Author + information
- Received September 12, 1997
- Revision received March 3, 1998
- Accepted March 16, 1998
- Published online July 1, 1998.
- Paolo Rubartelli, MDa,* (, )
- Luigi Niccoli, MD∗,
- Edoardo Verna, MD†,
- Corinna Giachero, MDa,
- Marco Zimarino, MD‡,
- Alessandro Fontanelli, MD§,
- Corrado Vassanelli, MD∥,
- Luigi Campolo, MD¶,
- Eugenio Martuscelli, MD#,
- Giorgio Tommasini, MD∗∗,
- Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche (GISSOC)
- ↵*Address for correspondence: Dr. Paolo Rubartelli, II Divisione di Cardiologia, Ospedale San Martino, 16132 Genoa, Italy
Objectives. In this multicenter, randomized trial we evaluated whether stent implantation after successful recanalization of a chronic coronary occlusion reduced the incidence of restenosis.
Background. Percutaneous transluminal coronary angioplasty (PTCA) in chronic total occlusions is associated with a higher rate of angiographic restenosis and reocclusion than PTCA in subtotal stenoses. Preliminary reports have suggested a decreased restenosis rate after stent implantation in coronary total occlusions.
Methods. We randomly assigned 110 patients with recanalized total occlusion to Palmaz-Schatz stent implantation, followed by 1 month of anticoagulant therapy versus no other treatment. The primary end point was the minimal lumen diameter (MLD) of the treated segment at follow-up, as determined by quantitative angiography at a core laboratory.
Results. Repeat coronary angiography was performed 9 months after the procedure in 88% of patients. The MLD (mean ± SD) at follow-up was 1.74 ± 0.88 mm in patients assigned to stent implantation and 0.85 ± .75 mm in patients assigned to PTCA (p < 0.001). Stent implantation was associated with a lower incidence of restenosis (defined as diameter stenosis ≥50% at follow-up) (32% vs. 68%, p < 0.001) and reocclusion (8% vs. 34%, p = 0.003) than balloon PTCA. Likewise, stent-treated patients had less recurrent ischemia (14% vs. 46%, p = 0.002) and target lesion revascularization (5.3% vs. 22%, p = 0.038), but experienced a longer hospital stay.
Conclusions. Palmaz-Schatz stent implantation after successful balloon PTCA of chronic total occlusions improves the midterm angiographic and clinical outcome and could be the preferred treatment option in selected patients with occluded vessels.
Percutaneous transluminal coronary angioplasty (PTCA) in chronic total occlusions has specific limitations. In this anatomic subset, the primary success rate is lower, whereas cost, fluoroscopy time and equipment use are higher than with PTCA in subtotal stenoses (1–3). In addition, chronic total occlusions that are successfully dilated have a higher rate of angiographic restenosis than subtotal stenoses (4,5). Although advances in PTCA technology and operator experience seem to have increased the success rate, the rate of angiographic restenosis does not appear to be lessened (3). Observational studies (6–9)have reported that implantation of the Palmaz-Schatz stent in chronic total occlusion was associated with a high immediate success rate and a restenosis rate lower than that reported for PTCA. Only one randomized trial (10)has compared balloon PTCA with Palmaz-Schatz coronary stent placement in selected patients with chronic total occlusion, showing a significant reduction in restenosis in the stent group.
Accordingly, we performed a multicenter, randomized trial to investigate whether Palmaz-Schatz stent implantation after successful balloon PTCA in a chronic total occlusion could improve the midterm angiographic and clinical results compared with balloon PTCA alone.
The study included patients scheduled to undergo PTCA of a chronic total occlusion at eight interventional cardiology centers with experience in Palmaz-Schatz coronary stenting. The study protocol was approved by the institutional review board at each participating center.
Both absolute occlusions (Thrombolysis in Myocardial Infarction [TIMI] flow grade 0), where no anterograde filling beyond the lesion was visible, and “functional” occlusions (TIMI flow grade 1) (11), where a faint, late anterograde flow with incomplete opacification of the distal vessel in the absence of a discernible lumen channel, were included. The duration of the occlusion was estimated from previous angiographic data or from the date of a myocardial infarction in the distribution of the occluded vessel. In the absence of these data, a worsening of anginal status was utilized to estimate the duration of the occlusion. Written informed consent was obtained from the eligible patients.
