Controversies in
Cardiovascular Medicine
Should Transcatheter Aortic Valve
Replacement Be Expanded to
Lower-Risk and Younger Patients?
Transcatheter Aortic Valve Replacement Indications Should
be Expanded to Lower-Risk and Younger Patients
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Stephan Haussig, MD; Axel Linke, MD
E
ven in the late 1950s, patients suffering from significant
aortic stenosis were confined to death owing to the absence
of treatment option for the disease. The invention of extracorporeal circulation revolutionized cardiac surgery.1–3 Complex
surgical intervention on the diseased heart became available,
including replacement of the stenotic aortic valve.4 Especially
in the early days of conventional aortic valve replacement
(AVR), however, in-hospital mortality was up to 25% because
of cardiac failure, bleeding or thromboembolic complications,
infections, or arrhythmias.4–9 The design of the first mechanical
heart valves left patients with peak gradients of ≥60 mm Hg.
Applying the updated standardized end-point definitions for
transcatheter aortic valve implantation (TAVI; Valve Academic
Research Consortium [VARC] 2) definitions10 to this patient
population would have resulted in a procedural success rate of
0%, and the US Food and Drug Administration probably would
have never approved the devices. The world has changed considerably since then. Half a century later, conventional aortic
valve surgery (AVR) can be considered a top turnaround story:
nowadays, the operation is fast and easy and yields excellent
outcomes in a broad patient population.11 This is the consequence of advances not only in technology but also in surgical
experience gained in millions of patients with aortic stenosis.
Today, minimally invasive techniques are applied that facilitate postoperative recovery, especially in elderly patients, and
reduce the likelihood of wound infections.12 The flow properties
of mechanical heart valves also improved remarkably, which
led to less rigid need for anticoagulation and lower bleeding
and thromboembolic complications.13 Stented and stentless
bioprosthetic valves have been shown to be long-lasting, which
reduces the need of reoperation in case of bioprosthetic valve
failure.14,15 The hemodynamic results are excellent with low
transvalvular gradients, regardless of whether mechanical or
bioprosthetic valves are used, usually in the absence of any
aortic regurgitation. The stroke rate is <5%,16,17 and the likelihood of postoperative permanent conduction abnormalities is
<8%.18 As a result of all these improvements, 30-day mortality
declined from up to 30% in 1960 to <3% in 2012,11,18–22 with
life expectancy normalized after a successful AVR.
Response by Falk on p 2331
Transcatheter AVR: The New Kid on the Block
In 2002, expectations were high when Dr Alain Cribier clinically introduced the concept of transcatheter AVR (TAVR).23
Whereas the surgeons developed conventional AVR in a
young patient population without comorbidities, Cribier and
his team treated the frailest patients to establish a completely
new technique. However, despite the fact that the first TAVR
patient was considered inoperable, procedural results like
in the 1960s would have never been accepted by the treating physicians, the patients, the medical community, or
competent authorities. After a few cases in inoperable, frail
patients, it became clear that the balloon-expandable devices
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Leipzig, Germany
This article is Part I of a 2-part article. Part II appears on p 2332.
Correspondence to Axel Linke, MD, Professor of Medicine, Department of Internal Medicine/Cardiology, University of Leipzig, Germany,
Strümpellstrasse 39, 04289 Leipzig, Germany. E-mail [email protected]
(Circulation. 2014;130:2321-2331.)
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.114.008144
2321
2322 Circulation December 23/30, 2014
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were too bulky and the procedure too complex and lengthy.24
This early experience triggered refinements of the CribierEdwards valve; the delivery system and concept changed the
transfemoral procedure from a transseptal antegrade to a retrograde approach.25 In parallel, a self-expanding prosthesis
was developed consisting of a porcine pericardial tissue valve
sutured into a self-expanding nitinol frame (CoreValve). The
beauty of this system was the smaller profile (18F) because
the space for the balloon as the valve carrier was saved.26
The results of the first studies in humans with both valves
appeared to be promising. The delivery of the valves was
reliable; the reduction in mean and peak gradients across the
stenotic aortic valve was excellent; and the mortality rates
for the patients considered inoperable were acceptable.24,27
However, the high rate of strokes, bleeding, and vascular
complications raised concerns because they were inevitably
linked with mortality.24,27 Nevertheless, the results were convincing enough to file for CE approval, which was received
for both the Edwards SAPIEN and Medtronic CoreValve
prosthesis in 2007. This allowed treatment of patients with
severe aortic stenosis in daily clinical practice. Unfortunately,
the data were only partially collected in registries, and most
of the events were investigator reported in the absence of
independent monitoring.24,27 In addition, clear end-point definitions of success and complications were missing, hampering the comparison of publications from different centers and
countries. This situation improved with the development of
the VARC28 and VARC210 criteria.
