DOI: 10.1161/CIRCULATIONAHA.114.012740
Death and Interventional Cardiology: A Tale of Two Trials
Running title: Dauerman; Death, Shock and Aortic Stenosis
Harold L. Dauerman, MD
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University of Vermont College of Medicine, Burlington, VT
A
dd
dress for Correspondence:
Corr
Co
rresspo
rr
p nd
nden
ence
en
ce::
ce
Address
Haro
Ha
old
l L. Da
aue
u rm
man, M
D
Harold
Dauerman,
MD
Divi
visi
sion
ion ooff Ca
ard
diol
iolog
logy, M
cCl
Clur
uree 1
Division
Cardiology,
McClure
University ooff Ve
Verm
rm
mon
ontt Me
Medi
diccall Ce
di
C
n err
nt
Vermont
Medical
Center
111 Colchester Avenue
Burlington, VT05401
Tel: 802-847-3602
Fax: 802-847-3637
E-mail: [email protected]
Journal Subject Code: Treatment:[23] Catheter-based coronary and valvular interventions:other
Key words: Editorial, transcatheter aortic valve, cardiogenic shock, aortic stenosis
1
DOI: 10.1161/CIRCULATIONAHA.114.012740
In this issue of Circulation, the 3 year follow up of the PARTNER B trial provides us with a
sobering final word on the natural history of severe aortic stenosis 1. As described 50 years ago,
severe aortic stenosis is a terminal illness of the elderly with a progression from symptoms to
death over an approximately 3 year period 2, 3. The current report of the 3 year follow up from
the PARTNER B trial confirms this dismal natural history: among patients randomized to
standard therapy in the initial trial and/or continued access study, 81% are dead after 3 years.
Transcatheter aortic valve replacement (TAVR) alters this natural history significantly, providing
a 47% reduction in the risk of death over 3 years (HR 0.53, 95% confidence interval 0.41-0.68, p
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
< 0.001). Based upon this demonstration of effective therapy for even surgically inoperable
t
rtic stenosis are comple
lete
te..
patients, the natural history studies
of untreated severe ao
aortic
complete.
The PARTNER B control arm is not the only group with a concerning outcome: the
ma
majo
jori
jo
rity
ri
ty ooff pa
patien
en
nts
ts randomized to TAVR are al
lso
s ddead
ead at 3 years
rss fol
llo
ow up. These grim
majority
patients
also
follow
outc
com
o es in both
both arms
arm
ms of the
the trial
tri
rial
all lead
lead
ead to
to two
tw
wo disturbing
distturbing
ng questions:
quesstio
stions
ns: 1)) W
as iitt ne
nece
ceesssar
aryy to
outcomes
Was
necessary
pe
perf
rfor
rf
orrm a randomized
rand
ra
ndom
om
mized
ized
d trial
trrial
rial in
in which
whic
wh
ichh the
ic
th
he control
con
ontrrol group
gro
oup was
was already
alrrea
e dy known
knoown
wn to
to have
havee an
an
perform
exceedinglyy high
high mortality
mor
o ta
tali
l ty
y rate?
rat
a e?? 2)
2) Were
Were eelderly
lde
derl
rlly pa
pati
t en
ti
nts w
ithh mu
it
m
lttip
iple
le ccomorbidities
omor
om
orrbi
bidi
d ti
di
ties
e
es
patients
with
multiple
unnecessarily included a randomized trial where any active intervention was predestined to be
futile?
Randomized Interventional Cardiology Trials and Death
The last two decades of interventional cardiology clinical trials has been dominated by the
combined endpoints, surrogate endpoints and goals of non-inferiority. The efficacy of PCI
pharmacology is generally defined by peri-procedural elevations in myocardial biomarkers. The
impact of coronary stents is demonstrated by either reduction or non-inferiority for a combined
endpoint of death, myocardial infarction or target vessel revascularization. Trials of new
2
DOI: 10.1161/CIRCULATIONAHA.114.012740
pathways, new technology and new pharmacology are rarely powered to show us that novelty
leads to less death for the simple reason that death rates in the studied populations are too low to
provide any realistic answers.
