Author + information
- Received August 9, 1999
- Revision received December 10, 1999
- Accepted February 3, 2000
- Published online June 1, 2000.
- ↵*Reprint requests and correspondence: Dr. Luc Maillard, Unité de Cardiologie Interventionnelle, Hôpital Trousseau, 37044 Tours Cedex, France
- Khalife Khalife, MD†
- Philippe Gabriel Steg, MD, FACC‡
- Patrick Serruys, MD, PhD, FACC‡
- Farzin Beygui, MD§
- Jean-Leon Guermonprez, MD∥
- Christian M. Spaulding, MD¶
- Jean-Marc Boulenc, MD#
- Janusz Lipiecki, MD∗∗
- Antoine Lafont, MD, PhD††
- Philippe Brunel, MD‡‡
- Gilles Grollier, MD§§
- Rene Koning, MD∥∥
- Pierre Coste, MD¶¶
- Xavier Favereau, MD##
- Bernard Lancelin, MD∗∗∗
- Eric Van Belle, MD, PhD†††
In a multicenter, randomized trial, systematic stenting using the Wiktor stent was compared to conventional balloon angioplasty with provisional stenting for the treatment of acute myocardial infarction (AMI).
Primary angioplasty in AMI is limited by in-hospital recurrent ischemia and a high restenosis rate.
A total of 211 patients with AMI <12 h from symptom onset, with an occluded native coronary artery, were randomly assigned to systematic stenting (n = 101) or balloon angioplasty (n = 110). The primary end point was the binary six-month restenosis rate determined by core laboratory quantitative angiographic analysis.
Angiographic success (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 and residual diameter stenosis <50%) was achieved in 86% of the patients in the stent group and in 82.7% of those in the balloon angioplasty group (p = 0.5). Compared with the 3% cross-over in the stent group, cross-over to stenting was required in 36.4% of patients in the balloon angioplasty group (p = 0.0001). Six-month binary restenosis (≥50% residual stenosis) rates were 25.3% in the stent group and 39.6% in the balloon angioplasty group (p = 0.04). At six months, the event-free survival rates were 81.2% in the stent group and 72.7% in the balloon angioplasty group (p = 0.14), and the repeat revascularization rates were 16.8% and 26.4%, respectively (p = 0.1). At one year, the event-free survival rates were 80.2% in the stent group and 71.8% in the balloon angioplasty group (p = 0.16), and the repeat revascularization rates were 17.8% and 28.2%, respectively (p = 0.1).
In the setting of primary angioplasty for AMI, as compared with a strategy of conventional balloon angioplasty, systematic stenting using the Wiktor stent results in lower rates of angiographic restenosis.
Primary coronary angioplasty for acute myocardial infarction (AMI) has been demonstrated to be a valuable method of reperfusion, resulting in lower rates of mortality, recurrent myocardial infarction and stroke, as compared with thrombolytic therapy (1–4). However, early recurrent ischemia still occurs in up to 15% of patients after an initially successful procedure (4,5), and late restenosis (40% to 50%) requiring repeat revascularization in the first six months remains disappointingly high (6–8). Compared with balloon angioplasty, elective coronary stenting has been shown to reduce both restenosis and the need for target lesion revascularization during follow-up, resulting in an improved late clinical outcome (9,10). Coronary stenting is no longer considered as a contraindication in thrombus-containing lesions (11,12) and may potentially overcome the limitations of balloon angioplasty in the setting of AMI (13–16). We report the results of the second STENTing In acute Myocardial infarction (STENTIM-2) study, a multicenter, randomized clinical trial comparing systematic coronary stenting using the Wiktor (Medtronic) stent to conventional balloon angioplasty with provisional stenting for the treatment of AMI.
STENTIM-2 is a multicenter, randomized trial comparing systematic coronary stenting using the Wiktor stent to conventional balloon angioplasty with provisional stenting for the treatment of AMI. The study was designed and powered to compare the rates of binary angiographic restenosis at systematic six-month angiographic follow-up.
