A Systematic Review - Circulation: Heart Failure

Transcription

Clinical Outcomes Following Continuous-Flow Left Ventricular Assist Device:
A Systematic Review
McIlvennan et al: Continuous-Flow LVAD Outcomes
Colleen K. McIlvennan, DNP, ANP1,5; Kate H. Magid2,4; Amrut V. Ambardekar, MD1;
Jocelyn S. Thompson, MA5; Daniel D. Matlock, MD, MPH3,5; Larry A. Allen, MD, MHS1,5
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 20, 2016
1
Division of Cardiology, 2Colorado Health Outcomes, and 3Division of General Internal
Medicine, University of Colorado School of Medicine, Aurora, CO;
CO; 4Br
Brown
Brow
ownn Un
ow
Uni
University,
i
lorado Cardiovascular Outcomes Research Consortium,
C
ti
ti
Denver,
D
Den
CO
Providence, RI; 5Colorado
Correspondence to
Colleen K. McIlvennan,
n , DNP,, ANP
nan,
School of Medicine,, Division
Divisiion of
of Cardiology
C rd
Ca
rdio
iolo
io
logy
lo
gy
th
12631 East 17 Avenue, Room 7208, Mailstop B130, Aurora, CO, 80045
Phone: 303-724-8361
Fax: 303-724-2094
Email: [email protected]
DOI: 10.1161/CIRCHEARTFAILURE.114.001391
Journal Subject Codes: congestive heart failure [110]; CV surgery: ventricular assistance [37]
Abstract
Background—Conveying the complex trade-offs of continuous-flow left ventricular assist
devices (CF LVAD) is challenging, and made more difficult by absence of an evidence summary
for the full range of possible outcomes. We aimed to summarize the current evidence on
outcomes of CF LVAD.
Methods and Results—PubMed and Cochrane Library were searched from January 2007–
December 2013, supplemented with manual review. Three reviewers independently assessed
each study for saliency regarding patient-centered outcomes. Data were summarized in tabular
form. Overall study characteristics encouraged inclusion of all indications
(destination
therapy
ndications (dest
stiin
st
and bridge to transplant) and prevented meta-analysis. The electronic
465
roniic search
seearrch identified
ide
den
abstracts, of which 50
met
inclusion
criteria;
manual
review
50 m
et inc
ncclus
u io
ionn cr
crit
iter
it
eria
er
ia;; ma
ia
manu
n al
al rev
evie
ev
iew
ie
w added
add
ded
e 2 aarticles
rtic
rt
i le
ic
less in
n ppress. The
articles included 10 industry-funded
multi-center
ind
ndus
nd
ustr
us
trry fu
tryfund
nded
nd
ed trials
tri
rial
ri
a s and
al
nd registries,
reg
egis
isstrriees, 110
0 mu
mult
l ilt
i-ce
ceent
nter
er rreports,
epor
ep
orrts
orts
ts,, and the
remainder single-center
observational
CF LVAD
nte
terr ob
obse
serv
se
rvat
rv
atiion
at
onal
al eexperiences.
xpper
erie
ienc
ie
nces
nc
es. Estimated
es
Esti
Es
tima
ti
mate
ma
tedd actuarial
te
actu
ac
tuar
tu
aria
ar
iall survival
ia
surv
su
rviv
rv
ival
iv
al after
a
ranged from 56-87% at 1-year, 43-84% at 2-years, and 47% at 4-years. Improvements in
functional class and quality of life were reported, but missing data complicated interpretation.
Adverse events were experienced by the majority of patients, but estimates for bleeding, stroke,
infection, right heart failure, arrhythmias, and rehospitalizations varied greatly.
Conclusions—The totality of data for CF LVADs show consistent improvements in survival and
quality of life counterbalanced by a range of common complications. While this summary should
provide a practical resource for health care provider-led discussions with patients, it highlights
the critical need for high-quality patient-centered data collected with standard definitions.
Key Words: heart-assist device, heart failure, left ventricular assist device, health outcomes
2
Left ventricular assist devices (LVADs) are becoming an increasingly viable treatment option for
patients with end-stage heart failure. Newer generation continuous-flow (CF) LVADs have taken
the place of the first generation pulsatile-flow (PF) LVADs due to their smaller size and greater
durability. Ideal informed consent and shared decision making for LVADs should be grounded in
a thorough review of expected risks and benefits.1 This process should compare and contrast
LVAD therapy to alternative approaches, and include not only estimates of survival but also
major adverse events, health-related quality of life (HRQoL), symptom burden, functional
limitations, and obligations for caregivers.2
Although a variety of trial and registry data are available to co
complement
omp
mple
leme
le
ment
me
n individual
nt
clinician experience and
and patient
pattie
ient
nt testimonials,
tes
esti
timo
ti
moni
mo
nial
ni
a s,
al
s th
there
her
e e iss ccurrently
urre
ur
rent
re
ntly
nt
l nno
ly
o co
comprehensive
omp
mpre
rehe
re
hens
he
nsiv
ns
iv systematic
review of CF LVADs
D tthat
Ds
hatt at
ha
atte
attempts
teemp
m ts
ts tto
o su
ssummarize
umm
mmaari
rize
ze aand
nd oorganize
rgan
rg
aniz
an
izee av
iz
avai
available
aila
ai
ila
labl
blee in
bl
information
nfo
f rm
rmaa
into a
practical format. Existing
i ti
isti
is
ting
ng guidelines
gui
uide
deli
de
line
li
ness and
ne
and standard
stan
st
anda
an
dard
da
rd consent
con
onse
sent
se
nt forms
for
orms
ms do
do not
not provide
p ov
pr
ovid
idee such summary
id
data with any degree of detail.3 This absence of accurate and easily accessible information from
which to anchor risk-benefit communication leads to a potentially non-standardized and variable
informed consent and decision-making process around LVADs that may be incomplete,
confusing, or biased.4-5
Therefore, we aimed to summarize the current evidence on risks and benefits of CF
LVADs. Our objectives were to: 1) capture contemporary clinical data regarding outcomes for
patients offered CF LVADs; 2) describe the nature and quality of this evidence; 3) organize the
data in a way that conveys the full range of expected outcomes for CF LVADs, with direct
comparisons to outcomes without implantation; and 4) identify critical gaps in the scientific data
that should be a priority of future research. Our primary goal was to provide a practical
3
document that could guide a more standardized informed consent process and future
development of decision aids for CF LVADs.
Methods
Search Strategy
Our methods directly adhered to the guidelines set forth in the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement.6 We searched PubMed
(MEDLINE) and the Cochrane Library full text databases for English-language studies
nd Decemberr 13,
13 2013 related
concerning human subjects published between January 1, 2007 and
he time
tim
imee wh
when
en data
da on
to CF LVAD outcomes. The year 2007 was chosen, as this was the
VAD
A s started
sttarrte
tedd to become
bec
ecom
omee available.
om
av
vai
a labl
ab e.. The
The
h search
sea
e rc
rchh algorithm,
algo
al
gori
go
rith
ri
hm, developed
dev
v
contemporary CF LVADs
and then
a y by ffour
acy
oouur members
mem
me
mber
erss of
o the
the study
stud
st
uddy team
udy
team (CKM,
(CK
CKM,
M K
HM, JS
HM
JST,
T L
replicated for accuracy
KHM,
LAA), included a
dic
ical
al Subject
Sub
ubje
j ct Headings
je
Hea
eadi
ding
di
nggs and
and free-text
fre
reee-te
etext
te
xt terms
ter
erms
ms related
rel
elaate
tedd to LVAD,
LVA
VAD
D, CF, and
combination of Medical
associated outcomes such as survival, HRQoL, bleeding, stroke, or infection (see Supplemental
Material: Figure 1). The original intent was to summarize data for LVAD used as destination
therapy (DT); however, due to the complexities around indication reporting and because many
aspects of LVAD therapy are applicable across indications, studies including both bridge to
transplant (BTT) and DT were included. Where possible, care was taken to clearly identify and
separate BTT-only and DT-only data within the review. We included all forms of research, such
as meta-analyses, trials, retrospective and prospective studies and expert opinion papers without
restriction by journal. The reference lists of selected studies were manually reviewed to identify
any relevant studies that were potentially missed in the database search.
4
Study Selection
Eligible articles were presented in English and provided primary data about outcomes of CF
LVADs. Two study team members independently reviewed all titles and abstracts for initial
selection for inclusion (AVA, LAA). When the title and abstract provided insufficient
information to determine study relevance, a full text copy of the article was retrieved and
reviewed. For final selection, full text copies of all initially selected articles were examined for
study eligibility.
The following exclusion criteria were applied: studies that included less than 50 patients
with CF devices, reviews or editorials on CF LVADs, studies that
non-human
at were non
huum or focused
on imagine with CF LVADs, studies that focused on surgical techniques,
studies
hniqu
ques
qu
es,, st
es
stud
udie
ud
ies restricted to
ie
pediatric populations,
temporary
devices
support,
ss,, studies
studies
e that
es
thatt reported
rep
epor
orte
or
tedd ou
te
ooutcomes
tccom
o es
es oon
n te
temp
mpor
mp
orrar
ary de
devi
vice
vi
cess or ppartial
ce
a
studies with a transplant
PF device,
p an
plan
nt focus,
focu
fo
c s,
cu
s studies
stu
udi
d ess that
tha
hatt did
did not
not separate
seepa
para
rate
ra
te data
dat
ataa based
bbaaseed on
o CF
CF versus
verr
ve
studies reporting on oother
intra-aortic
data on
ther
th
er ddevices
evic
ev
ices
ic
es such
such aass in
intr
tratr
a-ao
aaort
ao
rtic
rt
ic bballoon
allo
al
loon
lo
on ppumps,
ump
ps, sstudies
tudi
tu
dies
di
es rreporting
ep
p
risk modeling and CF LVADs, studies that were updated by newer publications, and subanalyses of previously reported results. Additionally, for serial publications updating longitudinal
registry findings, we included only the most recent publication that addressed a specific
outcome. We also excluded papers focused on risk modeling for which the overall outcome
frequency for the same population was published elsewhere. Exceptions were made for evidence
sources that were frequently referenced by more contemporary publications. See Figure 1 for a
summary of evidence search and selection. For each article excluded, a single most obvious
exclusion criterion was chosen, even though many articles met multiple exclusion criteria.
