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Increased Late Mortality
After Sirolimus-Eluting Stents Versus Bare Metal Stents
in Diseased Saphenous Vein Grafts:
Results from the Randomized DELAYED RRISC Trial
Pierfrancesco Agostoni, MD
On behalf of the DELAYED-RRISC (Death and Events at Long-term
follow up AnalYsis: Extended Duration of the Reduction of Restenosis
In Saphenous vein grafts with Cypher stent) Investigators
Antwerp Cardiovascular Institute Middelheim
Antwerp, Belgium
RRISC Trial
Reduction of Restenosis In
Saphenous vein grafts with Cypher stent
•
Prospective, randomized, double-blind, non
industry sponsored, single center, trial
comparing SES vs. BMS in SVG lesions
•
75 patients with 96 lesions localized in
80 diseased SVG were included
•
Enrollment: September 2003-November 2004
•
Primary endpoint : 6-month in-stent late loss
•
Secondary endpoints (all at 6 months follow up):
–
Binary angiographic restenosis (in-stent/in-segment)
–
Clinical events (death, MI, TLR, TVR)
Vermeersch, Agostoni et al. JACC 2006
RRISC Trial
Reduction of Restenosis In
Saphenous vein grafts with Cypher stent
Major Inclusion Criteria
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•
•
•
De novo lesion (stenosis >50%) in a diseased SVG
Diameter ranging between 2.5 and 4.0 mm
Diagnosis of angina pectoris
Osial stenoses & thrombotic/calcific stenoses were allowed
No maximum lesion length prespecified
Major Exclusion Criteria
•
•
•
•
•
•
•
•
Impaired renal function
Prior stent within 5 mm of target lesion
Totally occluded vein grafts
Documented LV Ejection Fraction <25%
Distal anastomotic stenosis
Prior brachytherapy in the index vessel
Recent MI (<7 days)
Vermeersch, Agostoni et al. JACC 2006
204 patients screened
(September 2003-November 2004)
Patients excluded (reason):
2 patients (age >85 years)
18 patients (acute MI)
7 patients (MI within the last 7 days)
3 patients (creatinine >3 mg/dL)
40 patients (vein graft with RVD >4.0 mm)
12 patients (distal anastomotic disease)
38 patients (restenotic lesions)
8 patients (enrolled in other trials)
1 patient (no informed consent)
75 patients (with 96 lesions)
meeting the inclusion criteria
randomization
37 patients (49 lesions)
randomized to BMS
38 patients (47 lesions)
randomized to SES
1 patient died
2 patients refused angio follow up
37 patients (49 lesions)
available for 6-month
angiographic follow up
35 patients (44 lesions)
available for 6-month
angiographic follow up
No patient was lost to follow up. All patients, but 1 (dead)
available for 6-month clinical follow up.
Vermeersch, Agostoni et al. JACC 2006
Baseline characteristics
BMS
(n=37)
SES
(n=38)
Pvalue
72 ± 8
73 ± 7
0.36
Men
33 (89%)
31 (82%)
0.36
Family history
29 (78%)
25 (66%)
0.23
Hypertension
21 (57%)
22 (58%)
0.84
Hypercholesterolemia
31 (84%)
33 (87%)
0.74
Current smoker
4 (11%)
2 (5%)
0.46
Diabetes Mellitus
5 (14%)
6 (16%)
0.78
26.4 ± 3.9
26.4 ± 3.1
0.97
7 (19%)
6 (16%)
0.72
Prior myocardial infarction
15 (41%)
17 (45%)
0.71
Prior coronary angioplasty
15 (41%)
12 (32%)
0.42
Unstable angina pectoris
19 (51%)
23 (60%)
0.41
72 ± 12
68 ± 18
0.37
12.6 ± 5.9
12.4 ± 4.6
0.92
Age (years)
Body mass index (Kg/m2)
History of heart failure
Ejection Fraction (%)
Age of the grafts (years)
Vermeersch, Agostoni et al. JACC 2006
Degenerated saphenous vein grafts
BMS
(lesions=49)
SES
(lesions=47)
Pvalue
17 (41.5%)
19 (48.7%)
0.51
Recipient native vessel territory
Left anterior descending/diagonal
0.11
6 (12.2%)
9 (19.2%)
Circumflex/obtuse marginal
26 (53.1%)
15 (31.9%)
Right coronary artery
17 (34.7%)
23 (48.9%)
12 (24.5%)
17 (36.2%)
0.21
Moderately/heavily calcified lesions
9 (18.4%)
8 (17%)
0.86
Number of stents per patient
1.46 ± 0.7
1.58 ± 0.7
0.45
Number of stents per lesion
1.11 ± 0.3
1.28 ± 0.5
0.14
Total stent length per patient (mm)
33.4 ± 18.2
36.9 ± 17.6
0.39
Total stent length per lesion (mm)
25.2 ± 11.9
29.9 ± 15.6
0.11
Stent diameter (mm)
3.36 ± 0.26
3.41 ± 0.19
0.72
Successful direct stenting
44 (89.8%)
44 (93.6%)
0.50
7 (14.3%)
14 (29.8%)
0.09
Maximal balloon diameter (mm)
3.44 ± 0.38
3.56 ± 0.37
0.09
Maximal inflation pressure (atm)
18.8 ± 2.2
18.7 ± 2.8
0.85
Angiographic evidence/suspect of thrombus
Post-dilatation
Vermeersch, Agostoni et al. JACC 2006
Late Loss Analysis
p=0.01
p=0.001
1.00
BMS
SES
0.80
0.60
p=0.6
p=0.9
0.40
0.20
0.17
0.17
Prox edge
0.79
0.38
In-stent
0.24
0.19
Dist edge
0.70
0.41
In-segment
Vermeersch, Agostoni et al. JACC 2006
Binary Restenosis
40
p=0.031
p=0.024
BMS
SES
30
AD=19.2%
RRR=0.63
20
AD=19.1%
RRR=0.58
10
30.6%
11.4%
In-stent
32.7%
13.6%
In-segment
Vermeersch, Agostoni et al. JACC 2006
6-month MACE
- Due to safety issues recently raised with DES
(ESC/WCC 2006), we decided to further follow up
BMS
SES
our patients, in order to analyze long-term events.