In this context, PARTNER B is an alarming trial defined by the highest imaginable rates
of death. Alternative trial designs could have limited the number of deaths in this trial:
PARTNER B could have used a combined surrogate primary endpoint (death, repeat
hospitalization, and improvement in heart failure symptoms) to subject a smaller group to
randomization. Or, PARTNER B could have favored a design similar to the Corevalve study
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which used a historical control group in place of a randomized medical therapy group 4. Finally,
PARTNER B could have been limited to those patients with Society of Thoracicc Su
Surgery
urg
ger
eryy (S
(ST
(STS)
TS)
TS)
surgical
urgical risk scores less than 15% to decrease mortality rates in both arms of the study.
Before
Befo
Be
forre w
fo
wee di
discount the death driven design
desig
ign of PARTNER
ig
RB
B,, an
n aalternative
lternative perspective
on death
dea
e th in interventional
inte
terv
rv
venti
tiion
onal
al cardiology
car
ardi
diol
olog
ogyy trials
og
trials is
is warranted:
warrranteed: this
th
hiss counterpoint
counter
nterppoint may
may be best
bes
estt illustrated
illlu
lusstra
st ated
by comparing
early
com
ompa
p riing the
pa
the first
fir
irst
stt TAVR
TAV
AVR
R trial
trria
iall to the
the first
fir
irsst completed
com
ompl
plletted trial
tri
rial
al of
of ea
arl
rlyy revascularization
revvasc
vasccul
ular
a izzat
ar
atiionn for
for
cardiogenic shock.
shhoc
o k. Similar
Sim
mil
i arr to
to the
th
he challenge
chal
ch
a leeng
ngee faced
fac
aced
ed by
by the
the PARTNER
PART
PA
RTNE
RT
N R investigators,
NE
inve
in
vest
ve
stig
st
i attor
ig
ors,
s the
s,
the
h SHOCK
trial investigators knew that patients with acute myocardial infarction complicated by
cardiogenic shock had a terminal illness5. Rather than look for a combined endpoint or a
hemodynamic surrogate, the SHOCK investigators faced the certainty of death with a trial design
that answered the essential question in a definitive manner: can we truly alter the natural history
of a terminal illness?
There are numerous similarities between these two landmark trials (Table 1) beginning
with a similar sample size (N= 300-350); neither of these trials is large in comparison to the
surrogate endpoint driven trials of pharmacology and technology that dominate interventional
3
DOI: 10.1161/CIRCULATIONAHA.114.012740
cardiology. In both of these trials, the expected benefit of the novel therapy (early
revascularization in SHOCK, TAVR in PARTNER B) was not presumed to be miraculous: for
both trials, the investigators hoped that the novel therapy would reduce death by approximately
33% thus leaving a clear expectation of plentiful death in both the control and active treatment
arms 5, 6. Both trials were multicenter national efforts requiring multiple years to complete
enrollment; their subsequent influence on guidelines and clinical practice is clear. While the
SHOCK trial may be the most influential trial in history to miss its primary endpoint, the benefit
of early revascularization demonstrated in continuing follow up has had a lasting influence on
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practice and guidelines7.