5
Data Extraction and Quality Assessment
From each study, two independent reviewers (KHM, JST) extracted total patients, total CF
patients, type of device (CF, PF), specific model of device (e.g. Thoratec HeartMate II (HMII),
HeartWare HVAD), duration of follow-up or defined time at risk, population characteristics
(BTT, DT), and outcome measures (survival, functional status, HRQoL, bleeding, neurological
events, infection, device malfunction, right heart failure, arrhythmia, aortic insufficiency, renal
failure, and rehospitalizaion). These outcomes were chosen by a group of clinicians, patients, and
families as most important to CF LVAD therapy. Definitions for each outcome are included in
Supplemental Material: Figure 2. A third reviewer (CKM) independently
reviewed
endently revie
ew and
confirmed all data abstracted. Disagreements were resolved through
discussion
ughh di
disc
scus
sc
ussi
us
sion
si
on bby the entire
study team. We aimed
ed to include
ed
incl
c ud
ude all
alll relevant
rellev
evan
antt studies
an
sttud
u iees that
th
hat reported
rep
epor
o teed outcomes
or
out
utco
ut
come
co
mess for
me
for CF
C devices that
met our stated inclusion
s on and
sion
andd exclusion
excl
c us
usio
i n criteria.
io
c it
cr
iterria
ia. Assessment
A se
As
s ss
ssme
ment
me
nt of
of quality
qual
qu
aallitty was
waas ba
w
bbased
s d on study design.
se
The studies were categorized
rigor:
teg
egor
oriz
or
ized
iz
ed iin
n tthe
he oorder
rder
rd
er ooff ri
rigo
g r: 1)
go
1) industry-funded
indu
in
dusstr
du
tryy fu
yfund
nded
nd
ed trials
tri
rial
alss and
al
and related
r
prospective registries, which included all controlled trials related to CF devices; 2) multicenter
registries; and 3) single center reports and case series.
Data Synthesis
Data was summarized in tabular form. The resulting tables were organized according to the
prospectively identified key patient-centered outcome domains of interest: survival, HRQoL and
functional status, and adverse events. Where necessary, we manually calculated cumulative
numbers when data was only reported separately for subgroups. When relevant data was only
presented in graphic form, quantitative estimates were extracted and reported. Narrative
syntheses of data were added to supplement the tables, incorporate nuanced information about
6
data generation and quality, and provide a holistic summary. In order to create a clinically useful
synopsis that may help facilitate communication with patients and families, we performed a
crude analytic summary of the existing data. After reviewing the literature for all reported
outcomes, we solicited feedback from physicians, physician assistants, nurse practitioners,
nurses, a social worker, patients, and their families about which outcomes should be included in
a summary figure. We consolidated hospitalization, bleeding, stroke, and infections, where
appropriate, for ease of understanding. Event rates at 1-year were chosen as many studies did not
report events past 1-year. Final outcomes are reported in Figure 2. We first collated the data from
all studies for each outcome and subsequently removed redundant
studies that
nt data. We excluded
ex
xcl
cu
did not report percentage data. Second, we applied the weighted avera
average
method
r ge m
ra
etho
et
hodd based on total
ho
study sample and percentage
reported.
weighted
method
provides
erce
er
centagee re
repo
port
po
rted
rt
ed. Th
ed
Thee we
w
ig
ght
h ed
ed aaverage
vera
ve
rage
ra
ge m
ethood pr
et
prov
ovid
ov
ides
id
es a summary
treatment effect that more
with
morree heavily
hea
eavi
vily
vi
ly emphasizes
emp
pha
h si
sizees data
data reported
rep
epor
orte
or
tedd from
te
from a registry
reg
egis
istrry wi
is
w
th a large number
of patients than a small
LVAD
m ll single
mall
ma
sin
ingl
g e center
gl
cent
ce
nter
nt
er study.
stu
tudy
dy
y. It assumes
ass
ssum
umes
um
es fixed
fix
ixed
ed eeffects
ffec
ff
fec
ects
ts ooff CF L
VAD
VA
D across studies.
The resultant weighted average included all trial, registry, and single-center studies and is
reported as an estimated mean for all data. Finally, we applied the weighted average method to
calculate the time period reported for each outcome. We were unable to calculate the summary
effect sizes due to a variety of barriers, including the clinically diverse nature of the studies and
lack of reporting standards.
Results
The electronic search identified 465 titles and abstracts. An additional 2 studies related to pump
thrombosis that were currently in press7-8 and not identified in the search were added. After
7
inclusion and exclusion criteria were applied, a total of 52 full-text articles were included and
reviewed (see Supplemental Material: Table 1).
The majority of studies were non-randomized, observational, small power, or single
center. The studies included 10 industry-funded trials, 10 multi-center reports (many were
different analyses of the same ongoing registry), and the remainder single-center observational
experiences. A number of the multi-center registry publications that highlighted particular
outcomes of interest were sub-analyses or post-hoc analyses of existing databases. Similarly,
ongoing registries tended to be used for serial publications regarding individual outcomes.
Based on the data extracted, we identified 10 relevant patient-centered
for
ient centered ooutcomes
u
which data was reported: survival, HRQoL, functional status, bleeding,
neurological
events,
eediing
ng,, ne
eur
urol
olog
ol
o
infection, device malfunction,
arrhythmias,
rehospitalizations.
All singlealfu
alf
lffunction,
n,, right
rig
ghtt heart
heaart ffailure,
aiilure
lu
ure
re, ar
rrh
hyt
ythm
hmiaas,, an
hm
andd re
eho
hosp
s it
sp
ital
aliz
al
izaat
iz
center studies and those
CF
summarized
h se wi
hos
with
th lless
esss th
es
than
a 1100
an
00
0C
F LV
LVAD
AD ppatients
atie
at
ient
ie
ntss are
nt
arre su
umm
mmar
arrizzed
d iin
n Supplemental
Material: Tables 2-4.
summary
one-year
using
weighted
4. A su
summ
mmar
mm
aryy of ssimplified
ar
impl
im
p if
pl
ifie
iedd on
ie
onee-ye
ey ar ooutcomes
ye
utco
ut
come
co
mess us
me
usin
ingg we
in
weig
ight
ig
htee averages,
ht
including all data is provided in Figure 2. A pictograph was developed according to accepted
patient communication methods9 and feedback from clinicians, nurses and patients was provided
on content and readability.
Survival (6 Industry Funded Trials and Related Registries10-14; 6 Multicenter Registries7,15-19; 9
Single Center Reports or Case Series. See Supplemental Material for all single-center studies and
those with less than 100 CF LVAD patients.)
Survival is the outcome of dominant importance to the majority of patients.20 Extending life is a
primary goal of LVADs, and therefore communicating statistics around mortality is critical.
Although survival is an objective measure, characterizing long-term survival after LVAD
8
implantation is complicated by a number of factors, including finite study time periods, patient
loss to follow-up, and censoring of patients at the time of transplantation. Even in the DT
population, a significant minority of patients will later become transplant eligible (approximately
10% in DT trial populations).12 Therefore, estimated actuarial survival is most often reported.
Most studies reported survival rates at times post-implantation ranging from 1 to 24
months, with less data beyond 2 years (Table 1). The pivotal HMII DT Trial showed estimated
actuarial survival at 2 years of 58%.12 The Interagency Registry for Mechanically Assisted
Circulatory Support (INTERMACS) Fifth Annual Report showed 1, 12, 24, 36, and 48-month
repressen
e some of the
survival at 95%, 80%, 70%, 59% and 47%, respectively.19 These values represent
most recent data as well as some of the highest rates of survival for CF LVAD
LVA
VAD
D patients.
p
pa
The
ADVANCE: HVAD
Protocol
D BTT
B T Trial
BT
T iaal Continued
Tr
Cont
Co
ntin
nt
inue
in
uedd Access
ue
A ce
Ac
cess
s P
ro
oto
toco
col (C
co
((CAP)
CAP
AP) al
AP
also
so iillustrated
lllus
ustr
trat
tr
a e improved
survival 6 months and
nd 1 ye
nd
year
a aafter
fte
terr de
ddevice
vice
vi
cee iimplantation
mpla
mp
lant
la
ntat
nt
attio
atio
on compared
comp
co
mpar
mp
ared
ar
ed with
wit
ithh trials
tria
tr
iaals performed
perrf
in earlier
years.14 However, to
ow
what
hatt ex
ha
exte
extent
tent
te
nt pprogressive
rogr
ro
g es
gr
essi
sive
si
ve im
impr
improvements
prov
pr
ovem
ov
emen
em
ents
en
ts iin
n su
surv
survival
rviv
rv
ival
iv
al rrepresent
ep
pre
rese
sent
se
ntt true
improvements in the use of the device versus patient selection into less sick populations is
unclear.
HRQoL and Functional Status (6 Industry Funded Trials and Related Registries10-14,21; 1
Multicenter Registry19)
One of the main goals of LVAD implantation is to improve the HRQoL and functional capacity
for patients with symptomatic heart failure. Improvements in New York Heart Association
functional class are common after LVAD implantation. Approximately 80% of patients
improved from New York Heart Association class IIIB or IV at baseline to New York Heart
Association class I or II symptoms after LVAD in the HMII BTT and DT trials.10,12 In addition,
9
instruments commonly used to assess HRQoL in heart failure patients that are often
prospectively collected in LVAD studies include heart failure disease-specific measures such as
the Minnesota Living with Heart Failure Questionnaire22, the Kansas City Cardiomyopathy
Questionnaire23, as well as general measures such as the European Quality of Life-5
Dimensions.24 In addition to subscales of HRQoL questionnaires, functional status is most
commonly assessed through 6-minute walk distance. Among patients who survive with LVADs,
HRQoL measures improve markedly from baseline (Table 2). The collective HMII studies
demonstrated significant improvements in Minnesota Living with Heart Failure Questionnaire
minute wa
alk distance from
and Kansas City Cardiomyopathy Questionnaire scores, as well as 66-minute
walk
10-12,21
100 12
12,21
on.10
Additionally,
Add
ddiit
i ti
the most
before surgery to all time points assessed after device implantation.
recent INTERMACS
S Annual
Annuaal Report
Repo
Re
port
po
rt demonstrated
dem
emon
onst
on
stra
st
raate
tedd overall
oveera
rall
ll improvements
imp
m ro
rove
v me
ment
nts in the
nt
the European
E
Quality of Life-5 Dimensions
imensions
meens
nsio
io
onnss visual
vis
i ua
uall analog
an
nallog scale,
sca
cale
le, an
le
andd fewer
fewe
fe
werr pa
we
pati
patients
t en
ti
e ts identified
ide
dent
nttiffieed th
tthemselves
h
as
having “extreme problems”
o le
oble
ob
lems
ms” with
ms
with self-care
self
se
lf-c
lf
-car
-c
aree and
ar
and usual
usua
us
uall ac
ua
acti
activities.
tivi
ti
viti
vi
ties
ti
es.19
es
It should be noted that HRQoL and functional status data has typically censored patients
at the time of death, which can progressively enrich for a “healthier” population. Additionally,
missing data for HRQoL and functional status measures are more common than for an outcome
like survival, with 13-38% of patients unable to complete health status or functional assessments
at a given time point.10,12 However this failure to complete health status assessments can itself be
informative, with worse outcomes commonly seen in these patients.10,12 Finally, the HRQoL
measures developed in patients with chronic heart failure may not perform as intended when
applied to the LVAD population, given that many heart failure-related symptoms are traded for
other unique symptoms and burdens.25
10
Common Adverse Events
Although LVADs offer patients the potential for improved survival, HRQoL, and functional
status, there are also several risks associated with LVAD therapy. Some of the most commonly
studied and reported major adverse events following LVAD implantation are bleeding,
neurological events, and infection. Definitions for all adverse events are included in
Supplemental Material: Figure 2.
