Error bars represent 95% confidence intervals.
Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, Schühlen H, Schmitt C, Dirschinger J, Schömig A, ISAR-DESIRE Study Investigators FT. Sirolimus-Eluting Stent or Paclitaxel-Eluting Stent vs Balloon Angioplasty
for Prevention of Recurrences in Patients With Coronary In-Stent RestenosisA Randomized Controlled Trial. JAMA. 2005;293(2):165-171. doi:10.1001/jama.293.2.165
Author Affiliations: Deutsches Herzzentrum,
Technische Universität (Drs Kastrati, Mehilli, von Beckerath, Dibra,
Pache, Schmitt, and Schömig) and Medizinische Klinik rechts der Isar,
Technische Universität (Drs Hausleiter, Schühlen, Dirschinger, and
Schömig), Munich, Germany.
Context In patients with de novo coronary lesions, drug-eluting stents have
drastically reduced restenosis risk compared with bare metal stents and conventional
balloon angioplasty. It is less clear whether drug-eluting stents are superior
to conventional balloon angioplasty for the treatment of patients with in-stent
Objectives To assess if drug-eluting stents are a more effective treatment of in-stent
restenosis than conventional balloon angioplasty, and to assess the relative
merits of 2 drug-eluting stents, a sirolimus-eluting stent and a paclitaxel-eluting
Design, Setting, and Participants Randomized, open-label, active-controlled trial conducted among 300
patients with angiographically significant in-stent restenosis in 2 tertiary
German centers from June 1, 2003, to October 20, 2003.
Interventions After pretreatment with 600 mg of clopidogrel for at least 2 hours before
intervention, all patients were randomly assigned to 1 of 3 treatment groups:
sirolimus stent, paclitaxel stent, or balloon angioplasty (100 patients in
Main Outcome Measures Primary end point: angiographic restenosis (diameter stenosis ≥50%)
at 6-month follow-up angiography based on “in-segment” analysis.
Primary analysis was comparison between stent groups and balloon angioplasty
groups; a secondary analysis compared sirolimus and paclitaxel stents.
Results Follow-up angiography was performed in 275 (92%) of 300 patients. The
incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty
group, 14.3% (13/91) in the sirolimus stent group (P<.001
vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared
with balloon angioplasty, receiving a sirolimus stent had a relative risk
(RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56);
a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of
target vessel revascularization was 33.0% (33/100) in the balloon angioplasty
group, 8.0% (8/100) in the sirolimus stent group (P<.001
vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group
(P = .02 vs balloon angioplasty). The secondary
analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target
vessel revascularization (P = .02) among
sirolimus stent patients compared with paclitaxel stent patients.
Conclusions In patients with in-stent restenosis, a strategy based on sirolimus-
or paclitaxel-eluting stents is superior to conventional balloon angioplasty
for the prevention of recurrent restenosis. Sirolimus-eluting stents may be
superior to paclitaxel-eluting stents for treatment of this disorder.
Restenosis affects 20% to 40% of de novo coronary lesions treated with
bare metal stents.1 Although it is often considered
a benign process, recent data indicate that in-stent restenosis has a negative
impact on long-term survival of patients treated with coronary stents.2 Another problem associated with in-stent restenosis
is the difficulty of finding appropriate treatment modalities to reduce the
excessive risk of recurrence. Plain balloon angioplasty is the first-line
treatment option for in-stent restenosis, yet its results have often been
disappointing with a recurrence rate above 40%.3 Repeated
use of bare stents appears to further exacerbate the risk of recurrence.3 Alternative interventional options, including rotational
atherectomy, excimer laser angioplasty, directional coronary atherectomy,
and cutting balloon, have not provided additional benefits.4,5 Although
brachytherapy is currently the treatment approach most supported by evidence
for in-stent restenosis,6 the complexity of
its application, concerns about the prolonged risk of vessel occlusion,4 and the decrease in benefit over time7 have
limited use of this strategy.
The frequent failure of local approaches in the treatment of in-stent
restenosis has stimulated major interest in the use of systemic therapies.
