomized HeartWare HVAD BTT experience revealed
similar risk of stroke in comparison with other VADs, with
0.10 ischemic and 0.05 hemorrhagic strokes/patient-year, and
an overall risk of disabling stroke of 0.06 events/patientyear.30 Long-term stroke risk with the HVAD pump will be
clarified with the extended enrollment phase of the Evaluation of the HeartWare Ventricular Assist Device for the
Treatment of Advanced Heart Failure (ADVANCE) trial.
Anticoagulation regimens may ultimately be device specific,
and the relatively low-level anticoagulation recommended for
the HM II may be inadequate for the HVAD. Stroke risk with
the Jarvik 2000 has not been published.
The optimum level of antiplatelet and anticoagulant therapy to minimize both thromboembolic and hemorrhagic
stroke is unknown, and few comparative data exist. The HM
II has relatively low thrombotic risk provided patients are on
an anticoagulation regimen that features an antiplatelet agent
such as aspirin along with warfarin with an international
normalized ratio goal of 1.5 to 2.0.22,31 As LVAD use
expands into older patient populations, it must be remembered that advanced age remains the most potent risk factor
for stroke. Indeed, stroke has become such a crucial safety
end point that stroke-free survival will be used as the primary
endpoint for the Evaluation of the HeartWare Ventricular
Assist System for Destination Therapy of Advanced Heart
Failure (ENDURANCE) clinical trial, the ongoing randomized study of the HVAD compared with contemporary
continuous-flow pumps for DT.32 Careful adjudication of
neurological events is now central to MCS trial design. Stroke
risk may be particularly relevant for those patients intended
as BTT because disabling stroke may render them ineligible
for transplant. Stroke risk should be part of counseling before
elective MCS, particularly as extended or lifetime mechanical
support becomes increasingly common and stroke risk may
not abate with time.
Device-related infection also remains common with MCS
and has been described as the Achilles heel of circulatory
assist.33 The majority of infections involve the percutaneous
driveline, pump pocket, or both. Rotary blood pumps with
smaller surface areas and thinner drivelines may be less prone
to infection than pulsatile pumps. Pump design, patient
selection, surgical technique, and driveline care appear to be
the primary determinants of infectious risk.34 Immobilization
of the driveline may help avoid torsion and breakdown of the
cutaneous junction, the most common entry point for infections. Transcutaneous energy transfer systems may one day
eliminate the need for a percutaneous driveline, although
progress has been hampered by high-power requirements that
outstrip current battery technology.35 Fortunately, infection
involving the blood surface interface of the pump, known as
pump endocarditis, is rare. Pump infections have dire consequences because they are so difficult to eradicate. Devicerelated infection even allows upgrade to United Network for
Organ Sharing status IA. For those ineligible for transplant,
device infection represents an incurable and often fatal
complication of MCS.
Multiple distinct and largely unanticipated complications
of continuous (or nonpulsatile) blood flow have emerged that
were not experienced with pulsatile pumps. Continuous-flow
VADs have been associated with bleeding from cerebral and
gastrointestinal arteriovenous malformations.36,37 In addition
to stimulating the formation of arteriovenous malformations,
continuous axial flow produces high-shear stress that disrupts
circulating high-molecular-weight multimers of von Willebrand factor, leading to an acquired von Willebrand syndrome with defective platelet aggregation.38,39 Mucosal
bleeding risk is compounded by the requirement for anticoagulation. In addition, chronic aortic insufficiency may develop with prolonged continuous flow and can represent
either an exacerbation of mild preexisting regurgitation or de
novo insufficiency.23,40 Development of aortic insufficiency
has been attributed to expansion of the aortic sinus, infrequent
valve opening, and greater aortic diastolic pressures, each of
which can contribute to leaflet fusion and valvular incompetence.41 The cumulative risk of stroke, infection, bleeding,
and aortic insufficiency will shape the debate about the
eventual cost-effectiveness of rotary LVADs for chronic
heart failure.
Future Prospects for Pulsatile Flow, Biventricular
Therapies, and Partial Support
Despite the ascendancy of continuous-flow pumps, pulsatile
platforms still have an important role in the modern era. In
acute cardiogenic shock, pulsatile flow maximizes both
perfusion pressure and unloading of the pulmonary circuit
and right heart.42 Pulsatile technology also has an exclusive
role in the BTT setting when biventricular support or replacement is required, either in the form of biventricular assist
devices or TAH. Pulsatile devices also allow for easier
conversion from an LVAD to biventricular support with a
single platform should right ventricular failure develop.