Did SHOCK need a death endpoint or a randomized control group with an
n eexpected
xppec
ecte
tedd
te
mortality of 80%? The evidence supporting this design is quite clearr from a subsequent story in
this
hiss field:
fie
ield
ld:: pathophysiologic
ld
path
pa
thop
phy
hysi
s ologic observations and hemodynamic
heemo
m dynamic endp
endpoint
poi
o nt sstudies
tuddies suggested that a
tu
oxide
inhibitor,
would
superior
therapy
nnovel
ovvel
ve nitric oxi
xide
d ssynthase
de
ynth
yn
thaase
ase in
nhi
hibbittor
or, ttilarginine,
ilaargin
nin
ne, w
ould
d clea
cclearly
leaarlly bbee sup
upeeriior to sstandard
tand
ta
ndaard
nd
ard th
herap
erap
py
for
patients
with
acute
myocardial
cardiogenic
shock
fo
or pa
pati
tien
ti
ents
tss w
ithh ac
it
cut
utee myoc
m
yocar
a di
ar
dial
al iinfarction
nfarccti
nfa
tion
on ccomplicated
ompl
om
pliicaated
ated bby
y ca
car
rdio
rdio
oge
g nicc sh
hoc
o k8. Wh
W
When
en
n aan
n
nternational,
l, multicenter
mullti
tice
c nt
ce
n er
e mortality
mor
ortaalit
ityy driven
d iv
dr
ven
n trial
tri
r al
a w
ass pperformed,
erfo
er
form
fo
rmed
rm
ed,, tthe
ed
h ssurrogate
he
urro
ur
roga
ro
gate
ga
t eendpoints
te
ndpo
nd
poin
po
in
nts
t proved
international,
was
useless and tilarginine had no effect on mortality9. Similarly, the superiority of TAVR seems
clear retrospectively, but the benefit was much less clear to patients and investigators during the
trial: among patients randomized to standard therapy in PARTNER B, all were offered TAVR
after the 12 months of initial follow up were completed. Yet, only a minority of patients and
clinicians chose the novel therapy: of 58 eligible patients who were alive a 12 months in the
standard therapy arm, only 20 patients crossed over to TAVR therapy10. Now, we have clarity in
both shock and aortic stenosis, and there will never be another control group randomized to
medical therapy alone for these disease states. Based upon the history of the SHOCK trial and its
4
DOI: 10.1161/CIRCULATIONAHA.114.012740
follow up studies, the PARTNER B investigators were right: they had to use a death defined
randomized trial design to definitively prove that TAVR alters the natural history of a terminal
illness.
Patient Inclusion and Subgroup Analysis
Kapadia et al report a 54% mortality at 3 year follow up of the TAVR arm of PARTNER B 1.
The authors speculate that this high mortality in the novel treatment arm “highlights the need for
better case selection, especially in those with multiple co-morbidities”. Support for this concept
comes from subgroup analysis demonstrating the interaction of TAVR effectiveness with
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baseline assessment of surgical risk. When patients are stratified according to 3 tertiles of STS
cores, the greatest absolute reduction in all-cause mortality (67%) is in the lowes
esst ST
STS
S
scores,
lowest
estimated risk < 5.0%) group with a much less impressive absolute reductions in mortality
(estimated
21%
%) among
amon
am
ongg patients
on
paati
tieents
en with STS scores over 15%.
15%
%. Thus,
%.
Thus, it is tempting
tem
mpt
p ingg to conclude that our
(21%)
eleect
c ion process
procces
esss for
forr TAVR
TAVR extreme
extre
xtreme
me risk
ris
iskk patients
paatieentss should
shouuld
uld begin
beegin with
with tthe
he ST
STS
S sc
scor
orre;
e elderly
eld
lderrly
ly
selection
score;
pa
pati
tien
ti
en
nts
t w
ithh ST
it
STS
S sc
scor
ores
ess oover
veer 15
15%
% ma
mayy re
repr
pres
pr
essen
e t th
he co
oho
horrt C of
of th
thee PA
PART
RT
TNE
NER
R tr
rialss—the
—thee
patients
with
scores
represent
the
cohort
PARTNER
trials—the
group whichh should
shou
sh
ould
ou
ld never
nev
ever have
hav
avee been
been
n randomized
ran
ando
an
domi
do
mize
mi
zedd in PARTNER
ze
PAR
ARTN
TNER
TN
ER A or
or B trials
tria
tr
ials
ia
l due
ls
due to
to futility
f tility of
fu
any aggressive therapy. Other risk scores have similarly been calculated to help guide clinicians
with better selection of patients for TAVR 11.
Once again, the SHOCK trial may provide an alternative perspective on this conclusion.