A strategy based on a 2-day pretreatment with a high dose of rapamycin followed
by a usual maintenance dose for a week after balloon angioplasty recently
resulted in a significant reduction of recurrences in patients with in-stent
restenosis.8 However, the need for a 2-day
pretreatment and, consequently, the impossibility to perform “ad hoc”
interventions will most probably prevent the widespread use of this approach.
Drug-eluting stents have emerged as the most successful strategy in
the primary prevention of restenosis. Randomized clinical trials including
patients with de novo lesions have shown that sirolimus and paclitaxel stents
lead to a marked reduction of restenosis with incidences below the limit of
10%.9,10 Although no data are
available from head-to-head comparisons, findings from recent studies suggest
that sirolimus and paclitaxel stents may have equivalent efficacy for treatment
of de novo lesions.9,10 Observational
studies have reported encouraging results with the use of drug-eluting stents
in in-stent restenosis lesions.11,12 However,
plain balloon angioplasty currently represents the most common form of therapy
used in patients with in-stent restenosis,13 and
no randomized trials have addressed the issue of whether drug-eluting stents
provide advantages over plain angioplasty. In addition, the particularly high
risk for recurrence associated with in-stent restenosis lesions is more demanding
and may render better evidence of subtle differences in performance between
various drug-eluting stents.
The primary objective of this trial was to assess whether 2 different
drug-eluting stents approved by the US Food and Drug Administration are more
effective for treatment of in-stent restenosis lesions than conventional balloon
angioplasty. The secondary objective of this trial was to assess the relative
merits of 2 drug-eluting stents—a sirolimus-eluting stent and a paclitaxel-eluting
stent—in the prevention of recurrences in patients with in-stent restenosis.
Eligible patients had angina pectoris and/or a positive stress test
and presented with angiographically significant in-stent restenosis (lumen
renarrowing of ≥50% at a previously stented segment) in native coronary
vessels. Acute myocardial infarction; in-stent restenosis lesions in the left
main coronary artery; lesions created by restenosis of drug-eluting stents;
and known allergy to sirolimus, paclitaxel, heparin, aspirin, or clopidogrel
were prespecified exclusion criteria. The study protocol was approved by the
institutional ethics committee, and all patients gave written informed consent
for participation in this trial.
From June 1, 2003, to October 20, 2003, 300 patients were enrolled and
randomly assigned to receive a sirolimus stent (n = 100), a paclitaxel
stent (n = 100), or balloon angioplasty (n = 100) (Figure 1). All patients received a loading dose
of 600 mg of clopidogrel at least 2 hours before coronary angiography. Eligible
patients who did not meet any exclusion criteria were enrolled in the study
immediately after coronary angiography. Randomization was done according to
a computer-generated random sequence with a block size of 30. Sealed envelopes
in the catheterization laboratories of the 2 participating hospitals, Deutsches
Herzzentrum and I. Medizinische Klinik rechts der Isar, both in Munich, Germany,
included the treatment arm to which the patients were assigned: sirolimus-eluting
stent (Cypher, Cordis Corporation, Miami Lakes, Fla), paclitaxel-eluting stent
(Taxus, Boston Scientific Corporation, Natick, Mass), or balloon angioplasty.
Sirolimus stents were available in diameters of 2.25 mm, 2.5 mm, 2.75 mm,
3.0 mm, and 3.5 mm, and in lengths of 8 mm, 13 mm, 18 mm, 23 mm, 28 mm, and
33 mm. Paclitaxel stents were available in diameters of 2.25 mm, 2.5 mm, 2.75
mm, 3.0 mm, and 3.5 mm, and in lengths of 8 mm, 12 mm, 16 mm, 20 mm, 24 mm,
28 mm, and 32 mm.
Both balloon angioplasty and stenting procedures were performed according
to standard techniques. The number and length of stents to be implanted were
left to the operator’s discretion, but the recommendation was to fully
cover the restenotic lesion. Among patients assigned to receive balloon angioplasty,
the use of stents was strongly discouraged. However, operators were allowed
to use only bare stents to cover large (≥5 mm) dissections created after
balloon angioplasty outside the previously stented area. The operators were
to decide whether to perform direct stenting or stenting after predilatation.
