Abbott Absorb GT1 Bioresorbable Vascular Scaffold System Manual page 6

12 Months 2 years 3 years
Hierarchical 6 Months
Rates (N = 30) (N = 29) (N = 29) (N = 29)
† †
Non-Q-
3.3 (1)* 3.4 (1)* 3.4 (1)* 3.4 (1)*
Wave MI
Ischemia-
0 0 0
driven TLR, %
by PCI 0 0 0
by CABG 0 0 0
Ischemia-
driven MACE
(cardiac
death, MI or 3.3 (1)* 3.4 (1)* 3.4 (1)* 3.4 (1)*
ischemia-
driven TLR),
% (n)
Scaffold
0 0 0
thrombosis, %
Notes:
• Denominator excludes subjects without follow-up data and who didn't experience any of
the following events: Death, MI, any revascularization (TLR, TVR, NTVR).
† One subject officially withdrew from the study after 6 months.
* This subject also underwent a TLR, not qualified as ID-TLR (DS = 42%) followed by
post-procedural troponin elevation qualified as non-Q MI and died from his Hodgkin's
disease at 888 days post-procedure.
8.2.3 Angiographic, IVUS, and OCT Outcomes at 180 Days and 2 Years
QCA results were collected from baseline, post-procedure, 180 days, and 2 years. The
180-day data demonstrated an acceptable in-scaffold late loss of 0.43 ±0.37 mm possibly
driven by bioactive remodeling or mechanical late recoil. From 180 days to 2 years, the
change in in-scaffold late loss was very low (0.48 ±0.28 mm).
The 180-day grey-scale intravascular ultrasound (IVUS) analysis showed a significant
reduction in the average lumen area (6.04 ±1.12 mm after procedure vs. 5.19 ±1.33 mm
2
at 180-day, p < 0.001). The vessel area remained constant between baseline and 180-
day follow-up (13.49 ±3.74 mm vs. 13.79 ±3.84 mm ), demonstrating the absence of
2 2
significant expansive or constrictive remodeling. At 2 years, the main observation provided
by grey-scale IVUS was the increase in minimal luminal area and average luminal area /
volume together with a significant decrease in plaque area / volume between 6 months and
2 years.
The 180-day OCT group (N = 13) provided a total of 671 apparent struts for visual
evaluation, which showed that 93% of struts evaluated were well apposed to the vessel wall,
and 99% of the struts were covered by tissue. The serial OCT group (N = 7) had serial data
post-procedure at 180 days and at 2 years (intention-to-treat population). The number of
apparent struts decreased from 403 at baseline to 368 at 180 days and to 264 at the 2-year
follow-up (34.5% reduction over two years), all well covered and apposed to the vessel wall.
Preclinical analysis directly comparing pre-explantation OCT to post-explantation histology
indicates there is no correlation between the presence or absence of OCT-visible features
(apparent struts) and the presence or absence of polylactide polymer in the vessel. Hence,
visual OCT features (apparent struts) are not always indicative of lack of resorption, but
absence of the apparent struts by OCT confirms resorption. The lumen shape was regular
with smooth, well-delineated borders in all cases, and no intraluminal tissue was observed.
Importantly, minimal and mean luminal area decreased significantly between post-procedure
and 180 days, but numerically enlarged between 180 days and 2 years.
8.2.4 Vasomotor Function Results at 2 Years
Vasomotor function proximal, within, and distal to the treated (scaffolded) segments
at 2 years was evaluated with either the endothelium-independent vasoconstrictive
methylergonovine maleate (Methergine, Novartis, Basel, Switzerland), or the endothelium-
dependent vasoactive agent acetylcholine (Ovisot, Daiichi-Sankyo, Tokyo, Japan), depending
on local practice.
