n engl j med 363;17 nejm.org october 21, 2010
1597
The new england
journal
of medicine
established in 1812
october 21, 2010
vol. 363 no. 17
Transcatheter Aortic-Valve Implantation for Aortic Stenosis
in Patients Who Cannot Undergo Surgery
Martin B. Leon, M.D., Craig R. Smith, M.D., Michael Mack, M.D., D. Craig Miller, M.D., Jeffrey W. Moses, M.D.,
Lars G. Svensson, M.D., Ph.D., E. Murat Tuzcu, M.D., John G. Webb, M.D., Gregory P. Fontana, M.D.,
Raj R. Makkar, M.D., David L. Brown, M.D., Peter C. Block, M.D., Robert A. Guyton, M.D.,
Augusto D. Pichard, M.D., Joseph E. Bavaria, M.D., Howard C. Herrmann, M.D., Pamela S. Douglas, M.D.,
John L. Petersen, M.D., Jodi J. Akin, M.S., William N. Anderson, Ph.D., Duolao Wang, Ph.D.,
and Stuart Pocock, Ph.D., for the PARTNER Trial Investigators*
ABSTR ACT
From Columbia University Medical Center/
NewYork–Presbyterian Hospital, New York
(M.B.L., C.R.S., J.W.M.); Medical City Dal-
las, Dallas (M.M., D.L.B.); Stanford Uni-
versity Medical School, Stanford (D.C.M.),
and Edwards Lifesciences, Irvine (J.J.A.,
W.N.A.) — both in California; Cleveland
Clinic Foundation, Cleveland (L.G.S.,
E.M.T.); University of British Columbia
and St. Paul’s Hospital, Vancouver, Canada
(J.G.W.); Cedars–Sinai Medical Center,
Los Angeles (G.P.F., R.R.M.); Emory Uni-
versity School of Medicine, Atlanta
(P.C.B., R.A.G.); Washington Hospital
Center, Washington, DC (A.D.P.); Hospi-
tal of the University of Pennsylvania,
Philadelphia (J.E.B., H.C.H.); Duke Uni-
versity Medical Center, Durham, NC
(P.S.D., J.L.P.); and London School of Hy-
giene and Tropical Medicine, London
(D.W., S.P.). Address reprint requests to
Dr. Leon at Columbia University Medical
Center/NewYork–Presbyterian Hospital,
173 Fort Washington Ave., Heart Center,
2nd Fl., New York, NY 10032, or at
ml2398@columbia.edu.
*The investigators, institutions, and re-
search organizations participating in
the Placement of Aortic Transcatheter
Valves (PARTNER) trial are listed in the
Supplementary Appendix, available at
NEJM.org.
This article (10.1056/NEJMoa1008232)
was published on September 22, 2010, at
NEJM.org.
N Engl J Med 2010;363:1597-1607.
Copyright © 2010 Massachusetts Medical Society.
Background
Many patients with severe aortic stenosis and coexisting conditions are not candi-
dates for surgical replacement of the aortic valve. Recently, transcatheter aortic-valve
implantation (TAVI) has been suggested as a less invasive treatment for high-risk
patients with aortic stenosis.
Methods
We randomly assigned patients with severe aortic stenosis, whom surgeons considered
not to be suitable candidates for surgery, to standard therapy (including balloon aortic
valvuloplasty) or transfemoral transcatheter implantation of a balloon-expandable
bovine pericardial valve. The primary end point was the rate of death from any cause.
Results
A total of 358 patients with aortic stenosis who were not considered to be suitable can-
didates for surgery underwent randomization at 21 centers (17 in the United States).
At 1 year, the rate of death from any cause (Kaplan–Meier analysis) was 30.7% with
TAVI, as compared with 50.7% with standard therapy (hazard ratio with TAVI, 0.55;
95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end
point of death from any cause or repeat hospitalization was 42.5% with TAVI as com-
pared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59;
P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart
Association class III or IV) was lower among patients who had undergone TAVI than
among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days,
TAVI, as compared with standard therapy, was associated with a higher incidence of
major strokes (5.0% vs. 1.1%, P = 0.06) and major vascular complications (16.2% vs.
1.1%, P<0.001). In the year after TAVI, there was no deterioration in the functioning
of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an
echocardiogram.