The primary end point was binary angiographic restenosis, defined as ≥50% residual stenosis on the follow-up angiogram. Secondary end points included procedural success, defined as residual stenosis <50%, associated with Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 (17,18) and a composite end point combining either: 1) death; 2) recurrent myocardial infarction, defined as recurrent symptoms lasting >30 min despite nitrate therapy with new electrocardiographic (ECG) changes and either recurrent elevation of cardiac enzymes or emergency angiographic confirmation of an occluded culprit vessel; or 3) repeat revascularization of the target lesion, which included either repeat angioplasty or bypass surgery of the target vessel for restenosis with objective myocardial ischemia. This composite end point was evaluated at 6- and 12-month follow-up.
Secondary end points also included 1) recurrent ischemia, defined as recurrent symptoms consistent with angina and ECG changes sensitive to nitroglycerin and lasting <30 min, with no recurrent elevation of cardiac enzymes; and 2) reocclusion of the infarct-related artery, defined as TIMI flow grade 0 or 1 with >50% residual diameter stenosis on the follow-up angiogram of a previously patent vessel.
Additional end points included cerebrovascular accidents, access site bleeding, need for vascular repair or transfusion. Revascularization of other lesions was not considered an end point.
Patients >18 years old with prolonged nitrate-resistant chest pain seen within 12 h of onset and ST segment elevation were selected. Exclusion criteria included participation in another study in the last month; thrombolytic therapy; cardiogenic shock; history of coronary artery bypass graft surgery; percutaneous transluminal coronary angioplasty (PTCA) within the previous six months; contraindications to heparin, aspirin or ticlopidine, such as allergy, thrombocytopenia or hemorrhagic diasthesis; severe renal or liver failure; and weight <40 or >100 kg. All patients had ECG and enzyme confirmation of an AMI.
Emergency management and catheterization
Patients received a 500-mg intravenous bolus of aspirin and at least 5,000 IU of intravenous heparin (additional boluses were given as appropriate, according to the duration of the procedure). Coronary and left ventricular (LV) angiography was performed with the femoral approach using standard techniques. Angiographic inclusion criteria included 1) vessel diameter <3.00 mm by local on-line quantitative coronary analysis after maximal dilation induced by intracoronary nitroglycerin; 2) TIMI flow grade <3; and 3) culprit lesion diameter stenosis >70%. Bifurcation lesions involving a major side branch, left main coronary artery disease (stenosis >50%) and massively calcified lesions were excluded. Patients were also excluded if the infarct-related artery could not be identified or if they presented with severe multiple-vessel disease requiring emergency bypass surgery.
After coronary angiography and before crossing the lesion with a guide wire, the patients were randomly assigned by computer to either conventional balloon angioplasty or stent placement. The randomization sequence was designed to ensure balanced randomization at each center. Recruitment was limited to 25 patients per center.
Angioplasty was performed using standard techniques. The 6F guiding catheters were recommended. Operators were instructed to attempt to achieve a residual stenosis <30%. Stenting was performed using the Wiktor GX stent (Medtronic), which is a 16-mm-long coil stent. Expansion is obtained by inflating the balloon catheter at 12 atm (19–21). Additional stents were placed according to operator judgment to treat residual dissections. In the balloon angioplasty group, cross-over to stent placement was allowed for occlusive (bail-out) or nonocclusive extensive (type C or more) dissections that could not be successfully treated by repeated prolonged balloon inflations (22), a suboptimal result with residual stenosis of >50% or persistent slow flow (TIMI flow grade <3) (23).
The femoral sheath was removed, and hemostasis was obtained by manual compression as soon as the activated partial thromboplastin time was <60 s. All patients then received 100 international U of activity of low molecular weight heparin subcutaneously twice daily for at least 48 h, as well as 160 to 300 mg/day of aspirin (24). In addition, ticlopidine (500 mg/day) was prescribed for one month to all patients with stents. Angiotensin-converting enzyme inhibitors and beta-blockers were administered according to established guidelines.
