Continuous flow LVADs: second and third generation
LVAD design evolved radically after the REMATCH trial
with the development of continuous flow (CF) LVADs. These were no longer
pulsatile. Instead, blood was propelled through a rotor. Flow was
continuous and not pulsatile as in native hearts. These devices as opposed
to the earlier HeartMate I required systemic anticoagulation. An initial
study of 133 patients awaiting cardiac transplantation underwent
implantation of the HeartMate II LVAD, a second generation VAD with an
axial flow design. Mean time of support was 126 days and the
survival rate was 75% at 6 months and 68% at 1 year . The latter
represented and improvement from the 52% 1 year survival seen at 1 year in
the REMATCH trial with the HeartMate. The functional status and Quality
of Life improved 3 months after implantation of the CF LVADs . Major
adverse events included right ventricular (RV) failure, postoperative
bleeding, stroke, percutaneous lead infection and pump thrombosis.
A subsequent study in patients not eligible for
cardiac transplantation compared the Heartmate II to the HeartMate I in a
2:1 randomization ratio. The 134 patients received the HeartMate II and 66
received the HeartMate I . At 2 years, patients receiving
the HeartMate II had a 58% survival compared to 24% for the HeartMate
I recipients. HeartMate II recipients had greater freedom from stroke or
VAD replacement indicating that the HeartMate II was a more
durable VAD than its predecessor . These results led to
FDA approval of the HeartMate II for MCS for DT and the obsolescence
of the HeartMate I which subsequently was no longer produced.
Third generation LVADs were CF devices which had
centrifugal flow which meant that flow in the VAD was perpendicular to
flow coming in from the left ventricle. These devices were smaller than the
HeartMate II and had a moving impeller suspended by magnetic and
hydrodynamic forces to reduce shear and prolong LVAD durability. The
archetype LVAD in this group is the HeartWare ventricular assist device
(HVAD) which was studied in the HeartWare™ Ventricular Assist System as
Destination Therapy of Advanced Heart Failure (ENDURANCE) study which was a
comparison to of the HVAD centrifugal flow VAD to the HeartMate II
axial flow device. The 446 patients were randomized in a 2:1 manner to the HVAD
(n=297) vs the HeartMate II (n=148) . The primary end point
was survival at 2 years free from disabling stroke or device removal for
malfunction or failure. The primary endpoint was achieved in 554.1% of
HVAD and 59.1% of HeartMate II patients (p=NS) . More patients in the HeartMate II group had VAD
malfunction or failure requiring replacement (16.2 vs 8.8%) while
the stroke rate was higher in the HVAD group compared to the
HeartMate II group (29.7 vs 12.1%). Strokes were associated with higher blood
pressures . Thus, while the HVAD appeared to be more durable than
the HeartMate II, it was associated with a higher stroke rate .
Complications of LVADs
Right ventricular failure
RV failure is a feared post-LVAD implantation
complication which heralds a 20% decrement in perioperative survival [5-7]. A
recent metanalysis of 36 studies reported an incidence of RV failure of
35% in 4,428 patients. The causes of post-LVAD implantation include the
unloading of the left ventricular (LV) after LVAD implantation which
results in septal shifts, increased RV preload and ultimately
decreased RV contractility and function. Prediction of post-operative RV
failure before LVAD implantation has been a challenge. Predictive scoring
systems have been developed but have not been very successful and
are not used often.
Often, RV failure will be manifested in the operating
room during LVAD implantation. This may necessitate implantation of a right
ventricular assist device (RVAD). Sometimes RV failure is diagnosed
clinically in the intensive care unit after LVAD implantation. This
is manifested clinically by decreased blood pressures, cardiac outputs and
urine outputs. Management would include implantation of an RVAD.
Often, RVADs can serve as bridges to RV recovery and after several
days to weeks, can be explanted as RV function improves.
