Sirolimus-Eluting versus Uncoated Stents in Acute Myocardial Infarction
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《新英格兰医药杂志》
ABSTRACT
Background Sirolimus-eluting stents reduce rates of restenosis and reintervention, as compared with uncoated stents. Data are limited regarding the safety and efficacy of such stents in primary percutaneous coronary intervention (PCI) for acute myocardial infarction with ST-segment elevation.
Methods We performed a single-blind, multicenter, prospectively randomized trial to compare sirolimus-eluting stents with uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation. The trial included 712 patients at 48 medical centers. The primary end point was target-vessel failure at 1 year after the procedure, defined as target-vessel–related death, recurrent myocardial infarction, or target-vessel revascularization. A follow-up angiographic substudy was performed at 8 months among 174 patients from selected centers.
Results The rate of the primary end point was significantly lower in the sirolimus-stent group than in the uncoated-stent group (7.3% vs. 14.3%, P=0.004). This reduction was driven by a decrease in the rate of target-vessel revascularization (5.6% and 13.4%, respectively; P<0.001). There was no significant difference between the two groups in the rate of death (2.3% and 2.2%, respectively; P=1.00), reinfarction (1.1% and 1.4%, respectively; P=1.00), or stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The degree of neointimal proliferation, as assessed by the mean (±SD) in-stent late luminal loss, was significantly lower in the sirolimus-stent group (0.14±0.49 mm, vs. 0.83±0.52 mm in the uncoated stent group; P<0.001).
Conclusions Among selected patients with acute myocardial infarction, the use of sirolimus-eluting stents significantly reduced the rate of target-vessel revascularization at 1 year. (ClinicalTrials.gov number, NCT00232830 .)
The use of sirolimus-eluting coronary-artery stents significantly reduces the incidence of restenosis after percutaneous coronary intervention (PCI), as compared with the use of uncoated stents.1,2,3 However, most randomized trials evaluating sirolimus-eluting stents have excluded patients with acute myocardial infarction with ST-segment elevation. Small series of patients with acute myocardial infarction have shown that the implantation of a sirolimus-eluting stent is associated with a low rate of restenosis.4,5 In the Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent vs. Abciximab and Bare-Metal Stent in Myocardial Infarction (STRATEGY) trial, the use of sirolimus-eluting stents reduced cardiovascular events, as compared with the use of uncoated stents, in a small group of patients undergoing primary PCI. However, the design of the trial specified the use of different glycoprotein IIb/IIIa inhibitors in each of the two groups to mitigate the greater cost of the drug-eluting stents, which raised the possibility that the benefit was influenced by the specific antiplatelet regimen.6
We therefore designed a prospective, randomized, multicenter trial comparing the effectiveness of sirolimus-eluting stents with that of uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation.
Methods
Enrollment and Assignment of Patients
We enrolled patients at 48 centers in 15 countries to participate in the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON). The study protocol was approved by the ethics committee at each participating institution and was conducted according to the principles of the Declaration of Helsinki. All patients gave written informed consent before enrollment. The study was conducted from October 2003 to October 2005.
Patients were eligible for the trial if their symptoms began less than 12 hours before catheterization and if the electrocardiogram showed ST-segment elevation (at least 1 mm in two or more standard leads or at least 2 mm in two or more contiguous precordial leads). Clinical criteria for exclusion included the administration of fibrinolytic agents for the index infarction, overt acute heart failure, a previously documented left ventricular ejection fraction of less than 30%, previous myocardial infarction, and an estimated life expectancy of less than 12 months.
Diagnostic Angiography and Primary Intervention
Patients were premedicated with aspirin (at least 100 mg) and unfractionated heparin (5000 to 10,000 IU). A loading dose of 300 mg of clopidogrel was administered either before or immediately after PCI. Coronary angiography was performed through the femoral or radial artery with the use of standard techniques.
Selection and Randomization
The trial protocol required visualization of the culprit lesion before randomization, in order to determine whether the angiographic criteria for inclusion or exclusion were met. Randomization was therefore performed either immediately after coronary angiography if the infarct-related vessel was spontaneously patent or after reestablishing coronary-artery blood flow by the placement of a guidewire or by balloon angioplasty.
Criteria for angiographic exclusion included previous PCI of the infarct-related vessel, excessive tortuosity or calcification, ostial or multiple lesions, massive thrombus in the infarct-related artery, bifurcation or left main coronary-artery disease, and severe multivessel disease requiring surgical revascularization. Patients were finally included and randomly assigned to a treatment group if the target lesion had a maximum length of 30 mm and was located in a native coronary artery with a reference-vessel diameter of 2.25 mm to 3.50 mm.
Random assignments to the treatment groups were generated in blocks of four or six and were distributed in sealed envelopes to each participating center. Patients were randomly assigned to the groups in a 1:1 ratio. Patients received either a sirolimus-eluting stent (Cypher or Cypher Select, Cordis, Johnson & Johnson) or any commercially available uncoated stent. Patients, but not investigators, were unaware of the treatment assignment.
Stent Implantation
Direct implantation of a stent without previous balloon angioplasty was allowed if the culprit lesion was adequately visualized either spontaneously or after guidewire placement. In the case of insufficient stent expansion, the stent was dilated after placement with another angioplasty balloon that was shorter than the total length of the stent. Oversizing and additional high-pressure dilation after the initial procedure were not recommended. If more than one stent was implanted, the same type of stent (sirolimus-eluting or uncoated) was recommended. Intervention in noninfarct-related arteries during the initial procedure was discouraged.