Bleeding. (7 Industry Funded Trials and Related Registries10-14; 3 Multicenter
Registries16,18-19; 14 Single Center Reports or Case Series. See Supplemental Material for all
ients.) Bleeding
ng is the most
single-center studies and those with less than 100 CF LVAD patients.)
commonly recorded adverse event of CF LVADS11-12,19, with thee majority
maj
ajor
aj
orit
or
i y of patients
it
pat
a
in all
published cohorts experiencing
xpe
xpe
perienci
ciing som
some
omee ty
om
type
pe ooff bl
bleeding.
lee
e diing.. Wh
When
en ppossible,
ossibl
os
ble,
bl
e bbleeding
e,
leeed
edin
ingg rates are
in
reported by <30 days
y (early)
ys
(ea
earl
rly)
rl
y) and
and >30
>30 da
days
ys (la
(late)
late
la
te)) in oorder
te
rd
derr tto
o he
help
lp ddifferentiate
ifffe
iffe
fere
rent
re
ntia
i te
t ppost-operative
o
bleeding from non-surgical
surg
su
rgic
ical
ic
al bleeding.
ble
leed
edin
ed
ing.
in
g. A recent
rec
ecen
entt study
en
stud
st
udyy of 139
ud
139 HMII
HMI
MIII patients
p ti
pa
tien
ents
en
ts showed
sho
howe
wee the greatest
risk of bleeding was within the first 2 weeks post-operatively and early bleeding was associated
with decreased survival.26 Later gastrointestinal bleeding is reported with rates as high as 13% in
the ADVANCE: HVAD BTT Trial CAP.14 A single-center study of 86 HMII patients reported
gastrointestinal bleeding as a frequent source of morbidity for patients but not a factor that
significantly impacts survival.27
Neurological Events. (7 Industry Funded Trials and Related Registries10-14; 4 Multicenter
Registries15-16,18,19; 9 Single Center Reports or Case Series. See Supplemental Material for all
single-center studies and those with less than 100 CF LVAD patients.) Neurological events,
including ischemic stroke, hemorrhagic stroke, and transient ischemic attack, are relatively
common and often severe complications following LVAD placement. In the INTERMACS
11
Annual Report, there was a 3% risk of stroke at 1 month, 5% at 3 months, 7% at 6 months, 11%
at 12 months, 17% at 24 months, and 19% at 36 months post-implant.19 Similarly, the HMII DT
Trial showed rates of ischemic and hemorrhagic stroke as high as 8% and 11%, respectively, in
the first 2 years after LVAD placement, with hemorrhagic stroke being the leading cause of
death among patients with a CF LVAD.12 The reported rates of stroke from other reports is quite
variable and likely reflects differences in study follow-up time and the patient population
studied; however, the overall annual risk of stroke in CF LVAD patients appears to be
substantial.
es10-14; 4 Mult
Multicenter
tic
ice
Infection. (7 Industry Funded Trials and Related Registries
Registries16,18-19,28; 9 Single Center Reports or Case Series. See Supp
Supplemental
pleeme
ment
ntal
nt
al M
Material for all
single-center studiess an
and thos
those
o e wi
os
with
th lless
esss th
es
than
an 1100
0 C
00
CF
F LV
LVAD
AD ppatients.)
atie
at
i ntts.
ie
s.)) Pa
Pati
Patients
tien
ti
ents
en
ts are
a at increased
risk of bacterial infections
ctions
ct
tio
ions
ns ffollowing
ns
o lowi
ol
lo
owi
wing
ng L
LVAD
VAD
VA
D im
impl
implantation,
plan
pl
an
nta
tati
tion
ti
on
n, oc
occu
occurring
curr
cu
r in
rr
ingg at tthe
he ddrivel
driveline,
riive
vel
pump
pocket, or systemically.
all
llyy. Driveline
Dri
rive
veli
ve
line
li
ne infections
inf
nfec
ecti
ec
tion
ti
onss in the
on
the International
Int
nter
erna
er
nati
na
tion
ti
onal
on
al HVAD
HVA
VAD
D Trial
Tria
Tr
iall are
ia
are reported at
18% at 1-year29, while the HMII BTT trial and trial registry report rates as high as 14% at 6
months.10-11 Developing any type of infection is associated with decreased survival and quality of
life;28 in one cohort, 2-year cumulative survival rate was 67% for patients with infections and
81% in those without.30
A summary of these outcomes, including all trial and registry data with greater than 100
CF LVAD patients, is provided in Table 3.
12
Other Adverse Events
Although bleeding, neurological events, and infection are dominant in adverse events reporting,
there are additional complications with CF LVAD therapy that can be equally devastating or
have an impact on HRQoL (Table 4).
Device Malfunction. (7 Industry Funded Trials and Related Registries10-14; 7 Multicenter
Registries7-8,12,16,18,31-32; 4 Single Center Reports or Case Series. See Supplemental Material for
all single-center studies and those with less than 100 CF LVAD patients.) Device malfunction is
a serious adverse event of LVADs, as treatment usually requires reoperation and its attendant
mat
a
risks. There are several causes of device malfunction, including thrombus form
formation
with
fract
ctur
ct
ures
ur
es wi
w
th eelectrical failure.
hemolysis, mechanical failure of the impeller, and driveline lead fractures
with
highestt rate
hi
rate of
of thrombosis
thro
th
romb
ro
mbos
mb
o iss rrequiring
os
eq
quiriing ppump
umpp ex
um
eexchange
chan
ch
han
ange
ge w
as inn the
In earlier reports, thee highest
was
2
DT
riaal at 88%
ri
% aatt 2 yyears.
e rs
ea
r .29
However,
H
owev
ow
ever
ev
err, a re
rece
recent
cent
ce
nntt sstudy
tudy
tu
dy ffrom
rroom th
three
hreee high volume
International HVAD
Trial
centers, including 837
3 H
37
HMII
MIII pa
MI
ppatients,
tien
ti
ents
en
ts, sh
ts
show
shows
owss an in
ow
incr
increase
crea
cr
ease
ea
se iin
n th
thee ra
rate
te ooff co
conf
confirmed
nfir
nf
irme
ir
medd pump
me
thrombosis at 3 months post-implant from 2.2% before March 2011 to 8.4% by January 2013.32
Analysis of the multicenter INTERMACS registry also confirmed a temporal increase in the
rates of HMII thrombosis.7 Temporal changes in thrombosis rates were not seen in a recent
analysis of the HeartWare HVAD.8 These recent studies illustrate the dynamic potential for rates
of adverse events over time, possibly reflecting changes in device technology, patient selection,
surgical technique, and post-implantation management.
Right Heart Failure. (8 Industry Funded Trials and Related Registries10-14,33; 3
Multicenter Registries16,18-19; 7 Single Center Reports or Case Series. See Supplemental Material
for all single-center studies and those with less than 100 CF LVAD patients.) Right heart failure
following LVAD implantation contributes to increased post-operative morbidity and mortality.
13
Outcomes of LVAD patients are dependent on right heart function due to the necessity of
adequate flow through the pulmonary circuit to the left heart. In the HMII DT Trial, 20% of
patients received extended inotropic therapy for persistent right heart failure and 4% required
placement of a right ventricular assist device.12 In the ADVANCE: HVAD BTT Trial CAP, 25%
of patients became dependent on inotropic therapy and 3% required a right ventricular assist
device.14 The HMII BTT Trial-Registry and an analysis of 484 patients enrolled in the HMII
BTT Trial reported right heart failure post-LVAD implantation is associated with a marked
reduction in rates of survival and longer hospital length of stay.10,33
Cardiac Arrhythmias. (6 Industry Funded Trials and Related
ated Registriess10-14; 3
Multicenter Registries16,18-19; 5 Single Center Reports or Case Series.
ries.. Se
Seee Su
Supp
Supplemental
pple
pp
l
Material
for all single-center studies
s udies and
st
an
nd those
th
hos
osee with
with lless
e s th
es
tthan
an
n 100
00 C
CF
F LV
LVAD
A ppatients.)
atie
at
ient
ie
nts.
nt
s.)) Ca
s.
C
Cardiac
a
arrhythmias, both ventricular
enttri
ent
ricu
c la
cu
lar and
and supraventricular,
suupr
prav
aven
av
entrric
icul
ular
ul
a , can
ar
cann develop
ca
deve
de
velo
ve
lopp after
lo
affte
ter
er LVAD
LVAD implantation.
imp
mp
A
study of 184 HMII de
ddevices
devi
vice
vi
cess sh
ce
show
showed
owed
ow
ed aan
n in
inci
incidence
cide
ci
denc
de
ncee of vventricular
nc
entr
en
tric
tr
icul
ic
ular
ul
ar aarrhythmias
rrhy
rr
hyyth
thmi
mias
mi
as uup
p to
o 32% postLVAD.16 Studies have reported conflicting associations of ventricular arrhythmias with survival.
A study of 61 patients reported patients with post-LVAD ventricular arrhythmias had a
significantly increased risk of mortality.34 In contrast, another cohort of 61 patients showed postLVAD ventricular arrhythmias had no association with survival but did have greater morbidity,
as patients with post-LVAD ventricular arrhythmias had greater rehospitalizaion rates.35 In
addition, patients with post-LVAD ventricular arrhythmias had higher rates of appropriate (31%)
and inappropriate (15%) defibrillator shocks.35
Rehospitalizations. (4 Industry Funded Trials and Related Registries10-12; 1 Multicenter
Registries18; 7 Single Center Reports or Case Series. See Supplemental Material for all singlecenter studies and those with less than 100 CF LVAD patients.) Recurrent hospital admissions
14
are a common occurrence in LVAD patients. One trial reported readmission rates as high as
94%12, and another reports up to 1.2 admissions per patient year.29 One study of 71 CF LVAD
patients found that patients are most often readmitted within 6 months of discharge, with
gastrointestinal bleeding as the most common cause.36
Additional Adverse Events. Renal function, neurocognitive function, and aortic
insufficiency are additional patient-centered outcomes identified in our electronic search. There
are limited studies that report this data; therefore, the outcomes were not included in the tables.
Remaining patient-centered outcomes included the following: 1) one study of 107 HMII patients
y post
LVAD im
found that 15% required some form of renal replacement therapy
post-LVAD
implantation;37 2)
one study of 96 HMII patients showed no change or improvement
nt inn ne
neur
neurocognitive
uroc
ur
ocog
oc
ognni
og
ni
testing post3
LVAD implantation;
n 38
n;
and 33)) on
onee st
stud
study
udyy of 558
ud
8 HM
H
HMII
II pat
patients
atie
at
ient
ie
n s sshowed
hoowe
w d that
th
ha aaortic
orti
or
ticc iinsufficiency of
ti
g es
gres
esse
ssees wi
w
th tthe
he dur
urat
ur
atio
at
ionn of L
io
VAD
VA
D su
supp
ppor
pp
ort.
or
t 3399
the native valve progresses
with
duration
LVAD
support.
