Structural Heart Disease
Two-Year Outcomes in Patients With Severe Aortic
Valve Stenosis Randomized to Transcatheter Versus
Surgical Aortic Valve Replacement
The All-Comers Nordic Aortic Valve Intervention
Randomized Clinical Trial
Lars Søndergaard, MD, DMSc; Daniel Andreas Steinbrüchel, MD, DMSc;
Nikolaj Ihlemann, MD, PhD; Henrik Nissen, MD, PhD; Bo Juel Kjeldsen, MD, PhD;
Petur Petursson, MD, PhD; Anh Thuc Ngo, MD, PhD; Niels Thue Olsen, MD, PhD;
Yanping Chang, MS; Olaf Walter Franzen, MD; Thomas Engstrøm, MD, DMSc;
Peter Clemmensen, MD, DMSc; Peter Skov Olsen, MD, DMSc; Hans Gustav Hørsted Thyregod, MD
Downloaded from http://circinterventions.ahajournals.org/ by guest on July 31, 2017
Background—The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize all-comers with severe
native aortic valve stenosis to either transcatheter aortic valve replacement (TAVR) with the CoreValve self-expanding
bioprosthesis or surgical aortic valve replacement (SAVR), including a lower-risk patient population than previous trials.
This article reports 2-year clinical and echocardiographic outcomes from the NOTION trial.
Methods and Results—Two-hundred eighty patients from 3 centers in Denmark and Sweden were randomized to either
TAVR (n=145) or SAVR (n=135) with follow-up planned for 5 years. There was no difference in all-cause mortality at
2 years between TAVR and SAVR (8.0% versus 9.8%, respectively; P=0.54) or cardiovascular mortality (6.5% versus
9.1%; P=0.40). The composite outcome of all-cause mortality, stroke, or myocardial infarction was also similar (15.8%
versus 18.8%, P=0.43). Forward-flow hemodynamics were improved following both procedures, with effective orifice
area significantly more improved after TAVR than SAVR (effective orifice area, 1.7 versus 1.4 cm2 at 3 months). Mean
valve gradients were similar after TAVR and SAVR. When patients were categorized according to Society of Thoracic
Surgeons Predicted Risk of Mortality (STS-PROM) (<4% versus ≥4%), there was no statistically significant difference
for TAVR and SAVR groups in the composite outcome for low-risk (14.7%, 95% confidence interval, 8.3–21.2 versus
16.8%; 95% confidence interval, 9.7–23.8; P=0.58) or intermediate-risk patients (21.1% versus 27.1%; P=0.59).
Conclusions—Two-year results from the NOTION trial demonstrate the continuing safety and effectiveness of TAVR in
lower-risk patients. Longer-term data are needed to verify the durability of this procedure in this patient population.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01057173. (Circ Cardiovasc Interv. 2016;9:e003665. DOI: 10.1161/CIRCINTERVENTIONS.115.003665.)
Key Words: bioprosthesis ◼ hemodynamics ◼ myocardial infarction ◼ stroke
◼ transcatheter aortic valve replacement
A
ortic valve stenosis carries a poor prognosis after the
onset of symptoms.1–3 Surgical aortic valve replacement
(SAVR) has been the standard treatment for this condition,
but some patients are not candidates for surgery.4 Randomized
trials of transcatheter aortic valve replacement (TAVR) have
proven both safety and efficacy in patients who are inoperable
or at high surgical risk compared with conservative and surgical treatment, respectively.5,6 Furthermore, propensity-score–
matched TAVR and SAVR patients with low and intermediate
surgical risk have demonstrated similar clinical outcomes,
including mortality, stroke, myocardial infarction, or coronary
revascularization, which were not statistically different after 1
year, but there were some differences in secondary outcomes,
reflecting the inherent differences between the 2 procedures.7–13
The Nordic Aortic Valve Intervention (NOTION) trial was
the first trial to randomize all-comer patients with severe aortic valve stenosis to either TAVR or SAVR, including a patient
population at lower surgical risk than has been previously
Received December 14, 2015; accepted April 27, 2016.