Like PARTNER, SHOCK had prespecified subgroup analyses, generally intended to determine
the consistency of a novel treatment effect. In SHOCK, there was a glaring inconsistency: among
patients over age 75, the benefit of an early revascularization approach was not seen 5. In fact,
there was a 41% increased risk of death among elderly patients undergoing early
revascularization as compared to intensive medical therapy (p=0.01). This subgroup analysis
5
DOI: 10.1161/CIRCULATIONAHA.114.012740
had an impact: initial guideline statements restricted the Class I recommendation for early
revascularization in the setting of shock to only those patients who were not elderly7. The scope
of this restricted recommendation was not small: like aortic stenosis, cardiogenic shock is a
disease of the elderly and older age is the strongest predictor of shock complicating acute
myocardial infarction. Thus, withholding the SHOCK early revascularization strategy among
elderly patients could eliminate nearly 40% of affected patients with the disease from qualifying
for the only proven therapy to impact mortality 12. If one looks carefully at the SHOCK elderly
subgroup analysis, caution is clearly warranted: there were only 56 randomized elderly patients
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in the SHOCK trial and thus any conclusions from this subgroup analysis are necessarily
ambiguous. Furthermore, subsequent large registry studies failed to demonstratee any
any clear
clea
cl
ear
ar harm
harm
of early revascularization (and suggested potential benefit) in the elderly shock patient thus
ca
alllin
ingg into
into qquestion
uest
sttio
ionn a restricted guideline and po
poin
intting towards cclinical
l nica
li
caal judgement
ju
rather than
calling
pointing
12-14
ubggroup analy
lysi
s s ass a m
si
eanns of
ea
of ppatient
atie
at
iennt sele
ecttion12.
subgroup
analysis
means
selection
The
The analogy
analog
anal
ogyy with
og
with
th
h PARTNER
PAR
ARTN
TNER
TN
ER reminds
rem
min
indds
ds us
us to
to goo slow
slo
low
w inn applying
app
pply
lyin
ly
in
ng the
the findings
f nd
fi
n in
ngs of
of subgroup
suubg
grooup
analysis to ou
our
ur cl
cclinical
in
nic
ical
all ppractice:
raact
c ic
ice:: w
while
hile
hi
l iimproved
mpro
mp
rove
ro
v d se
ve
sele
selection
leect
c io
on of ppatients
atie
at
i nt
ie
ntss fo
forr TA
TAVR
VR iiss cl
clea
clearly
e rly
warranted, the temptation to exclude any single subgroup based upon the PARTNER B analysis
should be avoided. Like SHOCK, randomizing approximately 350 patients means that each
subgroup of the novel treatment group consisted of a small number of patients. Only 104
patients in PARTNER B had an STS score over 11 and at three year follow up, the p value for
interaction between STS score and mortality was strikingly non-significant (p=0.74) 1 : similar to
the 56 elderly patients in SHOCK, this small sample size makes it hard to be certain of the
futility of TAVR in higher STS score patients. While we may be concerned with application of
TAVR to elderly patients in whom it may be futile, the European experience suggests that the
6
DOI: 10.1161/CIRCULATIONAHA.114.012740
opposite has occurred: inoperable and high risk patients with terminal aortic stenosis appear to be
undertreated and these untreated extreme risk patients are repeating a potentially unnecessary
natural history study 15. Thus, both SHOCK and PARTNER B subgroup analyses should be used
primarily to guide future investigations; we cannot definitively conclude from underpowered
subgroup observations that the trial or our clinical practice would be better off excluding the
patients who are older, sicker and have more extensive coronary artery disease.
Conclusion
The 3 year follow up of PARTNER B is a disturbing final reminder of the natural history of
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
severe aortic stenosis. Even with the implementation of an exciting new technology, we are still
facing death: in this extreme risk population, the majority of TAVR patients wi
illl bbee de
dead
ad aatt 3
will
years. In the face of so much death, we are indebted to the PARTNER investigators for providing
uss with
wit
ithh a definitive
defi
de
finiti
fi
tiive trial design that makes a final
finaal statement:
sttatement: the cconclusions
o cl
on
clus
usiions
us
io of PARTNER B,
ikee S
HOCK, re
requ
quirre noo ffurther
qu
urth
ur
theer
th
er pproof
roof
ro
of inn sub
bseequeent tri
riials.
als. T
h se cconclusions
he
oncl
on
c usio
cl
ions
ns ffrom
rom
ro
m th
thee 35
58
like
SHOCK,
require
subsequent
trials.