A summary of
o tthese
hese
he
se ooutcomes,
utco
ut
come
co
mes,
me
s,, iincluding
ncl
clud
udin
ud
ingg al
in
alll tr
tria
trial
iall an
ia
andd re
regi
registry
g st
gi
stry
ry
y ddata
ataa wi
at
with
th greater
g
than 100
CF LVAD patients, is provided in Table 4.
Discussion
Permanent mechanical circulatory support in the form of a CF LVAD offers the potential to
fundamentally change the clinical course of severe heart failure. Existing evidence shows that,
for populations of carefully selected patients, LVADs improve survival, HRQoL, and functional
status. Because outcomes in these domains are so dismal without an LVAD, the absolute benefit
is marked, with number needed to treat that dwarfs most existing medical therapies. However,
despite these dramatic improvements in survival and heart failure symptoms, LVAD therapy
remains associated with a significant residual risk of mortality after implantation and the
15
potential for major adverse events in a significant percentage of patients. Thus, for eligible
patients, whether to pursue these therapies should involve a careful assessment of the totality of
expected risks and benefits over time and how these may relate to a patient’s values, goals, and
preferences.
Given the complex tradeoffs of LVAD therapy, necessary components for shared
decision making around CF LVAD must include optimal patient selection, extensive informed
consent, and adequate time to review expected risks, benefits, and burdens. To ensure this,
LVAD programs are required by the Joint Commission to have a process around education,
decision making, and informed consent. While the ethical mandate
ate surrounding
ng informed
consent is clear,2 achieving true informed consent in this setting
g is ch
chal
challenging.
a leng
al
leeng
ngin
ing.
in
g 1 Additionally,
providing accurate information
n ormati
nfo
nf
tiion too patients
pati
pa
t en
ents
ts in
in ann understandable
und
derst
stan
st
anda
an
dabl
da
b e fo
bl
fformat
rm
mat tto
o fa
faci
facilitate
cili
ci
litaa sharedli
decision making is com
ccomplicated.
mplic
pliccat
pl
a ed
ed.
There have been
bee
eenn other
othe
ot
herr re
he
revi
reviews
view
vi
ewss re
ew
rega
regarding
g rd
ga
rdin
ingg LV
in
LVAD
AD ooutcomes
utco
ut
come
co
mess40; however,
me
howe
ho
weve
we
verr, there has been
ve
no major attempt at systematically reviewing this data according to accepted scientific
standards in a patient-focused manner. Several studies have found that graphical presentation of
risks and benefits enhances understanding of statistics for patients and families of varying
numeracy and literacy skills.41 The pictograph developed from this systematic review (Figure 2)
provides patients, their families, and clinicians an estimate of the full range of CF LVAD
outcomes based on weighted averages of all trial, registry, and single-center data published to
date. Research has shown that patients differ in their decision-making processes, with some
patients viewing survival and quality of life as paramount while others weigh risks and burdens
more heavily.20, 42 In response to this, the pictograph provides both benefits and risks; therefore,
patients can weigh those outcomes they feel are most important to them. This pictograph could
16
be easily incorporated into existing educational materials and informed consent documents.
While the pictograph does not provide tailored risk estimates and does not show measures of
uncertainty for individual patients, we feel it is a significant improvement over existing
educational materials.43
The importance of considering tradeoffs for LVAD therapy is particularly salient to the
subgroup of patients with a DT indication, who should expect to live the remainder of their life
dependent on an LVAD and for whom the reasons making them transplant ineligible will usually
persist (advanced age, comorbidity, and frailty). As such, the initial goal of this systematic
erapy. Howeve
veer,
r the overall
review was to summarize the risks and benefits of DT LVAD therapy.
However,
ntedd with
with a DT
DT indication—and
i
paucity of studies reporting outcomes confined to patients implanted
DT and BTT
BTT patients
pati
pa
tien
ti
en
ents
nts in
in some
s me reporting—led
so
rep
porrti
ting
ng—l
ng
—led
—l
ed
d to
to the
th
he inclusion
incl
in
cllus
usio
ionn of data from
io
the intermixing of DT
ell.
el
l. T
l.
h s allowed
hi
a lo
al
owed for
for a wi
wide
derr ra
de
ang
ngee of eevidence;
vide
vi
denc
de
n e; hhowever,
owev
ow
e er
ev
e , tthe data for BTT
BTT populations as wel
well.
This
wider
range
d ta for
da
for informed
inf
nfor
orme
or
medd decision
me
deci
de
cisi
ci
sion
si
on making
mak
akin
ingg around
in
arou
ar
ound
ou
nd D
T LV
LVAD
AD. Th
AD
Thee tw
w indications
patients is not ideal data
DT
LVAD.
two
yield different populations and different outcomes for a variety of reasons, including the
temporary nature of BTT and the younger age and lower comorbidity of the BTT-eligible
population. This limitation is not peculiar to the systematic review, but rather to the state of
LVAD research and reporting. Where reported, we have recognized the DT versus BTT
indication to help refine interpretation.
As only one device is currently approved in the United States for the DT indication, and
only one large high-quality trial (HMII DT Trial) was conducted to describe outcomes in this
setting, clinicians and patient educational materials for DT often default to the event rates
reported from this study.12 This approach is reasonable given possible threats to scientific
validity from lower quality observational data. However, the HMII DT Trial has a number of
17
limitations that encourage supplementation from other sources. Although a randomized
controlled trial, the study compared CF DT LVAD to the older PF LVAD, not to a control group
of optimal medical therapy patients (OMT). Additionally, this comparison was un-blinded. The
trial included only 133 patients in the HMII CF device arm, such that estimates of rare events are
potentially unstable. Further, the randomized controlled trial setting, with highly selected patients
treated at a limited number of participating centers, may not be particularly generalizable to the
usual care setting. Recent reports of higher than expected pump thrombosis rates illustrate these
potential concerns.7,32 Therefore, systematically reviewing all of the published literature for
bular form hopefully
hope
pef
pe
individual outcomes and then summarizing those estimates in tabular
offers a
more complete picture of the expected range of risks and benefitss th
that
hat
a cclinicians
l ni
li
nici
cian
ci
anss can convey to
an
patients considering L
LVAD.
VAD.
In addition to
o ssummarizing
umma
um
mari
ma
rizi
ri
izi
zing
ngg eexisting
xiist
stin
in
ng da
data
data,
ta, the
ta
th
he co
conduct
ond
nduc
uctt of tthis
uc
hhiis sy
syst
systemic
stem
st
mic
i rreview
ev
also
clarifies deficienciess iin
n th
thee su
sum
m of eexisting
xist
xi
stin
st
ingg da
in
data
data.
ta. Da
ta
Data
ta rregarding
eg
gar
ardi
ding
di
ng
g ssurvival
urvi
ur
viva
vi
vall fo
va
forr DT eligible patients
who decline LVAD and continue with OMT are relatively sparse and dated. All studies showed a
higher survival rate at every increment of time for patients who received an LVAD as compared
to patients who were treated with OMT.44-46 Further, the COSI trial showed a dismal 6% survival
at one year for patients with end-stage heart failure managed with continuous inotropic support.46
With ranges in 2-year survival of 60-70% for CF DT LVAD12 and 6-8% for OMT44, the number
needed to treat to save one life over a 2-year span is less than 2 patients. Although survival is
significantly improved with LVAD implantation, the absolute rates of death remain relatively
high with less than half of patients still alive 4 years after implantation.19 With improvements in
technology, surgical technique, peri-operative care, and patient selection,47 summary data
suggest that for the near term, CF DT LVAD patients should expect actuarial survival rates in the
18
2-years after implantation on the order of 65-75%. BTT survival rates are better, with 2-year
survival reported as high as 79-84%.14,29 In a perfect world, studies would randomly compare DT
LVADs to OMT. While randomizing patients to this comparison is essentially unfeasible in most
contexts, obtaining additional data on outcomes among OMT populations is possible. The
recently launched Medical Arm of INTERMACS (MEDAMACS)48 and Randomized Evaluation
of VAD InterVEntion before Inotropic Therapy (REVIVE-IT)49 studies should provide
additional data regarding the outcomes of OMT in a group of non-inotrope dependent advanced
heart failure patients. Additionally, due to variation in outcomes by indication, future studies
ased on BTT vversus
e
er
should aim to separate data collection and outcomes reporting based
DT
ovid
de im
impo
port
po
rtan
rt
a t comparator
an
implantation status. Patients who decline DT LVAD may also provide
important
information.
ackk of rrigorous
ac
ig
igor
gor
orou
ous st
ou
stan
an
nda
d rd methodology
met
e ho
hodo
dolo
do
logy
lo
gy decreases
dec
ecre
reas
re
asses
es th
thee ut
uutility
illitty of study
Furthermore,, llack
standard
n-u
-uni
nifo
ni
form
fo
rm reporting
rep
por
orti
ting
ti
ng
g of
of event
even
ev
entt rates
en
rate
ra
tess limits
te
limi
li
mits
mi
ts the
the ability
abi
bili
lity
li
ty
y to
to pool
pool data
d across
information. The non-uniform
studies. While events per patient time may be statistically sound, it complicates interpretation for
patients with lower numeracy. Similarly, there is no standardized or patient-centered method for
accounting for loss to follow up (e.g. death during longitudinal measures of quality of life) or
alternative end points (e.g. transplantation when calculating survival in DT). Additionally, with
standardized reporting, summarizing data for longitudinal outcomes reporting would be less
problematic. Finally, due to the rapid evolution of mechanical circulatory support, flexible and
efficient systems must be developed to help patients and their health care providers stay updated
on contemporary rates of outcomes. Ultimately, not only is there a desperate need for additional
high-quality data, but this data must be collected using standard event definitions, such as the set
used by the INTERMACS registry, and reported in units that are mostly clinically meaningful.
19
Limitations
In addition to the above issues with mixing of BTT and DT, data quality, and non-standardized
reporting, there are several additional limitations that deserve recognition. First, the vast amount
of data was difficult to present in a complete and simultaneously understandable format, such
that some detail was sacrificed for ease of interpretation, both in terms of excluding smaller
studies and in simplifying the studies that were included. Second, we included all data on
outcomes of CF LVADs without a rigorous exclusion process based on the quality of the study;
therefore, interpretation of the data should be guided by the categorized rigor of the study. In
depth review of individual studies may ultimately be required by individual hea
health
eaal care providers
to better answer nuanced clinical questions.