The True Evidence of TAVR: Data From
Randomized, Controlled Trials
Our scientific evidence concerning TAVI is derived primarily from cohorts A29 and B30 of the Placement of Aortic
Transcatheter Valve Trial (PARTNER; NCT00530894),
a true landmark study. Cohort B of PARTNER aimed to
evaluate the impact of TAVR compared with conventional
medical therapy, which could include balloon valvuloplasty,
on inoperable patients with severe aortic stenosis. Almost 360
patients were randomized, 179 to receive transfemoral TAVR
with the Edwards-SAPIEN valve and 179 to medical treatment, which involved aortic balloon valvuloplasty in 84% of
the patients (Figure 1). The mean age was >80 years of age
(83.1±8.6 years for TAVR versus 83.2±8.3 years for standard
medical therapy); the mean logistic euroSCORE was >25
(26.4±17.2 for TAVR versus 30.4±19.1 for standard medical
therapy); and the mean Society of Thoracic Surgeons (STS)
score was ≈11 (11.2±5.8 for TAVR versus 12.1±6.1 for standard medical therapy). The 1-year mortality was 30.7% in
the TAVR group and therefore 20% lower than for patients
treated medically (1-year mortality, 50.7%).31 Therefore, in
later clinical studies evaluating other transcatheter valves
like the Medtronic CoreValve, it was considered unethical
to randomize the patients against medical treatment only
(NCT01240902; Figure 2). However, the extreme-risk population in the Medtronic CoreValve pivotal study was similar
to that in PARTNER. The mean age was 83.1±8.6 years; the
logistic euroSCORE was 22.7±17.4; and the STS score was
10.3±5.6%. Total mortality was 7.9% and 24% at 30 days and
1 year and rates of any stroke were 3.9% and 6.7%, respectively.32 These data underline that treatment of inoperable
patients with severe aortic stenosis with the self-expanding
Medtronic CoreValve prosthesis is also safe and associated with a good short-term outcome. Hence, in inoperable
patients with severe aortic stenosis, there is just no alternative
to transfemoral TAVR.
Cohort A of the PARTNER study aimed to investigate
whether TAVI with either the transfemoral or the transapical
approach was noninferior to conventional AVR with regard
to the 1-year mortality in operable, high-risk patients.29 In
cohort A, 699 patients were treated: 492 within the transfemoral arm (244 were randomized to TAVR and 246 had conventional surgery) and 207 within the transapical arm (104
Figure 1. Flow chart summarizing study design of
the Placement of Aortic Transcatheter Valve Trial
(PARTNER). High-risk patients with symptomatic
severe aortic stenosis (cohort A) were randomly
assigned to conventional surgery or transcatheter
aortic valve replacement (TAVR; transapical or
transfemoral). Patients with symptomatic severe
aortic stenosis who were not suitable for conventional surgery (cohort B) were randomly assigned
to standard therapy (including balloon aortic valvuloplasty) or transfemoral TAVR. Patients were
enrolled at 26 sites.
Haussig and Linke TAVR in Lower-Risk and Younger Patients 2323
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Figure 2. Flow chart summarizing study design of CoreValve
US pivotal trials. High-risk patients are randomly assigned to
conventional surgery or transcatheter aortic valve replacement
using the Medtronic CoreValve System. The primary objective
of the trial is to demonstrate that the safety and efficacy of the
Medtronic CoreValve System are noninferior to those of surgical aortic valve replacement. Extreme-risk patients with suitable
iliofemoral access are treated with the Medtronic CoreValve
System; the other patients are treated via noniliofemoral access.
The aim of the study is to evaluate the safety and efficacy of the
Medtronic CoreValve system for treatment of patients with ≥50%
predicted risk of operative mortality or serious, irreversible morbidity at 30 days.