In the methergine group (N = 7), significant vasoconstriction was observed in proximal and
scaffolded segments (Figure 1). In the acetylcholine group (N = 9), although the overall
change in vessel dimension was not statistically significant, vasodilatation was observed
in five patients. Nitrates induced a significant vasodilatation in the scaffolded and distal
segments, relative to baseline (pre-acetylcholine) at 2 years. These results suggest the
potential restoration of vasomotor function in the treated segments when the Absorb Cohort
A BVS had resorbed. Further data on vascular responses will be collected from ongoing
clinical trials.
Paired comparisons between the different time points were done by a Wilcoxon's signed rank
test for continuous variables.
Figure 1: Results of Acetylcholine and Methergine Testing in Proximal, Scaffolded, and
Distal Segments
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8.2.5 Discussion
4 years 5 years
In this prospective, single-group, open-label study, the Absorb BVS demonstrated acute
(N = 29) (N = 29)
† † †
success and safety following the first 30 days after implantation: 100% procedure success;
94% device success; and successful revascularization of the target lesion evident from
3.4 (1)* 3.4 (1)*
post-procedure angiographic and IVUS analyses. The excellent clinical safety persists
through 5 years with no cardiac deaths, no ID-TLRs or scaffold thrombosis recorded, and
0 0 0
only one non-Q-wave MI by 5 years. Despite the discontinuation of thienopyridine drugs, no
scaffold thrombosis occurred, and no additional ischemia-driven target lesion restenosis was
0 0 0
evident by 5 years.
The use of multiple imaging modalities yielded several important findings. At 180 days,
0 0 0
an acceptable angiographic in-scaffold late loss of 0.43 mm was seen; this was higher
than previously observed in XIENCE V at 6 months (SPIRIT FIRST), and possibly driven by
bioactive remodeling or mechanical late recoil. The IVUS results showed low intrascaffold
neointimal hyperplasia: 5.32% in-scaffold volume obstruction, 4.09 mm
3.4 (1)* 3.4 (1)*
neointimal volume. This confirmed a positive drug effect in inhibiting restenosis.
At 2 years, angiographic results showed an acceptable 2-year in-scaffold late loss of
0.48 mm with minimal changes from 6 months (0.43 mm) to 2 years. By contrast, both
the IVUS and OCT data showed late luminal enlargement from 6 months to 2 years.
The contrasting findings in late lumen dimensional changes between angiography and
0 0 0
intracoronary imaging await confirmation in future clinical studies.
At 2 years, reduction in molecular weight and mass had occurred to such an extent
that echogenicity was lost and that struts were no longer recognizable by intravascular
ultrasound, leaving behind few IVUS-visible features. OCT-visible features related to
vessel healing were present in some patients. In these patients, OCT showed an optically
homogeneous vessel wall structure that, taken together with the potential restoration of
vessel movement, suggests healing of the artery.
8.3 ABSORB Cohort B
8.3.1 Methodology and Current Status
Based upon the strong safety profile observed for the Absorb Cohort A BVS System in
Cohort A, Cohort B of the ABSORB trial was initiated on March 19, 2009 to evaluate the
Absorb BVS System in a prospective, open-label, multicenter registry. Subjects with up
to two de novo native coronary artery lesions in separate epicardial vessels with visually
estimated nominal vessel diameters of 3.0 mm and lesion(s) length ≤ 14 mm were enrolled,
and received a single 3.0 x 18 mm Absorb BVS per lesion treated. Twelve clinical sites
2
located in Europe, Australia, and New Zealand participated in this study.
Enrollment of 101 patients (45 patients in Group 1 with imaging follow-up at 180 days
and 2 years, and 56 patients in Group 2 with imaging follow-up at 1 year and 3 years) in
Cohort B was completed on November 6, 2009. Currently, clinical data are available for
post-procedure, 6 months, 9 months, 1 year, 2 years, and 3 years. Additionally, 2-year
angiographic and IVUS results are available for Group 1 subjects, and similar data at 1 year
and 3 years are available for Group 2 subjects. Follow-up is ongoing. Patients will be
followed through 5 years.