From the Departments of Cardiology (L.S., N.I., A.T.N., N.T.O., O.W.F., T.E.) and Cardiothoracic Surgery (D.A.S., P.S.O., H.G.H.T.), The Heart Centre,
Rigshospitalet, Copenhagen University Hospital, Denmark; Departments of Cardiology (H.N.) and Cardiothoracic and Vascular Surgery (B.J.K.), Odense
University Hospital, Denmark; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden (P.P.); Department of Statistics, Medtronic,
Mounds View, MN (Y.C.); and Department of Medicine, Nykoebing F Hospital and University of Southern Denmark, Odense, Denmark (P.C.).
Correspondence to Lars Søndergaard, MD, DMSc, Department of Cardiology, Section 2011, Rigshospitalet, Copenhagen University Hospital,
Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
1
DOI: 10.1161/CIRCINTERVENTIONS.115.003665
2 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
population. Furthermore, in a post hoc analysis TAVR was
noninferior to SAVR on the primary outcome (P=0.01) using
a noninferiority margin of 7.5%.16 Improvements in valve
hemodynamics and functional class were sustained at 1 year
post procedure.16 Presently, data on lower-risk patients are limited. The objective of the current analysis is to evaluate 2-year
clinical and echocardiographic outcomes among lower-risk
patients who underwent TAVR or SAVR in the NOTION trial.
WHAT IS KNOWN
• Transcatheter
aortic valve replacement has proven
to be noninferior or even superior to surgical aortic
valve replacement in patients with severe aortic stenosis, who are at intermediate or high surgical risk.
• The Nordic Aortic Valve Intervention (NOTION) trial indicated that these results also apply to patients at
lower surgical risk; however, it is uncertain whether
these findings apply at midterm follow-up.
Methods
Trial Design
WHAT THE STUDY ADDS
The NOTION trial is an investigator-initiated, randomized, nonblinded, superiority trial conducted at 3 centers in Denmark and Sweden.
The design of the trial has been described previously.16,17 Twohundred eighty patients were randomly assigned to TAVR (n=145) or
SAVR (n=135) with follow-up planned for 5 years.
The trial was conducted according to the principles of the
Declaration of Helsinki, and the regional ethical review board at each
site approved the protocol. All patients provided written informed
consent. Data were collected and stored by the investigators and were
fully monitored by an independent monitoring unit. The trial is registered at https://www.clinicaltrials.gov, identifier: NCT01057173.
All authors vouch for the accuracy and completeness of the data and
analyses, and confirm that the trial was conducted according to the
protocol.
• At 2 years, the NOTION trial did not find a signifiDownloaded from http://circinterventions.ahajournals.org/ by guest on July 31, 2017
cant difference in the composite rate of death from
any cause, stroke, or myocardial infarction between
transcatheter aortic valve replacement and surgery.
• These results suggest that transcatheter aortic valve
replacement is a reasonable option to surgical valve
replacement.
reported in other randomized trials.14,15 The primary outcome
was a composite rate of death from any cause, stroke, or myocardial infarction at 1 year; and although TAVR was not demonstrated to be statistically superior to SAVR for the primary
outcome, the therapy was safe and effective in this lower-risk
Procedures
Patients were randomized 1:1 to either TAVR or SAVR and stratified
according to trial site, age (70–74 years or ≥75 years), and history
All Enrolled
N=280
ITT TAVR
n=145
RANDOMIZATION
Crossover
TAVR to SAVR
n=1
Died prior to procedure
n=3
AT TAVR
n=142
ITT SAVR
n=135
Crossover
SAVR to TAVR
n=1
Died prior to procedure
n=1
AT SAVR
n=134
Died
n=7
Died
n=9
1 Year
n=133
1 Year
n=120
Missed visits
n=2
Missed visits
n=5
Died
n=6
Died
n=6
2 Years
n=123
2 Years
n=113
Missed visits
n=6
Missed visits
n=6
Figure 1. Patient disposition to 2 years. ITT
indicates intention-to-treat; SAVR, surgical
aortic valve replacement; and TAVR, transcatheter aortic valve replacement.
