Coronary

Coronary Collateral
Collateral Function
Function Long
Long After
After Drug-
Drug-
Eluting
Eluting Stent
Stent Implantation
Implantation

Coronary Collateral Function Long After

Drug-Eluting Stent Implantation

Pascal Meier, M.D.; Rainer Zbinden, M.D.; Mario Togni, M.D.;

Peter Wenaweser, M.D.; Stephan Windecker, M.D.;
Bernhard Meier, M.D., F.A.C.C., F.E.S.C.;
and Christian Seiler, M.D., F.A.C.C., F.E.S.C

Published in JACC
January 2, 2007
Clinical Trial Results . org
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation : Background

• Drug-eluting stents (DES) have been

demonstrated to decrease restenosis rates
compared to bare-metal stents (BMS) and have
diminished re-intervention rates.
• However, DES may have a heightened risk of late
stent thrombosis and impairment of endothelial-
dependent vasomotion.

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Background

• Togni et al. and Hofma et al. respectively described

flow-induced (physical exercise) acetylcholine-induced
endothelial dysfunction in only 3 of 16 patients
following BMS implantation but in the vast majority (18
or 21) patients after DES implantation. Considering
that endothelial dysfunction can be regarded as the
earliest stage of atherosclerosis, and its presence
predicts adverse cardiovascular events, an
unfavorable clinical impact related to DES could be
hypothesized.

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation : Background (cont.)

• In addition, DES have an inhibitory effect on the

production of cytokines, chemotactic proteins, and
growth factors, and thus may negatively affect
coronary collateral growth.
• Therefore, this study was designed to
quantitatively compare coronary collateral flow in
patients six months after BMS or DES implantation.

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Rise in Biomarkers by Use of Stent Type

Rise in CRP
After PCI • In a recent study by Gibson et al, drug-
4 eluting stent use was associated with
p=0.006 3.5 reductions in peri-procedural markers of
inflammation.
• PCI results in the upregulation of
CRP Rise post PCI (mg/L)

3 IQ 0.8, 11.1
inflammatory cytokine production within
the vessel wall which in turn results in the
2.1 activation of inflammatory cells.
2 • Intereleukin-6 (IL-6) is a major stimulus
of CRP production and local release of IL-
IQ 0.5, 6.5
6 release from the epicardial artery or
myocardium in response to PCI could
1
result in an increase in CRP production by
the liver.
N=612 N=129 • Sirolimus reduces both inflammatory
0 cytokine production and adhesion
molecule expression by the endothelium
Drug-Eluting Bare Metal
in response to inflammatory stimuli.
stimuli
Stent Stent

Gibson CM et al, Am J Cardiol. 2006; 97(10):1473-7.

Clinical Trial Results . org
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation : Study Design

120
120 patients
patients 60
60++10
10 yrs
yrs old
old with
with 1-
1- to
to 3-vessel
3-vessel long-term
long-term stable
stable coronary
coronary artery
artery
disease
disease (CAD)
(CAD) after
after stent
stent implantation
implantation
but
but excluding
excluding those
those with
with previous
previous Q-wave
Q-wave infarction,
infarction, baseline
baseline ECG
ECG ST-segment
ST-segment abnormalities,
abnormalities,
and
and non-stable
non-stable CAD
CAD

BMS
BMS DES
DES
Matched
Matched for:
for: Matched
Matched for:
for:
1)
1) stenosis
stenosis severity
severity of
of the
the vessel
vessel 1)
1) stenosis
stenosis severity
severity of
of the
the vessel
vessel
undergoing
undergoing collateral
collateral flow
flow index
index undergoing
undergoing collateral
collateral flow
flow index
index
(CFI)
(CFI) measurement
measurement at at baseline
baseline && (CFI)
(CFI) measurement
measurement at at baseline
baseline &&
2)
2) for
for the
the duration
duration of
of follow-up
follow-up 2)
2) for
for the
the duration
duration of
of follow-up
follow-up
n=60
n=60 n=60
n=60

6 mos. follow-up



Primary
Primary Endpoint:
Endpoint: Invasively
Invasively determined
determined coronary
coronary collateral
collateral function
Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Baseline Characteristics

Characteristic BMS DES p value

Age (yrsSD) 5910 6113 0.21

Male gender 51 50 1.0

Duration of Chest 1.22.2 1.42.5 0.63

Pain (months)
Positive treadmill 26 28 0.82
exercise ECG
BMI 283 3021 0.21

Smoking 20 19 0.85

Hypercholesterolemia 40 44 0.70

Hypertension 34 34 0.99

Obesity 21 26 0.23

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Baseline Characteristics (cont.)
Characteristic BMS DES p value
Family History of CAD 16 17 0.45

Diabetes mellitus 8 4 0.24

Acetylsalicylic acid 56 56 1.0

Beta-blockers 45 52 0.17

Calcium antagonists 12 11 0.92

Nitrates 16 14 0.77
Angiotensin-converting 19 21 0.88
enzyme inhibitor
Statin 45 46 0.92
Diuretics 9 11 0.65

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary
Coronary Collateral
Collateral Function
Function Long
Long After
After Drug-Eluting
Drug-Eluting Stent
Stent
Implantation:
Implantation: Primary
Primary Endpoint
Endpoint

• Despite equal in-

p =0.0049
stent stenosis
0.224 ± 0.142
Coll. Flow Index Endpoint

0.4
0.4 severity and equal
follow-up duration
0.154 ± 0.097 for both groups,
0.3
0.3 collateral flow
index (CFI) was
0.2 diminished in the
0.2
DES versus BMS
group.
0.1
0.1

00
DES
DES BMS
BMS

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary
Coronary Collateral
Collateral Function
Function Long
Long After
After Drug-Eluting
Drug-Eluting Stent
Stent
Implantation:
Implantation: Primary
Primary Endpoint
Endpoint

p =0.001 • In addition, the

100%
100% rate of collaterals
83.3%
83.3%
Insufficient collateral flow

insufficient to
80%
80% prevent ischemia
during occlusion
was higher in the
60%
60% 55.0%
55.0%
DES group than in
the BMS group.
40%
40%

20%
20%
n=50 n=33
0%
0%
DES
DES BMS
BMS

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Limitations

• This study was a cross-sectional rather than longitudinal

observation of collateral function.
• The ideal study design would have been a randomized
group allocation with baseline and follow-up CFI
measurement allowing intra- and inter-group
comparisons; however, the ethics of such a design would
have been questionable.
• The quality of matching was not absolute; however, it was
so high that, statistically, an influence of stenosis severity
and/or follow-up duration on the study’s main outcome
can be excluded.

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Summary

• The novel result of this study is that coronary

collateral function 6 months after implantation
of a DES is 30% to 40% lower than that
obtained equally long after BMS implantation.
Considering the salvaging effect of well-grown
collaterals, a potential clinical impact of this
finding is that in the presence of stent
thrombosis, myocardial infarct size and
potentially mortality may be larger in DES- than
in BMS-treated patients.
Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.
 Coronary Collateral Function Long After Drug-Eluting
Stent Implantation: Summary (cont.)

• Furthermore, an additional clinical risk could arise from

endothelial dysfunction and a deficit of endothelial progenitor
cells.

• In support of this notion, 6-month mortality after BMS stent

thrombosis has been found to amount to 11% (10 of 95 stent
thromboses in 6,058 patients) to 21% (11 of 53 stent
thromboses in 6,219 patients), whereas that after DES-stent
thrombosis has been 29% (2 of 7 stent thromboses in 2,006
patients) to 45% (13 of 29 stent thromboses in 2,229 patients).

Clinical Trial Results . org Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.