Conclusion
The totality of data ffor
CF
LVADs
or C
F LV
LVAD
ADss sh
AD
show
ow cconsistent
onsi
on
sist
si
steent iimprovements
st
mp
pro
rove
veme
ve
ment
me
ntss in ssurvival
nt
urvi
ur
viva
vi
vall and
va
an
n quality of life
counterbalanced by a range of common complications. While this summary of outcomes data for
CF LVAD should help frame consent, education, and decision making around durable
mechanical circulatory support, future action is required to remedy the lack of high quality data
for CF LVAD, particularly in the DT setting. Additional randomized controlled trials with larger
patient populations are needed to further examine survival, HRQoL and frequency of
complications. Supplementary trials that report outcomes for a timeline that mirrors the lifespan
of DT patients are also necessary. Further, registries for patients on OMT who decline LVAD
therapy are critical. An exponential expansion in LVAD use without such information is likely to
diminish the overall value that patients and society can derive from this remarkable therapy.
20
Acknowledgements
The authors would like to thank Molly Magid for providing comments and revisions on the
manuscript.
Sources of Funding
x
Dr. Ambardekar is supported by a Scientist Development Grant from the American Heart
Association and by the Boettcher Foundation’s Webb-Waring Biomedical Research
Program.
x
Dr. Matlock is supported by a career development award from the Nat
National
tio
ionn Institutes on
Aging (K23AG040696). Dr. Matlock is also supported byy thee University
Uni
nive
verrsi
ve
sity
t of Colorado
ty
Department ooff M
Medicine
Early
Career
edici
cine
ci
ne E
arl
rlyy Ca
Care
reer
re
e Scholars
er
Sch
cholaarss Program.
Prog
Pr
ogra
og
raam.
x
Dr. Allen is sup
National
Heart,
Lung,
and
Blood
Institute
supported
ppo
p rtted bby
y th
thee Na
N
ati
tiional
al H
eeaart
rt, Lu
Lung
ng, aan
ng
nd Bl
nd
Bloo
oo
ood
od In
Inst
sttittut
ute
te oof the National
Institutes of He
H
Heal
Health
alth
al
th uunder
nder
nd
er A
Award
ward
wa
rd N
Number
um
mbe
b rK
K23HL105896.
23HL
23
HL10
HL
10
058
896
96. Th
Thee co
cont
content
n en
nt
entt is solely the
responsibility of the authors and does not necessarily represent the official views of the
National Institutes of Health. Dr. Allen is also supported by the University of Colorado
Department of Medicine Early Career Scholars Program.
Disclosures
None.
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25
Table 1. Estimated Actuarial Survival of CF LVAD - All Trial and Registry Data with Greater Than 100 CF Patients
Study
First
Author
Year
Total
CF
BTT
DT
1
Mo
6
Mo
12
Mo
Industry-Funded Trials and Related Registries
HMII BTT Trial10
Miller
2007
133
133
0
89% 75% 68%
HMII BTT Trial Registry11
Pagani
2009
281
281
0
92% 82% 73%
HMII DT Trial12
Slaughter
2009
133
0
133
68%
ADVANCE: HVAD BTT Trial13
Aaronson
2012
140
140
0
99% 94% 86%
Slaughter
2013
ADVANCE: HVAD BTT Trial CAP14
332
332
0
97% 91%
Mutlicenter Registries
INCOR Analysis15
Schmid
2008
216
56%
64 European Institutions16*
Lahpor
2010
411
300
86
74% 72%
U of Minnesota, Pittsburgh, &
Boyle
2011
101
86
15
77%
Columbia17
John INTERMACS18
John
2011 1496
496
6 14
1496
96
0
89% 85
85%
INTERMACS 201319
Kirklin
2013 5436
436
36 3742
374
7442 1694
742
1694
95%
95%
80%
80%
INTERMACS Thrombosis7
Kirklin
2014 6910
910
10
995%
95
% 87
887%
% 80%
800%
* See Supplemental Material for all single-center studies or those with
t less
th
less than 10
1100
0 co
ccontinuous
ntinuous flow
flo
low patients
p ti
pa
tientts
† Study includes alternative indications for implant (e.g. bridge to decision,
cision, bridg
bridge
ge to
o ccandidacy)
andi
an
dida
di
dacy
da
c )
cy
24
Mo
36
Mo
48
Mo
58%
84%
-
-
43%
-
-
-
70%
70%
669%
69
%
559%
558%
47%
46%
BTT=bridge to transplant; CAP=continued access protocol; CF=continuous-flow;
ttinuous-flow;
ti
nuou
nu
ouss-fl
flow
fl
ow;; DT=destination
DT=d
DT
=d
ddestination
esti
es
tina
ti
nati
tion
ti
on therapy;
thera
herapy
he
py;; HMII=
HMII
HM
II=
II
= HeartMate
HeartMat
H
He
artM
ar
tMat
tM
at II;
HVAD=HeartWare ventricular assist device; INCOR=INCOR left ventricular assist device; INTERMACS=Interagency Registry for
Mechanically Assisted Circulatory Support; mo=month; LVAD=left ventricular assist device
Table 2. HRQoL and Functional Status of CF Devices
KCCQ - Scores range from 0 to 100. A higher score illustrates a better health status.
First
#
Study
Year
Baseline*
Author
CF
HMII BTT Trial10
33±19
Miller
2007 113
36±21
Pagani
2009 90
HMII DT Trial12
27±16
Slaughter 2009 115
HMII BTT DT Trial Registry21
Rogers
2010
BTT
226
26(m)
DT
318
24(m)
35±19
Aaronson 2012 128
Slaughter 2013 169
37±22
MLHFQ - Scores range from 0 to 105. A lower score illustrates a better quality of life.
First
#
Study
Year
Baseline
Author
CF
10
73±25
HMII BTT Trial
Miller
2007 114
69±23
Pagani
2009 92
75±18
HMII DT Trial12
Slaughter 2009 116
Rogers
2010
BTT
224
2 4
22
75(m)
DT
3323
23
3
75(m)
75(
5(m)
m
#
CF
77
89
57±20
63±19
#
CF
90
-
58(m)
68(m)
-
119
240
70
169
3 Mo*
167
262
-
#
CF
77
89
45±25
37±22
7±22
7±
22
164
258
258
42(m)
42
34(m)
34((m)
m
3 Mo
63±23
-
#
CF
76
60(m)
72(m)
67±21
68±19
203
-
6 Mo*
#
CF
92
9
41±25
11
115
1
23
234
23
38(m)
32(m)
EQ-5D VAS - Scores ranges from 0 to 100, 0 representing the worst possib
possible
ss ble health
hea
ealt
lth
lt
th state
s atte and
st
and 100
100 re
representing
esenti the best.
First
#
#
#
Study
Yearr
Baseline
Base
Ba
seli
se
eli
line
ne
3 Mo
Author
CF
C
CF
CF
C
40±24
72
Aaronson 2012 130
Slaughter 2013 178
44±25
178
INTERMACS 201319
41(m)
528
69(m)
466
Kirklin
2013 852
6 Mo
6 Mo
70±20
72±19
73(m)
#
CF
76
197
#
CF
281
6MWD - Evaluates an individual’s functional exercise capacity by measuring the distance, in meters, he or she can walk in six minutes.
First
#
#
#
#
Study
Year
Baseline
3 Mo
6 Mo
Author
CF
CF
CF
CF
42±97
56 292±212
HMII BTT Trial10
Miller
2007 25
201±140
109 347±179
Pagani
2009 14
182±140
77 319±191
61
HMII DT Trial12
Slaughter 2009 50
Rogers
2010
BTT
38
214±215
97 372±199
DT
129 204±150
199 350±198
-
66±20
#
CF
47
70(m)
-
97
-
12 Mo*
34±22
#
CF
44
32(m)
90
12 Mo
12 Mo
72(m)
#
CF
-
24 Mo*
70±19
74(m)
-
24 Mo
30±22
34(m)
24 Mo
-
318±164
#
CF
36
372±191
-
75
360±210
12 Mo
24 Mo
* Time was reported variably among studies: mean/SD (x ± y), mean (x(m))
27
#=number; 6MWD=6 minute walk distance; BTT=bridge to transplant; CAP=continued access protocol; CF=continuous-flow; DT=destination therapy; EQ-5D=European
Quality of Life-5 Dimensions; HRQoL=health-related quality of life; HMII=HeartMate II; HVAD= HeartWare ventricular assist device; INTERMACS=Interagency
Registry for Mechanically Assisted Circulatory Support; KCCQ=Kansas City Cardiomyopathy Questionnaire; MLHFQ=Minnesota Living with Heart Failure
Questionnaire; mo=month; VAS=Visual Analogue Scale.
28
Schmid
Lahpor
John
Goldstein
2008
2010
2011
2012
216
16
8
84
184
1496
2006
1496
830
0
291
Kirklin
2013
5358
-
-
Other
0
Sepsis
332
Pocket
332
32
Driveline
2013
Local
Slaughter
Other
6 mo
6 mo
24 mo
6 mo
TIA
0
0
133
0
Hemorrhagic
Defined Time at
Riskll
133
281
0
1140
4
40
Infection
Ischemic
DT
133
281
133
40
40
140
Neurological Event
GI
BTT
2007
2009
2009
2012
Late > 30 days
Total CF
Miller
Pagani
Slaughter
Aaronson
Early 30 days
Year
Bleeding
First Author
Study
Table 3. Common Adverse Events
of CF LVAD - All Trial and Registry
Data with Greater Than 100 CF
Patients*
75%
8%
%
69% 23%
%
111%
26% 11%
%
11%
6%
55%
%
88%
%
7%
%
2%
3%
11%
6%
4%
2%
4%
6%
5%
22%
-
28%
30%
49%
-
14%
14%
12%
0%
2%
-
20%
17%
36%
11%
35%
-
3-36
3 m
36
mo
o
15
15%
5%
14%
%
13%
%
8%
8%
8%
5%
-
-
17%
-
17%
-
48 m
mo
o
8±7
8±
7 mo
9±7 mo
12 mo
-
-
10%
-
18%
18
%
8%
4%
4
%
2%
4%
2%
1.8/100 ptmo
4%
-
4%
-
20%
23%
22%
13%
19%
5%
2%
-
30%
3%
20%
26%
-
-
-
HMII BTT Trial10†
HMII BTT Trial Registry11†
HMII DT Trial12†
ADVANCE: HVAD BTT Trial13‡
ADVANCE: HVAD BTT Trial
CAP14‡
Mutlicenter Registries
INCOR Analysis15
64 European Institutions16§
John INTERMACS18‡
Goldstein INTERMACS28‡§
19
INTERMACS 2013 ‡
12 mo
52%
5
2%
36%
-
-
9.5/100 pt-mo
8.0/100 pt-mo
Adverse events definitions in Supplemental Material: Figure 2.
* See Supplemental Material for all single-center studies or those with less than 100 continuous flow patients
† Study uses HeartMate II definitions for adverse events.
‡ Study uses INTERMACS definitions for adverse events.
§ Study includes alternative indications for implant (i.e. bridge to decision, bridge to candidacy).
ll Time at risk was variable among studies: truncated time point (x mo), mean/SD (x ± mo), range (x-y mo).