Inclusion and exclusion criteria
Patients symptomatic for chest pain or demonstrating inducible ischemia in the territory supplied by the occluded artery were selected for the study. The patients were suitable candidates for coronary artery bypass graft surgery. Patients with an acute myocardial infarction within 30 days or chest pain at rest within 7 days, as well as patients with contraindication to aspirin or warfarin sodium, were excluded. Total occlusions at a site of a previous PTCA and occlusions <30 days in duration were not considered.
Patients with significant left main disease were excluded. Vessels <3 mm in diameter or presenting severe tortuosity and lesions >13 mm or involving a major side branch were also excluded from consideration. In addition, evidence after recanalization of diffuse disease, additional stenosis >50% of the lumen diameter in the distal segment and complex dissection (type C to F according to Dorros et al. ) were exclusion criteria. The evaluation of these angiographic criteria was made by the investigators on visual inspection.
The target occlusion was treated by conventional balloon angioplasty. In some cases, the Magnum-Meier system (Schneider AG, Bülach, Switzerland) was used (13). In case of successful recanalization, defined as restoration of anterograde TIMI grade 2 or 3 flow with a residual stenosis <50% of the lumen diameter by visual estimation, the angiogram was immediately evaluated to establish whether all the angiographic inclusion criteria were met. The patients were then randomized, by means of sealed envelopes, to undergo stent implantation or no additional treatment.
All patients received aspirin (150 to 325 mg daily) and a calcium channel blocking agent starting at least 24 h before PTCA. During the procedure, heparin was given to maintain the activated clotting time >250 s.
In patients assigned to stent implantation, a standard Palmaz-Schatz stent (two 7-mm segments connected by a single 1-mm bridging strut) was manually crimped onto a conventional balloon catheter, usually the same balloon used to dilate the occlusion, and deployed to the target site. After implantation, the stent was further dilated by the same or a larger balloon to minimize the residual narrowing. Intravascular ultrasound imaging was not used. Four to 8 h after hemostasis at the site of arterial access was achieved, oral warfarin and heparin infusion were begun. The dosage was adjusted according to the prothrombin time and the activated partial thromboplastin time, respectively. Heparin infusion was continued until an international normalized ratio of 2.5 to 3.5 was obtained. Warfarin was continued for 1 month and aspirin indefinitely. Administration of intravenous low molecular weight dextran during the procedure and oral dipyridamole before or after the procedure was left to the investigator’s choice.
In patients randomized to PTCA alone, further balloon dilatations aimed to optimize the angiographic result were allowed. Crossover to stent implantation was considered in the case of worsening of the residual stenosis to >50% of the lumen diameter. After the procedure, oral aspirin was prescribed, but heparin or warfarin was not.
Patients were asked to return for clinical evaluation at 3, 6 and 9 months after the procedure. An exercise test was scheduled at 9 months. Coronary angiography was repeated at 9 months, or earlier if clinically indicated. An unscheduled angiogram obtained before 6 months could substitute for the follow-up angiogram if either a revascularization procedure of the target lesion was subsequently performed or a diameter stenosis >50% by quantitative coronary angiography was found.
The cineangiograms were reviewed at a central laboratory by an experienced cardiologist (G.T.) not involved in patient recruitment and treatment. For quantitative analysis, three angiograms taken just before and just after the procedure and at follow-up were considered for each patient. In all cases, angiography was performed in two orthogonal views after intracoronary injection of 0.2 mg of nitroglycerin. An end-diastolic frame in the projection best showing the lesion severity was selected and digitized by means of a cine video converter and a frame grabber mounted on a personal computer. Quantitative analysis was performed by a validated (14)edge detection algorithm (Intelligent Images QCA, Genoa, Italy). In validation studies on Plexiglas phantoms (14), this system was able to measure absolute dimensions with an accuracy of 0.028 mm and a precision of 0.054 mm.
The untapered section of the tip of either a 7F or 8F catheter was used for calibration. On the preintervention angiogram, the diameter of the vessel proximal to the occlusion was measured, and the minimal lumen diameter (MLD) was assumed to be 0. On the follow-up and post-intervention angiograms, the MLD and the interpolated reference diameter (RD), the latter defined as the computer-calculated estimation of the original coronary dimension at the site of the obstruction, were assessed. In case of a total occlusion at follow-up, either absolute or “functional” according to the same criteria used for preintervention occlusions, the MLD was assumed to be 0, and the diameter of the vessel proximal to the occlusion was substituted for the RD.