Heparin was administered throughout the procedure in order to maintain an activated clotting time of 250 seconds or longer. Administration of platelet glycoprotein IIb/IIIa–receptor inhibitors was left to the investigator's discretion.
Follow-up
Clinical follow-up was performed at 30 days and at 6 and 12 months after the procedure. Combined antiplatelet therapy included daily administration of aspirin (100 mg) and either clopidogrel (75 mg) or ticlopidine (250 mg). Dual antiplatelet therapy was recommended for at least 6 months, and aspirin therapy was recommended indefinitely. Noninvasive testing to assess for evidence of ischemia was recommended before repeated revascularization. Patients were unaware of their treatment assignments throughout the follow-up period.
Angiographic follow-up at 8 months was planned for 200 patients at 12 centers. In these selected centers, consecutive patients were enrolled in the angiographic substudy until the total number of patients reached 210.
Quantitative Coronary Angiography
Technicians at an independent angiographic core laboratory (BioImaging, Leiden, the Netherlands), who were unaware of treatment assignment, analyzed all angiographic images with the use of edge-detection techniques.7 Binary restenosis was defined as stenosis of more than 50% of the luminal diameter. Late luminal loss was calculated as the difference between the minimum luminal diameter immediately after the procedure and at 8 months. Flow in the infarct-related vessel was graded according to the Thrombolysis in Myocardial Infarction (TIMI) trial classification.8
Primary and Secondary End Points
The primary end point of the study was target-vessel failure, defined as the composite of target-vessel revascularization, recurrent infarction, or target-vessel–related death at 1 year. The clinical events committee reviewed and adjudicated all serious clinical events, including stent thrombosis.
Target-vessel revascularization was defined as repeated PCI or bypass grafting of the target vessel, driven by clinical symptoms of myocardial ischemia, a positive stress test, electrocardiographic evidence of ischemic changes at rest attributable to the target vessel, or an in-lesion stenosis of more than 70% of the reference luminal diameter by visual estimate.
Recurrent infarction was defined as the recurrence of clinical symptoms or the occurrence of electrocardiographic changes accompanied by a new elevation in levels of creatine kinase, creatine kinase MB enzyme, or both. The level of creatine kinase required for the diagnosis of reinfarction depended on the interval from the index infarction: the creatine kinase level had to be at least 1.5 times the previous value if new symptoms appeared within 48 hours and at least 3 times the upper limit of normal if new symptoms appeared after 48 hours.
Death from cardiac causes included death from acute myocardial infarction, cardiac perforation, or pericardial tamponade; an arrhythmia or conduction abnormality; complications of the interventional procedure at baseline; stroke (including bleeding) within 30 days after the procedure or in connection with the procedure; and all deaths that could not be clearly attributed to a noncardiac cause.
The secondary end points of the trial included the rate of successful treatment of the lesion, defined by residual stenosis of less than 50% of the reference luminal diameter on quantitative coronary analysis and a TIMI flow grade of 3, and in-stent late luminal loss on quantitative coronary analysis at 8 months.
Definition of Stent Thrombosis
Stent thrombosis was classified as acute if it occurred within 24 hours after the index procedure, subacute if it occurred between 1 and 30 days, and late if it occurred after 30 days. Acute and subacute stent thrombosis were defined as angiographic proof of vessel occlusion, any recurrent Q-wave myocardial infarction in the territory of the stented vessel, or any death from cardiac causes. Late stent thrombosis was defined as any recurrent myocardial infarction with angiographic proof of vessel occlusion.
Study Design and Administration
Our study was proposed to the industry sponsor by four of the academic investigators: Drs. Henry, Spaulding, Teiger, and Slama. The same investigators wrote the final version of the protocol in collaboration with the industry sponsor, and the steering committee approved the design. Dr. Spaulding designed the statistical-analysis plan in collaboration with the sponsor.
Data were collected with the use of an electronic case-report form through a secured Internet-based Web site. A clinical research organization (Hesperion, Allschwil, Switzerland) performed all study monitoring, data management, and statistical analysis. The industry sponsor had no direct role in the collection or analysis of data. The steering committee had unrestricted access to the data and made all decisions about publication independently of the sponsor. Dr. Spaulding assumes overall responsibility for the integrity of the data, the accuracy of the data analyses, and the completeness of the material reported.
Statistical Analysis
The planned enrollment of 700 patients provided a statistical power of 80% to detect a 47% reduction in the rate of the primary end point at 1 year (from 17% in the uncoated-stent group to 9% in the sirolimus-stent group) with a 5% rate of false positive results in a two-sided test. The estimated enrollment for the angiographic substudy was based on an assumed in-stent late luminal loss of 0.43 mm in the sirolimus-stent group and 0.76 mm in the uncoated-stent group at 8 months, with an SD of 0.7 mm for both groups.2,9 After correction for loss to follow-up, we estimated that the enrollment of 200 patients provided 80% power with a false positive rate of 5% in a two-sided test.