The most common source of bleeding in patients with CF
LVADs is from the GI tract. GI bleeding rates in LVAD patients ranges from
10-61% [8-11]. A metanalysis of 1,697 patients showed a GI
bleeding rate of 23% . The most common etiology of GI bleeding in
LVAD patients is arteriovenous malformations or angiodysplasia which occur in
29% of LVAD patients. It is thought that the CF in the second
and third generation LVADs may contribute to the development of
angiodysplasias. The most common location of GI bleeding in these patients is
the upper GI tract (48%) of patients . The pathophysiology of GI
angiodysplasia in CF LVAD patients is incompletely understood but there is
evidence that the hypoxia-inducible factor (HIF)-1α/angiopeptin pathway
may be involved [13, 14].
Although the incidence of GI bleeding is higher in
recipients of second and third generation LVADs compare to the first
generation pulsatile LVADs, mortality from GI bleeds is actually lower in
recipients of the newer, CF LVADs compared to the pulsatile
LVADs (20.9 vs 43.7%, respectively) . From the DT clinical trial
comparing HeartMate II to HeartMate I, there was no difference in GI
bleeding episodes that required transfusions or surgery. Increasing
experience with managing the newer CF LVADs has resulted in
a reduction in GI bleeding incidence. Mortality from GI bleeding has also
Pump thrombosis and strokes
Patients with second and third generation CF LVADs are
at risk of the sequelae of thromboembolic events despite receiving
systemic anticoagulation and having acquired Von Willebrand Syndrome.
The incidence of strokes ranges from 2-42 to 2-5% for transient
ischemic attacks [15-18]. A more ominous complication is pump thrombosis.
The incidence of pump thrombosis increased from 2% in 2011 to 5%
in 2015 at 6 months post implant in HeartMate II LVADs (p<0.0001) in date from 6,251 patients
from INTER-MACS . In a review from 3 institutions of 837 patients in
whom 895 HeartMate II devices were implanted between 2004 and 2011. The 72 pump
thromboses were observed in 66 patients . From March 2011, the incidence
of pump thrombosis increased from 2.2% at 3 months post-implant to 8.4%
in March 2013. The median time post-implant to thrombosis declined from
18.6 months before March 1, 2011 to 2.7 months afterward. Pump thrombosis
in these patients was managed by cardiac transplantation in 11
patients and LVAD replacement in 21. Of the remaining 40 patients with pump
thromboses but who did not get a cardiac transplant or pump
exchange, mortality was high at 48.2% at 6 months after pump exchange
was diagnosed . The PREVENTION of HeartMate II Pump Thrombosis through
Clinical Management (PREVENT) study of 300 patients who underwent HeartMate II
implantation at 24 medical centers showed a pump thrombosis rate of 2.9%
at 3 months and 4.8% at 6 months 21]. Heparin bridging within 48
hours post-operatively, initiation of warfarin at 48 hours with a target
INR of 2.0-2.5, and addition of aspirin (81-325 mg daily) 2-5 days post
implantation if there was no bleeding and maintaining pump speeds
>9,000 RPMs reduced the incidence of pump thrombosis from 8.9 to 1.9% (p<0.01) and the incidence of ischemic
stroke from 17.7 to 5.7% (p<0.01) at
6 months post implant.
Recent data from INTERMACS indicates that the
incidence of HeartMate II pump thrombosis at 6 months peaked at 8% in 2013
but declined to 5% in 2014 . Results from the HVAD Evaluation
of the HeartWare Left Ventricular Assist Device for the Treatment of
Advanced Heart Failure (ADVANCE) study showed that this device had a 4%
pump thrombosis incidence at 6 months.
For those patients who cannot get heart transplants
rapidly or who are receiving LVADs as DT, a pump exchange with explantation of
the old LVAD and replaced with a new LVAD are definitive treatments of
this problem. Thrombolytic therapy should be avoided given the risk of
intra-cranial hemorrhage with this therapy.