P value
n=37
n=38
In-hospital
-In September 2006, a new approval was obtained
0 to extend 0the follow-up.
fromDeath
the local Ethics Committee
Repeat revascularization
0
0
(2.7%)
2 (5.3%)
-A newPeriprocedural
informed MI
consent was1obtained
from
Between
and 6 months
all thedischarge
patients.
Death
0
1 (2.6%)
-All patients
were
contacted between
September
Myocardial
infarction
0
1 (2.6%)
and December
2006 (no lost
to follow up).
TLR (per-patient)
8 (21.6%)
2 (5.3%)
TVR (per-patient)
10 (27%)
2 (5.3%)
-Blinding was maintained for patients and
referring
physicians/cardiologists.
Cumulative
6-month
MACE
11 (29.7%)
6 (15.8%)
0.99
0.99
0.99
0.047
0.012
0.15
Vermeersch, Agostoni et al. JACC 2006
MACE after 6-month
up to 32 months (median f.u.)
BMS
n=37
SES
n=38
P value
0
10 (26.3%)
0.001
Myocardial infarction
1 (2.7%)
4 (10.5%)
0.35
TLR
3 (8.1%)
7 (18.4%)
0.30
TVR
4 (10.8%)
11 (28.9%)
0.05
Death
Kaplan-Meyer Curves
Cumulative MACE
BMS
n=37
SES
n=38
P value
0
11 (28.9%)
<0.001
2 (5.4%)
7 (18.4%)
0.15
TLR
11 (29.7%)
9 (23.7%)
0.55
TVR
14 (37.8%)
13 (34.2%)
0.74
MACE
15 (40.5%)
22 (57.9%)
0.13
Other PCI (not TLR/TVR)
14 (37.8%)
12 (31.6%)
0.57
Double anti-platelet therapy
19 (51.4%)
19 (50%)
0.91
Single anti-platelet therapy
14 (37.8%)
15 (39.5%)
0.88
No anti-platelet therapy
4 (10.8%)
4 (10.5%)
0.97
Statin therapy
27 (73%)
29 (76.5%)
0.74
Death
Myocardial infarction
Stent Thrombosis
(ARC criteria)
BMS
n=37
SES
n=38
Definite
0
2 (5.2%)
Probable
0
0
Possible
0
3 (7.9%)
Total
0
1 fatal at 13 months
1 non fatal at 30 months
1 sudden death at 7.5 months
1 sudden death at 11.5 months
1 sudden death at 35 months
5 (13.1%)
P value
0.49
0.30
0.054 Fisher Exact
0.022 Log Rank
Causes of Death
Time
Cause of death
Anti-thrombotic therapy
5 months
progressive heart failure
TP
7.5 months
sudden out-of-hospital death
TP, W
11.5 months
sudden out-of-hospital death
ASA, TP
14.5 months
progressive heart failure after MI due to
thrombosis of the index stent
(suspended 1 week before MI for knee surgery)
16 months
metastatic urothelial carcinoma
(stop 1 month before for severe anemia)
19 months
metastatic colon carcinoma
(stop 2 months before for anorexia)
22 months
progressive MOF after peri-operative (limb ischemia) MI
(no stent thrombosis of the stent)
(suspended 1 week before MI for AICD change)
23.5 months
post-operative (AVR and ReDo CABG
for progression of CAD) infection
ASA, TP
30 months
progressive Parkinson disease
ASA, TP
33 months
progressive MOF after ReDo CABG
(documented in-stent restenosis)
ASA, TP
35 months
sudden out-of-hospital death
ASA, TP
Conclusions
The use of BMS was associated with
lower long-term mortality than the use of
SES for SVG disease.
•
• Also the 6-month reduction in repeated
revascularization procedures shown with
the use of SES was lost at longer-term
follow-up.
Did
David (BMS)
defeat
Goliath (SES)
???
Caravaggio, David with the head of Goliath, 1610
However...
Secondary post-hoc
analysis
“Chance”
could have played
a major role
Hieronymus Bosch, The magician, 1475-80
Moreover...
The sample size
was small, thus prone
to type I and II
statistical errors
Caspar David Friedrich, The wanderer above the sea of fog, 1818
Thus...
Additional larger
studies
are needed to finally
determine if SES
are really harmful
in SVG
Vittore Carpaccio, St.Agostino in his studio, 1502
DELAYED-RRISC Investigators
Steering Committee:
Pierfrancesco Agostoni, MD
Paul Vermeersch, MD
Other Investigators:
Stefan Verheye, MD, PhD
Glenn Van Langenhove, MD, PhD
Frank Van den Branden, MD
Paul Van den Heuvel, MD
Carl Convens, MD
Data Monitoring:
Christine Jacobs, RN
Nancy Aerts, RN
Anne-Rose Gustin
(Incubate, Cardiac Solutions)
CEC Committee:
Giuseppe M. Sangiorgi, MD
Giuseppe G.L. Biondi-Zoccai, MD
Statistical Analysis:
Pierfrancesco Agostoni, MD
For further slides on these topics please feel
free to visit the metcardio.org website:
http://www.metcardio.org/slides.html