had TAVR with the Edwards SAPIEN valve and 103 had conventional surgery). The mean age was >83 years (83.6±6.8
years for TAVR versus 84.5±6.4 years for AVR); the mean
log euroSCORE was 29% (29.3±16.5% versus 29.2±15.6%);
and the STS score was 11 (11.8±3.3 versus 11.7±3.5). In the
transfemoral cohort, 30-day mortality was 3.3% after TAVR
compared with 6.2% after conventional AVR. In addition,
there was no difference in the 1-year mortality rates either:
22.2% after transfemoral TAVR versus 26.4% after conventional AVR (P=NS).29
A similar study was conducted to evaluate the impact of
Medtronic CoreValve implantation compared with conventional surgery in patients with increased surgical risk
(NCT01586910; Figure 2). A total of 795 patients with significant aortic stenosis who were considered at increased risk
of surgery were randomized to TAVR (394 patients) with
the self-expandable Medtronic CoreValve or to conventional
AVR (401 patients). The patients had a mean age of ≈83
years (83.2±7.1 years for TAVR versus 83.5±6.3 years for
AVR); the mean log euroSCORE was 18% (17.6±13.0% versus 18.4±12.8%); and the STS score was 7.4 (7.3±3.0 versus
7.5±3.2). The rate of death resulting from any cause at 1 year
was significantly lower in the TAVR group than in the surgical
group (14.2% versus 19.1%; P<0.05). In addition, TAVR was
noninferior in terms of echocardiographic measure of valve
stenosis, functional status, or quality of life.33 Of note, patients
in the latter study had much lower risk scores as determined
by the STS and log euroSCORE compared with patients
in the PARTNER trial. This is indicative of the fact that an
Figure 3. Flow chart summarizing study design of Treatment
of Severe, Symptomatic Aortic Stenosis in Intermediate Risk
Subjects Who Need Aortic Valve Replacement (SURTAVI).
Intermediate-risk patients with symptomatic severe aortic stenosis are randomly assigned to conventional surgery or transcatheter aortic valve replacement (TAVR) with the Medtronic CoreValve
System. Patients are enrolled globally at up to 75 sites.
assessment of TAVR results in lower-risk patients has already
begun in randomized, clinical trials.
Moving Toward Lower-Risk Patients:
Circumstantial Evidence From
Registries and Meta-Analyses
However, we are still missing data from randomized, controlled
trials assessing TAVR in younger, low-risk patients. Hence,
data from Edwards transcatheter valve registries,34–38 Medtronic
Core valve registries,39–43 and mixed multicenter and national
registries44–51 containing a broad range of patients treated transfemorally, transapically, or with a direct aortic, subclavian, and
carotid approach are the only resources potentially supporting an
expansion of indications. The predominant valves evaluated in
these registries were the balloon-expandable Edwards SAPIEN,
the Edwards SAPIEN XT, and the self-expandable Medtronic
CoreValve prosthesis. This variegated patient population makes
it difficult to decide whether TAVI is able to compete with conventional surgery in younger, low-risk patients. In the abovementioned registries, the logistic euroSCORE as an estimate
of operative risk varied between 14.5% and 36%, with mortality rates at 30 days and 1 year reported to be between 0% and
18% and 0% and 37%, respectively (Table). Stroke rates at 30
days varied between 1 and 10%, whereas a new pacemaker was
implanted in up to 40% of the patients.34–52 In general, patients
treated through the transfemoral approach had fewer comorbidities and hence better short- and long-term survival. Interestingly,
30-day mortality rates after TAVR dropped by >50% from 9.5%
in 2009 to 4.2% in 2013, with stroke rates also halved (Table).
However, this was at least partially attributed to the decline in
the number of patients with multiple comorbidities over time.
It suggests that expansion of indications already had occurred,
preceding true evidence from randomized, clinical studies.
2324 Circulation December 23/30, 2014
Table. Edwards Transcatheter Heart Valve Registries, Medtronic CoreValve Registries, and Mixed Multicenter and National
Registries
Valve
Type
ES
Year of
Publication
Type of
Access
Patients,
n
Rodés-Cabau et al34
2010
TF
162
Thomas et al35,36
2010/2011
TF
463
Wendler et al37
2012
TF
920
Authors
Wendler
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Mixed
Mortality at
30 d, %
Mortality at
1 y, %
9
…
9.5
25.0
…
14.5
6.3
18.9
…
23.9
7.5