Conclusions
In patients with severe aortic stenosis who were not suitable candidates for surgery,
TAVI, as compared with standard therapy, significantly reduced the rates of death from
any cause, the composite end point of death from any cause or repeat hospitalization,
and cardiac symptoms, despite the higher incidence of major strokes and major vascular
events. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)
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n engl j med 363;17 nejm.org october 21, 2010
1598
A
ortic stenosis is an insidious disease
with a long latency period
1
followed by
rapid progression after the appearance
of symptoms,
2-5
resulting in a high rate of death
(approximately 50% in the first 2 years after symp-
toms appear) among untreated patients.
1,6-8
Sur-
gical replacement of the aortic valve reduces symp-
toms and improves survival in patients with aortic
stenosis,
9-11
and in the absence of serious coexist-
ing conditions, the procedure is associated with
low operative mortality.
12,13
However, in clinical
practice, at least 30% of patients with severe symp-
tomatic aortic stenosis do not undergo surgery
for replacement of the aortic valve, owing to ad-
vanced age, left ventricular dysfunction, or the
presence of multiple coexisting conditions.
14-17
For
these patients, who are at high surgical risk,
18,19
a less invasive treatment may be a worthwhile al-
ternative.
Transcatheter aortic-valve implantation (TAVI)
is a new procedure, in which a bioprosthetic valve
is inserted through a catheter and implanted
within the diseased native aortic valve. Since 2002,
when the procedure was first performed,
20,21
there
has been rapid growth in its use throughout the
world for the treatment of severe aortic stenosis in
patients who are at high surgical risk.
22-32
The
most recent clinical studies showed that the rate of
death from any cause at 1 year among patients
treated with TAVI was approximately 25%.
27-29,31
Thus far, all the studies of TAVI have been obser-
vational registry studies, without standardization
of end-point definitions
33,34
(and unpublished data)
and without control populations. There is a paucity
of rigorous, evidence-based clinical data to sub-
stantiate the incremental benefits of TAVI as com-
pared with current standard therapies.
The Placement of Aortic Transcatheter Valves
(PARTNER) trial was a multicenter, randomized
clinical trial comparing TAVI with standard ther-
apy in high-risk patients with severe aortic steno-
sis, including a prespecified cohort of patients who
were not considered to be suitable candidates for
surgery. In this article, we report the outcomes
with TAVI as compared with standard therapy
among the patients in the PARTNER trial who
were not suitable candidates for surgery.
Methods
Patient Selection
We enrolled in the PARTNER trial patients with
severe aortic stenosis and cardiac symptoms for
whom conventional surgery to replace the aortic
valve was associated with high risk. Severe aortic
stenosis was defined as an aortic-valve area of less
than 0.8 cm
2
, a mean aortic-valve gradient of
40 mm Hg or more, or a peak aortic-jet velocity
of 4.0 m per second or more. All the patients had
New York Heart Association (NYHA) class II, III,
or IV symptoms. Patients were divided into two
cohorts: those who were considered to be candi-
dates for surgery despite the fact that they were
at high surgical risk, as defined by a Society of
Thoracic Surgeons (STS) risk score of 10% or
higher
35
(on a scale of 0% to 100%, with higher
scores indicating greater surgical risk) or by the
presence of coexisting conditions that would be
associated with a predicted risk of death by 30
days after surgery of 15% or higher, and those
who were not considered to be suitable candi-
dates for surgery because they had coexisting
conditions that would be associated with a pre-
dicted probability of 50% or more of either death
by 30 days after surgery or a serious irreversible
condition. At least two surgeon investigators had
to agree that the patient was not a suitable can-
didate for surgery. In this article, we report the
results for the patients with aortic stenosis who
were not considered to be suitable candidates
for surgery. The randomized trial involving pa-
tients at high surgical risk who were neverthe-
less considered to be candidates for surgery
(also NCT00530894) is ongoing.
Pertinent exclusion criteria were a bicuspid or
noncalcified aortic valve, acute myocardial infarc-
tion, substantial coronary artery disease requir-
ing revascularization, a left ventricular ejection
fraction of less than 20%, a diameter of the aortic
annulus of less than 18 mm or more than 25 mm,
severe (>3+) mitral or aortic regurgitation, a tran-
sient ischemic attack or stroke within the previ-
ous 6 months, and severe renal insufficiency. The
complete list of inclusion and exclusion criteria
is provided in
Table 1
in the Supplementary Ap-
pendix, available with the full text of this article
at NEJM.org.