Clinical and angiographic follow-up
Clinical follow-up was obtained at six months and one year. Six-month repeat coronary angiography was performed after a routine stress test. Angiography performed before four months was allowed on the basis of clinical indications. If restenosis was not found, a new angiogram was required after four months. All angiograms were sent to a core laboratory (Cardialysis, Rotterdam, the Netherlands) for analysis using the Cardiovascular Angiography Analysis System and previously described methods (25). The TIMI frame count was performed on all angiograms (23).
Clinical and angiographic data were forwarded to the Data Coordinating Center at the University of Tours, France for statistical analysis. All adverse events were analyzed by the members of the Critical Events Committee. Analysis was done on an intention-to-treat basis.
Study centers and investigators were selected on the basis of their experience with primary angioplasty for AMI. A yearly case load of >150 per center and >50 per investigator was required.
The study protocol was approved by the Institutional Review Board of the Tours Hospital according to French law, and written consent was obtained from all patients. The study was conducted according to the Declaration of Helsinki.
Sample size estimates (n = 180) were based on an assumed rate of restenosis of 50% (including a 10% occlusion rate) in the angioplasty group and a 50% relative reduction in the stent group (two-sided test with an alpha error of 0.025 and a power of 0.95). To compensate for unsuccessful interventions and losses to follow-up, the sample was enlarged by 10% (n = 200). Results are expressed as the mean value ± SD for continuous variables. The two-tailed t test was used to assess differences between the treatment groups. Categoric data are presented as rates and were compared using the chi-square test or the Fisher exact test. Freedom from clinical end points was analyzed using Kaplan-Meier survival curves. Differences between the treatment groups were compared using the log-rank test.
Between September 1997 and September 1998, 216 patients were randomly assigned to either balloon angioplasty (n = 112) or systematic stent implantation (n = 104). Of these 216 patients, five successfully treated patients were excluded by the Critical Events Committee because of major protocol violations. The final study group comprised 211 patients, with 101 and 110 patients in the stent and balloon angioplasty groups, respectively (Fig. 1). Baseline clinical (Table 1) and angiographic characteristics (Table 2) were similar between the groups.
Angiographic success (TIMI flow grade 3 and residual diameter stenosis <50%) was achieved in 86% and 82.7% of patients in the stent and balloon angioplasty groups, respectively (p = 0.5). Of the 101 patients assigned to stenting, three did not receive a stent—one because of failure to cross the lesion and two because of stent delivery failure. Those three patients were treated with balloon angioplasty only. Of the 110 patients assigned to balloon angioplasty, 40 ultimately required a stent. Cross-over to stenting was thus seen in 36.4% of the balloon angioplasty group, whereas cross-over to balloon angioplasty was seen in 3% of the stent group (p < 0.001). Indications for cross-over to stenting included bail-out in 17.5%, nonocclusive extensive dissections in 15%, a suboptimal result in 57.5% or persistent slow flow (TIMI flow grade 1 or 2) in 10% of patients. No stent delivery failure was observed in this group. Procedural results are provided in Table 3. The patients’ mean hospital stay was 10.0 ± 5.5 days in the balloon angioplasty group and 10.4 ± 8.9 days in the stent group (p = 0.71). In-hospital clinical events are shown in Table 4; there were no differences between the groups. One death occurred in the stent group due to free wall rupture. Freedom from in-hospital major adverse cardiac events was similar in both groups (95% in the stent group vs. 94.5% in the balloon angioplasty group, p = 0.87).
Angiographic results (Table 5 )
There was no difference in the baseline culprit lesion angiographic characteristics. The minimal lumen diameter after the procedure was greater in the stent group than in the balloon angioplasty group (2.38 ± 0.39 vs. 2.11 ± 0.49 mm, p < 0.001), resulting in a larger early gain (2.28 ± 0.48 vs. 1.99 ± 0.53 mm, p < 0.001). Six-month angiographic follow-up was obtained in 90% of eligible patients. The binary restenosis rate was 25.3% in the stent group and 39.6% in the balloon angioplasty group (p = 0.04); this included 7.2% and 6.3% reocclusion rates in each group, respectively (p = 0.79). Cumulative distributions of minimal lumen diameter and percent stenosis are illustrated in Figure 2.