All analyses were based on the intention to treat. The differences between the treatment groups were evaluated by analysis of variance or Wilcoxon rank-sum scores for continuous variables, if appropriate. Fisher's exact test was used for the analysis of categorical variables. The rate of survival free from target-vessel failure during the 1-year follow-up period was analyzed by the Kaplan–Meier method, and the difference in survival curves between the groups was assessed with the log-rank test. To test whether initial differences between the two treatment groups influenced the difference in outcome, multiple logistic-regression analysis was performed, controlling for all variables that were found to be significantly different at baseline. All statistical analyses were performed with the use of SAS software, version 8.2 (SAS Institute), and all reported P values are two-sided.
Results
Study Patients
Between October 2003 and September 2004, 2019 patients were screened and 715 were randomly assigned to the two treatment groups (356 to the sirolimus-stent group and 359 to the uncoated-stent group) (Figure 1). The most frequent reason for exclusion was fibrinolytic therapy for the index infarction. After randomization and treatment with the assigned stent, one patient in the sirolimus-stent group and two in the uncoated-stent group withdrew their consent to participate in the study.
Figure 1. Enrollment and Outcomes.
A subgroup of 210 patients were enrolled in the angiographic follow-up study; of these patients, 174 actually returned for follow-up angiography and 170 had qualifying angiograms.
Baseline Characteristics and Medications Used
Patients in the uncoated-stent group were slightly older and had a higher rate of previous PCI involving a nontarget coronary vessel, a lower rate of culprit lesions in the left anterior descending coronary artery, and a higher rate of triple-vessel disease (Table 1). In both groups, the median time from the onset of chest pain to hospital admission was less than 4 hours, and the median interval between arrival at the hospital and inflation of the balloon catheter was 60 minutes. The rate of use of glycoprotein IIb/IIIa–receptor inhibitors and the specific agents used did not vary significantly between the two groups (Table 2).
Table 1. Baseline Characteristics of the Patients.
Table 2. Procedural Results and Use of Medication during the Trial.
Clinical Outcome at 1 Year
The primary end point of the study — target-vessel failure at 1 year — occurred in 7.3% of patients in the sirolimus-stent group and in 14.3% in the uncoated-stent group (P=0.004) (Table 3). This difference was due almost entirely to significant differences in the rates of target-vessel revascularization. There was no significant difference between the sirolimus-stent group and the uncoated-stent group in the rates of death (2.3% and 2.2%, respectively; P=1.00), recurrent myocardial infarction (1.1% and 1.4%, respectively; P=1.00), or in-stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The actuarial rate of survival free from target-vessel failure was significantly higher in the sirolimus-stent group than in the uncoated-stent group (92.5% vs. 85.2%, P<0.001) (Figure 2).
Table 3. Clinical Events at 1 Year.
Figure 2. Actuarial Rate of Survival Free from Target-Vessel Failure among Patients Who Received Either a Sirolimus-Eluting Stent or an Uncoated Stent.
The rate of event-free survival was significantly higher in the group receiving a sirolimus-eluting stent than in the uncoated-stent group (P<0.001 by the log-rank test).
Multivariate analysis of the primary end point was performed to control for all significant variables in Table 1 and Table 2, including the use of clopidogrel, at 6 months. On the basis of this adjusted analysis, patients in the sirolimus-stent group were less than half as likely as those in the uncoated-stent group to have target-vessel failure (odds ratio, 0.41; P=0.001).
Angiographic Follow-up Study
Of the 210 patients included in the angiographic substudy, 174 underwent angiography at 8 months (82.8%) and 170 had qualifying angiograms (81.0%) (Figure 1 and Table 4). Patients in the angiographic study, as compared with those not in the study, tended to have higher rates of target-vessel failure (13.3% vs. 9.8%, P=0.19) and revascularization (12.4% vs. 8.4%, P=0.12), although these differences were not significant. However, the reduction in target-vessel failure in the sirolimus-stent groups was similar whether or not follow-up angiography was performed. At 8 months, sirolimus-eluting stents, as compared with uncoated stents, were associated with significant mean reductions in in-stent late luminal loss (0.14±0.49 mm vs. 0.83±0.52 mm, P<0.001) and in-stent restenosis (3.5% vs. 20.3%, P=0.001).
Table 4. Angiographic Measurements Obtained at the Time of the Index Procedure and at Follow-up at 8 Months
Discussion
In our trial, the use of sirolimus-eluting stents during primary PCI was associated with a reduction in the incidence of target-vessel failure at 1 year, as compared with the use of uncoated stents (7.3% vs. 14.3%, P=0.004). This difference was mainly driven by a reduction in the incidence of target-vessel revascularization. The results of the angiographic follow-up study suggest that the mechanism of benefit involves the suppression of neointimal proliferation among patients receiving sirolimus-eluting stents. The average in-stent late luminal loss in the sirolimus-stent group in our study was similar to that in previous studies of patients undergoing elective procedures.2,3,10
Rates of stent thrombosis were similar in the sirolimus-stent and uncoated-stent groups (3.4% and 3.6%, respectively; P=1.00). These rates were higher than those in previous studies. Reported rates of stent thrombosis vary according to the clinical presentation and the definition used. In recent trials of sirolimus-eluting stents that included only elective cases and used the same definition that we used in our trial, cumulative rates of stent thrombosis ranged from 0 to 1.1%.1,2,3,10 A higher rate (2.0%) was reported for sirolimus-eluting stents in the Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent for Coronary Revascularization (SIRTAX) trial (a comparison of the Cypher stent and the Taxus stent), which included both patients with and those without acute myocardial infarction.11 Elsewhere in this issue of the Journal, Laarman et al.12 report the results of the Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial, which showed a lower overall rate of stent thrombosis (1%) than did our study. However, angiographic proof was required for the diagnosis of stent thrombosis, and adjudication was not performed by an independent clinical events committee. The rates of stent thrombosis in the STRATEGY trial were 0% in the group receiving sirolimus-eluting stents and 3% in the group receiving uncoated stents.6 The 1-month rate of stent thrombosis in trials and registries with uncoated stents in acute myocardial infarction ranges from 0.9 to 4.3%.9,13,14,15,16,17,18,19
Procedural factors may have contributed to in-stent thrombosis in our study. Suboptimal procedural regimens of aspirin and heparin were allowed, with minimal aspirin doses of 100 mg and a minimal activated clotting time of 250 seconds, in contrast to recent recommendations.20 Furthermore, incomplete stent deployment favoring in-stent thrombosis cannot be ruled out, since the mean residual stenosis after the procedure was higher in both groups than that in previous studies.1,2 Finally, our definition of acute and subacute thrombosis was broad and included both death and repeated myocardial infarction if angiographic proof of stent patency was not available. In contrast, the definition of late thrombosis required angiographic proof of stent thrombosis. Accordingly, 30-day rates of stent thrombosis may have been overestimated and those of late thrombosis underestimated.