After investigators screened the patients for
eligibility, Web-based conference calls were con-
ducted by the executive committee to further re-
view and approve the selection of all patients be-
fore randomization. Of the 3105 patients with
aortic stenosis who were screened by the investi-
gators and the executive committee, approximately
12% ultimately underwent randomization as part
of the PARTNER trial and were assigned to the
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Transcatheter Aortic-Valve Implantation for Stenosis
n engl j med 363;17 nejm.org october 21, 2010
1599
cohort of patients who were not considered to be
suitable candidates for surgery.
Study Device and Procedure
The Edwards SAPIEN heart-valve system (Edwards
Lifesciences) consists of a trileaflet bovine peri-
cardial valve and a balloon-expandable, stainless-
steel support frame. The heart valve is shown in
Figure 1 in the Supplementary Appendix. The TAVI
procedure was performed in a sterile environment
(catheterization laboratory or operating room),
with the patient under general anesthesia; the
procedure was performed with the use of trans-
esophageal echocardiography. A standard balloon
aortic valvuloplasty was performed, followed by
transfemoral insertion of either a 22- or 24-French
sheath, depending on the selected size of the valve
(23 mm or 26 mm). The bioprosthetic heart valve,
crimped onto a balloon catheter, was advanced
across the native aortic valve. During rapid right
ventricular pacing, balloon inflation of the crimped
heart valve and support frame simultaneously de-
ployed the bioprosthetic valve and expanded the
frame, which was secured to the underlying aor-
tic-valve annulus and leaflets (see videos 1 and 2,
available at NEJM.org). Adjunctive pharmacologic
therapy included heparin during the procedure and
dual antiplatelet therapy (aspirin and clopidogrel)
for 6 months after the procedure.
Study Design and Oversight
The PARTNER study incorporated two parallel
prospective, multicenter, randomized, active-treat-
ment–controlled clinical trials. The overall study
design is shown in Figure 2 in the Supplemen-
tary Appendix. Patients were randomly assigned
with the use of a computer-generated scheme,
blocked separately at each participating site and
for each of the trial cohorts. The PARTNER study
was approved by the institutional review board at
each participating site, and all patients provided
written informed consent.
The trial was designed by the sponsor (Edwards
Lifesciences) and members of the executive com-
mittee, which included the two academic coprin-
cipal investigators, three interventional cardiolo-
gists, and three cardiac surgeons. The sponsor
funded the studies and participated in the selec-
tion and management of the sites and the collec-
tion and monitoring of the data. The executive
committee met in person every 6 to 8 weeks to
monitor all aspects of the conduct of the trial. The
coprincipal investigators and the executive com-
mittee had unrestricted access to the data after
the database was locked, made the decision to
submit the manuscript for publication, prepared
all drafts of the manuscript, and attest to the
integrity of the trial and the completeness and
accuracy of the reported data, as well as to the
fidelity of the report to the trial protocol. The
protocol, including the statistical analysis plan,
is available at NEJM.org.
Data Management
All serious adverse events were adjudicated by an
independent clinical events committee. A data and
safety monitoring board met frequently and had
access to all study data and treatment assignments
when requested; the board recommended after
each meeting that the study be continued with-
out modification. All data were sent for analysis
to independent consulting biostatisticians. Inde-
pendent core laboratories analyzed all echocar-
diograms and electrocardiograms. The members
of the committees, the institutions, and the re-
search organizations participating in the PARTNER
trial are listed in
Table 2
in the Supplementary
Appendix.