The following indexes were derived from the MLD and RD: Diameter stenosis(DS) was defined 1 minus (MLD divided by RD). Late losswas defined as the postintervention MLD minus the MLD at follow-up. Loss indexwas defined as late loss divided by the postintervention MLD, indicating the fraction of the lumen gain obtained with the procedure that is lost during follow-up. MLD and RD are measured in mm.
The primary end pointof the trial was the MLD at follow-up. The secondary angiographic end pointwas restenosis, defined as stenosis >50% of the lumen diameter at follow-up.
Secondary clinical end pointswere major ischemic events (death, myocardial infarction, coronary artery bypass graft surgery, repeat angioplasty, target lesion revascularization), symptomatic status at follow-up and hemorrhagic events (intracranial bleeding or complications requiring vascular surgery or blood transfusion). All evaluations were performed according to the intention to treat principle.
We calculated that, assuming a reduction in the restenosis rate from 50% (3)to 25%, with a sample size of 110 patients, the study would have had the power of 0.80 to detect a difference between the two groups with an alpha error of 0.05. We also considered that the use of MLD as a continuous variable, instead of a categoric approach (restenosis yes/no), would increase the power of the study to detect a difference between the two groups with the same sample size (15), compensating for losses at follow-up.
Categoric variables are expressed as absolute numbers and percent value. Continuous variables are expressed as mean value ± SD. Differences between groups were assessed with a continuity-adjusted chi-square test for categoric variables and with a two-tailed unpaired Student ttest for continuous variables; p < 0.05 was considered significant. Stepwise logistic regression analysis (SAS procedure, release 6.11 for Windows) was used to assess the relation between the MLD at follow-up and multiple clinical and angiographic variables, including demographics, coronary risk factors, symptom status, assigned treatment, occlusion type and location, vessel size and postprocedural angiographic data.
Baseline and procedural data
The study included 111 patients enrolled from June 1992 to May 1995. One patient assigned to balloon PTCA was subsequently excluded because the treated lesion was found to be subtotal. Thus, the study group included 56 patients assigned to stent placement and 54 patients assigned to balloon PTCA. The baseline clinical and angiographic characteristics are shown in Tables 1 and 2. ⇓A higher prevalence of previous myocardial infarction, single-vessel disease and left circumflex coronary artery occlusion was observed in the PTCA group, whereas the stent group had a higher prevalence of hypercholesterolemia and right coronary artery occlusion. However, these differences were not statistically significant. Other baseline clinical and angiographic characteristics were well matched.
In five patients assigned to stent placement (8.9%), implantation of a second stent was required. One patient assigned to balloon PTCA experienced intraprocedural reocclusion of the dilated lesion and underwent successful stent implantation. In four patients in the stent group and five in the balloon PTCA group, another subtotal lesion was dilated in addition to the study occlusion.
In the stent group, the maximal balloon diameter and the maximal balloon pressure were significantly higher than those used in the balloon PTCA group, a result of increasing use during the study period of slightly oversized balloons at high pressure for postimplantation dilation of the stent (16).
Follow-up angiography was performed at 9.1 ± 3.3 months in 97 patients (88%). Angiography was not repeated in 13 patients; 6 patients in each group refused the procedure; and 1 patient in the PTCA group died suddenly before follow-up angiography.
The quantitative coronary angiographic results are shown in Table 3. Stent implantation resulted in a larger postprocedural MLD than did PTCA, and this difference was maintained at follow-up (Fig. 1). Accordingly, the restenosis rate was 32.0% in the stent group versus 68.1% in the PTCA group. Likewise, a remarkable difference in the reocclusion rate was observed (8% in the stent group, 34% in the PTCA group). Late loss was not significantly different between the two groups, but the loss index was higher in the PTCA group. This difference was maintained when only nonoccluded vessels at follow-up were analyzed.
Stepwise logistic regression analysis identified assignment to stent implantation as the most important predictor of MLD at follow-up (p < 0.001). In addition, the presence of diabetes (p = 0.01) and the value of postprocedural diameter stenosis (p = 0.02) were negatively associated with MLD at follow-up.
Clinical events in-hospital and during follow-up
The clinical outcome of the patients is shown in Table 4. The rate of target lesion revascularization was significantly higher in the PTCA group than in the stent group (22% and 5.3%, respectively). Recurrent ischemia, defined as either angina or objective evidence of ischemia, was significantly more frequent in patients assigned to PTCA than in those assigned to stent placement (46% and 14%, respectively). All patients who underwent a repeat revascularization procedure had recurrent ischemia.