In comparison with our study, trials and registries of primary PCI in patients with acute myocardial infarction with ST-segment elevation have reported lower rates of repeated revascularization. In fact, our rates are similar to those of previous studies in patients in stable condition.9,13,14,15,16,17,18 This finding may be related to the effect of angiographic follow-up in a subgroup of patients, since revascularization rates tended to be higher among patients undergoing follow-up angiography. Nevertheless, the significant difference in the rates of target-vessel failure was maintained in the subgroup of patients without angiographic follow-up. Furthermore, noninvasive testing was performed on a routine basis at 6 months, an approach that may have led to an increased rate of ischemia-driven revascularization. Another factor may have been the speed of intervention (median interval from arrival at the hospital to inflation of the balloon catheter, 60 minutes), which left patients with a relatively large amount of viable myocardium at risk. In the PASSION trial, the revascularization rate in the group receiving uncoated stents was surprisingly low, and the incidence of the primary end point was lower than the expected rate. The enrollment of fewer patients with diabetes and more patients with larger target vessels in the PASSION trial may account for these differences.12
Our results cannot be generalized to all patients with acute myocardial infarction, since high-risk patients were excluded. Furthermore, our findings cannot be extended to other drug-eluting stents. Despite adjudication of events by an independent clinical events committee, the single-blind study design is an obvious limitation. This is especially true since the beneficial effect of sirolimus-eluting stents on the primary end point was almost entirely due to a reduction in target-vessel revascularization, which was performed by investigators who were not specifically blinded to the study assignment of each patient. Although an analysis that was adjusted for differences between treatment groups in baseline characteristics did not change the findings, other variables might have influenced them. Finally, an assessment of long-term safety and durability will require longer follow-up of a larger cohort of patients.
In summary, in our study, patients with acute myocardial infarction with ST-segment elevation who received sirolimus-eluting stents had a significantly lower rate of target-vessel failure than those who received uncoated stents. This difference was due almost entirely to a significant reduction in the rate of target-vessel revascularization. An angiographic follow-up study showed significant reductions in in-stent restenosis and in-stent late luminal loss.
Supported by Cordis, Johnson & Johnson.
Drs. Spaulding, Henry, Teiger, Beatt, Carrié, Slama, Varenne, and Bode report having received consulting or lecture fees from Cordis, Johnson & Johnson; and Dr. Beatt, grant support from Cordis, Johnson & Johnson. Drs. Cebrian, Stoll, and Snead are full-time employees of Cordis, Johnson & Johnson, and Drs. Stoll and Snead report holding equity interest in the company. No other potential conflict of interest relevant to this article was reported.
We are indebted to the patients who agreed to participate in the study; to the study coordinators, technicians, and nurses in the participating centers; and to Rita Dalal and Lorraine Wheeler for their editorial assistance.
* Members of the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON) are listed in the Appendix.
Source Information
From Assistance Publique–H?pitaux de Paris (AP–HP) Cochin Hospital, Paris 5 Medical School Rene Descartes University and INSERM U780, Paris (C.S., O.V.); AP–HP Lariboisiere Hospital, Paris 7 Medical School University Denis Diderot, Paris (P.H.); AP–HP Henri Mondor Hospital, Paris 12 Medical School, Créteil (E.T.); Hospital Rangueil, Toulouse (D.C.); and AP–HP Antoine Béclère Hospital, Paris 12 Medical School Paris Sud University, Clamart (M.S.S.) — all in France; Mayday University Hospital, London (K.B.); Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia (E.B.), and Azienda Universitaria Ospedaliera Careggi, Florence (M.M.) — both in Italy; Semmelweis University, Budapest (B.M.); Pauls Stradins University Hospital, Riga, Latvia (A.E.); Cordis (Johnson & Johnson), Waterloo, Belgium (A.C., H.-P.S.) and Warren, NJ (D.B.S.); and the University of Freiburg, Freiburg, Germany (C.B.).
Address reprint requests to Dr. Spaulding at Cochin Hospital, 27 rue du Faubourg St. Jacques, 75014 Paris, or at christian.spaulding@cch.ap-hop-paris.fr.