Clinical follow-up was available for all patients (Table 4). At six months, the event-free survival rates were 81.2% in the stent group and 72.7% in the balloon angioplasty group (p = 0.14) (Fig. 3), and the repeat revascularization rates were 16.8% and 26.4%, respectively (p = 0.1) (Fig. 4). There was a nonsignificant trend toward fewer repeat angioplasties in the stent group versus the balloon angioplasty group (15.8% vs. 26.4%, p = 0.06). These trends were sustained at one-year follow-up; the event-free survival rates were 80.2% and 71.8% (p = 0.16) and the repeat revascularization rates were 17.8% and 28.2% in the stent group and balloon angioplasty group, respectively (p = 0.1).
This randomized, multicenter trial shows that systematic coronary stenting during primary angioplasty for AMI significantly reduces the rates of six-month angiographic binary restenosis. This difference was associated with fewer clinical events and the need for target vessel revascularization at six-month and one-year follow-up.
Use of ticlopidine and aspirin
Systematic stenting in the setting of primary angioplasty was feasible and safe (13–15), as demonstrated by the high success rate for stent deployment (97%) and the low in-hospital mortality and morbidity rates. This may be partially ascribed to the adjunctive prescription of ticlopidine and aspirin, which has been shown to reduce major events after elective coronary stenting (24,26–29), and to the selection of experienced centers and operators.
In contrast to other trials of stenting in primary angioplasty (30–32), in STENTIM-2 randomization was performed before attempted recanalization, avoiding a bias toward selection of “ideal” lesions for stenting. Our results are therefore relevant to daily clinical practice. Despite these broad angiographic inclusion criteria, the in-hospital rates of occlusion and the need for repeat revascularization appear to be low in both groups, in comparison to previously reported reocclusion rates up to 15% after balloon angioplasty for AMI (4,5), and are comparable to those of nonrandomized trials of stenting for AMI (16). The cross-over rate to provisional stenting (36.4%) was higher than previously reported (30–32) and probably reflects the current momentum of clinical practice toward wider indications for stenting after incomplete or unsatisfactory balloon angioplasty results (33). This may in part explain the very low rate of in-hospital deaths and complications.
Restenosis rate and event-free survival
This study was designed and powered to evaluate the six-month angiographic restenosis rate. Systematic stenting, compared with balloon angioplasty, significantly reduced the restenosis rate. This was associated, at six-month follow-up, with a 31.3% relative reduction in coronary ischemic events and a 36.8% relative reduction in the need for target vessel revascularization in the stent group versus the balloon angioplasty group, even though the protocol mandated that revascularization be driven by noninvasive demonstration of ischemia. At one-year follow-up, 80.2% of patients in the stent group were event free. The study was not powered to detect differences in clinical outcome or LV ejection fraction, although there appears to be an interesting and consistent improved event-free survival in the stent group at six- and 12-month follow-up. The similar event-free survival rates between the groups during the hospital period and the benefit in the stent group at both six and 12 months are likely due to the reduction in restenosis rates, as suggested by similar survival and revascularization rates at six months. A larger sample may have yielded a greater clinical benefit of systematic stenting.
The results of the study must be interpreted with caution given the sample size and the exclusion of high risk patients, such as those with hemodynamic compromise or failed thrombolysis. In addition, the protocol did not mandate adjunctive use of glycoprotein IIb/IIIa inhibitors. Recent studies have suggested benefit in terms of procedural and short-term results with abciximab during primary PTCA (34–36), although this benefit was not sustained at six months (35). Only a small fraction of the patients enrolled in STENTIM-2 received abciximab (3% in each group). Ongoing randomized trials are currently evaluating the association between abciximab and primary stenting for AMI. One of the limitations of the present study was that only patients with stents received ticlopidine. However, in this open trial, it was deemed unethical by the Institutional Review Board to administer ticlopidine to the patients not receiving stents, considering the potential for severe, life-threatening hematologic complications, even though these are rare. In addition, ticlopidine has not been shown to have any impact on restenosis, which was the primary end point of the trial. Despite these potential limitations, STENTIM-2 involved randomization of unselected lesions and incorporated rigorous and blinded adjudication of clinical and angiographic end points. Our results are therefore clinically relevant.