3 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
echocardiography, reported out to 2 years. All outcomes were defined
according to Valve Academic Research Consortium-2 definitions.19
Statistical Analysis
For clinical outcomes, a time-to-event analysis was conducted using
Kaplan–Meier estimates, and comparisons between the treatment
groups were done using the log-rank test. The as-treated population,
defined as patients in whom 1 of the 2 trial procedures was attempted, was used for all analyses. Event rates are given for the following
postprocedural time windows: 0=0 to 29 days, 1 month=30 to 182
days, 6 months=183 to 364 days, 12 months=365 to 729 days, and 24
months=≥730 days.
Subgroup analyses of all-cause mortality at 2 years were conducted
for several baseline characteristics. The Cox Proportional Hazard model was used to examine the interactions between treatment and each
baseline characteristic. Categorical variables were compared using the
Fisher exact test or the χ2 test as appropriate. Continuous variables were
presented as means±SD and compared with the use of the Student t
test. Ordinal variables were compared using the Mantel–Haenszel test.
All testing used a 2-sided α level of 0.05. P values were not adjusted for
multiple comparisons. All statistical analyses were performed with the
use of SAS software, version 9.2 (SAS Institute, Cary, NC).
Outcome Measures
P-value (Log-rank) = 0.43
30%
20%
15.7%
10%
0%
6
No. at risk:
C
18.8%
15.8%
11.3%
0
12
Months Post-Procedure
18
Patients were enrolled from December 2009 through April
2013. Two-hundred eighty patients were eligible for the study.
Four patients died before the procedure; therefore, aortic valve
replacement was attempted in 276 patients, resulting in an
as-treated population of 142 TAVR and 134 SAVR patients
B
SAVR
TAVR
40%
Patients
50%
All-Cause Mortality (%)
50%
Results
SAVR
TAVR
40%
P-value (Log-rank) = 0.54
30%
20%
9.8%
8.0%
7.5%
10%
0%
24
4.9%
0
6
No. at risk:
12
Months Post-Procedure
18
24
134 118
115
113
66
134 128
125
123
72
142 133
129
124
68
142 139
137
132
75
50%
SAVR STS <4%
TAVR STS <4%
40%
P-value (Log-rank) = 0.58
30%
20%
10%
0%
16.8%
14.7%
13.9%
10.2%
0
6
No. at risk:
108 96
118 111
94
108
12
Months Post-Procedure
93
104
18
24
D
All-Cause Mortality, Stroke, or MI (%)
A
All-Cause Mortality, Stroke, or MI (%)
The primary outcome was the composite rate of death from any
cause, stroke, or myocardial infarction at 1 year after the procedure.16
Two-year outcomes reported here include the composite outcome as
well as prespecified clinical outcomes, including all-cause mortality,
cardiovascular mortality, stroke, myocardial infarction, pacemaker
implantation, and aortic valve reintervention. Hemodynamic outcomes include aortic valve effective orifice area, mean pressure gradient, and degree of total aortic valve regurgitation, as measured by
All-Cause Mortality, Stroke, or MI (%)
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of coronary artery disease as previously described.16 All SAVR patients received a bioprosthesis with the specific type and size determined during the procedure. Patients randomized to TAVR received
the CoreValve self-expanding bioprosthesis (Medtronic, Minneapolis,
MN), predominantly via femoral artery access (96%) with some
patients undergoing left transaxillary access (4%). All available
CoreValve sizes (23, 26, 29, or 31 mm) were used. The procedure was
performed under general or local anesthesia as previously described.18
All TAVR and SAVR patients received similar periprocedural prophylactic antibiotics and postoperative antiplatelet and anticoagulation regimes as previously described.16,17 All procedures were performed by
senior cardiac surgeons and interventional cardiologists.