References
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Background Sirolimus-eluting stents reduce rates of restenosis and reintervention, as compared with uncoated stents. Data are limited regarding the safety and efficacy of such stents in primary percutaneous coronary intervention (PCI) for acute myocardial infarction with ST-segment elevation.
Methods We performed a single-blind, multicenter, prospectively randomized trial to compare sirolimus-eluting stents with uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation. The trial included 712 patients at 48 medical centers. The primary end point was target-vessel failure at 1 year after the procedure, defined as target-vessel–related death, recurrent myocardial infarction, or target-vessel revascularization. A follow-up angiographic substudy was performed at 8 months among 174 patients from selected centers.
Results The rate of the primary end point was significantly lower in the sirolimus-stent group than in the uncoated-stent group (7.3% vs. 14.3%, P=0.004). This reduction was driven by a decrease in the rate of target-vessel revascularization (5.6% and 13.4%, respectively; P<0.001). There was no significant difference between the two groups in the rate of death (2.3% and 2.2%, respectively; P=1.00), reinfarction (1.1% and 1.4%, respectively; P=1.00), or stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The degree of neointimal proliferation, as assessed by the mean (±SD) in-stent late luminal loss, was significantly lower in the sirolimus-stent group (0.14±0.49 mm, vs. 0.83±0.52 mm in the uncoated stent group; P<0.001).
Conclusions Among selected patients with acute myocardial infarction, the use of sirolimus-eluting stents significantly reduced the rate of target-vessel revascularization at 1 year. (ClinicalTrials.gov number, NCT00232830 .)
The use of sirolimus-eluting coronary-artery stents significantly reduces the incidence of restenosis after percutaneous coronary intervention (PCI), as compared with the use of uncoated stents.1,2,3 However, most randomized trials evaluating sirolimus-eluting stents have excluded patients with acute myocardial infarction with ST-segment elevation. Small series of patients with acute myocardial infarction have shown that the implantation of a sirolimus-eluting stent is associated with a low rate of restenosis.4,5 In the Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent vs. Abciximab and Bare-Metal Stent in Myocardial Infarction (STRATEGY) trial, the use of sirolimus-eluting stents reduced cardiovascular events, as compared with the use of uncoated stents, in a small group of patients undergoing primary PCI. However, the design of the trial specified the use of different glycoprotein IIb/IIIa inhibitors in each of the two groups to mitigate the greater cost of the drug-eluting stents, which raised the possibility that the benefit was influenced by the specific antiplatelet regimen.6
We therefore designed a prospective, randomized, multicenter trial comparing the effectiveness of sirolimus-eluting stents with that of uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation.
Methods
Enrollment and Assignment of Patients
We enrolled patients at 48 centers in 15 countries to participate in the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON). The study protocol was approved by the ethics committee at each participating institution and was conducted according to the principles of the Declaration of Helsinki. All patients gave written informed consent before enrollment. The study was conducted from October 2003 to October 2005.
Patients were eligible for the trial if their symptoms began less than 12 hours before catheterization and if the electrocardiogram showed ST-segment elevation (at least 1 mm in two or more standard leads or at least 2 mm in two or more contiguous precordial leads). Clinical criteria for exclusion included the administration of fibrinolytic agents for the index infarction, overt acute heart failure, a previously documented left ventricular ejection fraction of less than 30%, previous myocardial infarction, and an estimated life expectancy of less than 12 months.
Diagnostic Angiography and Primary Intervention
Patients were premedicated with aspirin (at least 100 mg) and unfractionated heparin (5000 to 10,000 IU). A loading dose of 300 mg of clopidogrel was administered either before or immediately after PCI. Coronary angiography was performed through the femoral or radial artery with the use of standard techniques.
Selection and Randomization
The trial protocol required visualization of the culprit lesion before randomization, in order to determine whether the angiographic criteria for inclusion or exclusion were met. Randomization was therefore performed either immediately after coronary angiography if the infarct-related vessel was spontaneously patent or after reestablishing coronary-artery blood flow by the placement of a guidewire or by balloon angioplasty.
Criteria for angiographic exclusion included previous PCI of the infarct-related vessel, excessive tortuosity or calcification, ostial or multiple lesions, massive thrombus in the infarct-related artery, bifurcation or left main coronary-artery disease, and severe multivessel disease requiring surgical revascularization. Patients were finally included and randomly assigned to a treatment group if the target lesion had a maximum length of 30 mm and was located in a native coronary artery with a reference-vessel diameter of 2.25 mm to 3.50 mm.
Random assignments to the treatment groups were generated in blocks of four or six and were distributed in sealed envelopes to each participating center. Patients were randomly assigned to the groups in a 1:1 ratio. Patients received either a sirolimus-eluting stent (Cypher or Cypher Select, Cordis, Johnson & Johnson) or any commercially available uncoated stent. Patients, but not investigators, were unaware of the treatment assignment.
Stent Implantation
Direct implantation of a stent without previous balloon angioplasty was allowed if the culprit lesion was adequately visualized either spontaneously or after guidewire placement. In the case of insufficient stent expansion, the stent was dilated after placement with another angioplasty balloon that was shorter than the total length of the stent. Oversizing and additional high-pressure dilation after the initial procedure were not recommended. If more than one stent was implanted, the same type of stent (sirolimus-eluting or uncoated) was recommended. Intervention in noninfarct-related arteries during the initial procedure was discouraged.