BTT=bridge to transplant; CAP=continued access protocol; CF=continuous-flow; DT=destination therapy; GI=gastrointestinal; HMII= HeartMate II; HVAD=HeartWare ventricular
assist device; INCOR=INCOR left ventricular assist device; INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support; mo=month; TIA=transient ischemic
attack
29
Table 4. Other Adverse Events of CF LVAD - All Trial and Registry Data with Greater Than 100 CF Patients*
Other Requiring
Exchange
Inotropic Support
RVAD
133
281
0
484
140
332
0
0
133
0
0
0
6 mo
18 mo
24 mo
o
12 mo
o
6 mo
3-36
6 mo
mo
2%
2%
2%
22%
%
4%
2%
3%
88%
55%
55%
13%
13%
20%
14%
16%
25%
4%
6%
4%
6%
3%
3%
2010
20
010
2011
2013
201
13
184
184
8
14996
1496
2816
2816
1496
1496
-
0
-
8±77 mo
8±
9±77 mo
9±
m
36 mo
mo
22%
%
2013
2014
2014
5358
6910
382
382
-
12 mo
10%
00.9%
.9%
9% 0.8%
0.
11.6/100
6/100
6/10
6/
1000 ppt10
mo
5%
5%
-
20%
12%
1%
1.8/100 ptmo
-
Rehospitalization
Thrombosis Requiring
Exchange
133
281
133
484
140
332
Other
Defined Time at Riskll
2007
2009
2009
2010
2012
22013
0133
01
Arrhythmia
VA
DT
Kirklin
Kirklin
Najjar
BTT
INTERMACS 201319‡
Total CF Pts
HMII BTT Trial10†
Miller
HMII BTT Trial Registry11†
Pagani
HMII DT Trial12†
Slaughter
HMII BTT Trial Registry-RVF33†
Kormos
ADVANCE: HVAD BTT Trial13‡
Aaronson
ADVANCE: HVAD BTT Trial CAP14‡
Slaughterr
Multicenter Registries
64 European Institutions16§
Lahpor
John INTERMACS18‡
John
Holman INTERMACS31‡
Holman
Right Heart
Failure
Year
First Author
Device
Malfunction
Study
24%
20%
56%
21% 20%
21% 21%
41%
68%
94%
-
32%
28%
4.7/100 ptmo
-
50%
-
INTERMACS Thrombosis7‡
12 mo
Najjar ADVANCE BTT & CAP8‡
12 mo
Cleveland Clinic, Barnes-Jewish, &
Starling
2014 837
8-11 mo
4%
Duke32
Adverse events definitions in Supplemental Material: Figure 2.
* See Supplemental Material for all single-center studies or those with less than 100 continuous flow patients
‡ Study uses INTERMACS definitions for adverse events.
§ Study includes alternative indications for implant (i.e. bridge to decision, bridge to candidacy)
ll Time at risk was variable among studies: truncated time point (x mo), mean/SD (x ± y mo), range (x-y mo), mean (x mo(m))
BTT=bridge to transplant; CAP=continued access protocol; CF=continuous-flow; DT=destination therapy; HMII= HeartMate II; HVAD=HeartWare ventricular
assist device; INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support; mo=month; pt=patient; RVAD=right ventricular assist device;
RVF=right ventricular failure; VA=ventricular arrhythmia; yr=year.
30
Figure Legends
Figure 1. Search Flow Diagram
Figure 2. Simplified One-Year Outcomes Using Weighted Averages for Left Ventricular Assist
Device (Combined Bridge-to-Transplant and Destination Therapy)
Identification
Screening
2 articles identified through
other sources
467 records screened
Eligibility
Included
465 articles identified through
MEDLINE search
52 articles included in systematic review
Industry-funded trials and related registries = 10
Multicenter registries = 10
Single center reports and case series = 32
415 records excluded
<50 continuous-flow = 102
Review/editorial = 103
Technical, imaging or non-human = 35
Surgical technique = 29
Pediatric = 29
Temporary device/partial support = 28
Transplant focus = 21
Pulsatile flow = 18
Other devices = 15
Risk model = 13
Updated by newer publication = 12
Sub-analysis reported results = 10
Figure 2. Simplified One-Year Outcomes Using Weighted Averages for Left Ventricular Assist
Device (Combined Bridge-to-Transplant and Destination Therapy)
Survival
1 year
Benefits
80%
Quality of Life*
Before LVAD = 28
1 year after LVAD = 70
100
Best
Rehospitalized for Any Cause
55%
Major
Maj
jor Bleeding†
Blee
eding
g†
0-1 month
h after
after LVAD
LV
VAD
D (typically
(ty
typica
ty
ally surgical)
surg
rg
giccal
al))
30%
1-12
1--12
2 months
m
after LVAD
20%
1 year
Stroke‡
St
S
t k ‡
Risks
0
Worst
10%
Serious Device-Related Infection§
20%
Device Malfunction Due to Clotting
5%
Ongoing Heart Failure¶
18%
Shaded=Affected; White=Not affected. All timeframes are time since LVAD implant. LVAD=left ventricular assist device. *Kansas
City Cardiomyopathy Questionnaire score; †Requiring transfusion or urgent medical attention; ‡Ischemic=5%±5,
Hemorrhagic=5%±4; §Driveline=18%±2, Pump Pocket=2%±2; Typically requiring surgery to replace the device; ¶Requiring
inotropes >2 weeks after implant=15%±7, Requiring right ventricular assist device=3%±2.
Standard Deviations (not reported above): Survival=80%±10; Quality of Life baseline=28±27, 1 year=70±0;
Rehospitalization=55%±2; Bleeding 0-1 month=30%±5, 1-12 months=20%±6; Device Malfunction=5%±2.
For more information, go to www.patientdecisionaid.org
Clinical Outcomes Following Continuous-Flow Left Ventricular Assist Device: A Systematic
Review
Colleen K. McIlvennan, Kate H. Magid, Amrut V. Ambardekar, Jocelyn S. Thompson, Daniel D.
Matlock and Larry A. Allen
Circ Heart Fail. published online October 7, 2014;
Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3289. Online ISSN: 1941-3297
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circheartfailure.ahajournals.org/content/early/2014/10/07/CIRCHEARTFAILURE.114.001391
Data Supplement (unedited) at:
http://circheartfailure.ahajournals.org/content/suppl/2014/10/07/CIRCHEARTFAILURE.114.001391.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
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SUPPLMENTAL MATERIAL
Figure 1. Search Algorithm
PubMed / MEDLINE Search Algorithm:
((heart-assist devices* OR left ventricular assist device[tiab] OR lvad[tiab] OR mechanical
circulatory support[tiab])
AND
(destination therapy[tiab] OR continuous flow[tiab] OR nonpulsatile[tiab] OR axial flow[tiab]
OR heartmate ii[tiab] OR thoratec[tiab] OR heartware[tiab] OR hvad[tiab])
AND
(clinical trial[tiab] OR benefit[tiab] OR risk[tiab] OR survival[tiab] OR death[tiab] OR quality of
life[tiab] OR complication[tiab] OR bleeding[tiab] OR stroke[tiab] OR infection[tiab] OR
sepsis[tiab] OR renal failure[tiab] OR right ventricular assist device[tiab] OR
hospitalization[tiab] OR readmission[tiab] OR device malfunction[tiab] OR pump
replacement[tiab] OR reoperation[tiab] OR cardiac arrhythmia[tiab] OR arrhythmia[tiab] OR
defibrillator shock[tiab])) AND "humans"[Filter] AND "english"[Filter] AND (2007[pdat] OR
2008[pdat] OR 2009[pdat] OR 2010[pdat] OR 2011[pdat] OR 2012[pdat] OR 2013[pdat] OR
2014[pdat])
Figure 2. Adverse Event Definitions
Term
HeartMate II Trial1-3
Definition
Infection localized to any organ system or region without evidence of systemic
involvement which requires treatment or is ascertained by standard clinical
Localized Non-Device methods and either associated with evidence or bacterial, viral, fungal, and
Infection
protozoal infection, by standard clinical pathologic/laboratory methods. This
definition includes positive blood cultures that are not considered to be septic in
etiology.
Infection of the percutaneous drive line site evidenced by the need to treat with
Percutaneous Site
antimicrobial therapy, when there is clinical evidence of infection such as pain,
Infection
fever, drainage, and or leukocytosis. This definition includes any positive
cultures identified at the time of pump explant.
Infection of the pump pocket area evidence by the need to treat with
antimicrobial therapy, when there is clinical evidence of infection such as pain,
Pump Pocket Infection
fever, drainage, and or leukocytosis. This definition includes any positive
cultures identified at the times of pump explant.
A systematic response to a serious infection, usually manifested by fever,
tachycardia, tachypnea, leukocytosis and vasodilation requiring use of IV
antimicrobial therapy. It may or may or may not be associated with a localized
site of infection. It may of or may not be accompanied by a positive
Sepsis
microbiological culture from the blood, the localized site of infection, or other
evidence of bacterial, viral, fungal, or protozoal infection using standard clinical
pathologic/ laboratory methods. This definition excludes routine prophylactic
treatment with IV antimicrobial therapy.
An episode of internal of external bleeding that causes death, re-operation,
Bleeding
permanent injury, or necessitates transfusion of > 2 units of red blood cells
within 24 hours.
Any new, temporary or permanent, focal or global, neurological deficit
Neurologic Event
including TIA, metabolic encephalopathy, seizure, etc. The event must be subcatagorized to document the type of neurologic event.
A neurologic deficit lasting more than 24 hours, or lasting 24 hours or less with
a brain imaging study showing new infarction. A TIA is a neurological deficit
Stroke
lasing 24 hours and if an imaging study is performed, shows no evidence of new
infarction. Each stroke must be subcategorized as either ischemic or
hemorrhagic.
Symptoms of RHF (e.g. drop in right ventricular ejection associated with right
sided congestion including hepatic congestion, peripheral edema, jugular
RHF
venous distension, etc. requiring either RVAD implantation at any time, or
inotropic therapy > 14 days following implant.
Any symptomatic or asymptomatic arrhythmia that requires intervention. The
Cardiac Arrhythmias investigator should distinguish four types of events: 1) cardiac arrest, 2) VA, 3)
supraventricular arrhythmia, 4) atrial arrhythmia.
Abnormal kidney function requiring dialysis in patients who did not require this
Renal Failure
procedure prior to the implant.
Impairment of respiratory function requiring reintubation and/or tracheostomy
Respiratory Failure
at any time or the inability to discontinue ventilator support after six days (144
hours) of device support.
Suspected Device
Malfunction/Failure
INTERMACS4
An instance when any component of the system fails to perform its intended
function. Losses of the display, inability to operate on batteries, or pump
stoppage are examples. Event consequences can be captured on the case report
form and will include: hemodynamic compromise, re-operation, death, urgent
transplant or initiation of inotropes.
Infection localized to any organ system or region (e.g. mediastinitis) without
Localized Non-Device evidence of systemic involvement (see sepsis definition), ascertained by
Infection
standard clinical methods and either associated with evidence of bacterial, viral,
fungal or protozoal infection, and/or requiring empirical treatment.