Follow-up assessments were performed before discharge and 1,
3, 12, and 24 months after the procedure and consisted of a physical
examination, documentation of trial-specified outcomes and adverse
events, New York Heart Association (NYHA) classification, blood
sampling, and a 12-lead ECG. Transthoracic echocardiography was
performed at baseline and 3, 12, and 24 months. Echocardiograms
were evaluated by experienced cardiologists, and all clinical outcomes were confirmed by national electronic medical records. When
a neurological event was suspected, an independent neurologist performed an evaluation, and cerebral imaging studies were performed.
50%
SAVR STS ≥4%
TAVR STS ≥4%
40%
P-value (Log-rank) = 0.59
30%
21.1%
16.7%
10%
0%
0
6
12
Months Post-Procedure
21
21
20
20
No. at risk:
53
58
27.1%
23.1%
20%
26
24
22
22
18
24
13
10
Figure 2. Kaplan–Meier curves depicting (A) a composite rate of all-cause mortality, all stroke, and myocardial infarction (MI); (B) all-cause
mortality; (C) composite rate of all-cause mortality, all stroke, and MI in transcatheter aortic valve replacement (TAVR) and surgical aortic
valve replacement (SAVR) patients with Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) <4%; and (D) composite
rate of all-cause mortality, stroke, and MI in TAVR and SAVR patients with STS-PROM ≥4%.
4 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
Table 1. Clinical Outcomes at 2 Years in the As-Treated Population
No. of Patients With Events (%)*
Characteristic
Transcatheter
Surgical
P Value
11 (8.0)
13 (9.8)
0.54
9 (6.5)
12 (9.1)
0.40
13 (9.7)
10 (7.8)
0.67
Stroke
5 (3.6)
7 (5.4)
0.46
Transient ischemic attack
8 (6.0)
4 (3.3)
0.30
Myocardial infarction
7 (5.1)
8 (6.0)
0.69
New-onset or worsening atrial fibrillation
32 (22.7)
80 (60.2)
<0.001
Permanent pacemaker implantation
55 (41.3)
5 (4.2)
<0.001
All-cause death
Cardiovascular death
Neurological events
*Percentages are Kaplan–Meier rates. P values were calculated from log-rank tests.
All-Cause Mortality, Stroke, or Myocardial
Infarction at 2 Years
The primary outcome measure, a composite of all-cause
mortality, stroke, or myocardial infarction at 1 year, was not
statistically different between TAVR and SAVR.16 After 2
years, TAVR and SAVR patients had a similar composite outcome (15.8% versus 18.8%; P=0.43; Figure 2). Rates of each
P = 0.99
100%
80%
Percentage of Patients
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(Figure 1). Patient characteristics have been described previously.16 Briefly, TAVR patients were slightly younger than
the traditional TAVR patient (mean age, 79.1±4.8 years) and
more commonly male (53.2%). The overall mean Society of
Thoracic Surgeons Predicted Risk of Mortality (STS-PROM)
score was 3.0±1.7%, and the mean logEuroSCORE I was
8.6±4.8%. At 2 years post procedure, 94.6% of TAVR patients
and 95.8% of SAVR patients had completed the follow-up.
1.4%
3.0%
P = 0.23
3.5%
5.2%
25.9%
20.9%
individual component of the composite outcome were also not
statistically different between the groups (Table 1). Between
1 and 2 years, 4 deaths occurred in the TAVR group and 3 in
the SAVR group, but the overall mortality (8.0% versus 9.8%;
P=0.54) as well as cardiovascular mortality (6.5% versus
9.1%; P=0.40) remained low at 2 years (Table 1). There were
2 additional strokes between 1 and 2 years of follow-up—1 in
the TAVR group and 1 in the SAVR group—resulting in low
2-year stroke rates (3.6% versus 5.4%; P=0.46). Between 1
and 2 years, 2 additional TAVR patients experienced a myocardial infarction, resulting in a 2-year rate comparable with
that of the SAVR group (5.1% versus 6.0%; P=0.69).
Secondary Clinical Outcomes at 2 Years
Additional secondary outcomes are presented in Table 1.