Heparin was administered throughout the procedure in order to maintain an activated clotting time of 250 seconds or longer. Administration of platelet glycoprotein IIb/IIIa–receptor inhibitors was left to the investigator's discretion.
Follow-up
Clinical follow-up was performed at 30 days and at 6 and 12 months after the procedure. Combined antiplatelet therapy included daily administration of aspirin (100 mg) and either clopidogrel (75 mg) or ticlopidine (250 mg). Dual antiplatelet therapy was recommended for at least 6 months, and aspirin therapy was recommended indefinitely. Noninvasive testing to assess for evidence of ischemia was recommended before repeated revascularization. Patients were unaware of their treatment assignments throughout the follow-up period.
Angiographic follow-up at 8 months was planned for 200 patients at 12 centers. In these selected centers, consecutive patients were enrolled in the angiographic substudy until the total number of patients reached 210.
Quantitative Coronary Angiography
Technicians at an independent angiographic core laboratory (BioImaging, Leiden, the Netherlands), who were unaware of treatment assignment, analyzed all angiographic images with the use of edge-detection techniques.7 Binary restenosis was defined as stenosis of more than 50% of the luminal diameter. Late luminal loss was calculated as the difference between the minimum luminal diameter immediately after the procedure and at 8 months. Flow in the infarct-related vessel was graded according to the Thrombolysis in Myocardial Infarction (TIMI) trial classification.8
Primary and Secondary End Points
The primary end point of the study was target-vessel failure, defined as the composite of target-vessel revascularization, recurrent infarction, or target-vessel–related death at 1 year. The clinical events committee reviewed and adjudicated all serious clinical events, including stent thrombosis.
Target-vessel revascularization was defined as repeated PCI or bypass grafting of the target vessel, driven by clinical symptoms of myocardial ischemia, a positive stress test, electrocardiographic evidence of ischemic changes at rest attributable to the target vessel, or an in-lesion stenosis of more than 70% of the reference luminal diameter by visual estimate.
Recurrent infarction was defined as the recurrence of clinical symptoms or the occurrence of electrocardiographic changes accompanied by a new elevation in levels of creatine kinase, creatine kinase MB enzyme, or both. The level of creatine kinase required for the diagnosis of reinfarction depended on the interval from the index infarction: the creatine kinase level had to be at least 1.5 times the previous value if new symptoms appeared within 48 hours and at least 3 times the upper limit of normal if new symptoms appeared after 48 hours.
Death from cardiac causes included death from acute myocardial infarction, cardiac perforation, or pericardial tamponade; an arrhythmia or conduction abnormality; complications of the interventional procedure at baseline; stroke (including bleeding) within 30 days after the procedure or in connection with the procedure; and all deaths that could not be clearly attributed to a noncardiac cause.
The secondary end points of the trial included the rate of successful treatment of the lesion, defined by residual stenosis of less than 50% of the reference luminal diameter on quantitative coronary analysis and a TIMI flow grade of 3, and in-stent late luminal loss on quantitative coronary analysis at 8 months.
Definition of Stent Thrombosis
Stent thrombosis was classified as acute if it occurred within 24 hours after the index procedure, subacute if it occurred between 1 and 30 days, and late if it occurred after 30 days. Acute and subacute stent thrombosis were defined as angiographic proof of vessel occlusion, any recurrent Q-wave myocardial infarction in the territory of the stented vessel, or any death from cardiac causes. Late stent thrombosis was defined as any recurrent myocardial infarction with angiographic proof of vessel occlusion.
Study Design and Administration
Our study was proposed to the industry sponsor by four of the academic investigators: Drs. Henry, Spaulding, Teiger, and Slama. The same investigators wrote the final version of the protocol in collaboration with the industry sponsor, and the steering committee approved the design. Dr. Spaulding designed the statistical-analysis plan in collaboration with the sponsor.
Data were collected with the use of an electronic case-report form through a secured Internet-based Web site. A clinical research organization (Hesperion, Allschwil, Switzerland) performed all study monitoring, data management, and statistical analysis. The industry sponsor had no direct role in the collection or analysis of data. The steering committee had unrestricted access to the data and made all decisions about publication independently of the sponsor. Dr. Spaulding assumes overall responsibility for the integrity of the data, the accuracy of the data analyses, and the completeness of the material reported.
Statistical Analysis
The planned enrollment of 700 patients provided a statistical power of 80% to detect a 47% reduction in the rate of the primary end point at 1 year (from 17% in the uncoated-stent group to 9% in the sirolimus-stent group) with a 5% rate of false positive results in a two-sided test. The estimated enrollment for the angiographic substudy was based on an assumed in-stent late luminal loss of 0.43 mm in the sirolimus-stent group and 0.76 mm in the uncoated-stent group at 8 months, with an SD of 0.7 mm for both groups.2,9 After correction for loss to follow-up, we estimated that the enrollment of 200 patients provided 80% power with a false positive rate of 5% in a two-sided test.