Study End Points
The primary end point was the rate of death from
any cause over the duration of the trial. All pa-
tients were followed for at least 1 year, and cross-
over from the standard-therapy group to the TAVI
group was not permitted. The coprimary end point
was the rate of a hierarchical composite of the
time to death from any cause or the time to the
first occurrence of repeat hospitalization (after the
index procedure) due to valve-related or procedure-
related clinical deterioration. This composite end
point was also reported with the use of more con-
ventional Kaplan–Meier nonhierarchical analyti-
cal methods. Prespecified secondary end points
included the rate of death from cardiovascular
causes, NYHA functional class, the rate of repeat
hospitalization due to valve-related or procedure-
related clinical deterioration, the distance covered
during a 6-minute walk test,
36
valve performance
(assessed by echocardiography), and the rates of
myocardial infarction, stroke, acute kidney injury,
vascular complications, and bleeding. A major
stroke was defined as a focal or global neurologic
deficit associated with a score of 2 or higher on
the modified Rankin scale, which has a range of
0 to 6, with 0 indicating no symptoms and 6 in-
dicating death. Specific definitions of other im-
Two videos show-
ing deployment
of the valve and
animation of the
TAVI procedure
are available at
NEJM.org
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n engl j med 363;17 nejm.org october 21, 2010
1600
portant end points are provided in Table 3 in the
Supplementary Appendix. All patients were fol-
lowed during the index hospitalization; at 30 days,
6 months, and 1 year; and yearly thereafter.
Statistical Analysis
We estimated that with a sample of 350 patients,
the study would have at least 85% power to show
the superiority of TAVI over standard treatment
with respect to the primary end point, assuming
that 1-year mortality would be 37.5% in the stan-
dard-treatment group and 25% in the TAVI group.
In calculating the size of the sample, we also as-
sumed that deaths would follow a constant haz-
ard distribution, that follow-up would continue for
12 months after the last patient was enrolled, and
that the rate of loss to follow-up would be 10%.
The analysis of the coprimary end point — the
hierarchical composite of death or repeat hospi-
talization — was performed with the use of a
nonparametric method described by Finkelstein
and Schoenfeld.
37
With this method, multiple pair-
wise comparisons are performed for all patient
pairs, first with respect to the time to death and
then with respect to the time to repeat hospital-
ization, if necessary. On the basis of a simulation
with the use of SAS software, we estimated that
with a total sample of 350 patients, the power for
this coprimary end point would be more than
95%. The Hochberg procedure was used to make
multiple corrections of the primary and coprimary
end points.
Categorical variables were compared with the
use of Fisher’s exact test. A generalized linear
model was used to calculate risk ratios in the sub-
group analysis and to test for interactions. Con-
tinuous variables, which are presented as means
(±SD), were compared with the use of Student’s
t-test. All the analyses were performed with data
from the intention-to-treat population, which in-
cluded all patients who underwent randomization,
regardless of the treatment actually received.
Survival curves for time-to-event variables were
constructed on the basis of all available follow-
up data with the use of Kaplan–Meier estimates
and were compared with the use of the log-rank
test. A two-sided alpha level of 0.05 was used for
all superiority testing. All statistical analyses
were performed with the use of SAS software,
version 9.2.
Results
Patients and Enrollment
Between May 11, 2007, and March 16, 2009, a total
of 358 patients with severe aortic stenosis who
were not suitable candidates for surgery were en-
rolled at 21 sites (17 in the United States) and were
randomly assigned to TAVI (179 patients) or stan-
dard therapy (179 patients). All the patients were
followed for at least 1 year (median follow-up pe-
riod, 1.6 years; maximum, 2.8 years). The num-
bers of patients who underwent randomization
and follow-up are shown in Figure 3 in the Sup-
plementary Appendix.
The baseline characteristics of the patients in
the two groups were generally well balanced (
Ta-
ble 1
). The overall patient population was at high
risk (STS score, 11.6±6.0%). However, there were
many patients with low STS scores but with co-
existing conditions that contributed to the sur-
geons’ determination that the patient was not a
suitable candidate for surgery, including an ex-
tensively calcified (porcelain) aorta (15.1%), chest-
wall deformity or deleterious effects of chest-wall
irradiation (13.1%), oxygen-dependent respiratory
insufficiency (23.5%), and frailty, as determined
by the surgeons according to prespecified crite-
ria (23.1%).
Procedural Outcomes
Of the 179 patients assigned to TAVI, 6 (3.4%)
did not receive a transcatheter heart valve (2 pa-
tients died before the scheduled implantation,
transfemoral access was unsuccessful in 2 patients,
and the intraprocedural annulus measurement
was too large in 2 patients). After randomization,
the median time to TAVI was 6 days (interquartile
range, 3 to 11). During the TAVI procedure or in
the first 24 hours after the procedure, 2 patients
(1.1%) died, 3 (1.7%) had major strokes, 1 (0.6%)
had a valve embolization, and 2 (1.1%) underwent
multiple (≥2) valve implantations; no patient un-
derwent urgent cardiac surgery to manage com-
plications. In the first 30 days after the proce-
dure, 11 of the 173 patients who underwent TAVI
(6.4%) died.