Nevertheless, continuous-flow configurations for biventricular assist devices are being actively explored, and case reports
of successful biventricular HM II and HVAD support have
been published.43,44
The TAH offers full circulatory replacement therapy for
patients with irreversible biventricular failure, although only
2% to 3% of current MCS implants are TAHs.13 The
pneumatically driven SynCardia TAH was FDA approved for
BTT in 2004, and received Centers for Medicare and Medicaid Services coverage in 2008. It requires no surgical
pocket, can provide up to 10 L/min flow with physiological
control through both pulsatile pumping chambers, and has the
shortest blood path of any circulatory device. However, the
TAH requires adequate mediastinal space to accommodate
the dual-chambered pump, and its utility has been limited by
a large controller requiring permanent hospitalization.45 Syn-
Stewart and Givertz
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Cardia’s next-generation portable pneumatic controller (Freedom Driver) is small enough at 5.9 kg that patients can be
discharged from the hospital and remain relatively independent despite orthotopic mechanical replacement. The Freedom Driver is undergoing investigational device exemption
investigation with the previously approved TAH as a BTT.46
Perhaps most importantly, the TAH is currently the only
MCS option for transplant candidates with restrictive or
infiltrative cardiomyopathies with ventricular cavities too
small to accommodate apical inflow cannulae. Such patients
were previously relegated to prolonged hospitalization on
inotropes, and now they too have an MCS option that could
allow discharge from the hospital while awaiting transplant.
Device malfunction, along with bleeding, stroke, and infection, remain concerns with TAH technology.
Another important trend in pump development has been
miniaturization, even at the expense of flow rate. Implantable
miniature pumps may be able to deliver long-term partial
circulatory support to allow recovery of ventricular function
after an acute insult or provide durable assistance. The
CircuLite Synergy micropump, under investigation, can provide up to 3 L/min of flow from the left atrium into the
subclavian artery and can be implanted without cardiopulmonary bypass via a minithoracotomy.47 Investigators have also
described using the continuity between the posterior aortic
wall and left atrium as another means of providing LV
support without entering the ventricle.48 As surgery becomes
less invasive and successful strategies for long-term percutaneous support are realized, MCS implantation will likely
become more proactive and move into less sick patients with
earlier stage heart failure.
Changing Patient Populations
As pump design has evolved, so has the population of patients
with advanced heart failure receiving MCS. With the recent
expansion in use of the HM II for DT, there is now a
meaningful cohort of patients receiving lifetime LVAD support. The success of LVAD therapy has generated debate
about the degree of heart failure that should prompt implant
and has altered decisions about listing for transplantation.
Elements of the preimplant assessment have also been reconsidered, such as right ventricular (RV) function, nutritional
status and age. LVAD programs have in turn evolved to meet
the needs of the ever-expanding and varying group of patients
living with MCS.
Evolving Role for LVADs and Transplantation
Since 1999, more than a third of all listed adult heart
transplant candidates and 75% of those initially listed as
United Network for Organ Sharing status IA have received
MCS.49 Implantation of an LVAD in status I patients allows
them to undergo transplantation relieved of the burden of
chronic congestion, with improved end-organ function and
nutritional status. Although United Network for Organ Sharing status I was originally conceived for patients with less
than a week to live, the average waiting time in status I is now
⬎6 months, during which patients with end-stage heart
failure are exposed to risks of infection, blood clots, and
pressure ulcers, and experience exhaustion of family support.
Mechanical Circulatory Support in Evolution
1309
In this era of prolonged waitlist times, LVAD therapy can
allow patients to return home with an improved quality of life
while waiting for a donor organ to become available.50 Early
referral for device therapy may also be reasonable in patients
listed for transplant who are anticipated to have a long
waiting time because of blood type, large body size, or a high
degree of allosensitization.