8.3.2 Clinical Outcomes for Full Cohort B
Table 5 shows clinical outcomes through 4 years for all subjects in the ABSORB Cohort B
Trial (101 subjects).
Table 5: Hierarchical Clinical Outcomes for Cohort B (ITT Population)
30 Days 6 Months 9 Months 1 year
N = 101 N = 101 N = 101 N = 101 N = 100* N = 100* N = 99**
Cardiac
0
Death, %
MI, % (n) 2.0 (2)
Q-Wave
0
MI
Non-Q-
2.0 (2)
Wave MI
Ischemia-
driven TLR, 0
% (n)
by PCI 0
by CABG 0
Ischemia-
driven MACE,
(cardiac
death, MI or 2.0 (2)
ischemia-
driven TLR),
% (n)
Scaffold
0
thrombosis
(%)
Data are % (number of patients); MACE = (cardiac death, MI or Ischemia-driven TLR)
* One subject was lost to follow-up after the 2-year visit.
** One patient was terminated early having had no safety events, and therefore removed
from the numerator and denominator in the 4 Years column.
For the full Cohort B (101 patients), there were three non-Q-wave MIs that occurred, two
during hospitalization, and one at 43-day post-procedure. Seven ID-TLR by PCI have been
reported through 4 years. The overall MACE rate at 4 years was 10.1% and there have been
no cases of cardiac death or scaffold thrombosis per protocol or per ARC definitions.
The 4-year full Cohort B (101 patients) outcomes are numerically higher than the Cohort
A (30 patients) outcomes at 4 years. The clinical outcomes at 48 months reveal a MACE
rate of 3.4% and 10.1% in the ABSORB Cohort A and full Cohort B groups, respectively.
Furthermore, there were no cases of cardiac death or scaffold thrombosis in either group.
The Cohort B clinical results continue to support the performance and safety established in
the Cohort A investigation.
8.3.3 Angiographic, IVUS, and OCT Outcomes at 180 Days, 1, 2 and 3 Years
The 180-day angiographic results from Cohort B Group 1 (Cohort B1) demonstrated a late
loss of 0.19 mm (N = 42) which compares well to the 0.10 mm late loss (N = 23) of
the 3.0 x 18 mm XIENCE V Everolimus Eluting Coronary Stent System (XIENCE V EECSS)
observed in the SPIRIT FIRST First-In-Man trial, and show favorable improvement from the
0.43 mm late loss (N = 26) from Cohort A.
in-scaffold
3
2 years 3 years 4 years
0 0 0 0 0 0
3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3)
0 0 0 0 0 0
3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3) 3.0 (3)
2.0 (2) 2.0 (2) 4.0 (4) 6.0 (6) 7.0 (7) 7.0 (7)
2.0 (2) 2.0 (2) 4.0 (4) 6.0 (6) 7.0 (7) 7.0 (7)
0 0 0 0 0 0
5.0 (5) 5.0 (5) 6.9 (7) 9.0 (9) 10.0 (10) 10.1 (10)
0 0 0 0 0 0
Printed on : 04/29/2015
At 180 days, the IVUS results from Cohort B1 showed limited intrascaffold neointimal
hyperplasia, the volume obstruction (VO) was 1.2% (N = 40) and the neointimal hyperplasia
area was 0.08 mm (N = 40). These results compare favorably with XIENCE V EECSS in
2
SPIRIT FIRST (VO of 8.0% [N = 21] and NIH area of 0.56 mm
(VO of 5.3% [N = 25] and NIH area of 0.29 mm [N = 25]). As observed in Cohort A,
2
the 6-month IVUS results showed a significant reduction in the average lumen area
(6.60 ±1.22 mm [N = 37] after procedure vs. 6.37 ±1.12 mm
2
p = 0.0048). The vessel area remained comparable between baseline and 180-day follow-up
(14.22 ±3.75 mm [N = 37] vs. 14.49 ±3.67 mm [N = 37]) demonstrating the absence
2 2
of significant expansive or constrictive remodeling.