Of the 179 patients assigned to standard thera-
py, balloon aortic valvuloplasty was performed in
114 patients (63.7%) during the 30 days after
randomization and in an additional 36 patients
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Transcatheter Aortic-Valve Implantation for Stenosis
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1601
Table 1. Baseline Characteristics of the Patients and Echocardiographic Findings.*
Characteristic
TAVI
(N = 179)
Standard Therapy
(N = 179) P Value
Age — yr 83.1±8.6 83.2±8.3 0.95
Male sex — no. (%) 82 (45.8) 84 (46.9) 0.92
STS score† 11.2±5.8 12.1±6.1 0.14
Logistic EuroSCORE‡ 26.4±17.2 30.4±19.1 0.04
NYHA class — no. (%) 0.68
II 14 (7.8) 11 (6.1)
III or IV 165 (92.2) 168 (93.9)
Coronary artery disease — no. (%) 121 (67.6) 133 (74.3) 0.20
Previous myocardial infarction — no./total no. (%) 33/177 (18.6) 47/178 (26.4) 0.10
Previous intervention — no./total no. (%)
CABG 58/155 (37.4) 73/160 (45.6) 0.17
PCI 47/154 (30.5) 39/157 (24.8) 0.31
Balloon aortic valvuloplasty 25/154 (16.2) 39/160 (24.4) 0.09
Cerebral vascular disease — no./total no. (%) 48/175 (27.4) 46/167 (27.5) 1.00
Peripheral vascular disease — no./total no. (%) 54/178 (30.3) 45/179 (25.1) 0.29
COPD — no. (%)
Any 74 (41.3) 94 (52.5) 0.04
Oxygen-dependent 38 (21.2) 46 (25.7) 0.38
Creatinine >2 mg/dl (177 μmol/liter) — no./total no. (%) 10/178 (5.6) 17/178 (9.6) 0.23
Atrial fibrillation — no./total no. (%) 28/85 (32.9) 39/80 (48.8) 0.04
Permanent pacemaker — no./total no. (%) 35/153 (22.9) 31/159 (19.5) 0.49
Pulmonary hypertension — no./total no. (%) 50/118 (42.4) 53/121 (43.8) 0.90
Frailty — no./total no. (%)§ 21/116 (18.1) 33/118 (28.0) 0.09
Extensively calcified aorta — no. (%) 34 (19.0) 20 (11.2) 0.05
Deleterious effects of chest-wall irradiation — no. (%) 16 (8.9) 15 (8.4) 1.00
Chest-wall deformity — no. (%) 15 (8.4) 9 (5.0) 0.29
Liver disease — no./total no. (%) 6/177 (3.4) 6/178 (3.4) 1.00
Echocardiographic findings
Aortic-valve area — cm
2
0.6±0.2 0.6±0.2 0.97
Mean aortic-valve gradient — mm Hg 44.5±15.7 43.0±15.3 0.39
Mean LVEF — % 53.9±13.1 51.1±14.3 0.06
Moderate or severe mitral regurgitation — no./total no. (%)¶ 38/171 (22.2) 38/165 (23.0) 0.90
* Plus–minus values are means ±SD. CABG denotes coronary-artery bypass grafting, COPD chronic obstructive pulmonary disease, LVEF left
ventricular ejection fraction, NYHA New York Heart Associa tion, PCI percutaneous coronary intervention, and TAVI transcatheter aortic-valve
implantation.
† The Society of Thoracic Surgeons (STS) score measures patient risk at the time of cardiovascular surgery on a scale that ranges from 0% to
100%, with higher numbers indicating greater risk. An STS score higher than 10% indicates very high surgical risk.
‡ The logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), which measures patient risk at the time of cardiovascular
surgery, is calculated with the use of a logistic-regression equation. Scores range from 0% to 100%, with higher scores indicating greater
risk. A logistic EuroSCORE higher than 20% indicates very high surgical risk.
§ Frailty was determined by the surgeons according to prespecified criteria.
¶ Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.
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