For patients listed as United Network for Organ Sharing status
II, survival without transplant or LVAD has been improving,
with 81% 1-year and 74% 2-year survival in the era between
2000 and 2005.51 Improved outcomes while listed may reflect
better medical therapies or earlier listing (eg, lead-time bias) and
have occurred despite older age and a greater burden of comorbidities. Survival with heart failure while listed as status II is
similar to that with the current second-generation continuousflow LVADs. However, mechanical support may offer improved functional capacity and quality of life in comparison with
optimal medical therapy, including home inotropes. With limited donor organ availability, only 14% of all heart transplants in
2009 occurred in status II patients, highlighting the potential for
expanded LVAD use.49 Because of the success of LVAD
therapy, transplant without MCS may be best reserved for
patients with dominant RV dysfunction, structural obstacles to
isolated left ventricular support, or unacceptably high risk for
reoperation. With extended LVAD durability, the eventual goal
may be to avoid transplant and its attendant complications for as
long 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 candidacy
in patients with potentially reversible or relative contraindications to transplant. Encouraging data exist for the reversal
of secondary pulmonary hypertension in select patients,
although, in many cases, RV dysfunction may persist even
with LVAD support.52–55 If pulmonary vascular resistance
remains elevated, sildenafil may be considered.56 Other contraindications to transplant such as severe chronic kidney
disease or morbid obesity seldom improve to a degree that
allows listing. Given the scarcity of donor organs and
improving outcomes with LVAD support, recipients who are
not transplant candidates at time of implant should be
prepared for the possibility of lifetime mechanical support.
Earlier Timing for Durable Support
The INTERMACS profiles have been developed to define
clinically important differences in the severity of disease
among patients with advanced heart failure (Table 4).57
Nearly 70% of all registered VADs have been implanted in
the sickest subset of patients with heart failure, those with
critical cardiogenic shock (INTERMACS level 1) or progressive end-organ dysfunction despite inotropic support
(INTERMACS level 2). Worsening INTERMACS profile has
been consistently associated with higher perioperative mortality.58 In the past 2 years, the field has moved away from
implanting primary LVADs in level 1 patients because of
poor outcomes.59 Many are now receiving temporary percutaneous circulatory support, sometimes referred to as bridge
to bridge, as a way to support circulation and triage the
sickest patients for eventual durable LVAD. Waiting for
end-organ failure or even more subtle signs of debilitation
1310
Circulation
Table 4.
Level
1
March 13, 2012
INTERMACS Patient Profile Levels
Patient Characteristics
Implants*
(1/2009 – 6/2010), %
Inotrope
Dependent
Critical cardiogenic shock despite escalating support
17
⫹
Target for
REVIVE-IT
DT Study
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 able
to perform activities of daily living with slight
difficulty
3
⫹
6
Exertion limited; able to perform mild activity, but
fatigued 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; and
REVIVE-IT, Randomized Evaluation of VAD InterVEntion before Inotropic Therapy.
*Data from Kirklin et al.13
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before moving to LVAD support is no longer acceptable.59
Similarly, destination LVAD should be considered an elective procedure in medically stable candidates rather than a
bailout for the patient sliding into refractory low-output heart
failure despite inotropic or temporary circulatory support.
Some patients may require an inpatient medical tune-up with
vasoactive or diuretic therapy immediately before LVAD
surgery.
Dependence on intravenous positive inotropes has traditionally been considered the threshold that prompts consideration of advanced therapies. Patients with advanced systolic
heart failure, however, are currently eligible for destination
LVAD coverage even if they are not dependent on inotropes,
provided they have symptoms at rest and a peak oxygen
consumption ⬍14 mL 䡠 kg⫺1 䡠 min⫺1 on optimal oral
therapies (INTERMACS levels 4 and 5) (Table 5). Only 18%
Table 5.
Characteristic
Device
Patient
Requirements for Destination Therapy Coverage
Requirement
FDA-approved device for DT (HeartMate XVE, HeartMate II)
Chronic NYHA class IV heart failure
Not a candidate for heart transplant
Did not respond to optimal medical management for 45 of
last 60 d (including ␤-blockers and ACE inhibitors if
tolerated), or IABP for 7 d, or IV inotrope for 14 d
LVEF ⱕ25%, and severe functional limitation with peak
VO2 ⬍14 mL 䡠 kg⫺1 䡠 min⫺1, unless on IABP or
inotropes, or physically unable to complete test
Facility
Experienced surgeon (ⱖ10 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 Mechanically
Assisted Circulatory Support; IV, intravenous; NYHA, New York Heart Association; TAH, total artificial heart; VAD, ventricular assist device; and VO2, oxygen
consumption.