All patients received intravenous aspirin (500 mg) and heparin (140
U/kg of body weight) during the procedure. Postinterventional antiplatelet
therapy consisted of aspirin (100 mg twice daily indefinitely) and clopidogrel
(75 mg twice daily until discharge and once daily for ≥6 months). Other
medications, including statins, β-blockers, and angiotensin-converting
enzyme inhibitors, were given if considered necessary by the attending physician.
Patients stayed in hospital for at least 48 hours after randomization.
During the in-hospital period, electrocardiograms were recorded and blood
was collected for determination of creatine kinase (CK) and its MB isoenzyme
before randomization and every 8 hours for the first 24 hours after randomization
and daily afterward. Patients were contacted by phone after 30 days (± 7
days) to assess their clinical status. All patients were asked to return for
coronary angiography between 6 and 8 months after randomization or earlier
if they had anginal symptoms. Telephone interviews were repeated at 9 months
(±1 month) and 12 months (±1 month). All patients reporting
symptoms of chest pain were requested to come to the outpatient clinic for
clinical, electrocardiographic, laboratory, and, eventually, angiographic
assessment. Relevant data were collected and entered into a computer database
by specialized personnel of the Clinical Data Management Center. All data
were verified against source documentation and an events committee blinded
to the treatment groups adjudicated all adverse clinical events.
Coronary angiograms at baseline after completion of the procedure and
at follow-up were digitally recorded and sent for assessment to the Quantitative
Angiographic Core Laboratory (Deutsches Herzzentrum, Munich, Germany). Angiographic
readers were wholly unaware of the stent model used and study allocation.
Digital angiograms were analyzed with use of an automated edge detection system
(CMS, Medis Medical Imaging Systems, Nuenen, the Netherlands). In-stent restenosis
patterns at baseline were defined angiographically according to the system
proposed by Mehran et al.14
All measurements were performed on cineangiograms recorded after intracoronary
nitroglycerin administration. The same projections were used at all time points.
The contrast-filled nontapered catheter tip was used for calibration. Quantitative
parameters measured included the reference diameter of the vessel, the minimal
lumen diameter, percent diameter stenosis (difference between the reference
diameter and minimal lumen diameter/reference diameter×100), late lumen
loss (difference between minimal lumen diameter at the end of the procedure
and minimal lumen diameter at follow-up), and net lumen gain (difference between
minimal lumen diameter at follow-up and minimal lumen diameter before the
procedure). For patients assigned to the stent arms, quantitative analysis
was performed in the “in-stent” area (“in-stent” analysis)
and in the “in-segment” area including the stented segment as
well as both 5-mm margins proximal and distal to the drug-eluting stent implanted
during the index procedure (“in-segment” analysis).
The primary end point of the study was binary angiographic restenosis
defined as a diameter stenosis of 50% or greater at follow-up angiography
on the basis of the “in-segment” analysis. Secondary end points
were net lumen gain (a continuous quantitative angiographic parameter), target
vessel revascularization due to restenosis, and the combined incidence of
death or myocardial infarction during 1 year of follow-up. Two types of analyses
were planned to be done by protocol: the primary analysis consisting of separate
comparisons of the sirolimus and paclitaxel stent arms on one side with the
angioplasty arm on the other side, and a comparison between the 2 stent arms,
sirolimus and paclitaxel, with each other.
The diagnosis of myocardial infarction during the follow-up was established
whenever new Q-waves appeared in the electrocardiogram and/or the CK-MB value
rose to 3 or more times the upper limit of normal. Target vessel revascularization
was defined as any repeat percutaneous coronary intervention or aortocoronary
bypass surgery involving the target vessel due to lumen renarrowing associated
with symptoms or objective signs of ischemia.
To calculate sample size, we assumed an angiographic restenosis rate
of 40% in the angioplasty arm3 and 20% in both
the sirolimus stent and paclitaxel stent arms and incorporated the method
appropriate for more than 2 groups described by Lachin.15 We
intended to give 80% power to the study and chose an α level of .025
(the usual α level of .05 corrected for the 2 planned comparisons in
the primary analysis according to the Bonferroni method16).