19.9
Stroke at
30 d, %
Stroke at
1 y, %
Need for New
PPM, %
2
…
3.6
2.4
4.5
6.7
2.9
…
6.7
2013
TF
1685
…
19.8
4.2
15.0
3.4
…
…
Rodés-Cabau et al34
2010
TA
177
10.5
…
11.3
22.0
1.7
…
6.2
Thomas et al35,36
2010/2011
TA
575
…
16.3
10.3
27.9
2.6
4.5
7.3
D’Onofrio et al52
2011
TA
504
11.0
26.3
8.3
18.8
3.0
…
5.4
Wendler et al
2012
TA
1387
…
27.6
10.9
25.8
2.5
…
7.1
2013
TA
894
…
21.9
10.0
27.2
4.1
…
…
38
33
Wendler38
MCV
Log.EuroScore, %
STS (%)
Piazza et al40
2008
TF
646
…
23.1
8.0
…
1.9
…
9.3
Petronio et al43
2010
TF
460
…
19.4
6.1
…
1.7
…
16.1
Tamburino et al37
2011
TF
663
…
23.0
5.4
15.0
2.5
2.5
17.4
Buellesfeld et al41
2011
TF
126
…
23.0
15.2
28.2
9.6
13.5
26.2
Petronio et al43
Adams et al33
Popma et al32
2012
2014
2014
SC
TF, SC,
DA
TF
141
390
489
…
7.3
10.3
23.7
17.6
22.6
5.7
4.5
9.8
…
14.2
26.0
2.1
4.9
4.0
…
8.8
7.0
24.7
19.8
21.6
Zahn et al44
2011
TF, TA,
SC, DA
679
…
20.5
12.4
…
2.8
…
39.3
Eltchaninoff et al45
2011
TF, TA,
SC
244
18.9
25.6
12.7
…
3.6
…
11.8
Bosmans et al46
2011
TF, TA
SC, DA
328
…
28.0
9.7
24.0
4.1
…
15.6
Moat et al47
2011
TF, TA,
SC, DA
870
…
18.5
7.1
21.4
4.1
…
16.3
Gilard et al48
2012
TF, TA, SC
3195
14.4
21.9
12
24.0
3.4
4.1
15.6
Chieffo et al49
2013
TF
453 MCV
340 ES
8.1
8.9
21.4
23.0
12
12
16.2
12.3
2.9
1.0
…
…
22.5
5.9
Di Mario et al50
Hamm et al51
2013
2013
TF, TA
SC, DA
TF, TA
SC, DA
4571
3876
…
…
20.2
25.9 TV
24.5 TA
…
…
1.8*
1.7 TV*
2.2 TA*
…
…
13.2*
23.7 TV*
9.9 TA*
…
…
DA indicates direct aortic; ES, Edwards Sapien Valve; EuroSCORE, European System of Cardiac Operation Risk Evaluation; MCV, Medtronic CoreValve; PPM, permanent
pacemaker; SC, subclavian; STS, Society of Thoracic Surgeons; TA, transapical; TAVI, transcatheter aortic valve implantation; TF, transfemoral; and TV, transvascular.
*In hospital.
Preparing for the Head-to-Head Comparison in
Younger, Low-Risk Patients: Advantages and
Disadvantages of TAVR and Conventional AVR
To estimate the results of a head-to-head comparison between
conventional AVR and TAVR in younger, low-risk patients,
one has to recall the advantages and disadvantages of both
methods (Figure 4). Conventional AVR is an easy operation
established for decades that has excellent results with low
transvalvular gradients and hardly any aortic regurgitation.
On the other hand, it is invasive, requiring full or partial thoracotomy, intubation, and mechanical ventilation, as well as
the use of an extracorporeal circulation. In younger, low-risk
patients, the thoracotomy and mechanical ventilation probably
do not drive mortality, but the extracorporeal circulation might
expose the patient to an inflammatory activation, potentially
leading to death. In a recent meta-analysis involving data from
700 000 patients, operative and/or 30-day mortality after conventional AVR was found to be 3.8% in patients between 70
and 79 years of age and 6.1% in patients >80 years of age.18
These data are in favor of the hypothesis that the 30-day mortality after TAVR in younger, lower-risk patients might be at
least equal to the risk after conventional AVR.
TAVR is clearly less invasive if the procedure is performed
with a transfemoral approach, intubation and mechanical ventilation is not required, and the procedure can be performed without extracorporeal circulatory support. However, it is a relatively
Haussig and Linke TAVR in Lower-Risk and Younger Patients 2325
Figure 4. Advantages and limits of conventional
aortic valve replacement (AVR) and transcatheter
aortic valve replacement (TAVR).
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new method, with interventionalists still being in the learning
phase. Therefore, operator failures can easily drive mortality.
Moreover, the results of TAVR are suboptimal in patients with
severe calcification53; there are still too many vascular complications; and the design of the first-generation transcatheter valves
evaluated in the above-mentioned studies was not yet optimal
(Figure 5). To justify a treatment of younger, low-risk patients,
who have an excellent outcome after conventional AVR, the
TAVR limitations first have to be addressed. However, the transfemoral TAVR systems are getting smaller, and the development
of balloon-expandable, recollapsible sheaths and inline sheath
concepts allows transfemoral TAVR even in patients with a vascular access size <6 mm, which further reduces the need for
alternative TAVR access, especially with a transapical approach.