Adapted from National Coverage Determination (NCD) for Artificial Hearts and
Related 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.
of durable adult LVADs are currently implanted in patients
not yet dependent on intravenous inotropes.13 Low implant
rates in ambulatory heart failure may reflect reluctance of
both physicians and patients. Ambulatory patients with advanced heart failure should have ongoing discussions about
the trade-offs of living with heart failure in comparison with
undergoing VAD operation to identify preferences and
thresholds for considering elective LVAD therapy.60
Fortunately, the evidence base to guide LVAD use before
inotrope dependence is growing. Equipoise now exists for the
study of smaller, more reliable continuous-flow pumps for
DT in “less sick” patient with advanced heart failure. The
NIH has sponsored the Randomized Evaluation of VAD
Intervention before Inotropic Therapy (REVIVE-IT) trial to
study LVAD therapy in patients who have advanced heart
failure with significant functional impairment and who are
ineligible for transplant, but who have not yet manifested
serious consequences of end-stage heart failure, such as
severe end-organ dysfunction, immobility, or cardiac cachexia.61 The REVIVE-IT pilot study is in the advanced
planning stages and will randomly assign 100 patients with
moderately advanced heart failure in a 1:1 ratio to the
HeartWare HVAD, an intrapericardially implanted
continuous-flow centrifugal pump, or optimal medical therapy.62 The upcoming industry-sponsored ROADMAP (Risk
Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory
Heart Failure Patients) trial will be a prospective, nonrandomized observational study of NYHA IIIB/IV patients not
yet on inotropes that will compare the postmarketing effectiveness of the HM II for DT on optimal medical therapy. In
addition, as part of the ongoing INTERMACS effort a
parallel registry of medically managed chronic systolic heart
failure patients with refractory NYHA class III or IV symptoms is being assembled as part of the Medical Arm of
Mechanically Assisted Circulatory Support (MEDAMACS)
initiative. This prospective, observational medical registry
will have a particular focus on INTERMACS profiles 4 to 6
to help define the natural history of ambulatory advanced
heart failure and refine patient selection in this crucial
Stewart and Givertz
Table 6.
Triggers for Referral for VAD Evaluation
Inability to wean inotropes or frequent inotrope use
Peak VO2 ⬍14 –16 mL 䡠 kg⫺1 䡠 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, New
York Heart Association; and VO2, oxygen consumption.
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spectrum of disease where the greatest expansion in LVAD
use is anticipated.
Mechanical Circulatory Support in Evolution
1311
and cardiac cachexia. Ventricular tachycardia refractory to
medical and ablative therapies, even in the absence of severe
heart failure, is also an indication for considering MCS
support.
The Seattle Heart Failure Model has been applied broadly
to estimate mortality and anticipate benefits from medical or
device therapies.66 This model also predicts mortality after
LVAD implant, although it may underestimate the risk of
VAD or urgent transplant listing among ambulatory patients.67,68 Patients with anticipated mortality ⬎15% at 1 year
or ⬎20% at 2 years based on the Seattle Heart Failure Model
should be considered high risk and evaluated for MCS
candidacy. For patients not facing imminent death, but who
have severe symptom burden, the functional benefits alone
may justify referral for LVAD therapy. The HM II has been
shown to increase 6-minute walk distance ⬎200 m, with most
patients improving to NYHA class I or II.69 Patients approaching any of these signposts should be considered for
referral to an advanced heart disease program to determine
candidacy for transplant, MCS, or both (Figure 2).