All analyses were based on the intention to treat. The differences between the treatment groups were evaluated by analysis of variance or Wilcoxon rank-sum scores for continuous variables, if appropriate. Fisher's exact test was used for the analysis of categorical variables. The rate of survival free from target-vessel failure during the 1-year follow-up period was analyzed by the Kaplan–Meier method, and the difference in survival curves between the groups was assessed with the log-rank test. To test whether initial differences between the two treatment groups influenced the difference in outcome, multiple logistic-regression analysis was performed, controlling for all variables that were found to be significantly different at baseline. All statistical analyses were performed with the use of SAS software, version 8.2 (SAS Institute), and all reported P values are two-sided.
Results
Study Patients
Between October 2003 and September 2004, 2019 patients were screened and 715 were randomly assigned to the two treatment groups (356 to the sirolimus-stent group and 359 to the uncoated-stent group) (Figure 1). The most frequent reason for exclusion was fibrinolytic therapy for the index infarction. After randomization and treatment with the assigned stent, one patient in the sirolimus-stent group and two in the uncoated-stent group withdrew their consent to participate in the study.
Figure 1. Enrollment and Outcomes.
A subgroup of 210 patients were enrolled in the angiographic follow-up study; of these patients, 174 actually returned for follow-up angiography and 170 had qualifying angiograms.
Baseline Characteristics and Medications Used
Patients in the uncoated-stent group were slightly older and had a higher rate of previous PCI involving a nontarget coronary vessel, a lower rate of culprit lesions in the left anterior descending coronary artery, and a higher rate of triple-vessel disease (Table 1). In both groups, the median time from the onset of chest pain to hospital admission was less than 4 hours, and the median interval between arrival at the hospital and inflation of the balloon catheter was 60 minutes. The rate of use of glycoprotein IIb/IIIa–receptor inhibitors and the specific agents used did not vary significantly between the two groups (Table 2).
Table 1. Baseline Characteristics of the Patients.
Table 2. Procedural Results and Use of Medication during the Trial.
Clinical Outcome at 1 Year
The primary end point of the study — target-vessel failure at 1 year — occurred in 7.3% of patients in the sirolimus-stent group and in 14.3% in the uncoated-stent group (P=0.004) (Table 3). This difference was due almost entirely to significant differences in the rates of target-vessel revascularization. There was no significant difference between the sirolimus-stent group and the uncoated-stent group in the rates of death (2.3% and 2.2%, respectively; P=1.00), recurrent myocardial infarction (1.1% and 1.4%, respectively; P=1.00), or in-stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The actuarial rate of survival free from target-vessel failure was significantly higher in the sirolimus-stent group than in the uncoated-stent group (92.5% vs. 85.2%, P<0.001) (Figure 2).
Table 3. Clinical Events at 1 Year.
Figure 2. Actuarial Rate of Survival Free from Target-Vessel Failure among Patients Who Received Either a Sirolimus-Eluting Stent or an Uncoated Stent.
The rate of event-free survival was significantly higher in the group receiving a sirolimus-eluting stent than in the uncoated-stent group (P<0.001 by the log-rank test).
Multivariate analysis of the primary end point was performed to control for all significant variables in Table 1 and Table 2, including the use of clopidogrel, at 6 months. On the basis of this adjusted analysis, patients in the sirolimus-stent group were less than half as likely as those in the uncoated-stent group to have target-vessel failure (odds ratio, 0.41; P=0.001).
Angiographic Follow-up Study
Of the 210 patients included in the angiographic substudy, 174 underwent angiography at 8 months (82.8%) and 170 had qualifying angiograms (81.0%) (Figure 1 and Table 4). Patients in the angiographic study, as compared with those not in the study, tended to have higher rates of target-vessel failure (13.3% vs. 9.8%, P=0.19) and revascularization (12.4% vs. 8.4%, P=0.12), although these differences were not significant. However, the reduction in target-vessel failure in the sirolimus-stent groups was similar whether or not follow-up angiography was performed. At 8 months, sirolimus-eluting stents, as compared with uncoated stents, were associated with significant mean reductions in in-stent late luminal loss (0.14±0.49 mm vs. 0.83±0.52 mm, P<0.001) and in-stent restenosis (3.5% vs. 20.3%, P=0.001).
Table 4. Angiographic Measurements Obtained at the Time of the Index Procedure and at Follow-up at 8 Months
Discussion
In our trial, the use of sirolimus-eluting stents during primary PCI was associated with a reduction in the incidence of target-vessel failure at 1 year, as compared with the use of uncoated stents (7.3% vs. 14.3%, P=0.004). This difference was mainly driven by a reduction in the incidence of target-vessel revascularization. The results of the angiographic follow-up study suggest that the mechanism of benefit involves the suppression of neointimal proliferation among patients receiving sirolimus-eluting stents. The average in-stent late luminal loss in the sirolimus-stent group in our study was similar to that in previous studies of patients undergoing elective procedures.2,3,10
Rates of stent thrombosis were similar in the sirolimus-stent and uncoated-stent groups (3.4% and 3.6%, respectively; P=1.00). These rates were higher than those in previous studies. Reported rates of stent thrombosis vary according to the clinical presentation and the definition used. In recent trials of sirolimus-eluting stents that included only elective cases and used the same definition that we used in our trial, cumulative rates of stent thrombosis ranged from 0 to 1.1%.1,2,3,10 A higher rate (2.0%) was reported for sirolimus-eluting stents in the Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent for Coronary Revascularization (SIRTAX) trial (a comparison of the Cypher stent and the Taxus stent), which included both patients with and those without acute myocardial infarction.11 Elsewhere in this issue of the Journal, Laarman et al.12 report the results of the Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial, which showed a lower overall rate of stent thrombosis (1%) than did our study. However, angiographic proof was required for the diagnosis of stent thrombosis, and adjudication was not performed by an independent clinical events committee. The rates of stent thrombosis in the STRATEGY trial were 0% in the group receiving sirolimus-eluting stents and 3% in the group receiving uncoated stents.6 The 1-month rate of stent thrombosis in trials and registries with uncoated stents in acute myocardial infarction ranges from 0.9 to 4.3%.9,13,14,15,16,17,18,19
Procedural factors may have contributed to in-stent thrombosis in our study. Suboptimal procedural regimens of aspirin and heparin were allowed, with minimal aspirin doses of 100 mg and a minimal activated clotting time of 250 seconds, in contrast to recent recommendations.20 Furthermore, incomplete stent deployment favoring in-stent thrombosis cannot be ruled out, since the mean residual stenosis after the procedure was higher in both groups than that in previous studies.1,2 Finally, our definition of acute and subacute thrombosis was broad and included both death and repeated myocardial infarction if angiographic proof of stent patency was not available. In contrast, the definition of late thrombosis required angiographic proof of stent thrombosis. Accordingly, 30-day rates of stent thrombosis may have been overestimated and those of late thrombosis underestimated.