Infections can occur anywhere throughout the LVAD
circuit including the LVAD pocket where the LVAD is implanted, the LVAD
itself or the cannulae that go from the left ventricle to the VAD and
from the LVAD to the aorta and the driveline which goes from the LVAD
through the skin to the LVAD power source. The latter is the most common
site of LVAD infections because it represents a pathway from
the external environment to the LVAD interior. The most common
organisms causing LVAD infections are skin flora such as Staphylococcus
aureus and coagulase-negative staphylococci. These are particularly common in
driveline infections. Infections of the LVAD and other internal components
can be caused by other organisms as well such as Serratia,
Klebsiella, and Enteroccocus species, Pseudomonas aeruginosa. Candida
can cause up to ten percent of infections . Bacteremia from another
infection can seed the LVAD and infect it. Infections have declined
from 38% of patients reported in the first year of INTER-MACS to 17.6%
reported in 2014 by INTERMACS. Mortality from sepsis has declined from 41%
reported in the REMATCH study to 8.8% in recent INTERMACS reports
The management of LVAD related infections includes debridement
of infected tissue and administration of intravenous antibiotics. Often, the
driveline site where the driveline traverses the skin can provide insight into
the presence of infection as there may be erythema and purulent discharge.
When the VAD or the cannulae are infected, the only cure is
explantation. If the patient is on the transplant list, an LVAD related
infection will raise the patient on the priority list allowing for earlier
transplantation and removal of the infected LVAD. Antibiotics can
be used to suppress the infection. For DT patients, the infected LVAD
may need to be explanted. Temporary nondurable support with an Impella can
be used to support the patient hemodynamically until the infection is
eradicated at which point a new LVAD can be implanted.
The HeartMate 3: further advances in LVAD technology
the Multicenter Study of MagLev Technology in Patients
Undergoing Mechanical Circulatory Support Therapy with HeartMate 3
(MOMENTUM 3) study was a pivotal LVAD clinical trial involving the
randomization of 294 patients to receive the HeartMate 3, a fully
magnetically levitated centrifugal CF LVAD to the axial flow HeartMate II
(see fugire). The 152 patients received the HeartMate 3 while 142 received
the axial flow HeartMate II . The primary end point was a
composite of survival free of disabling stroke or survival free of
reoperation to replace or remove the device at 6 months after
implantation. The 131 (86.2%) patients in the HeartMate 3 group
reached the primary endpoint vs 109 (76.8%) patients in the HeartMate
II study. There was no significant difference in rate of deaths or disabling
strokes in the two groups. However, reoperation for pump
malfunction was less common in the HeartMate 3 group vs. the HeartMate II group
[1 (0.7%) vs 11 (7.7%), p=0.002]. No
suspected or confirmed pump thromboses were seen in the HeartMate 3 group
vs 14 (10.1%) patients in the HeartMate II group.
In a follow up study, 366 patients were enrolled, 190
of whom received the HeartMate 3 and 176 of whom received the HeartMate II
. The primary end point was a composite of survival free of
disabling stroke or survival free of reoperation to replace or remove the
device at 2 years after implantation . The 151 (79.5%) of HeartMate 3
patients reached the primary endpoint compared to 106 (60.2%) in the
HeartMate II group. Reoperation for pump malfunction was less common in the
HeartMate 3 group compared to the HeartMate II group [3 (1.6%) s
30 (7.0%), p=0.01]. Death rates
were similar between the two groups but rate of disabling strokes was
less in the HeartMate 3 group compared to the HeartMate II group
(10.1% vs 19.2%, p=0.02) .