These
358
pati
pa
patients
tien
ti
en
nts
t in
in PARTNER
PART
PA
RT
TNER
NER B (and
(and
d the
the subsequent
sub
ubssequ
sequ
quen
ent continued
en
conntin
co
nt nueed access
acccess
ac
cess study)
stu
tudy
dy)) are
dy
are both
bo
oth
h narrow
nar
arro
row
ro
w an
and
nd
powerful: TA
AVR saves
sav
aves
e lives
es
liv
ves
e in
in extreme
extr
ex
trrem
emee risk
risk patients
pat
a ieentss with
wit
ithh severe
seve
se
vere
ve
re symptomatic
sym
ympt
ym
ptom
pt
omat
om
a icc aortic
at
aor
orti
ticc stenosis.
ti
s enosis.
st
TAVR
Due to PARTNER B, we have a good therapy for a patient group at extreme risk for death and
we have hypotheses to generate the future clinical trials focusing on improving selection,
pharmacology and technology to guide our therapy16, 17.
Conflict of Interest Disclosures: Dr. Dauerman is a consultant for Medtronic, Boston Scientific
and The Medicines Company. He has received research grants from Abbott Vascular and
Medtronic.
7
DOI: 10.1161/CIRCULATIONAHA.114.012740
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DOI: 10.1161/CIRCULATIONAHA.114.012740
Table 1. Interventional Cardiology Trials at the Extreme of Mortality.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Characteristics
Study Design
Years of Enrollment
Randomized Sample Size
Primary Endpoint
Expected Mortalityy in Control Groupp
Expected
cted Impact of Novel Therapy
Achieved
eved Mortality in the Novel Treatment Arm
ary Endpoint Achieved
Primary
Key Secondary
Second
ndaryy Endp
Endpoint
dpoi
o nt
Exploratory
orator
or
o y Subgroup
or
up A
Analyses
n ly
na
yses
es
eque
eq
quent
n or Planne
nt
ned
ed Co
onfir
f matory
a r Trials
Tri
rial
ia s
Subsequent
Planned
Confirmatory
SHOCK
Randomized Clinical Trial
1993-1998
N=302
Death at 30 days
75% at 30 days
y
20% Absolute Reduction in Death at
30 Days
47% at 30 Days
No
Significant M
Mortality
ortality Reduction with
Early Revasc
Revascularization
scul
sc
u ar
a ization at 6 Mon
Month
nth
Follow
Foll
llow U
Up
p
N B
No
Benefit
ene
n fit
ne
it of E
Early
arly R
ar
Revascularization
ev
evas
vascu
c la
l ri
riza
zation
za
on
in tthe
he E
Elderly
lder
der
e ly
No
*PARTNER
TNER
TN
ER B
B:: 91
9 A
Additional
ddit
dd
itio
tiona
n l Pa
P
Patients
tien
ti
ients
ts W
Were
e e En
er
E
Enrolled
roll
oll
l ed
dD
During
urin
ur
ing
ng th
thee Co
Cont
Continued
ont
ntin
inue
in
u d Ac
A
Access
cees P
cess
Phase
hase
s
se
10
PARTNER B*
Randomized Clinical Trial
2007-2009
N=358
Death at 1 year
37.5% at 1 year
y
12.5% Absolute
Absolu
utee Reduction
Red
educ
ucti
uc
tion
ti
onn in
in Death
D ath at
De
1 Year
Y ar
Ye
Year
31%
% att 1 Y
ear
Yes
Sign
Si
g ificant Mortality Reduction with
w
Significant
TAVR Persisting for 3 Years
No
N Benefit
Ben
nef
efit
it ooff TA
TAVR
VR inn Pa
Pati
Patients
tients
nt w
with
STS
STS Score
S or
Sc
o e > 15%
1 %
15
N
No
Death and Interventional Cardiology: A Tale of Two Trials
Harold L. Dauerman
Circulation. published online September 9, 2014;
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