Systematic stenting during primary angioplasty for AMI is safe and feasible. It is associated with a reduction in six-month restenosis and fewer clinical events and target vessel revascularization at six months and one year. This suggests that systematic stenting may be of benefit for patients with AMI treated with primary PTCA.
We are indebted to C. Cassiram and C. Aublant for their technical assistance.
Institutions and investigators
CHU Tours (n = 25): L. Maillard, B. Desveaux, L. Quilliet, G. Pacouret, B. Charbonnier and Ph. Raynaud; CH Mulhouse (n = 25): J.-P. Monassier and M. Hamon; CH Metz (n = 25): K. Khalife, F. Aboujaoude, J.-P. Rinaldi, F. Benhamed, M. Boursier and S. Alsagher; CHU Bichat, Paris (n = 23): P. G. Steg, H. Benamer, L. Feldman, D. Himbert, P. Aubry and J.-M. Juliard; CHU Necker, Paris (n = 17): F. Beygui, C. Le Feuvre, D. Catuli and J.-P. Metzger; CHU Broussais, Paris (n = 14): J.-L. Guermonprez, S. Battaglia, K. Boughalem and P. Henry; CHU Cochin, Paris (n = 13): C. Spaulding, R. Cador, J. Monsegu, A. Py, K. Benhamda, P. Richard and F. Belaouchi; Clinique St. Joseph, Colmar (n = 13): J.-M. Boulenc, A. Verdun, O. Katz, Y. Gottwalles, P.-L. Clermont and P. Valentin; CHU Clermont-Ferrand (n = 10): J. Lipiecki, B. Citron and L. Sarfati; CHU Boucicaut, Paris (n = 10): A. Lafont, S. Rahal, P. Durand, K. Bougrini, F. Addad and F. Labarthe; CHU Nantes (n = 10): Ph. Brunel and D. Crochet; CHU Caen (n = 10): G. Grollier, E. Lecluse, R. Sabatier, B. Valette, J. C. Potier and M. Hamon; CHU Rouen (n = 9): R. Koning, H. Eltchaninoff, C. Tron, B. Baala and A. Cribier; CHU Bordeaux (n = 4): P. Coste, S. Sempe, P. Jais and P. Besse; CC Marie Lannelongue, Le Plessis Robinson (n = 4): B. Lancelin, S. El Hadad, C. Caussin and C.-Y. Angel; CMC Parly 2, Le Chesnay (n = 4): X. Favereau, Y. Guerin and T. Corcos; CHU Lille (n = 1): E. Van Belle, E. McFadden and M. E. Bertrand. (The number of patients enrolled at each center is given in parentheses.)
D. Blanchard, A. Cribier, J.-P. Metzger and P. G. Steg
Critical events committee
J. Boschat, P. Joly, J. Puel and B. Valeix
M. Hamon, E. McFadden, A. Lafont, L. Maillard, C. Spaulding and P. G. Steg
Medtronic Bakken Research Center, Maastricht, the Netherlands: M. Janssen and E. Kerkhofs; CHU Tours, France: P. Ardwidson
Core angiographic laboratory
Cardialysis, Rotterdam, the Netherlands: P. W. Serruys
M. Hamon, L. Maillard, J.-P. Monassier and Ph. Raynaud
↵§§§ The remaining investigators in the STENTing In acute Myocardial infarction (STENTIM-2) study group are listed in the Appendix.
☆ This study was supported in part by a grant from the Medtronic Corporation, France.
- acute myocardial infarction
- electrocardiogram or electrocardiographic
- left ventricle or ventricular
- percutaneous transluminal coronary angioplasty
- second STENTing In acute Myocardial infarction study
- Thrombolysis In Myocardial Infarction trial
- Received August 9, 1999.
- Revision received December 10, 1999.
- Accepted February 3, 2000.
- American College of Cardiology
- Mayo Coronary Care Unit and Catheterization Laboratory Groups,
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