Chin Med J 2008;121(17):1670-1674
1670
Original article
Long term efficacy and safety of Chinese made sirolimus eluting
stents: results, including off label usage, from two centres over
three years
ZHANG Qi, XU Bo, YANG Yue-jin, QIAO Shu-bin, ZHANG Rui-yan, ZHANG Jian-sheng, HU Jian,
QIN Xue-wen, CHEN Ji-lin, SHEN Wei-feng and GAO Run-lin
Keywords: coronary artery disease; sirolimus; stent; off label; outcomes
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Background Multiple randomized clinical trials have demonstrated that drug eluting stents can significantly reduce the
rates of restenosis and subsequent adverse events across lesion and patient. We investigated the medium term clinical
efficacy and safety of Firebird sirolimus eluting stent (SES) in coronary artery disease.
Methods The sample was 509 consecutive patients with coronary artery disease (CAD) who were treated by Firebird
SES and finished three-year clinical follow-up. The occurrences of major adverse cardiac events (MACE) and Academic
Research Consortium defined stent thrombosis (ST) were evaluated in patients with and without diabetes mellitus.
Results Three hundred and thirty three patients (65. 4%) were treated by Firebird SES by off label indications.
Angiographic success was achieved in 98.3% of the lesions. MACE and target vessel revascularization rates at 6-month,
1 year’s and 3 years’ clinical follow-up were 2.4% and 1.4%, 4.1% and 2.8%, 7.9% and 5.1%, respectively. The
cumulative 3-year MACE free survival rate was 92.1%. After 3 years, DM patients had significantly higher rates of MACE
(13.7% vs 6.4%, P <0.05) and TVR (9.8% vs 4.0%, P <0.05) and the cumulative MACE free survival rate was very
significantly lower in the DM group (86.4% vs 93.6%, P <0.05). ST occurred in 7 patients (1. 4%) at the end of 3 years’
follow-up, 5 of them had definite ST with 4 cases presenting with myocardial reinfarction and 1 with unstable angina, the
other 2 with probable ST had reinfarction in the stented coronary territory without angiographic follow-up. There was no
difference in occurrence of ST between off label (1.5%) and on label groups (1.1%, P=0.07).
Conclusions In daily practice, about 2/3 of patients were treated by Firebird SES by off label indications. Medium term
clinical follow-up of 3 years indicated CAD patients treated by Firebird SES had a low MACE and acceptable ST rate. DM
patients had higher rates of adverse events and than non DM.
Chin Med J 2008;121(17):1670-1674
严
ong term clinical outcomes from randomized clinical
trials have shown the persisting benefit of drug
eluting stent (DES) in inhibiting neointimal hyperplasia
and subsequent restenosis, as compared to the bare metal
stent (BMS).1-4 Inevitably, randomized trials have strict
enrolment criteria, but DES is often used in other
situations: so called “off label” indications.5 In China,
different kinds of DES have been used in clinics for the
last five years and short term clinical outcomes have been
reported focusing on the Chinese made DES.6,7 The long
term clinical efficacy and safety of the domestic DES are
still under investigation. Here we report the three-year
clinical outcomes of patients who received the Firebird
sirolimus eluting stent (SES, Microport, Shanghai, China)
by analyzing the data from two large percutaneous
coronary intervention (PCI) centres in China.
METHODS
Sample
From January 2003 to March 2005, 509 consecutive
patients, who were diagnosed with coronary artery
disease (CAD) and received Firebird sirolimus eluting
stents (333 cases with off label indication) in Shanghai
Ruijin or Beijing Fuwai hospitals provided data for this
retrospective analysis. Patients who were implanted with
other kinds of stent at the index procedure or whose
available follow-up duration was less than three years
were excluded.
PCI procedure
All PCI procedures were performed following the current
standard procedural guidelines as previously described.8
Aspirin (100 mg/d) and ticlopidine (250 mg, twice a day)
or clopidogrel (75 mg/d) were given to all patients at least
two days before PCI. Patients receiving primary PCI with
stent implantation for acute myocardial infarction, had
aspirin and clopidogrel with doses of 300 mg
Department of Cardiology, Ruijin Hospital, Shanghai Jiao tong
University School of Medicine, Shanghai 200025, China (Zhang
Q, Zhang RY, Zhang JS, Hu J and Shen WF)
Department of Cardiology, Cardiovascular Institute and Fuwai
Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing 100037, China (Xu B, Yang YJ, Qiao SB,
Qin XW, Chen JL and Gao RL)
The first two authors contributed equally to this article.