However, the size of transapical systems also was reduced considerably during the last years, and apical closure systems were
developed to reduce access site complications, thereby potentially improving the outcome after transapical TAVR. Currently
the percentage of younger, low-risk patients in recent registries
is too small to estimate whether transapical TAVR is able to beat
conventional surgery in these patients.
TAVR in Younger, Lower-Risk Patients:
Are the Requirements Met?
Despite the fact that residual aortic regurgitation was more frequent after TAVR and elucidated a predictor of mortality,48,54–56
mortality rates were not higher after TAVR over the long term
compared with conventional surgery in high-risk operable
patients. If the degree of paravalvular AR could be reduced by
transcatheter heart valve refinements, would this translate into
a better long-term survival after TAVR? This question remains
unanswered at the moment, but studies evaluating the next-generation devices, which are able to seal paravalvular leaks much
better, are on the way.57–60 The majority of the patients after TAVR
and conventional AVR are dying as a result of their comorbidities and procedural complications.18 Because of the improved
knowledge of patient screening, assessment of the access vessels and annulus, prosthesis selection, procedural planning, and
safety networks (eg, crossover wires) to avoid the deleterious
outcome after vascular insults, complications are prevented or
treated at an early stage of occurrence, which has made TAVR
much safer in 2014 compared with 2006.37,48,51 This is underlined by the fact that vascular and bleeding complications lost
their deleterious effects on outcome in recent studies. Recently,
Wenaweser and coworkers61 assessed clinical outcomes among
patients with estimated low (STS score <3%) or intermediate
(STS score, 3%--8%) surgical risk undergoing transfemoral
TAVR. Patients with a low risk (STS score, 2.3±0.4: log euroSCORE, 13.1±6.4) were younger (79.5±4.3 versus 83.5±4.7
years) and less often had prevalent chronic renal failure (39%
versus 67%) compared with the intermediate-risk patients
(STS score, 5.2±1.4; log euroSCORE, 21.4±12.0). At 30 days,
Figure 5. Limits of Medtronic CoreValve (MCV) and
Edwards SAPIEN XT Valve.
2326 Circulation December 23/30, 2014
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all-cause mortality was 0% and 3.5%, the rate of cerebrovascular
events was 0% versus 4.5%, and the rate of major strokes was
0% versus 3.5% in the low- and intermediate-risk group, respectively. There were no differences between the 2 groups with
regard to major or life-threatening bleeding, the occurrence of
acute renal failure, and major or minor access site complications.
At 1 year, all-cause mortality was 9.3% versus 14.8%, cardiovascular mortality was 6.3% versus 9.3%, the cerebrovascular
event rate was 7.7% versus 4.5%, and the combined end point of
all-cause death, or stroke occurred in 16.3% versus 16.7% in the
low- and intermediate-risk groups.61 These data clearly underline that the outcome in low- and intermediate-risk patients after
TAVR with the transfemoral approach is equivalent to the results
achieved in a similar cohort with conventional aortic valve
surgery. This is further confirmed by data from the CoreValve
Advance International Post Market Study (ADVANCE) study
(NCT01074658).62 The aim of the ADVANCE study was to
evaluate outcomes after implantation of a self-expanding transcatheter aortic valve system (Medtronic CoreValve) in a fully
monitored, multicenter, “real world” patient population (>1000
patients) in highly experienced centers. To understand whether
patients at low and intermediate risk (according to the logistic
euroSCORE) benefit equally from the TAVI procedure, outcomes were assessed separately in the group of patients with
logistic euroSCORE ≤10% (low risk) and between 10% and
20% (intermediate risk). The age was 77.6±6.9 versus 81.7±6.1
years, the median STS score was 3.2% versus 5.1%, and the
median log euroSCORE was 7.9% versus 14.7% in the low- and
intermediate-risk group, respectively. Overall, the procedural
complication rates were low with no cases of annular rupture
or coronary compromise. At 30 days, mortality was 2.6% and
4.4%, the rate of stroke (according to VARC) was 1.8% and
4.2%, and the combined end point of death resulting from any
cause or major stroke occurred in 2.6% and 5.7% in the lowand intermediate-risk group, respectively.62 At 1 year, all-cause
mortality was 11.1% versus 20.6%, the stroke rate (VARC) was
3.6% versus 5.1%, and the composite of death resulting from
any cause or major stroke occurred in 11.1% versus 17.5% of
the patients in the low- and intermediate-risk groups.62 These
results compare favorably with data from the German Aortic
Valve Registry in 2011, which contains data from 4109 patients
who had isolated conventional AVR because of significant aortic
stenosis. These patients had a mean age of 69.5 years; 80% had
a logistic euroSCORE <10%; and the median logistic euroSCORE was 7.9%. The mortality at 30 days was 2.4% and therefore almost identical to that in the TAVR-treated low-risk cohort
in ADVANCE.62 Additional information on this topic is provided
by the Italian OBservational Study of Effectiveness of AVR‐
TAVI procedures for severe Aortic Treatment (OBSERVANT)63
which assessed the outcome of TAVR compared with conventional surgical AVR for severe aortic stenosis in an intermediate-risk propensity-matched patient population. The matched
population comprised a total of 266 patients, 133 in the TAVR
group (mean logistic euroSCORE, 9.4±10.4%; age, 79.4±7.4
years) and 133 in the surgical group (mean logistic euroSCORE,
8.8±9.5%; age, 78.8±6.9 years). Mortality at 30 days was completely identical at 3.8% in both groups. However, the number of
patients with more than trace aortic regurgitation and the number
of patients requiring a new pacemaker were higher after TAVR
and the mean gradient was lower compared with conventional
surgery.63 In addition, in the United States, a downward creep of
risk is evident in the Transcatheter Valve Therapy registry, which
contains results from all eligible US TAVR cases (n=7710).