Evolving Preimplant Considerations
Triggers for Evaluation of MCS Candidacy
The clinical sign posts that mark a downward trajectory of
patients with chronic heart failure, and that may serve as
triggers for referral for MCS, are often missed or recognized
only in retrospect (Table 6). Common indicators of increased
mortality in heart failure include two or more hospitalizations
for acute decompensation in a 12-month period, development
of a circulatory or renal limitation to angiotensin-converting
enzyme inhibitor therapy, hypotension in response to
␤-blocker therapy, a peak oxygen consumption ⬍14 to 16
mL 䡠 kg⫺1 䡠 min⫺1 or ⬍50% predicted, symptoms at rest
(NYHA class IV) on most days, failure to respond to cardiac
resynchronization therapy, or 6-minute walk distance ⬍300
m.63– 65 Other high-risk clinical and laboratory features include worsening right heart failure and secondary pulmonary
hypertension, diuretic refractoriness associated with worsening renal function, persistent hyponatremia, hyperuricemia,
Considerable effort has gone into developing risk scores to
predict perioperative outcomes after LVAD implant. Risk
factors for perioperative mortality focus on indices of hepatic
and renal dysfunction and poor nutrition, which may be
manifestations of right heart failure that are unaddressed by
left-sided support alone.70,71 Risk scores developed in the
pulsatile flow era may be less discriminating when applied to
continuous-flow devices, in part, because of improved outcomes.72 The latest HM II risk score showed that multivariable preoperative predictors of mortality included older age,
higher creatinine, low albumin, and implant center inexperience.71 Right heart failure after LVAD implant results in up
to a 6-fold increase risk of death and is a major contributing
factor in prolonged hospitalizations.73 Accurate assessment of
RV function is required before LVAD implant, particularly
when transplant is not an option, because biventricular
support is not yet feasible (or approved) for DT. RV dysfuncFigure 2. Decision tree for elective mechanical circulatory support in advanced heart failure. This is a suggested algorithm for decision
making about elective mechanical circulatory
support in advanced heart failure. Once a
trigger for VAD evaluation has been identified,
patients should be referred to an experienced
MCS center where all advanced therapies,
including transplant and VAD, can be considered. Decisions about MCS are contingent on
eligibility for transplantation, and the likelihood
of RV failure after LVAD implant, as well.
Patients ineligible for heart transplant with
high VAD implant risk or RV failure risk after
LVAD have few MCS options. Unless the preoperative risk is reversible (eg, infection),
these patients are candidates for medical
therapy alone and may benefit from early
referral to supportive cardiology. AKI indicates
acute kidney injury; BIVAD, biventricular assist
device; BTT, bridge to transplant; DT, destination therapy; LVAD, left ventricular assist
device; MCS, mechanical circulatory support;
RV, right ventricular; and TAH, total artificial
heart.
1312
Circulation
Table 7.
March 13, 2012
Predictors of Right Ventricular Failure after VAD Implantation
Definition of RV Failure
Matthews et al73
Fitzpatrick et al74
Drakos et al75
RVAD or ECMO
RVAD
RVAD
Inhaled NO ⱖ48 h
Inhaled NO ⱖ48 h
Inotrope ⱖ14 d
Inotrope ⱖ14 d
Home inotrope
Predictors
Vasopressor requirement
Cardiac index ⬍2.2 L 䡠 min⫺1 䡠 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, intraaortic
balloon pump; NO, nitric oxide; PVR, pulmonary vascular resistance; RV, right ventricle; and RVAD, right ventricular assist device.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
tion present with inotropic support before LVAD appears to
persist after implant, with uncertain long-term consequences.55 In the meantime, multiple RV clinical risk scores
have been developed to anticipate RV failure and plan for
biventricular support (Table 7).73–75 However, none of these
scores was derived in a DT cohort or with newer continuousflow LVADs, which may be even more sensitive to RV
failure because of greater systemic venous return and exaggerated interventricular dependence.
Proactive relief of congestion in the hospital, often guided
by a pulmonary artery catheter, is indicated to prepare the
patient for implant. Early postoperative use of inotropes or
inhaled pulmonary vasodilators, or proactive right ventricular
assist device placement may allow the best chance for
recovery of RV function.76 The ability to adjust continuous
pump speed in real time under echocardiographic guidance
may also help optimize RV contractile geometry and minimize residual tricuspid regurgitation.22 Although some surgeons advocate prophylactic tricuspid valvuloplasty, other
surgeons have shown no benefit.77,78 Selection of patients for
isolated LVAD will also be informed by our improved
understanding of load-independent RV function (eg, RV
stroke work index), pulmonary impedance, and RV contractile reserve. The right heart is central to all decisions
surrounding LVAD therapy.
Adequate nutritional support reduces the risk of postoperative infection and improves functional recovery after LVAD
placement. Yet patients with end-stage heart failure have
profound metabolic imbalances, particularly when hepatic
and gastrointestinal congestion is a prominent presenting
feature. Patients with cachexia and a low prealbumin and/or
elevated C-reactive protein are at particularly high risk for
perioperative death, often from infection.79 Other markers of
poor nutritional status include reduced levels of serum albumin, total protein, total cholesterol, and lymphocyte count.