Correspondence to: Dr. SHEN Wei-feng, Department of
Cardiology, Shanghai Ruijin Hospital, Shanghai 200025, China (Tel:
86-21-64370045. Fax: 86-21-64457177. Email: rjshenweifeng@
yahoo.com.cn); Dr. GAO Run-lin, Department of Cardiology,
Cardiovascular Institute & Fuwai Hospital, Beijing 100037, China
文章来源：Chinese Medical Journal
Chinese Medical Journal 2008; 121(17):1670-1674
1671
administered before the procedure. Results of coronary
angiography and PCI procedures were assessed by at least
two
experienced
interventional
cardiologists.
Unfractionated heparin was given intravenously to
maintain the activated clotting time >250 seconds during
the procedure. Stenting success was defined as residual
stenosis <20% by visual estimation and in the presence of
Thrombolysis In Myocardial Infarction (TIMI) grade 3
flow in the target vessel.8 After procedure, all patients
were advised to maintain lifelong aspirin and clopidegrel
(75 mg/d) for at least 12 months.
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Study endpoint and definitions
The primary endpoint was a major adverse cardiac event
(MACE), defined as any death, nonfatal myocardial
infarction (MI) or target vessel revascularization (TVR).
MI was diagnosed by an increase in creatine kinase MB
fraction of 3 times the upper limit of normal; Q wave or
non Q wave MI was defined as the presence or absence of
new pathological Q wave in the ECG.9 Occurrence of stent
thrombosis (ST) was classified as definite, probable or
possible according to the Academic Research Consortium
recommendation.10 The timing of ST was categorized early
(<30 days after stent implantation), late (30 days to 1 year)
or very late (>1 year). Off label indications of stent
implantation included: small and long lesions; chronic total
occlusion; bifurcation lesion; left main disease; instent
restenosis; multivessel disease; lesions in saphenous vein
grafts and acute myocardial infarction.5
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Follow-up
All patients received telephone contact or outpatient
department interview after discharge. Follow-up data for
all patients were obtained from hospital records. For the
patients lost during the follow-up or those with follow-up
duration longer than 3 years, the survival status at last
contact or 3 year was chosen as the final follow-up status.
Statistical analysis
Categorical variables were expressed as percentages and
continuous variables as mean ± standard deviation. The
cumulative incidence of adverse events was estimated
according to the Kaplan Meier method and curves were
compared using the log rank test in the subgroup analysis.
A P value less than 0.05 was considered statistically
significant. All statistical analyses were performed using
SPSS software (Version 10.0, SPSS Chicago).
Figure 1. Lesion Distribution. LM: left main; LAD: left anterior
descending coronary artery; LCX: left circumflex coronary
artery; RCA: right coronary artery; SVG: saphenous vein graft.
Figure 2. ACC/AHA Lesion Type.
implantation were (3.0±0.4) mm and (88±9)%,
respectively. Direct stent implantation was performed in
27.8% of the lesions, stent to lesion length ratio was 1.
35±0.12 and the number of stent per patient was 1.7±0.9.
The final angiographic success rate was 98.3% of the
treated lesions.
Table 1. Baseline characteristics (n=509)
Variables
Male
Prior MI
Prior PCI
Prior CABG
Diabetes mellitus
IDDM
Hypertension
Hyperlipidaemia
CAD family history
Current smoker
Unstable angina
Case numbers
374
196
74
9
103
21
302
172
22
191
385
%
73. 5
38. 5
14. 5
1. 8
20. 2
4. 1
59. 3
33. 8
4. 3
37. 5
75. 6
RESULTS
Baseline and PCI characteristics
The mean age of patients was 61.8±11.1 years, 73.5%
were male, 20.2% were diabetic and the mean left
ventricular ejection fraction of the patients was
(60.7±8.8)% (Table 1). Six hundred and forty-seven
lesions were treated of which 333 patients (65.4%) were
stented in off label indications. The lesion distribution
and lesion type are listed in Figures 1 and 2. The mean
reference vessel diameter and diameter of stenosis before
Clinical outcomes
The follow-up rates were 100.0%, 99.8%, 99.6% and
99.4% at the time of in hospital, 6 months, 1 year and 3
years, respectively. The cumulative 3 years’ MACE free
survival rate was 92.1%. The details of survival status
were listed in Table 2.