These patients had a mean age of 84 years, and the median STSpredicted risk of mortality was 7%. At 30 days, the incidence of
mortality was 7.6%, and a stroke had occurred in 2.8%.64 Stroke
after TAVR remains a major problem because it has been recognized as predictor of poor patient outcome. However, a recently
published prospective study showed a higher stroke rate in
patients after surgical AVR than reported previously, underlining
the need of a rigorous assessment of neurological function not
only after TAVR but also after conventional surgery.65
From the data of the studies mentioned above, there is no
reason to believe that TAVR in younger, lower-risk patients
with significant aortic stenosis would be associated with a
higher short-term mortality or more complications compared
with conventional AVR.
The Future: Better Results With
Next-Generation TAVI Devices?
To really compete with surgery in younger, low-risk patients,
outcomes have to be as good as those after conventional surgery. However, one has to keep in mind that not all low-risk
patients are good TAVR candidates. Currently, depending on
the TAVR device used, deployment and accurate positioning
are still difficult in patients with horizontal aorta. The experience in patients with bicuspid valves, which are more frequent in younger patients, is limited largely to case reports,
and there are still cases in which the annulus is too big or
too small to accommodate the current transcatheter heart
valves. Heavily calcified valves still represent a challenge in
transcatheter valve implantation because they are often associated with significant residual postprocedural paravalvular
leak with residual aortic regurgitation affecting survival or an
annular tear if the sizing was too aggressive.18,47 Although in
patients with relevant coronary artery disease a combination
of TAVR and percutaneous coronary intervention is possible,
the impact on long-term prognosis compared with coronary
artery bypass graft surgery and conventional AVR still needs
to be determined in randomized, controlled trials. In some
studies, there appears to be a higher risk of stroke and transient ischemic attack, which is not restricted to the perioperative period after TAVR; there are still vascular and bleeding
complications potentially affecting mortality, a higher rate of
permanent pacemaker implantations, and uncertainties about
valve durability.18,51 These limitations have been at least partially addressed by the engineers, providing us with improved
second-generation TAVR devices (Figure 6). Patients treated
with the transapical version of the JenaValve,66 which consists
of a porcine pericardial tissue valve sutured into a nitinol stent,
Haussig and Linke TAVR in Lower-Risk and Younger Patients 2327
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Figure 6. Next-generation transcatheter aortic valve implantation devices. Edwards Life Sciences CENTERA valve (A); bovine pericardial tissue valve, self-expandable nitinol frame with polyethylene terephthalate skirt, no aortic regurgitation in angiography (B). Symetis
ACURATE valve (C); porcine pericardial tissue valve, self-expandable nitinol alloy stent, no aortic regurgitation in angiography (D). Boston
Scientific Lotus valve (E); bovine pericardial tissue valve, self-expandable, braided nitinol frame, no aortic regurgitation in angiography
(F). Edwards Life Sciences SAPIEN 3 valve (G); bovine pericardial tissue valve, balloon-expandable, cobalt chromium frame, no aortic
regurgitation in angiography (H). St. Jude Medical Portico valve (I); bovine pericardial tissue valve, self-expandable nitinol frame, porcine
pericardial cuff, mild aortic regurgitation in angiography (J). Edwards Life Sciences SAPIEN XT valve (K); bovine pericardial tissue valve,
balloon-expandable, cobalt chromium frame, valve-in-valve implantation into a failing bioprosthetic valve, no aortic regurgitation in angiography (L). Medtronic CoreValve Evolut (M); porcine pericardial tissue valve, self-expandable nitinol frame, valve-in-valve implantation
into a failing bioprosthetic valve, no aortic regurgitation in angiography (H).