Cumulative rates of new-onset or worsening atrial fibrillation
P = 0.01
3.0%
P = 0.44
3.3%
3.5%
15.0%
29.5%
27.2%
32.5%
42.1%
46.1%
3.3%
60%
40%
68.9%
47.5%
52.6%
5.0%
2.3%
SAVR
(n=133)
75.7%
81.7%
67.4%
69.3%
64.2%
20%
0%
TAVR
(n=141)
Baseline
TAVR
(n=135)
SAVR
(n=115)
TAVR
(n=132)
3 Months
NYHA I
NYHA II
SAVR
(n=120)
1 Year
NYHA III
TAVR
(n=123)
SAVR
(n=114)
2 Years
NYHA IV
Figure 3. New York Heart Association (NYHA) class over time. SAVR indicates surgical aortic valve replacement; and TAVR, transcatheter
aortic valve replacement.
5 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
remained significantly lower in the TAVR group compared
with the SAVR group (22.7% versus 60.2%; P<0.001),
whereas the pacemaker implantation rate remained higher in
the TAVR group (41.3% versus 4.2%; P<0.001). Four new
permanent pacemaker implantations occurred between 1 and
2 years in the TAVR group, all in patients who developed
third-degree atrioventricular block. There were no aortic valve
prosthesis reinterventions in either group.
Functional Status
Echocardiographic Outcomes
Echocardiographic measurements are summarized in Figure 4. Aortic valve performance, as measured by mean aortic valve gradient and effective orifice area, improved after
both TAVR and SAVR (Figure 4). Furthermore, effective
A
Effective Orifice Area (cm2)
2.5
2.0
50
1.7
43.4
1.6
EOA Change From Baseline
1.4
1.3
12.2
12.5
8.3
8.6
0.7
30
20
0.7
Baseline
P < 0.001
3 Months
P < 0.001
1.2
1.0
0.8
0.6
0.4
0.2
3 Months
1.3
40
1.0
1.4
0.0
1.7
1.5
1 Year
C
Mean Gradient Change From Baseline
P < 0.001
60
SAVR
44.9
0.0
1.6
Subgroup analyses of all-cause mortality at 2 years were performed to determine the relationship between several baseline
characteristics and all-cause mortality at 2 years by the treatment group (Table 2). A statistically significant interaction
was observed for medically treated hypertension but no other
characteristics. A post hoc analysis of mortality stratified by
TAVR
0.5
B
Subgroup Analyses of Mortality
1 Year
TAVR
SAVR
2 Years
0
Mean Gradient (mmHg)
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Both patients in the TAVR and SAVR groups experienced significant improvements in NYHA functional class that were
sustained over time (Figure 3). No patients were in NYHA
class IV at 2 years. At 1 year, symptomatic dyspnea was more
common in the TAVR group because of a higher number of
patients in NYHA class II. However, at 2 years this difference
was no longer present because more patients in the SAVR
group changed from NYHA class I to II (Figure 3).
orifice area significantly improved more after TAVR compared with SAVR at each time point (P<0.001), including at
2 years (Figure 4B). Improvements in mean valve gradient
from baseline were not statistically different between TAVR
and SAVR (Figure 4C). Total aortic regurgitation (AR) was
higher in the TAVR group at each time point compared with
SAVR, including at 2 years (moderate/severe AR, 15.4%
versus 0.9%, P<0.001; Figure 5). These findings were comparable when using paired data at all follow-up time points
(moderate/severe AR, 15.0% versus 1.0%, P<0.001). In addition, paired data showed that the percentage of patients with
mild AR decreased from 61.9% at 3 months to 54.9% at 1
year and 38.9% at 2 years. Moderate AR did not change over
time, but none/trace increased from 22.1% at 3 months to
29.2% at 1 year and to 46.0% at 2 years, suggesting improvements over time.