Diabetic compared with nondiabetic patients
The prognosis of diabetic patients (n=103, 20.2%) was
poorer than non-diabetics (n=406, 79.8%, Table 3). At
文章来源：Chinese Medical Journal
Chin Med J 2008;121(17):1670-1674
1672
Table 2. Clinical results at 3-year follow-up (n (%))
Events,
Nonfatal MI
Q wave
Non Q wave
TVR
PCI
CABG
Death
Cardiac
Non Cardiac
MACE
In hospital
(n=509)
1 (0. 2)
6-month
(n=508)
2 (0. 4)
1-year
(n=507)
2 (0. 4)
3-year
(n=506)
8 (1. 6)
4 (0. 8)
1 (0. 2)
4 (0. 8)
6 (1. 2)
5 (1. 0)
13 (2. 6)
7 (1. 4)
22 (4. 3)
0 (0)
0 (0)
1 (0. 2)
1 (0. 2)
1 (0. 2)
2 (0. 4)
4 (0. 8)
5 (1. 0)
0 (0)
12 (2. 4)
1 (0. 2)
21 (4. 1)
3 (0. 6)
40 (7. 9)
0 (0)
5 (1. 0)
Figure 4. Dual antiplatelet therapy and stent thrombosis.
Angiographic follow-up
One hundred and sixty-seven patients with 223 stented
lesions received angiographic follow-up at a mean
duration of 10.3±4.9 months. The angiographically
instent and in segment restenosis rates were 5.3% and
6.4%, respectively. Most of the restenosis types were type
I (40%) and type II (40%), the remaining were type IV
(20%).
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3 years’ follow-up, death and nonfatal MI were not
significantly higher in the diabetic group, but the TVR
and MACE rates were 9.8% and 4.0%, 13.7% and 6.4%,
respectively,（both P <0.05). The cumulative MACE free
survival rate was significantly lower in the diabetic group
(Figure 3).
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DISCUSSION
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Figure 3. Three years’ MACE free survival rate between
diabetic and non diabetic group.
Dual antiplatelet therapy and stent thrombosis
Aspirin was administered to all patients after the procedure
and the mean duration of using clopidogrel after procedure
was 12.2±3.4 months. Stent thrombosis occurred in 7 cases (1.
4%) by 3-year follow-up; 5 were angiographically identified
definite ST (one case of acute, one of late and three very late)
with 4 cases of recurrent MI and 1 of unstable angina. Two
patients with probable ST had recurrence of MI in the stented
coronary without angiographic follow-up. The relationship
between antiplatelet therapy and ST is listed in Figure 4.
There was no statistical significance between the off label and
on label groups regarding the occurrence of ST (1.5% and
1.1%, P=0.07).
In this report, we described the medium term clinical
outcomes following the use of Chinese made Firebird
SES in all patients. The results demonstrated that the
Firebird SES has high procedural success rate (98.4%) as
a treatment for patients with CAD in daily practice,
although about two thirds of the patients were treated in
off label indications. The results of 3-year clinical
follow-up indicated that the Firebird SES were effective
and safe, with cumulative rates for death of 1.6%, Re-MI
of 3.0%, TVR of 5.1% and MACE of 7.9%. The
cumulative Academic Research Consortium definite or
probable stent thrombosis rate was 1.4% at 3 years’
follow-up: grouped as acute ST of 0.2%, late ST of 0.4%
and very late ST of 0.8%.
There is clear evidence of high efficacy of DES in
reducing restenosis rate and subsequent TVR compared
with BMS in randomized clinical trials of highly selected
patients with de novo lesions of moderate length and
diameter stenosis: listed as label indications by the
manufactures.1,4,11,12 The data regarding the long term
efficacy of DES in treating CAD other patients was
limited. Recently, results from a pooled analysis, by Stone
et al,13 which included patients implanted with Ravel,
Sirius, E Sirius or C Sirius stents, indicated that 4 years’
rate of target lesion revascularisation (TLR) was
Table 3. Clinical outcomes between diabetic and non diabetic patients (n (%))
Re MI
TVR
MACE
DM
Non-DM
DM
Non-DM
DM
Non-DM
DM
Non-DM
In-hospital
0 (0)
0 (0)
2 (1. 9)
3 (0. 7)
1 (1. 0)
0 (0)
2 (1. 9)
3 (0. 7)
6-month
1 (1. 0)
0 (0)
3 (2. 9)
3 (0. 7)
3 (2. 9)
3 (0. 7)
6* (5. 9)
6 (1. 5)
3 (0. 7)
6 (5. 9)*
8 (2. 0)
10 (9. 8)*
11 (2. 7)
1-year
2 (2. 0)
1 (1. 0)
4 (3. 9)*
3-year
3 (2. 9)
5 (1. 2)
6 (5. 9)
9 (2. 2)
10 (9. 8)*
16 (4. 0)
14 (13. 7)*
26 (6. 4)
DM: diabetes mellitus, Re MI: reoccurrence of myocardial infarction, TVR: target vessel revascularization, MACE: major adverse cardiac event; *P <0. 05, as comparing
to the non DM group.