had mild or and absence of perivalvular leak in 97.6% after the
procedure, and the rate of permanent pacemaker implantation
was 12.5%. The initial results of the transfemoral version of
the Portico valve (St. Jude Medical, St. Paul, MN),67 which
is partially recapturable, repositionable, and retrievable, are
also encouraging. This valve consists of a bovine pericardial
tissue valve sutured into a self-expanding nitinol frame. At 30
days, 95% of the patients had either no or only mild aortic
regurgitation, which does not affect long-term survival,67 and
the rate of neurological complications and permanent pacemaker dependency was also low. Implantation of the SAPIEN
3 (Edwards Life Sciences, Irvine, CA), consisting of a bovine
pericardial tissue valve in a balloon-expandable cobalt chromium stent, which is delivered through a 14F sheath with
dynamic expansion mechanism, had a procedural success
rate of 100% in the first-in-humans series.58 There were no
death, no stroke, and no patients with aortic regurgitation
more than mild, and only 6.7% of patients required a permanent pacemaker implantation. The data from Repositionable
Percutaneous Replacement of Stenotic Aortic Valve Through
Implantation of Lotus™ Valve System: Evaluation of Safety
and Performance (REPRISE) II evaluating the Lotus valve
(Boston Scientific, Natick, MA) confirm the ease of use of the
second-generation transcatheter valves.68 Lotus consists of a
bovine pericardial tissue valve sutured into a self-expanding
braided nitinol frame, which is 1 of the 2 transcatheter valves
that are fully repositionable, recapturable, and retrievable. The
procedural success in REPRISE II was 100%, with no patient
with more than mild aortic regurgitation, but 8.7% had an ischemic stroke and >25% required a permanent pacemaker.68 The
Direct Flow Medical valve (Direct Flow Medical, Santa Rosa,
CA) is the second valve to be fully repositionable, recapturable, and retrievable. It consists of a bovine pericardial tissue
valve between 2 polymer rings filled with polymer solution.69
Data from the multicenter prospective trial of the direct flow
medical transcatheter aortic valve (DISCOVER CE) trial evaluating this valve reported 2.7% with major strokes, 16% with
permanent pacemaker implantation, with 99% with absent
2328 Circulation December 23/30, 2014
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or only mild aortic regurgitation.69 These data are in line
with the recent experience from the ACURATE TF study,70
investigating the performance of the Symetis ACURATE
valve (Symetis, Ecublens, Switzerland). The procedural success was high; 13% required a permanent pacemaker; and
95% had mild or absent perivalvular leak at 30 days after
implantation. Although these are only small trials with a limited number of patients, they all speak a similar language:
TAVR, especially through a transfemoral access, has become
safer for the patient. The success rate (according to VARC2)
increased to almost 100%; the vascular and bleeding complications dropped secondary to better patient screening and the
smaller profiles of the valve; the level of perivalvular regurgitation was almost negligible, most likely not affecting longterm survival in a negative way; and the rate of permanent
pacemaker implantation came down to values around 10%.
However, larger randomized, multicenter studies are necessary to confirm that these second-generation devices represent
a major breakthrough in the treatment of a broad range of
patients with severe aortic stenosis. The Safety and Efficacy
Study of the Medtronic CoreValve® System in the Treatment
of Severe, Symptomatic Aortic Stenosis in Intermediate Risk
Subjects Who Need Aortic Valve Replacement (SURTAVI;
NCT01586910) and PARTNER 2 trial (NCT01314313) will
provide the scientific answer. The SURTAVI trial (Figure
3) is comparing the performance of Medtronic CoreValve
implantation with conventional surgery in younger, lowerrisk patients, and the PARTNER 2 trial (cohort A) is studying performance in intermediate-risk patients. It is tempting to
speculate that US Food and Drug Administration approval for
TAVI in lower-risk patients in the United States will likely be
dependent on demonstration of noninferiority of TAVR compared with conventional surgery in these studies.
Beside investigation of TAVR in lower-risk patients, future
studies should focus on comparison of one TAVR device with
another and on strategies to minimize the degree of aortic
regurgitation and paravalvular leakage because even the presence of mild aortic regurgitation impairs outcome.29 To date, to
the best of our knowledge, the A Comparison of Transcatheter
Heart Valves in High Risk Patients With Severe Aortic Stenosis
(CHOICE) trial is the first study to compare a balloon-expandable system with a self-expandable system.71 The REPRISE III
trial will compare the performance and outcome of the Boston
Lotus valve system with the Medtronic CoreValve in patients
at increased risk for conventional surgery. This study will shed
more light into the head-to-head comparison of different transcatheter heart valves and help the treating physician to select
the right transcatheter heart valve for the right patient.