13.0
9.0
2 Years
10
0
3 Months
1 Year
2 Years
-10
-20
-30
-40
-50
-60
TAVR
SAVR
Figure 4. Aortic valve hemodynamics to 2 years. Effective orifice area (EOA) and mean gradient over time (A), EOA change from baseline
(B), and mean gradient change from baseline (C). In (A), P<0.001 between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) at 3 months, 1 year, and 2 years for both EOA and mean gradient. Error bars in B and C represent SDs.
6 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
P < 0.001
100%
0.8%
P < 0.001
1.8%
14.5%
19.8%
0.8%
0.9%
14.9%
16.8%
P < 0.001
0.9%
15.4%
15.2%
Percentage of Patients
80%
39.0%
60%
55.4%
61.3%
40%
83.9%
82.3%
78.4%
45.5%
20%
28.9%
23.4%
0%
Figure 5. Change in total aortic regurgitation
over time. EOA indicates effective orifice
area; SAVR, surgical aortic valve replacement; and TAVR, transcatheter aortic valve
replacement.
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TAVR
(N=124)
SAVR
(N=111)
TAVR
(N=121)
3 Months
SAVR
(N=113)
TAVR
(N=123)
1 Year
None/Trace
Mild
Moderate
SAVR
(N=112)
2 Years
Severe
permanent pacemaker implantation in TAVR patients revealed
no significant difference in mortality between patients who
received a pacemaker within 30 days after the procedure and
those who did not (P log-rank=0.62). Furthermore, no significant difference in mortality at 2 years according to the
degree of AR at 3 months was demonstrated for the TAVR
group (Figure 6; P log-rank=0.57). Improvement in mild
AR in the TAVR group was statistically significant at 2 years
(P<0.001) but not at 1 year (P=0.17). Among patients with an
STS-PROM <4%, the composite outcome of all-cause mortality, myocardial infarction, or stroke at 2 years was not significantly different between those who underwent TAVR and
those who underwent SAVR (14.7% versus 16.8%; P=0.58;
Figure 2). Similarly, there was no statistically significant difference in the composite outcome between TAVR and SAVR
patients with an STS-PROM ≥4% (21.1% versus 27.1%;
P=0.59; Figure 2).
Discussion
The NOTION trial was the first randomized trial comparing
TAVR and SAVR to include patients at lower surgical risk.16
The outcomes reported here demonstrate comparable safety and
effectiveness of TAVR and SAVR in lower-risk patients at 2 years.
Randomized trials in high-risk patients have reported
similar all-cause mortality rates for TAVR and SAVR after 2
years in patients treated with a balloon-expandable prosthesis (33.9% versus 35.0%, P=0.78)20 and better survival after
TAVR (22.2% versus 28.6%, P<0.05) with the same selfexpandable prosthesis as used in the current trial.21 In this
analysis, the TAVR group had numerically lower-rates than
the SAVR group for all outcomes, yet no statistically significant differences between the groups were observed. The subgroup analysis only demonstrated a nonintuitive statistically
significant interaction between all-cause mortality at 2 years
and medically treated hypertension. Intermediate-risk patients
had a higher-rate of the composite outcome for both TAVR
and SAVR compared with low-risk patients, but there was no
significant difference between the treatment groups, supporting the efficacy and safety of TAVR in low-risk patients.
Prosthesis durability at 2 years remained consistent with
1-year data. At each time point, the TAVR group had significantly more improvement in effective orifice area compared
with the SAVR group. AR continued to be higher in the TAVR
group compared with the SAVR group, with unchanged rates
of moderate/severe AR from 3 months to 2 years. This has
also been demonstrated in other trials randomizing patients
to TAVR or SAVR.14,15 The improvement in mild AR at 2
years is consistent with other data supporting an improvement in the severity of paravalvular regurgitation over time
with a self-expandable bioprosthesis, presumably because of
the ongoing remodeling at the interface of the bioprosthesis
and native annulus,22 as well as neoendothelialization of the
stented region of the bioprosthesis. Other secondary adverse
outcomes remained low in both the groups with no significant differences between TAVR and SAVR, with the exception of the cumulative rate of atrial fibrillation that was higher
in SAVR patients and permanent pacemaker implantation that
was higher in TAVR patients. These outcomes were characteristics of the immediate postprocedural period and rarely lateonset events. At 2 years, no difference in NYHA class was
present in the two. The higher pacemaker rate with TAVR is
in concordance with other studies using first-generation selfexpanding technology TAVR prostheses.