Time
Death
文章来源：Chinese Medical Journal
Chinese Medical Journal 2008; 121(17):1670-1674
1673
paclitaxel eluting stent) after 3 years, with an ongoing
incidence of late ST of 0.6% per year. In the current
analysis, we found that the overall rate of ST (definite
1.0% and probable 0.4%) was 1.4% after 3 years in
patients receiving Firebird SES, which was similar to that
observed in randomized trials or meta analyses. However,
the occurrence of ST in patients receiving the stent with
off label indications was higher (1.5% and 1.1%, P=0.07).
It still remains unclear whether prolonged dual
antiplatelet therapy would prevent or decrease the
incidence of ST, especially late ST.24 In our study, three
patients with sub-acute definite or probable ST were on
dual antiplatelet therapy at the time of the event.
The current study was a retrospective analysis with data
derived from two high volume centres, but low
angiographic follow-up may underestimate the rate of
TVR and subsequent MACE. Only patients who received
Firebird SES were included and with no control group,
we could not perform comparative analyses. Multivariate
analysis over subgroups, especially for predictors of ST,
could not be performed with sufficient statistical power
due to the small number of patients with the event.
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significantly reduced in the SES group as compared with
the BMS group (7.8% and 23.6, P <0.001), with no
differences in the comparisons of stent thrombosis (1.2%
and 0.6%, P=0.20), death (6.7% and 5.3%, P=0.23) and
MI (6.4% and 6.2%, P=0.86).13 Three years’ follow-up
results of RESEARCH study have shown that the Cypher
SES was effective in reducing MACE (18.9%) and TLR
(7.5%) compared to the BMS group (24.7% and 12.6%,
respectively), which beneficial effects persisted after 2
years’ follow-up and there was no evidence of clinical
late “catch up” phenomena in restenosis.14 The results of
our study indicated that the Firebird SES had relatively
lower rates of cumulative MACE (7.9%), TVR (5.1%),
MI (3.0%) and death (1.6%), when compared with
Cypher SES, despite the clinical scenarios of patients
treated in off label indications may be more complex than
those in RAVEL, SIRIUS or even the RESEARCH study.
Different dosages of sirolimus loaded on the stent may
lead to different degrees in inhibiting neointimal
hyperplasia and subsequent MACE and TLR events. For
each Firebird SES, 9 µg of sirolimus was loaded on per
millimetre stent length,7 while the Cypher SES was
loaded with 140 µg of sirolimus per square centimetre.15
In addition, relatively lower angiographic follow-up rate
may underestimate the rate of TVR.16
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Patients with diabetes mellitus (DM) usually present with
accelerated atherosclerosis, more diffuse disease,
concomitant comorbidities and have increased risks for
restenosis.17 For these patients, studies have shown that
DES significantly reduced the restenosis compared with
BMS.18,19 DIABETES trial showed that after 9 months,
TLR and MACE in the SES treated group were 7.3% and
11.3%, respectively.19 In another recently study of
diabetic patients, the DESSERT study, after 12 months
the rate of MACE was 22.1%, TLR 5.9% and TVF of
14.7%.20 Two years’ clinical follow-up from a multicentre
registry showed a TLR rate of 11.6% in the DES group.21
The current study showed that three years’ TVR rate was
9.8% in the DM group, which was significantly higher
than the non DM patients (4.0%, P<0.05). In addition,
MACE at 3-year follow-up was significantly higher in the
DM group (13.7% and 6.4%, P<0.05), which was mainly
due to the higher rate of TVR in the DM group. Current
results supported the idea that DM patients have higher
rates of MACE and TVR following implantation of a
DES.19
ST remains the major concern following DES
implantation; especially the occurrence of late and very
late ST.10 There were several recent reports addressing the
safety of DES, with particular regard to ST. No
significant difference was found in the rates of mortality
or ST between SES and BMS at 4 years’ clinical
follow-up in two analyses of major randomized SES
trials.13,22 The rate of definite ST varied from 1.2% to
2.3% for Cypher SES in different studies.23,24 Daemen et
al25 reported that the overall incidence of ST occurred in
2.9% of patients receiving DES (including sirolimus or
In conclusion, by analyzing data of all patients who
received Firebird SES in two large PCI volume centres,
we could assess the treatment safty and efficacy of
Firebird SES, especially in the off label indications
patients group in daily practice. At 3 years’ clinical
follow-up, a low MACE and acceptable ST rates were
found. The safety and efficacy profiles of Firebird SES in
treating coronary artery disease patients in daily clinical
setting could be proved, although dual antiplatelet therapy
longer than 12 months for patients receiving the stent in
off label indications might be recommended.
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(Received June 17, 2008)
Edited by WANG Mou-yue and LIU Huan
文章来源：Chinese Medical Journal