A positive culture from the skin and/or tissue surrounding the drive line or from
Percutaneous Site and/or the tissue surrounding the external housing of a pump implanted within the
Pocket Infection
body, coupled with the need to treat with antimicrobial therapy, when there is
clinical evidence of infection such as pain, fever, drainage, or leukocytosis.
Internal Pump
Infection of blood-contacting surfaces of the LVAD documented by positive site
Component or Outflow
culture.
Tract Infection
Evidence of systemic involvement by infection, manifested by positive blood
Sepsis
cultures and/or hypotension.
An episode of suspectived internal or external bleeding that results in one or
more of the following: death, re-operation, hospitalization, transfusion of
Major Bleeding
PRBCs as follows: 1) during first 7 days post implant = ≥ 4 units PRBC within
any 24 hour period or 2) after 7 days post implant any transfusion of PRBCs
Any new, temporary or permanent, focal or global neurologic deficit, including
Neurological
TIA that resolves within 24 hours, and ischemic or hemorrhagic intracranial
Dysfunction
CVA that persists beyond 24 hours or less than 24 hours with infarction on an
image study.
Symptoms and signs of persistent right ventricular dysfunction [central venous
pressure > 18 mmHg with a cardiac index <2.3 L/min/m2 in the absence of
elevated left atrial/pulmonary capillary wedge pressure (greater than 18 mmhg),
Right Heart Failure
tamponade, ventricular arrhythmias or pneumothorax] requiring RVAD;
implantation; or requiring inhaled nitric oxide or inotropic therapy for a duration
of more than 1 week at any time after LVAD implantation.
Denotes a failure of one or more of the components of the device system which
Device Malfunction either directly causes or could potentially induce a state of inadequate
circulatory support (low cardiac output state) or death.
Any documented arrhythmia that results in clinical compromise (e.g.,
Cardiac Arrhythmia diminished LVAD flow, oliguria, pre-syncope or syncope) that requires
hospitalization or occurs during a hospital stay.
American College of Chest Physicians and Society of Critical Care Medicine (ACCP/SCCM)5
Defined as a systemic inflammatory response syndrome (two or more of: 1)
temperature 38°C or 36°C; 2) heart rate 90 beats/min; 3) respiratory rate 20
Sepsis
breaths/min or PaCO2 32 mm Hg; or 4) white blood cell count 12,000
cells/mm3, 4,000 cells/mm3 or 10% immature bands) resulting from a
confirmed infectious process.
6
Schmid et al., 2008
Stroke was a clinical diagnosis, defined as cerebral ischemia with consecutive
Stroke
neurologic symptoms persisting for 24 hours, irrespective of findings in cranial
CT.
Cerebral bleeding, caused either by spontaneous rupture of a blood vessel
Cerebral Bleeding
within the head or after stroke, mandated confirmation by CT scan, regardless of
present symptoms.
7
Lahpor et al., 2009
RHF
Starling et al., 20138
Confirmed Pump
Thrombosis
Suspected Pump
Thrombosis
Crow et al., 20099
GI Bleeding
Martin et al., 201010
Infection
Topkara et al., 201011
The post-operative need for temporary right ventricular mechanical support or
inotropic support for more than 14 days following the implantation.
Confirmed pump thrombosis was defined as a thrombus found on the bloodcontacting surfaces of the HeartMate II, its inflow cannula, or its outflow
conduit at pump replacement, urgent transplantation, or autopsy.
Suspected pump thrombosis was defined as a clinical diagnosis of pump-related
malfunction in which the clinical or device variables suggested a thrombus on
the blood-contacting surfaces of the pump, cannulae, or grafts.
Defined as a guaiac-positive stool and a hemoglobin drop requiring transfusion
of at least 2 units of PRBCs.
Defined as 1) a positive bacterial or fungal culture taken from the bloodstream
attributable to the device, andyor from the driveline site, andyor the operative
bed, that was treated with antimicrobial agents by the clinicians caring for the
patient, or 2) a clinically suspected infection of the device that was surgically
debrided and treated with antimicrobial therapy regardless of culture data.
Defined as those that required treatment with antimicrobial therapy, when there
Driveline/Pump Pocket Infection
is clinical evidence of infection such as pain, fever, drainage, and or
leukocytosis.
Defined as those limited to any organ system or region without evidence of
Local Infections
systemic involvement that requires treatment or is ascertained by standard
clinical method.
Uriel et al., 201012
Minor Bleeding
Defined as observable blood loss without the need for transfusion.
Major Bleeding
Defined as need for blood transfusion 7 days after device insertion.
Defined as any neurologic event lasting 24 hours and categorized as having a
Stroke
hemorrhagic or thromboembolic etiology according to the results of intracrantial
imaging.
Pump thrombosis was defined as any thrombus within the device or its conduits
Pump Thrombosis
associated with clinical signs of impaired pump performance
Demirozu et al., 201113
Patients were considered to have GI bleeding if they had 1 or more of the
following symptoms: guaiac-positive stool; hematemesis; melena; active
bleeding at the time of endoscopy or colonoscopy; and blood within the
GI Bleeding
stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied
by a decrease of 1 g/dl in the patient’s hemoglobin level, which was considered
to necessitate the transfusion of 2 units PRBCs.
14
Schaffer et al., 2011
Defined as either: 1) purulent drainage from the drive-line exit site (or device
pocket); 2) organisms isolated from an aseptically obtained culture of fluid or
Driveline/Pump Pocket tissue from the driveline exit site (or device pocket); or 3) an abscess or other
Infection
evidence of infection involving the drive-line tract (or device pocket) found on
direct examination, during re operation or by histopathologic or radiologic
examination.
Schaffer et al., 201115
Defined as bleeding with an identifiable GI source by
GI Bleeding
esophagogastroduodenoscopy, colonoscopy, or tagged red blood cell scan.
Aggarwal et al., 201216
Defined as bleeding above the ligament of Treitz and bleeding from the GI tract
GI Bleeding
distal to the ligament of Treitz, respectively.
Aggarwal et al., 201217
Defined as a culture-positive specimen obtained from any part of the device,
including driveline or pocket infections.
Must meet at least 1 of the following criteria: 1) a recognized pathogen cultured
from 1 or more blood cultures and organism cultured from blood is not related
to an infection at another site, 2) at least 1 of the following signs or symptoms:
Bloodstream Infection fever (>38°C), chills, or hypotension and signs and symptoms and positive
laboratory results are not related to an infection at another site and common skin
contaminant is cultured from 2 or more blood cultures drawn on separate
occasions
Brenyo et al., 201218
VA
Defined as the first ICD therapy for VA after the start of follow-up.
19
Morgan et al., 2012
Defined as melena, hematochezia or hematemesis along with a drop in
GI Bleeding
hemoglobin requiring transfusion.
Raasch et al., 201220
Device Infection
Sustained VA Event
Yuan et al., 201221
RHF
Device Failure
Borgi et al., 201322
RHF
Deo et al., 201323
RVF
Garan et al., 201324
VA
Morgan et al., 201325
RVF
Mulloy et al., 201326
VA
Sarosiek et al., 201327
Defined as a single episode of ventricular tachycardia lasting at least 30 seconds
or a VA necessitating termination via antitachycardia pacing or defibrillation.
Symptoms of RHF requiring RVAD implantation at any time or inotropic
support ≥14 days following LVAD implantation
All types of device malfunction, including mechanical failure, electrical failure,
and device thrombosis
Defined as the need for inotropic support for more than 1 week or the need for
RVAD support
Defined as the need for IV inotropes for more than 168 hours after the intial
surgery
Defined as ventricular tachyarrhythmia (ventricular tachycardia or ventricular
fibrillation) that received appropriate therapy (antitachycardia pacing or shock)
from an ICD or was sustained for >30 s in the absence of effective treatment.
Defined as the need for IV inotropes for >14 days post-operatively or an RVAD
Defined as more than 30 seconds of documented ventricular tachycardia or
ventricular fibrillation as seen on a rhythm strip, electrocardiographic tracing, or
implantable cardiac defibrillator readout.
Defined as heme-positive stool or hematemesis and a decrease in hemoglobin
>1 g/dl.
Wever-Pinzon et al., 201328
Defined by clinical evidence of bleeding (guaiac-positive stool, melena,
GI Bleeding
hematochezia, hematemesis, or the presence of blood in the GI tract on
endoscopic evaluation) and a decrease in hemoglobin ≥2g/dL.
Defined as an episode of suspected internal or external bleeding resulting in 1 of
Major Bleeding
the following: death, surgical intervention, hospitalization, or transfusion of
PRBCs as well as a documented decrease in hemoglobin ≥2g/dL.