Aggressive nutritional support, including enteral feeding,
should be considered in all LVAD candidates with any sign
of low nutritional reserve. In contrast to its role in transplant
listing, obesity is not a contraindication to LVAD implantation, nor does it appear to increase the risk of driveline
infection as previously feared.80 Low body mass index has
consistently been shown to be a greater predictor of mortality
after LVAD than elevated body mass index. Whereas LVAD
therapy has been proposed in BTC patients to facilitate
weight reduction, there are few data to support a bridge to
weight loss strategy,81 and such patients should be prepared
for the possibility of lifelong LVAD support.
Age is also one of the most commonly cited reasons for
transplant ineligibility, making older patients a target population for expanded LVAD use. Nearly 75% of patients with
heart failure are ⬎65 years of age, and the average age of
patients hospitalized in the United States with low ejection
fraction heart failure is 75 years.82 The interaction between
age and LVAD outcomes is evolving. In the INTERMACS
registry, age has been consistently associated with an increased hazard of early and late mortality, although the global
improvements in results with continuous-flow pumps may
diminish the relative impact of age on outcomes.13,83 Indices
of frailty, which may be independent of age, may be even
more potent predictors of outcome after cardiac surgery.84
Advancing age tracks with greater prevalence of comorbidities such as chronic kidney disease, diabetes mellitus, and
cerebrovascular disease, which may be greater drivers of
adverse outcomes. Improvement in survival and quality of
life after HM II therapy in select patients ⬎70 years,
including those self-referred from hospice, may not be
different from younger recipients, suggesting that age should
not be used as an independent contraindication to LVAD
therapy at experienced centers.85
Evolution of MCS Programs
Use of LVAD therapy is best accomplished within an
integrated program of advanced heart disease care. Successful
programs emphasize teamwork and offer optimization of
medical and device therapies, evaluation for transplant candidacy and MCS, and, when appropriate, a focus on palliative
care and end-of-life choices.86 A full menu of MCS options
should be available, from temporary percutaneous support to
the latest durable LVAD or biventricular assist technology, so
that device selection can be tailored to patient circumstances.
Center experience and procedural volume are of critical
importance given the complexity of patient care with
LVADs.87 Certification of a destination LVAD program
requires not only heart failure cardiologists and cardiac
Stewart and Givertz
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surgeons, but also committed providers from cardiovascular
imaging, nursing, psychiatry, social work, physical therapy,
nutrition, and financial counseling.88 In addition, subspecialists in infectious disease, gastroenterology, and nephrology
with a focus on LVAD care are critical to anticipating and
managing device-related complications. Quality assessment
and performance initiatives, along with frequent financial
review, further enhance program growth and development.
LVAD patients and their families require intensive education before implant and dedicated postoperative management
to prepare them for life outside the hospital.50 Patients and
their caregivers must master device alarm troubleshooting,
battery changes, and driveline care. In addition, local first
responders must be trained and power companies notified to
ensure access to back-up generators. Committed LVAD care
does not end with hospital discharge. Much of the responsibility for this rests on the shoulders of dedicated VAD
coordinators, each of whom is responsible for 15 or more
outpatients with LVADs.88 Routine outpatient encounters
with LVAD patients focus on blood pressure and volume
control, meticulous driveline care, anticoagulation adjustment, and counseling to facilitate reintegration into the
community and prevent caregiver burnout. Comprehensive,
multidisciplinary outpatient MCS clinics have evolved to
address these varied needs. Institutional commitment to MCS
program excellence is required to sustain the promising
outcomes achieved thus far with LVAD therapy.
Conclusions
The rapid progress of MCS technology in recent years has
extended survival and improved quality of life for select
patients with advanced heart failure. Indeed, mechanical
support has become central to the evidence-based care of
chronic, refractory heart failure. For the first time, there is a
meaningful option for lifelong support even in patients who
are not candidates for transplantation. Novel pump design has
improved clinical outcomes, altered the profile of MCS
candidates, and changed the structure of advanced heart
disease programs. With these advances have come new
challenges and opportunities. This article represents the first
in a series of invited reviews on Advances in Mechanical
Circulatory Support to appear in Circulation. Future articles
will address percutaneous circulatory support to treat cardiogenic shock, imaging of ventricular function and myocardial
recovery, 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 in
advanced heart failure.
Disclosures
None.
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KEY WORDS: cardiomyopathy
䡲
heart failure
䡲
ventricular assist device
Mechanical Circulatory Support for Advanced Heart Failure: Patients and Technology in
Evolution
Garrick C. Stewart and Michael M. Givertz
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Circulation. 2012;125:1304-1315
doi: 10.1161/CIRCULATIONAHA.111.060830
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