Furthermore, few data are available for patients with bicuspid valves because they are excluded in major trials. Some
case reports72,73 suggest that TAVR is feasible and safe in these
patients, but randomized, controlled trials are lacking.
Besides long-term valve durability, the only issue remaining is that of procedural neurological complications, which are
in the lower 1-digit range and therefore not higher compared
with conventional surgery (Table). However, they are always
deleterious for the patient. Devices have been developed to
prevent the occurrence of procedural, neurological complications (eg, Montage Dual Filter System, Claret Medical, Santa
Rosa, CA; Embrella Embolic Deflector System, Edwards Life
Sciences; TriGuard Cerebral Protection Device, Keystone
Heart Ltd, Caesarea Business Park, Keisarya, Israel). These
devices are currently under investigation (NCT01833052 and
NCT02070731), some in randomized, controlled trials, with
the first results expected by the end of the year. It will be exciting to see if they are able to make TAVR even safer.
Conclusions
TAVR is the treatment of choice—significantly improving prognosis—in inoperable patients with aortic stenosis. In addition,
TAVR is a potentially superior alternative to conventional AVR
in operable, high-risk patients. However, the major shortcomings of the first-generation devices were success rates <90%,
perivalvular leaks, bleeding and vascular complications, strokes
and transient ischemic attacks, and a high rate of pacemaker
implantations. These limitations have been addressed by engineers, providing us with improved second-generation TAVR
devices. Given the 30-day mortality rates of <1% in experienced centers, the excellent TAVR results in recently published
randomized, controlled trials, and the improved performance
of the second-generation transcatheter heart valve systems,
there is good reason to believe that TAVR will also prevail in a
younger, lower-risk cohort, given appropriate patient selection.
However, despite the fact that circumstantial evidence is compelling, one has to wait for the results of trials in intermediateand lower-risk patients like PARTNER 2 and SURTAVI before
further expansion of indications is scientifically justified.
Disclosures
Dr Linke is a consultant to Medtronic and St. Jude Medical. He
received speaker honoraria from Edwards, Medtronic, Boston
Scientific, and St. Jude Medical and is a proctor for Medtronic,
Edwards, and St. Jude Medical. Dr. Haussig reports no conflicts.
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Response to Haussig and Linke
Volkmar Falk, MD
Drs Linke and Haussig provide a thorough update of the current outcomes and results of transcatheter aortic valve replacement (TAVR) and try to make an argument for its use in low-risk patients. To support their argument, they refer to recent
articles on postmarket registries and CE trials of second-generation devices, some of which show improved outcomes for
TAVR. When interpreting these data, one has to consider that most of these trials were very selective in patient inclusion and
that follow-up is in general limited to 1 year. Patients with peripheral artery disease, renal failure, bicuspid valves, severe
annular calcification, and other known risk factors for TAVR were often excluded, especially in CE trials. This renders a
comparison with surgical aortic valve replacement all-comer data impossible. The authors discuss at length the work of
Wenaweser, who treated a number of low- and intermediate-risk patients with TAVR. Unfortunately, the original article is
largely misquoted. The 30-day mortality in low- and intermediate-risk patients was not 0% as referred to by the authors
but 2.4% and 3.9%, respectively. Likewise, the major stroke rate was not 0% but 2.4% in the low-risk and 3.2% in the
intermediate-risk group. Although it is true that the rate life-threatening bleeding was the same for low- (14.6%), intermediate- (14.2%), and high- (23.5%) risk patients, the rates exceed 14%, which for low-risk patients seems unacceptable. So
far, neither this article nor any other article quoted by the authors provides proof that TAVR provides better major adverse
cardiac event outcomes in low- or intermediate-risk groups of patients than surgical aortic valve replacement. What these
studies show is that the excess need for pacemakers, the problem of paravalvular aortic leakage, and vascular complications
after TAVR remain an issue. In addition, its long-term durability is still unknown. Before the indication can be expanded to
low-risk groups, randomized, controlled trials with appropriate follow-up have to be completed.
Transcatheter Aortic Valve Replacement Indications Should be Expanded to Lower-Risk
and Younger Patients
Stephan Haussig and Axel Linke
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Circulation. 2014;130:2321-2331
doi: 10.1161/CIRCULATIONAHA.114.008144
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