The 1-year angiographic results from Cohort B Group 2 (Cohort B2) demonstrated a late
loss of 0.27 mm (N = 56) which compares well to the 0.23 mm late loss (N = 22) of the
3.0 x 18 mm XIENCE V observed in the SPIRIT FIRST trial. At 1 year, the IVUS results from
Cohort B2 (N = 54) showed limited intrascaffold neointimal hyperplasia, the percentage
of in-scaffold area obstruction and the neointimal hyperplasia area were minimal (1.43%
and 0.09 mm , respectively). Over time there was a statistically significant but not
2
clinically relevant increase in total plaque area with a concomitant increase in vessel area.
Furthermore, average lumen area remained stable from post-procedure (6.31 ±0.95 mm
to 1 year (6.33 ±1.17 mm ). By OCT, there was no significant change in the mean and
2
minimum scaffold area between post-procedure and 1 year (N = 21). There was a reduction
in minimal lumen area and mean luminal area decreased significantly as a result of mean
neointimal area growth (1.34 ±0.67 mm ) but was not clinically significant. The lumen
2
area stenosis increase was statistically significant from 20.2% post-procedure to 26.9% at
1 year but not clinically relevant. These data further supported that there was no reduction
in scaffold area.
Imaging results at 2 years from Cohort B Group 1 (Cohort B1) demonstrated in-scaffold
angiographic late loss of 0.27 mm (N = 38), which matches the late loss observed at
1 year for Cohort B Group B2 but is lower than the 0.33 mm (N = 83) reported from
XIENCE V in SPIRIT II. The IVUS data at 2 years (N = 33) revealed a finding unique to
Absorb BVS, which is mean scaffold area enlargement between 6 months and 2 years
(6.42 versus 7.08 mm , p < 0.0001). This enlargement was greater than the observed
2
increase in neointimal hyperplasia and was accompanied by late increased mean lumen area
(6.36 versus 6.85 mm , p = 0.0105). IVUS findings were reported with comparative paired
2
(serial) analysis at post-procedure, 6 months, and 2 years. Similarly, OCT data (N = 23)
were reported with paired (serial) analysis, and showed that from 6 months to 2 years the
mean strut core area decreased from 0.20 to 0.15 mm (p < 0.0001), the mean neointimal
2
area increased but remained minimal at 2 years (1.43 versus 2.11 mm
mean lumen area was unchanged. Moreover, the mean scaffold area increased from 7.47
to 8.24 mm (p = 0.0155) from post-procedure to 2 years indicating loss of mechanical
2
integrity of the scaffold and potential expansion of the vessel. Scaffold strut coverage by
neointima was near completed at 6 months (98%) and 2 years (99%).
At 3 years post-procedure, IVUS results from Cohort B Group 2 (Cohort B2, N = 44)
revealed scaffold enlargement (average scaffold area of 6.35 ±0.99 mm
7.08 ±1.55 mm 2 at 3 years, p < 0.0001) and increased average lumen area
(6.35 ±1.17 mm at 1 year vs. 6.81 ±1.62 mm at 3 years, p = 0.0006). The late lumen
2 2
enlargement is of particular interest because the vessel area was preserved (average vessel
area of 14.43 ±2.64 mm at 1 year vs. 14.58 ±2.67 mm at 3 years, p = 0.407) despite
2 2
an increase in neointimal area (0.08 ±0.13 mm at 1 year vs. 0.28 ±0.41 mm
2
p < 0.0001). OCT results at 3 years (N = 18) also revealed scaffold enlargement between
1 and 3 years (mean scaffold area of 7.51 ±0.95 mm at 1 year vs. 8.64 ±2.15 mm
2
years, p = 0.0008). Lumen area remained relatively constant (6.01 ±1.29 mm
vs. 6.09 ±1.67 mm at 3 years, p = 0.679). The vessel area was not measured because
2
OCT cannot demarcate the external elastic lamina. Overall, the neointimal hyperplasia
remained small although there was an increase in neointimal hyperplasia between 1 year
and 3 years (mean neointimal area of 1.41 ±0.68 mm at 1 year vs. 2.35 ±0.68 mm
2
years, p < 0.0001).