A final phase of the MOMENTUM 3 trial enrolled 1,028
patients, of which 516 received the HeartMate 3 and 512 received the HeartMate
II . The composite primary end point was survival at 2 years free
of disabling stroke or reoperation to replace or remove a
malfunctioning device. The principal secondary end point was pump
replacement at 2 years. The 397 (76.9%) patients in the HeartMate 3 group
reached the primary endpoint compared to 332 (64.8%) in the HeartMate
II group . Pump replacement for malfunction was less common in the
HeartMate 3 group compared to the HeartMate II group [12 (2.3%) vs 57
(11.3%), p<0.001] . Patients
in the HeartMate 3 group had fewer strokes, major bleeding, GI bleeding or
ventricular arrhythmias than in the HeartMate II group. Thus, this newest
LVAD has fewer pump thromboses and LVAD replacements for LVAD
malfunction. There are unique aspects of this device which may account for
its superior outcomes: It has wide blood flow conduits which reduces
shear of the blood, it is frictionless without mechanical bearings
and it has an intrinsic pulse which is designed to reduce stasis and prevent
pump thrombosis. The intrinsic pulse may help to prevent
The ELEVATE registry, which is a voluntary,
multicenter, multi-national, observational registry in which HeartMate 3
consecutive patients in 26 centers were enrolled, evaluated patients who
received the HM3 as their primary implant (n=463) as well as the survival of the 540 patients in the full
cohort . The full cohort survival at 6 months was 82±2%. In the
enrolled primary implant patients, there was no incidence of pump
thrombosis, major bleeding was 25%, major infection 35%, and any stroke type 5%
. Functional capacity improved significantly (Δ6MWD 230±191 m) as
did QOL (ΔVAS 31±23). Freedom from unplanned rehospitalizations at 6
months was 68±2%. These 6-month outcomes of the HM3 LVAD demonstrate a highly reliable,
thrombosis-free device with low incidence of stroke and improved functional
capacity, and QOL.
The HeartMate 3 LVAD can also be used for
biventricular support as described in the multi-center report by Lavee and
colleagues, in which 14 patients at 6 medical centers underwent
implantation of a HeartMate 3 BIVAD. Eight of the 9 were
maintained on BiVAD support for 95 to 636 (mean 266) days: 7 at home,
and 1 successfully transplanted after 98 days of support. Nine of the patients
(64%) were alive at the time of the publication of the manuscript .
LVADs compared to cardiac transplantation
lVAD outcomes have improved consistently over the past
20 years since the results of the REMATCH trial. Outcomes for cardiac
transplantation have also improved mainly due to improvements in the
survival in the first 6 months to 1 year post-transplant as a result
of a lower incidence of rejection and infection in this time period and
better outcomes when these events occur. This is from the Registry on the
International Society of Heart and Lung Transplantation (ISHLT). Notably,
the incidence of cardiac allograft vasculopathy (CAV) and malignancy
post-transplant have declined modestly in recent years with
better outcomes. Despite this, survival beyond the first
year post-transplant has not changed substantially with CAV and
malignancy being the major causes of death in these patients .
The ISHLT Registry reports survival at 1 year in
excess of 90% . In contrast, the best 1 year survival reported for LVADs is
in the high 80s, inferior to transplants although there has been no
randomized comparison (fig.). Advantages of LVADs over transplant include
the fact that they are readily available, essentially
"off-the-shelf". The post-transplant complications, CAV,
malignancy, rejection, infection and nephrotoxicity (from immunosuppression) do
not occur in LVAD patients. There is no limits in LVADs as there is in
donor hearts and this explains why more LVADs are being performed than
cardiac transplants. As the heart failure population continues to age,
this will further shift the numbers toward LVADs.
Improvement in Survial Rates
Who should get transplants instead of LVADs? Generally
younger patients with few comorbidities should get transplants as transplants have kept many
patients alive for decades and longer than has been seen with LVADs. This
will likely improve over time. LVAD survival will likely improve with
improvements in technology. More durable, reliable VADs with
lower stroke rates, GI bleeding and pump thrombosis rates that are
totally implantable may give transplants competition in terms of outcomes.
At presents, VADs should be used in older patients with
co-morbidities including recent malignancies, and smoking should be
considered for VADs.
Management of advanced heart failure with LVADs and
transplant has improved dramatically over the past few decades. LVADs
represent a significant advance in that they allow patients who were
critically ill to survive to transplant and to function
including becoming physically active. As the technology has improved
and outcomes have improved, LVADs have become viable and realistic
alternatives for patients who might not be optimal transplant candidates.
As the technology continues to improve and disseminate worldwide, the
number of patients who receive LVADs will continue to grow. Eventually
with improved technology, LVADs may provide realistic competition
to cardiac transplantation in most patients.
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