A sample size of 85 patients in each group was calculated. We included 100
patients in each group to accommodate for possible losses to follow-up angiography.
All analyses relative to the sample size calculation were performed with nQuery
Advisor, Version 4.0 (Statistical Solutions, Cork, Ireland).
All analyses were done on the basis of the intention-to-treat principle,
ie, the analyses were based on all randomized patients, as randomized. Because
most of the quantitative angiographic data were not normally distributed,
continuous data are presented as median (interquartile range [IQR]). Categorical
data are presented as counts or proportions (percentage). Baseline clinical
and angiographic characteristics as well as procedural variables were checked
for statistically significant differences with analysis of variance (continuous
data) or contingency table analysis (categorical data). Differences between
groups in outcome variables were assessed using the χ2 test
or Fisher exact test (whenever an expected cell value was <5) for categorical
data, and the Kruskal-Wallis rank sum test and Wilcoxon rank sum test for
continuous data. The relative risk (RR) and its 95% confidence interval (CI)
were computed for outcome measures. A P value of
<.025 was considered statistically significant. Statistical software S-PLUS,
version 4.5 (S-PLUS, Insightful Corp, Seattle, Wash) was used for all analyses.
Baseline demographic, clinical, and angiographic characteristics are
shown in Table 1, and procedural characteristics
are shown in Table 2. A higher balloon
pressure was used in the 2 stent groups compared with the balloon angioplasty
group. In addition, final results were better in the 2 stent groups as shown
by a bigger minimal lumen diameter and a smaller diameter stenosis at the
end of procedure. Operators were unable to place a stent in 3 patients of
the sirolimus stent group and in 2 patients of the paclitaxel stent group.
A single stent was implanted in 92 patients of the sirolimus stent group and
in 89 patients of the paclitaxel stent group, and 2 stents were placed in
5 patients of the sirolimus stent group and in 9 patients of the paclitaxel
stent group. The median total length of stents implanted in each patient was
23.0 mm (IQR, 18.0-33.0 mm) in the sirolimus stent group and 20.0 mm (IQR,
16.0-26.0 mm) in the paclitaxel stent group (P = .60).
Operators used bare metal stents in only 4 of the 100 patients assigned to
the balloon angioplasty group. No patient experienced vessel closure during
the first 30 days after randomization.
Angiographic follow-up was performed after a median of 197 days (IQR,
176-203 days) in 92% of the patients (Figure 1). Table 3 shows the results
of the quantitative analysis performed on follow-up angiograms. The primary
end point of the trial—the incidence of angiographic restenosis (Figure 2)—was noted in 44.6% in the balloon
angioplasty group (41 of 92 patients), in 14.3% in the sirolimus stent group
(13 of 91 patients, P<.001 vs balloon angioplasty),
and in 21.7% in the paclitaxel stent group (20 of 92 patients, P = .001 vs balloon angioplasty). When compared with assignment
to receive balloon angioplasty, assignment to the sirolimus stent group was
associated with an RR of angiographic restenosis of 0.32 (95% CI, 0.18-0.56)
and assignment to the paclitaxel stent group was associated with an RR of
0.49 (95% CI, 0.31-0.76). In addition, net lumen gain, a secondary end point
of the trial, was greater in the 2 drug-eluting stent groups compared with
the balloon angioplasty group. Late total occlusions were observed in 1 patient
in the sirolimus stent group, 3 patients in the paclitaxel stent group, and
2 patients in the balloon angioplasty group.
One-year follow-up was completed in all but 5 patients (1.7%): 2 in
the sirolimus stent group, 2 in the paclitaxel stent group, and 1 in the balloon
angioplasty group. The length of follow-up interval in these 5 patients was
between 34 and 210 days (median, 182 days). Table
4 shows the adverse clinical events observed during 1 year. Although
there were no differences in mortality and in the incidence of myocardial
infarction, the need for target vessel revascularization (a secondary end
point of the trial) was significantly lower in the sirolimus and paclitaxel
stent groups (Figure 2). When compared
with assignment to receive balloon angioplasty, the assignment to the sirolimus
stent group was associated with an RR of target vessel revascularization of
0.24 (95% CI, 0.12-0.50), and assignment to the paclitaxel stent group was
associated with an RR of 0.58 (95% CI, 0.35-0.94).