8.3.4 Discussion
A total of 101 patients were enrolled with clinical data available out to 4 years for the full
Cohort. In addition, imaging data at 180 days and 2 years are available for the 45 patients
in Cohort B1, and at 1 year and 3 years for the 56 patients in Cohort B2. Overall, the Absorb
BVS System has demonstrated acute success (98% procedure success and 100% device
success) and safety up to 3 years after implantation. At 4 years, the MACE rate remained
low at 3.4% and 10.1% in the ABSORB Cohort A and Cohort B groups, respectively.
Furthermore, there were no cases of cardiac death or scaffold thrombosis in either cohort.
Based on these results, the performance and safety continue to be established in the Cohort
A and Cohort B studies.
Imaging of Cohort B indicated that angiographic late loss appears to stabilize between 1 and
3 years. In Group B1 and Group B2, IVUS results indicate a late expansion of scaffold and
lumen dimensions between 6 months and 2 years, and between 1 and 3 years, respectively,
which was consistent with the scaffold expansion observed by OCT. These results suggest
scaffold bioresorption accompanied by a loss of structural integrity. This phenomenon is
unique to bioresorbable vascular scaffolds and is in contrast with serial IVUS imaging of
metallic DES, where late lumen expansion has not been observed
Patients will be followed through 5 years.
8.4 ABSORB EXTEND
The primary objective of the ABSORB EXTEND study is to continue the assessment of the
safety and performance of the Absorb BVS System in a larger patient population across more
global geographies. This trial collects clinical data without the effects of extensive imaging.
Treated lesions are slightly more complex than those included in prior ABSORB trials. Longer
lesions are permitted by using planned overlap of the Absorb BVS, or by using longer Absorb
BVS sizes as they become available. The following section summarizes the study design and
interim clinical outcomes from the ABSORB EXTEND study.
8.4.1 Methodology and Current Status
ABSORB EXTEND is a prospective, single-arm, open-label clinical study that is planned to
register up to 1,000 subjects at up to 100 global sites. Each subject is to receive treatment
in up to a maximum of two de novo native coronary lesions with each lesion in a different
epicardial vessel. Subjects having target lesion length ≤ 28 mm and reference vessel sizes
that are suitable to be treated with an Absorb BVS can be registered in ABSORB EXTEND.
The 3.0 x 18 mm Absorb BVS has been available from the start of the trial registration. The
3.0 x 28 mm, 2.5 x 18 mm, 2.5 x 28 mm, 3.5 x 12 mm, 3.5 x 18 mm, and 3.5 x 28 mm
have been incorporated into the trial as they became available. Enrollment was completed
in ABSORB EXTEND with 812 patients in October 2013. Patients will be followed for up to
3 years.
Claessen BE, Beijk MA, Legrand V, Ruzyllo W, Manari A, Varenne O, Suttorp MJ, Tijssen
1
JG, Miquel-Hebert K, Veldhof S, Henriques JP, Serruys PW, Piek JJ. Two-year clinical,
angiographic, and intravascular ultrasound follow-up of the XIENCE V everolimus-eluting
stent in the treatment of patients with de novo native coronary artery lesions: the SPIRIT II
trial. Circ Cardiovasc Interv. 2009 Aug;2(4):339-47.
[N = 21]) and with Cohort A
2
[N = 37] at 180-day,
2
)
2
, p < 0.0001) and
2
at 1 year vs.
2
at 3 years,
2
at 3
2
2 at 1 year
at 3
2
. Follow-up is ongoing.
1