In comparison with our study, trials and registries of primary PCI in patients with acute myocardial infarction with ST-segment elevation have reported lower rates of repeated revascularization. In fact, our rates are similar to those of previous studies in patients in stable condition.9,13,14,15,16,17,18 This finding may be related to the effect of angiographic follow-up in a subgroup of patients, since revascularization rates tended to be higher among patients undergoing follow-up angiography. Nevertheless, the significant difference in the rates of target-vessel failure was maintained in the subgroup of patients without angiographic follow-up. Furthermore, noninvasive testing was performed on a routine basis at 6 months, an approach that may have led to an increased rate of ischemia-driven revascularization. Another factor may have been the speed of intervention (median interval from arrival at the hospital to inflation of the balloon catheter, 60 minutes), which left patients with a relatively large amount of viable myocardium at risk. In the PASSION trial, the revascularization rate in the group receiving uncoated stents was surprisingly low, and the incidence of the primary end point was lower than the expected rate. The enrollment of fewer patients with diabetes and more patients with larger target vessels in the PASSION trial may account for these differences.12
Our results cannot be generalized to all patients with acute myocardial infarction, since high-risk patients were excluded. Furthermore, our findings cannot be extended to other drug-eluting stents. Despite adjudication of events by an independent clinical events committee, the single-blind study design is an obvious limitation. This is especially true since the beneficial effect of sirolimus-eluting stents on the primary end point was almost entirely due to a reduction in target-vessel revascularization, which was performed by investigators who were not specifically blinded to the study assignment of each patient. Although an analysis that was adjusted for differences between treatment groups in baseline characteristics did not change the findings, other variables might have influenced them. Finally, an assessment of long-term safety and durability will require longer follow-up of a larger cohort of patients.
In summary, in our study, patients with acute myocardial infarction with ST-segment elevation who received sirolimus-eluting stents had a significantly lower rate of target-vessel failure than those who received uncoated stents. This difference was due almost entirely to a significant reduction in the rate of target-vessel revascularization. An angiographic follow-up study showed significant reductions in in-stent restenosis and in-stent late luminal loss.
Supported by Cordis, Johnson & Johnson.
Drs. Spaulding, Henry, Teiger, Beatt, Carrié, Slama, Varenne, and Bode report having received consulting or lecture fees from Cordis, Johnson & Johnson; and Dr. Beatt, grant support from Cordis, Johnson & Johnson. Drs. Cebrian, Stoll, and Snead are full-time employees of Cordis, Johnson & Johnson, and Drs. Stoll and Snead report holding equity interest in the company. No other potential conflict of interest relevant to this article was reported.
We are indebted to the patients who agreed to participate in the study; to the study coordinators, technicians, and nurses in the participating centers; and to Rita Dalal and Lorraine Wheeler for their editorial assistance.
* Members of the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON) are listed in the Appendix.
Source Information
From Assistance Publique–H?pitaux de Paris (AP–HP) Cochin Hospital, Paris 5 Medical School Rene Descartes University and INSERM U780, Paris (C.S., O.V.); AP–HP Lariboisiere Hospital, Paris 7 Medical School University Denis Diderot, Paris (P.H.); AP–HP Henri Mondor Hospital, Paris 12 Medical School, Créteil (E.T.); Hospital Rangueil, Toulouse (D.C.); and AP–HP Antoine Béclère Hospital, Paris 12 Medical School Paris Sud University, Clamart (M.S.S.) — all in France; Mayday University Hospital, London (K.B.); Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia (E.B.), and Azienda Universitaria Ospedaliera Careggi, Florence (M.M.) — both in Italy; Semmelweis University, Budapest (B.M.); Pauls Stradins University Hospital, Riga, Latvia (A.E.); Cordis (Johnson & Johnson), Waterloo, Belgium (A.C., H.-P.S.) and Warren, NJ (D.B.S.); and the University of Freiburg, Freiburg, Germany (C.B.).
Address reprint requests to Dr. Spaulding at Cochin Hospital, 27 rue du Faubourg St. Jacques, 75014 Paris, or at christian.spaulding@cch.ap-hop-paris.fr.
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