A secondary analysis was performed to compare measures of restenosis
between the 2 drug-eluting stent groups (Table
5). We found either a trend or a significant difference in favor
of the sirolimus stent group. When compared with the assignment to the paclitaxel
stent group, the assignment to the sirolimus stent group was associated with
an RR of angiographic restenosis of 0.66 (95% CI, 0.35-1.24). One of the 13
patients with restenosis in the sirolimus stent group and 3 of the 20 patients
with restenosis in the paclitaxel stent group had total occlusion in follow-up
angiography. Three of the 13 patients with restenosis in the sirolimus stent
group and 6 of the 20 patients with restenosis in the paclitaxel stent group
had diffuse restenosis morphology. Among the patients who received a single
drug-eluting stent, the angiographic restenosis rate was 14.1% (12 of 85 patients)
in the sirolimus stent group and 22.0% (18 of 82 patients) in the paclitaxel
stent group (P = .19). In addition, the
incidence of target vessel revascularization was significantly lower in the
sirolimus stent group (8.0%, 8 of 100 patients) than in the paclitaxel stent
group (19.0%, 19 of 100 patients) (P = .02).
When compared with assignment to the paclitaxel stent group, the assignment
to the sirolimus stent group was associated with an RR of target vessel revascularization
of 0.42 (95% CI, 0.19-0.92).
The main finding of this randomized clinical trial was a marked reduction
of recurrent restenosis with 2 drug-eluting stents (sirolimus and paclitaxel)
in patients with in-stent restenosis. When compared with balloon angioplasty,
both stents led to 51% to 68% reduction of the risk of angiographic restenosis
and to 42% to 76% reduction of the need for target vessel revascularization.
There was no increased risk of late total occlusion with drug-eluting stents.
We chose to use conventional balloon angioplasty as the control because
it is currently the most commonly used treatment strategy in this patient
population despite its known limitations.13 Several
randomized trials have been published on the value of brachytherapy in patients
with in-stent restenosis in native vessels.6,17- 20 Recurrent
restenosis at 6-month angiographic follow-up was reduced from 44% to 60% in
control groups of conventional balloon angioplasty to 22% to 32% in the brachytherapy
groups.6,18- 20 In
contrast to these favorable data, there have been concerning reports on the
late total occlusion and the limited durability of the initial benefit achieved
by brachytherapy. Among 308 patients enrolled in the brachytherapy
arm of different randomized trials, Waksman et al21 found
28 cases (9.1%) of late total occlusion (>28 days after application) of the
treated vessel frequently associated with severe ischemic events; this complication
occurred much less often in the control patients treated with balloon angioplasty
(1.2%). In addition, target vessel revascularization was required 3 times
more frequently in the brachytherapy group than in the control group after
the first 6 months after randomization.7 Although
our trial shows that drug-eluting stents are an effective treatment option
for patients with in-stent restenosis, we do not know whether they are superior
to brachytherapy, and the lack of a brachytherapy group as a control in this
study should be acknowledged as a limitation. Thus, the definitive answer
regarding the optimal treatment of in-stent restenosis will come after the
completion of ongoing trials that include both brachytherapy and drug-eluting
Both measures of restenosis in the 2 drug-eluting stent groups, the
incidence of angiographic restenosis and the degree of late lumen loss observed
in the sirolimus and paclitaxel stent groups, were higher than the respective
values recorded in previously published randomized trials on the value of
these devices for de novo lesions.9,10 In
our in-stent restenosis patients, we found an incidence of angiographic restenosis
of 14.3% and a median late lumen loss of 0.32 mm in the sirolimus stent group.
In the biggest randomized trial of the sirolimus stent for de novo lesions,
the angiographic restenosis rate was 8.9% and mean late lumen loss was 0.24
mm.9 We also found an incidence of angiographic
restenosis of 21.7% and a median late lumen loss of 0.55 mm in the paclitaxel
stent group. In the biggest randomized trial of the paclitaxel stent for de
novo lesions, the angiographic restenosis rate was 7.9% and mean late lumen
loss was 0.39 mm.10 A previous randomized trial
has also shown that the results of sirolimus stents in bifurcation lesions
are less favorable than those for less complex lesions.22 This
may indicate that more challenging lesions may require adjustments in the
dose regimen of the antiproliferative drugs and an “individualized”
drug-eluting stent platform tailored to lesion and patient characteristics
may be preferable in these situations.