GI Bleeding
Table 1. Summary of Evidence Sources
Device Type
Total Pts
Total CF Pts
BTT
DT
Other*
Unreported
HMII
HVAD
VentrAssist
MicroMed
DeBakey
DuraHeart
Jarvik 2000
INCOR
HM-XVE
IVAD
EXCOR
NOVACOR
ABIOMED
LionHeart
CardioWest
Unreported
Pulsatile Flow
Year
Continuous Flow
First Author
Abbreviation
Indication
Miller
Pagani
Slaughter
Kormos
Rogers
Strueber
Aaronson
Petrucci
Moazami
Slaughter
2007
2009
2009
2010
2010
2011
2012
2012
2013
2013
133
281
200
484
655
50
140
126
1128
332
133
281
134
484
655
50
140
96
1128
332
133
281
0
484
281
50
140
0
490
332
200
374
126
638
-
-
-
133
281
134
484
655
96
1128
-
50
140
332
-
-
-
-
-
66
30
-
-
-
-
-
-
-
-
Schmid
Lahpor
Boyle
John
Goldstein
Holman
Kirklin
Kirklin
Najjar
Starling
2008
2009
2011
2011
2012
2013
2013
2013
2013
2013
216
411
101
1496
2006
3302
6561
6910
382
837
216
411
101
1496
2006
2816
5515
6910
382
837
0
300
86
1496
830
3742
382
-
86
15
291
1694
-
25
854
-
216
31
3302
79
6910
837
411
74
1496
6910
837
382
-
27
-
-
-
-
216
-
-
-
-
-
-
-
-
2006
3302
6561
-
HMII BTT Trial 1
HMII DT Trial 3
HMII BTT Trial Registry RVF 29
HMII BTT DT Trial Registry 30
International HVAD Trial 31
ADVANCE: HVAD BTT Trial 32
HMII DT Trial NC 33 †
HMII BTT DT Trial Replacement34
ADVANCE: HVAD BTT Trial CAP 35
Multicenter Registries
INCOR Analysis 6
64 European Institutions7
U of Minnesota, Pittsburgh, & Columbia 36
John INTERMACS 37
Goldstein INTERMACS 38
Holman INTERMACS 39
INTERMACS 2013 4
INTERMACS Thrombosis 40
Najjar ADVANCE BTT & CAP 41
Cleveland Clinic, Barnes-Jewish, & Duke8
Single Center Reports and Case Series
University of Minnesota 9
Crow
2009
101
55
84
17
38
9
8
46
Medical University of Vienna 42
Sandner
2009
86
86
86
0
6
75
5
University of Michigan 43 †
Cowger
2010
78
53
69
9
53
25
10
The Ohio State University
Martin
2010
145
64
64
52
10
2
64
13
4
11
Washington University
Topkara
2010
81
81
57
24
64
17
12
Columbia University
Uriel
2010
79
79
64
15
79
Texas Heart Institute13
Demirozu
2011
172
172
172
172
Texas Heart Institute44 †
Demirozu
2011
107
107
107
107
German Heart Institute Berlin 45
Drews
2011
198
111
111
33
1
2
7
8
60
1
49
23
2
12
John
2011
130
130
102
17
11
130
14
Johns Hopkins
Schaffer
2011
133
86
93
40
86
47
15
Johns Hopkins
Schaffer
2011
86
86
57
29
86
16
Advocate Christ Medical Center
Aggarwal
2012
101
101
7
94
101
Advocate Christ Medical Center 17
Aggarwal
2012
87
87
87
87
University of Rochester 18
Brenyo
2012
61
61
44
17
58
3
Columbia University47
Kato
2012
307
140
307
140
167
19
Henry Ford
Morgan
2012
86
86
54
32
86
20
University of North Carolina
Raasch
2012
61
61
27
34
47
14
48
University of Minnesota
Sharma
2012
143
143
56
87
143
Johns Hopkins21
Yuan
2012
182
133
98
46
38
133
49
Henry Ford 22
Borgi
2013
100
100
68
32
100
Cleveland Clinic 49
Bunte
2013
139
139
55
31
53
139
University of Münster 50
Dell’ Aquila
2013
50
50
50
50
23
Deo
2013
126
126
55
71
126
51
Montefiore Medical Center
Forest
2013
71
71
19
27
25
58
9
4
Garan
2013
94
94
46
48
94
Hasin
2013
115
115
42
73
115
Henry Ford 25
Morgan
2013
130
130
76
54
122
8
26
University of Virginia
Mulloy
2013
50
50
50
50
53
German Heart Institute Berlin
Potapov
2013
225
225
225
225
27
Thomas Jefferson University
Sarosiek
2013
84
59
54
30
Utah Transplant Affiliated Hospitals 28
Wever-Pinzon
2013
134
134
68
52
14
134
* includes bridge to recovery, bridge to decision, and bridge to candidacy †Study not included in Tables. BTT=bridge to transplant; CAP=continued access protocol; CF=continuous-flow; DT=destination therapy; GI=gastrointestinal; HM-XVE=HeartMate XVE
ventricular assist device; HMII= HeartMate II; HVAD=HeartWare ventricular assist device; INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support; IVAD=implantable ventricular assist device; LVAD=left ventricular assist device;
mo=month; NC=neurocognition; PVAD=Paracorporeal ventricular assist device; RRT=renal replacement therapy; RVF=right ventricular failure
Table 2. Estimated Actuarial Survival of CF Devices - Single Center Studies or Those with Less Than 100 Continuous Flow Patients
Study
First
Author
International HVAD Trial31
Strueber
Medical University of Vienna42
Sandner
German Heart Institute Berlin45
Drews
46
John
Johns Hopkins15
Schaffer
Henry Ford19
Morgan
University of North Carolina20
Raasch
University of Münster50
Dell'Aquila
University of Minnesota23
Deo
Mulloy
University of Virginia26
Year
Total
CF
BTT
DT
1
Mo
6
Mo
12
Mo
24
Mo
36
Mo
48
Mo
2011
50
50
0
-
90%
84%
79%
-
-
2009
2011
2011
2011
2012
2012
2013
2013
2013
86
111
102
86
86
61
50
126
50
86
0
102
57
54
27
55
-
0
111
0
29
32
34
71
-
92%
95%
82%
98%
61%
84%
87%
88%
-
71%
79%
72%
87%
78%
-
70%
83%
76%
-
49%
-
-
BTT=bridge to transplant; CF=continuous-flow; DT=destination therapy; HVAD=HeartWare ventricular assist device; mo=month
Crow
Sandner
Martin
Topkara
Uriel
Demirozu
John
Schaffer
Schaffer
Aggarwal
Aggarwal
Brenyo
Kato
Morgan
Sharma
Borgi
Bunte
Dell'Aquila
Mulloy
Sarosiek
Wever-Pinzon
2009
2009
2010
2010
2010
2011
2011
2011
2011
2012
2012
2012
2012
2012
2012
2013
2013
2013
2013
2013
2013
55
86
64
81
79
172
102
86
46
86
57
64
102
57
9
0
24
15
0
29
36 mo
6 mo
18 mo
9±9 mo
12±16 mo
2±2 mo
11±10 mo
-
-
86
101
87
61
140
86
143
100
139
50
50
59
134
57
7
44
54
56
68
55
68
29
94
17
32
87
32
31
52
22%
30%
19%
18%
28%
23%
-
Other
-
Sepsis
12%
-
Pocket
GI
20%
9%
Driveline
Late > 30 days
24 mo
19±18 mo
Local
Early ≤30 days
0
-
Other
Defined Time at
Risk#
50
-
Infection
TIA
DT
50
72
Hemorrhagic
BTT
2011
2013
4%
-
-
14%
-
18%
-
-
10%
3%
-
10% 12%
3%
10%
9%
11%
11%
10%
4%
9%
9%
26%
4%
8%
-
-
-
-
-
-
37%
10%
-
17%
22%
26%
12%
6%
14%
-
22%
5%
0%
9%
6%
1%
2%
-
19%
64%
14%
-
-
Ischemic
Total CF
Neurological Event
Year
Bleeding
Strueber
Moazami
First Author
Study
Table 3. Common Adverse Events of CF LVAD – Single Center Studies or Those with
Less Than 100 CF Patients
International HVAD Trial31*
HMII BTT DT Trial Replacement34†
4%
8%
6%
The Ohio State University10
Washington University11§
Texas Heart Institute13
Johns Hopkins14§
Johns Hopkins15
Advocate Christ Medical Center16
Advocate Christ Medical Center17
University of Rochester18
Columbia University47*
Henry Ford19
University of Minnesota48‡
Henry Ford22
Cleveland Clinic49*ll
University of Münster50*
University of Virginia26
Thomas Jefferson University27
Utah Transplant Affiliated Hospitals28*ll
12 mo
12 mo
0-70 mo
19±14 mo
21 mo (m)
9±11 mo
0-15 mo
11±11 mo
0-12 mo
16 mo(m)
9 mo(m)
5-13 mo
34±19 mo
3 mo
26%
-
44%
17%
23%
-
18%
8%
58%
36% 20%
25%
22%
22%
26%
24%
17%
-
34%
10%
28%
-
Adverse events definitions in Appendix 2.
* Study uses INTERMACS definitions for adverse events.
‡ Study uses ISHLT consensus statement definitions for adverse events.
§ Study uses ACCP/SCCM consensus definition of sepsis.
ll Study includes alternative indications for implant (i.e. bridge to decision, bridge to candidacy).
# Time at risk was variable among studies: truncated time point (x mo), mean/SD (x ± mo), range (x-y mo).
ACCP/SCCM=American College of Chest Physicians and Society of Critical Care Medicine; BTT=bridge to transplant; CF=continuous-flow; DT=destination therapy;
GI=gastrointestinal; HMII= HeartMate II; HVAD=HeartWare ventricular assist device; INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support;
ISHLT=International Society of Heart and Lung Transplant; mo=month; TIA=transient ischemic attack.
Table 4. Other Adverse Events of CF Devices - Single Center Studies or Those with Less Than 100 Continuous Flow Patients
Rehospitalization
Other
Arrhythmia
VA
RVAD
Right Heart
Failure
Inotropic Support
Other Requiring
Exchange
Thrombosis Requiring
Exchange
Defined Time at Risk§
DT
BTT
Total CF
Year
First Author
Device
Malfunction
Study
International HVAD Trial31*
24 mo
8%
6%
6%
6%
4%
Strueber
2011
50
50
0
1.2 adm/pt-yr
HMII BTT DT Trial Replacement34†
2013
72
19±18 mo
2%
4%
9%
2%
Moazami
Single Center Reports and Case
Series
Sandner
2009
86
86
0
6 mo
6%
Drews
2011
111
0
111
23±8 mo
6%
2.8 adm/pt-yr
John
2011
102
102
0
11±10 mo
1%
2%
5%
Brenyo
2012
61
44
17
University of Rochester18
21 mo(m)
11%
31%
2012
61
27
34
University of North Carolina20
Raasch
0-12 mo
43%
20%
Yuan
2012
133
68
40
13±13 mo
Johns Hopkins21‡
12%
22%
22
Borgi
2013
100
68
32
0-12 mo
Henry Ford
11%
5%
24%
Dell'Aquila
2013
50
24%
4%
1.8 adm/pt-year
University of Münster50*
9 mo(m)
Deo
2013
126
55
71
15 mo(m)
25%
3%
Forest
2013
71
19
27
2±4 mo
Montefiore Medical Center51‡
79%
Garan
2013
94
46
48
4 mo(m)
23%
Hasin
2013
115
42
73
13±11 mo
1.6 adm/pt-yr
Morgan
2013
130
76
54
13 mo(m)
Henry Ford25
5%
4%
26
Mulloy
2013
50
University of Virginia
5-13 mo
32%
20%
Potapov
2013
225
8 mo(m)
5%
1%
Adverse events definitions in Supplemental Methods: Figure 2.
* Study uses INTERMACS definitions for adverse events.
‡ Study includes alternative indications for implant (i.e. bridge to decision, bridge to candidacy)
§ Time at risk was variable among studies: truncated time point (x mo), mean/SD (x ± y mo), range (x-y mo), mean (x mo(m))
adm=admission; BTT=bridge to transplant; CF=continuous-flow; DT=destination therapy; HMII= HeartMate II; HVAD=HeartWare ventricular assist device;
INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support; mo=month; pt=patient; RVAD=right ventricular assist device; RVF=right
ventricular failure; VA=ventricular arrhythmia; yr=year.
SUPPLEMENTAL FIGURE LEGENDS
Figure 1. Search Algorithm
Figure 2. Adverse Event Definitions
Abbreviations:
ACCP/SCCM=American College of Chest Physicians and Society of Critical Care
Medicine; CT=computed tomography; CVA=cerebrovascular accident;
GI=gastrointestinal; ICD=internal cardioverter defibrillator; INTERMACS=Interagency
Registry for Mechanically Assisted Circulatory Support; IV=intravenous; LVAD=left
ventricular assist device; PRBC=packed red blood cell; RHF=right heart failure;
RVAD=right ventricular assist device; TIA=transient ischemic attack; VA=ventricular
arrhythmia
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A Systematic Review - Circulation: Heart Failure

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