In the stent group, two patients underwent in-hospital emergency coronary artery bypass graft surgery because of stent thrombosis. Three patients required repeat PTCA: One underwent in-hospital PTCA because of stent thrombosis (this patient subsequently underwent emergency bypass surgery), and two underwent PTCA during follow-up (one for symptomatic reocclusion, one for progression of the disease in another vessel). Five patients with restenosis (one with total reocclusion) and recurrent ischemia were treated medically, and nine other patients with restenosis (two with a total reocclusion) remained asymptomatic.
In the PTCA group, one patient died suddenly 8 months after the procedure. Four patients underwent elective bypass surgery during follow-up (three for symptomatic reocclusion, one for progression of the disease in another vessel). Ten patients with symptomatic restenosis (four with total reocclusion) required an elective repeat PTCA during follow-up. Eighteen patients with restenosis (five with a total reocclusion) and recurrent ischemia were treated medically, and seven other patients with restenosis (four with a total reocclusion) remained asymptomatic.
Surgical repair of a femoral artery pseudoaneurysm was required in four patients assigned to stent implantation, two of whom also received a blood transfusion; no hemorrhagic complications were observed in the PTCA group.
Stenting versus PTCA
The Belgium and Netherland Stent (BENESTENT) study (17)and Stent Restenosis Study (STRESS) (18)compared balloon PTCA with the Palmaz-Schatz coronary stent in selected patients with subtotal stenoses and found a larger follow-up MLD and a lower restenosis rate in the stent group. However, this effect may not apply to chronic total occlusions because stent implantation in this lesion subset carries specific limitations, such as difficulty in assessing lesion length and vessel diameter, which may result in incomplete coverage of the lesion or incorrect stent expansion. In addition, a thrombus may be present in total occlusions, and the flow after recanalization is often slow, generally because of competitive collateral flow or distal embolization of thrombotic material. These aspects may favor thrombosis of the stent.
In the present trial, placement of a Palmaz-Schatz stent after balloon PTCA of a chronic total occlusion of a coronary artery was associated with markedly better angiographic results than those observed after PTCA alone (Table 3). At follow-up, the mean MLD in the stent group was twice as large as that in the PTCA group (1.74 vs. 0.85 mm), and the restenosis rate was half that of the PTCA group (32% vs. 68%). In addition, a fourfold reduction in the reocclusion rate was observed in patients assigned to stent implantation (8% vs. 34%). Accordingly, patients treated with a stent experienced a significant reduction in revascularization procedures and a better symptomatic status during follow-up. The longer hospital stay in patients assigned to stent implantation was due to institution of oral anticoagulant therapy. More recently, this strategy has been abandoned (7,9,16,19,20). Both the angiographic and clinical results in the present study are similar to those of the recently published Stenting in Chronic Coronary Occlusions (SICCO) study (10)despite methodologic differences between the two studies. In our study, cinefilms were evaluated at a core laboratory using a single method for quantitative angiography; in the SICCO trial, angiographic evaluation was performed at various clinical sites using different methods.
Mechanisms of benefit
Two recent studies (4,5)compared the midterm renarrowing process after PTCA of chronic total occlusions or subtotal stenoses by means of quantitative coronary angiography. These studies showed that the higher incidence of restenosis in recanalized total occlusions relates mainly to the higher rate of reocclusion at follow-up. Total occlusions demonstrated a reocclusion rate of 19% in both studies, whereas only 5% (4)or 7% (5)of subtotal stenoses treated by PTCA were found to be occluded at follow-up. When patients with reocclusion were excluded from analysis, the difference in restenosis between total occlusions and subtotal stenoses was no longer significant. An early reocclusion after successful PTCA may be clinically silent because of preexistent collateral flow and may be detected only at follow-up, contributing to the increased restenosis rate.
According to the currently available evidence, late restenosis is mainly due to vascular remodeling and neointimal proliferation; however, early reocclusion may share the mechanisms of post-PTCA abrupt closure—namely dissection, elastic recoil and thrombus formation. Another factor predisposing to early reocclusion may be a subintimal pathway of recanalization (21)as opposed to recanalization through the true lumen. This false lumen may be more prone to recoil or thrombotic occlusion.