The NOTION trial was designed in 2009 before the
introduction of routine cardiac CT scan to measure the aortic annulus. As a consequence, echocardiography was used
to determine the annulus diameter, which may have led to
prosthetic undersizing in TAVR patients and thus a higher
rate of AR. Although AR has been suggested as a predictor
for increased mortality,23 this could not be demonstrated in
the present trial. However, it is generally accepted that before
introducing TAVR on a more routine basis into younger and
lower-risk patients, the extent of paravalvular leakage needs
7 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
Table 2. Univariate Subgroup Analysis for 2-Year Mortality
No. of Events/No. of Patients (%)*
Subgroup
Transcatheter
Surgical
HR (95% CI)
Age, y
0.93
<75
1/29 (4.2)
1/27 (3.8)
0.88 (0.05–14.04)
≥75
10/113 (9.1)
12/107 (11.4)
0.77 (0.33–1.79)
Male
6/76 (7.9)
7/70 (10.2)
0.76 (0.26–2.26)
Female
5/66 (8.2)
6/64 (9.5)
0.80 (0.24–2.61)
Sex
0.95
BMI
0.91
≤30
10/117 (8.8)
>30
1/25 (4.0)
12/117 (10.4)
0.81 (0.35–1.87)
1/17 (5.9)
0.68 (0.04–10.92)
STS-PROM, %
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<4
≥4
0.92
7/118 (6.2)
8/108 (7.5)
4/24 (16.9)
5/26 (19.4)
0.78 (0.28–2.15)
0.85 (0.23–3.15)
LVEF
≤40%
>40%
1.00
1/9 (12.5)
2/117 (1.7)
0/10 (0.0)
NA
4/104 (3.9)
0.44 (0.08–2.40)
Hypertension
No
Yes
0.01
8/39 (21.3)
3/103 (3.0)
2/31 (6.5)
3.41 (0.72–16.08)
11/103 (10.9)
0.26 (0.07–0.92)
Peripheral
vascular disease
No
Yes
P Value
0.99
10/136 (7.6)
13/125 (10.6)
1/6 (16.7)
0.68 (0.30–1.56)
0/9 (0.0)
NA
Diabetes mellitus
0.98
No
9/118 (7.9)
Yes
2/24 (8.7)
10/106 (9.6)
3/28 (10.9)
0.78 (0.32–1.93)
0.77 (0.13–4.60)
BMI indicates body mass index; CI, confidence interval; HR, hazard ratio; LVEF, left ventricular ejection
fraction; and STS-PROM, Society of Thoracic Surgeons Predicted Risk of Mortality.
*Percentages are Kaplan–Meier rates.
to be comparable with that occurring with surgical prostheses. New data are encouraging because annulus measurement
by CT scan,19–22 optimization of the TAVR procedure, and
improvements in prosthesis design have helped to mitigate
paravalvular leakage24 as well as conduction abnormalities.
Subgroup analyses of all-cause mortality at 2 years were
conducted for several baseline characteristics. However, the
low number of deaths in either group allowed for the testing of
only a small number of characteristics. Similar 2-year mortality
between the groups was consistent across 6 clinical subgroups
except for baseline medically treated hypertension. No differences in antihypertensive medications were found between the
groups, making the significance of this finding uncertain.