Although not part of the primary analysis, the comparison between the
sirolimus-eluting stents and paclitaxel-eluting stents may be of particular
interest because it suggested that there may be differences between the 2
drug-eluting stents evaluated in their performance regarding prevention of
recurrences in patients with in-stent restenosis. An indirect comparison of
the results achieved with these 2 drug-eluting stents in independent trials
does not indicate any difference in the restenosis rates after treatment of
de novo lesions, despite the difference in late lumen loss favoring the sirolimus
stent.9,10 The definitive answer
about the relative merits of these 2 drug-eluting stent platforms for de novo
lesions will come from an ongoing “head-to-head” clinical trial.23 However, differences in performance between the sirolimus-eluting
stent and the paclitaxel-eluting stent may become apparent only when they
are used in lesions with a particularly high risk for restenosis such as restenotic
lesions. Previous publications support the concept that a higher lesion complexity
facilitates the distinction in performance between 2 different stents.24,25
In conclusion, the results of this randomized controlled trial demonstrate
that a strategy based on sirolimus- or paclitaxel-eluting stents is superior
to conventional balloon angioplasty for the prevention of recurrent restenosis
in patients with in-stent restenosis. They also suggest that in this high-risk
subset of patients, sirolimus-eluting stents may be superior to paclitaxel-eluting
Corresponding Author: Adnan Kastrati, MD,
Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany (firstname.lastname@example.org).
Author Contributions: As principal investigator,
Dr Kastrati had full access to all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kastrati, Schömig.
Acquisition of data: Kastrati, Mehilli, von
Beckerath, Dibra, Hausleiter, Pache, Schühlen, Schmitt, Dirschinger,
Analysis and interpretation of data: Kastrati,
Mehilli, Dibra, Schömig.
Drafting of the manuscript: Kastrati, Schömig.
Critical revision of the manuscript for important
intellectual content: Mehilli, von Beckerath, Dibra, Hausleiter, Pache,
Schühlen, Schmitt, Dirschinger.
Statistical analysis: Kastrati.
Obtained funding: Schömig.
Administrative, technical, or material support:
Kastrati, Mehilli, von Beckerath, Dibra, Hausleiter, Pache, Schühlen,
Schmitt, Dirschinger, Schömig.
Study supervision: Kastrati, Mehilli, Pache,
Schmitt, Dirschinger, Schömig.
Intracoronary Stenting and Angiographic Results: Drug-Eluting
Stents for In-Stent Restenosis (ISAR-DESIRE) Study investigators and
participating centers: Study OrganizationSteering Committee: A. Schömig (chairman), A. Kastrati (principal
investigator); Data Coordinating Center: J. Mehilli,
J. Hausleiter, H. Bollwein, C. Markwardt (Munich); Angiographic
Core Laboratory: A. Dibra, S. Piniek, S. Meier (Munich); Clinical Follow-Up Center: H. Holle, K. Hösl, F. Rodrigues, C.
Participating Centers and Investigators: Deutsches Herzzentrum, Munich: J. Pache (principal investigator),
C. Schmitt, M. Seyfarth, N. von Beckerath, R. Wessely; Klinikum rechts der Isar, Munich: J. Dirschinger (principal investigator),
H. Schühlen, M. Gawaz, M. Karch.
Funding/Support: This trial was supported by
grants from Deutsches Herzzentrum, Munich, Germany.
Role of The Sponsor: The funding source had
no role in the study design, data collection and analysis, data interpretation,
writing of the report, or decision to publish the findings.
Financial Disclosures: Dr Kastrati has received
research grants from Medtronic; Dr Schömig has received research grants
for the Department of Cardiology from Boston Scientific, Bristol-Myers Squibb,
Cordis/Johnson & Johnson, Guidant, Hoffmann-La Roche, and Lilly.