Stent implantation may reduce early reocclusions by preventing elastic recoil and sealing intimal dissection. The optimization of lumen geometry may also increase the flow and reduce shear stress, which in turn may decrease platelet aggregation and thrombus formation, outweighing the intrinsic thrombogenicity of the stent.
In addition to prevention of reocclusion, the beneficial effect of stent implantation on late MLD is most probably related to the larger initial diameter provided by the stent; loss during follow-up is not significantly different between the two groups.
It is noteworthy that in our patients, the mean late loss after stent implantation was 0.76 mm (Table 3), a value similar to that observed in the BENESTENT (0.65 mm) (17)and STRESS trials (0.74 mm) (18), whereas the mean late loss after PTCA was higher in our study (1.06 mm) than in the BENESTENT and STRESS trials (0.32 and 0.38 mm, respectively). In other words, balloon PTCA of chronic total occlusions is associated with a higher late loss than that for subtotal stenoses (4,5), but this difference between chronic total occlusions and subtotal stenoses is not evident after stent implantation.
As in most multicenter trials, our study patients were selected according to patient or physician consent, operator evaluation of each individual case and the likelihood of patient follow-up. Therefore, our patients may not be completely representative of the overall population of patients with chronic coronary occlusion.
The relatively small sample size may be an important limitation because the study does not have the power to detect potential differences between the two study groups with regard to infrequent clinical events, such as death, myocardial infarction or major bleeding.
Because the patients in the stent group, but not those in the PTCA group, followed an anticoagulant regimen for 1 month, a potential effect of this therapy on the restenosis or reocclusion rate cannot be ruled out. Other clinical studies (22–26)have excluded any effect of anticoagulant therapy on restenosis after PTCA. Additionally, observational data (7,9)on stent implantation in chronic total occlusions without subsequent anticoagulation showed low restenosis and reocclusion rates, comparable to that observed after stenting followed by anticoagulant therapy.
Because early angiography was performed only for recurrent symptoms, neither the early reocclusion rate after PTCA nor the thrombosis rate after stenting could be ascertained. In both treatment groups, the reocclusion rate at follow-up could not represent the early reocclusion rate because early thrombosis may result in spontaneous thrombolysis and, conversely, late reocclusion may result from progressive restenosis.
In the present study, the elective stent implantation was performed after successful balloon PTCA. In subtotal stenoses, nonelective stenting for abrupt or threatened closure or a suboptimal result carries a higher risk of acute complications and restenosis than does elective stenting (27–29). Thus, the observed results may not apply to nonelective stent implantation motivated by early recoil, occlusive dissection or abrupt reocclusion after PTCA of chronic total occlusions.
In recent years, the technique of stent deployment has evolved substantially. Intravascular ultrasound observations have shown (30)that high pressure balloon dilation may improve the apposition of the stent to the vessel wall and provide a larger lumen. This in turn may decrease the risk of stent thrombosis (31), as well as the restenosis rate, the latter being inversely related to the acute lumen diameter (18). In addition, therapy with ticlopidine and aspirin has been shown (19)to reduce the incidence of stent thrombosis compared with oral anticoagulant therapy. In our study, only 18% of patients underwent dilation of the stent at high pressure (≥16 atm), and all patients in the stent group received conventional anticoagulant therapy. Therefore, it remains to be determined whether these technical advances may further improve the results of stenting in chronic total occlusions. In addition, the results of our study cannot be extrapolated to other stent types.
Implantation of a Palmaz-Schatz stent after successful PTCA of a chronic total occlusion results in a larger MLD at follow-up and decreases the restenosis and reocclusion rates. Accordingly, patients treated with a stent experience a significant reduction of repeat revascularization procedures and a better symptomatic status during the follow-up. Thus, Palmaz-Schatz stent implantation could be the preferred treatment option in selected patients with occluded coronary arteries that can be recanalized with PTCA.
We are grateful to Francesco Copello, MD, PhD, Genoa, for statistical analysis, and Eric Bates, MD, FACC, Ann Arbor, for helpful advice.
- Belgium and Netherland Stent study
- diameter stenosis
- Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche
- minimal lumen diameter
- percutaneous transluminal coronary angioplasty
- reference diameter
- Stenting in Chronic Coronary Occlusions
- Stent Restenosis Study
- Thrombolysis in Myocardial Infarction
- Received September 12, 1997.
- Revision received March 3, 1998.
- Accepted March 16, 1998.
- American College of Cardiology
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