Limitations
Since the NOTION trial was an all-comers trial, and all risk
groups were included, the patient population was nonhomogeneous in operative risk. Moderate- and high-risk patients
had higher, although not significantly higher, rates of adverse
outcomes than low-risk patients. Because patients with significant concomitant coronary artery disease were excluded
from the NOTION trial, outcomes in those patients cannot be
extrapolated from this trial. The observed rate for the composite outcome in the TAVR group was higher than expected. The
study is not powered to definitively demonstrate a potential
significant difference between the 2 groups, and it is not powered for subgroup analysis. An independent echocardiographic
core laboratory was not used, which may limit the conclusions
that can be drawn from the AR findings. Finally, formal neurological assessments were not performed in all patients, so more
subtle neurological symptoms may not have been captured.
Conclusions
The NOTION trial was the first to randomize all-comers and
lower-risk patients to TAVR or SAVR. The 2-year results
presented here demonstrate the continuing safety and effectiveness of the TAVR procedure in these patients, but with
continued differences in AR, pacemaker implantation, and
8 Søndergaard et al TAVR vs SAVR 2-Year Outcomes
50%
None/Trace
All-Cause Mortality (%)
40%
Mild
Moderate/Severe
P-value (Log-rank) = 0.57
30%
20%
5.3%
3.4%
10%
0%
0.0%
0
6
12
Months Post-Procedure
18
24
5.3%
[0.0%, 15.3%]
3.4%
[0.0%, 10.1%]
1.6%
[0.0%, 4.7%]
No. at risk:
Downloaded from http://circinterventions.ahajournals.org/ by guest on July 31, 2017
29
29
28
28
16
76
76
75
74
45
19
19
19
18
8
Figure 6. All-cause mortality among patients who received transcatheter aortic valve replacement according to degree of aortic regurgitation (none/trace, mild, and moderate/severe) measured at 3 months post procedure.
atrial fibrillation. Longer-term follow-up is needed to ascertain the durability of TAVR in patients with lower surgical risk
and thus longer life expectancy.
Acknowledgments
We thank research nurses Line M. Kristensen, Lisette L. Larsen, Ane
L. Johansen, Ida Rosenlund, and Eva-Lena Pommer; senior medical
writer Jessica Dries-Devlin, PhD, Medtronic; and all patients participating in the trial.
Sources of Funding
This work was supported by the Danish Heart Foundation (grant
numbers: 09-10-AR76-A2733-25400, 12-04-R90-A3879-22733, and
13-04-R94-A4473-22762). Statistical analyses for this report were
conducted by a Medtronic statistician.
Disclosures
Dr Søndergaard is a proctor for Medtronic. Drs Steinbrüchel, P.S.
Olsen, Søndergaard, and Clemmensen have been involved in research
contracts with Medtronic. Drs Franzen, P.S. Olsen, and Søndergaard
have been involved in research contracts with St. Jude Medical. Drs
Ihlemann, Clemmensen, and Søndergaard have received speakers
fee from Medtronic. Dr Clemmensen has received grants and fees
from Eli-Lilly, Daichii-Sankyo, AstraZeneca, Bayer, BoehringerIngelheim, Sanofi, Pfizer, and BMS. Dr Ihlemann reports speaker
fees outside the submitted work. Dr Kjeldsen reports proctoring fees
from Edwards Lifesciences. Dr Nissen reports grants from Danish
Heart Foundation during the conduct of the study. Dr Franzen reports
consulting fees from Edwards Lifesciences. Y. Chang is an employee
of Medtronic. The other authors report no conflicts.
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Two-Year Outcomes in Patients With Severe Aortic Valve Stenosis Randomized to
Transcatheter Versus Surgical Aortic Valve Replacement: The All-Comers Nordic Aortic
Valve Intervention Randomized Clinical Trial
Lars Søndergaard, Daniel Andreas Steinbrüchel, Nikolaj Ihlemann, Henrik Nissen, Bo Juel
Kjeldsen, Petur Petursson, Anh Thuc Ngo, Niels Thue Olsen, Yanping Chang, Olaf Walter
Franzen, Thomas Engstrøm, Peter Clemmensen, Peter Skov Olsen and Hans Gustav Hørsted
Thyregod
Circ Cardiovasc Interv. 2016;9:
doi: 10.1161/CIRCINTERVENTIONS.115.003665
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