Major Benefit From Antiplatelet Therapy for Patients at High Risk for Adverse Cardiac Events After Coronary Palmaz-Schatz Stent Placement
Analysis of a Prospective Risk Stratification Protocol in the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial
Background The Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial is a randomized study in which antiplatelet therapy is compared with anticoagulant therapy after coronary stent placement, showing a significantly lower rate of noncardiac and cardiac events with antiplatelet therapy. The present study is a report of the analysis of a prospective risk stratification protocol in the ISAR Trial and the association with the incidence of adverse cardiac events and stent vessel occlusion.
Methods and Results In all 517 patients randomized in the ISAR Trial, risk stratification was done with a list of 18 clinical, procedural, and angiographic variables: 165 patients with two or fewer criteria were classified as low risk, 148 patients with three criteria were classified as intermediate risk, and 204 patients with four or more criteria were classified as high risk. Within a 30-day follow-up, cardiac event rate (death, myocardial infarction, repeat intervention) was 6.4% for high-risk, 3.4% for intermediate-risk, and 0% for low-risk patients (P<.01). Stent vessel occlusion occurred in 5.9%, 2.7%, and 0%, respectively (P<.01). There was no significant difference between anticoagulant and antiplatelet therapy in the low- and intermediate-risk groups. In high-risk patients, however, the cardiac event rate was 12.6% with anticoagulant therapy and 2.0% with antiplatelet therapy (P=.007), and the rate of stent vessel occlusion was 11.5% and 0%, respectively (P<.001).
Conclusions This risk stratification protocol can help to identify patients at risk for adverse cardiac events and stent vessel occlusion. Patients in the high-risk group had the most benefit from antiplatelet therapy. These data suggest that antiplatelet therapy is the therapy of choice after coronary stenting specifically for patients with acute ischemic syndromes, difficult procedures, or suboptimal final results.
Coronary stent placement is an established treatment for vessel closure after PTCA,1 2 3 and it reduces the rate of restenosis as an elective treatment in comparison with balloon angioplasty.4 5 Until recently, widespread clinical use was limited by severe and frequent hemorrhagic and peripheral vascular complications resulting from the stringent anticoagulant protocol after stent placement. This regimen had been recommended for the early period after the procedure to reduce the risk of thrombotic stent occlusions observed in earlier studies.6 7 However, this protocol did not eliminate this risk. More recently, several studies advocated the use of intensified antiplatelet therapy instead of anticoagulation, reporting a lower rate of noncardiac complications.8 9 However, this has been recommended only for patients considered to be at low risk for subsequent adverse cardiac events (ie, in patients with ≥3-mm-diameter arteries, without evidence for thrombus, in whom the stent has been optimally deployed, and in whom the indication for stenting had not been abrupt closure).10 We conducted the ISAR Trial, a prospective, randomized study, to compare the outcome of patients with two different antithrombotic regimens after coronary placement of Palmaz-Schatz stents: (1) combined antiplatelet therapy with ticlopidine plus aspirin or (2) conventional anticoagulant therapy with prolonged intravenous heparin, phenprocoumon (a coumarin derivative), and aspirin.11 Within a 30-day follow-up, there was a significant reduction in the risk for noncardiac as well as cardiac complications, and specifically for stent vessel occlusion in patients treated with combined antiplatelet therapy, compared with anticoagulation. The rationale of the ISAR Trial had been to include all patients with successful coronary stent placement, independent of any presumed risk factor or additional measurements of optimal stent expansion, such as intravascular ultrasound. During randomization for the ISAR Trial, all patients were prospectively stratified to three risk groups on the basis of the frequency of predefined risk criteria for subsequent adverse cardiac events. These clinical, angiographic, and procedural variables had been identified through previous experience in coronary stenting and PTCA. In the present study, we report the analysis of this prospective risk stratification protocol and the association of risk factors with the incidence of subsequent adverse cardiac events and stent vessel occlusion.
The study population consisted of patients with successful coronary stent placement who were randomized in the ISAR Trial.11 Indications for stenting were extensive coronary dissections after PTCA, complete vessel closure, residual stenosis of ≥30%, and lesions in venous bypass grafts. All patients with successful stenting (ie, stent at the desired position, residual stenosis <30%) who gave signed informed consent were eligible for randomization if there were no contraindications to the use of aspirin, ticlopidine, or phenprocoumon and no absolute indication for anticoagulation. Further exclusion criteria were stents primarily intended as a bridge to aortocoronary bypass grafting and cardiogenic shock or mechanical ventilation before PTCA.
Stent implantation of 7-mm or articulated 15-mm standard Palmaz-Schatz stents (Johnson & Johnson) was performed as previously described.3 Stents were hand-crimped on the angioplasty balloon catheters; balloon sizes for stent deployment were chosen with the intention of slightly oversizing the balloon. Additional high-pressure balloon catheters were used in the majority of patients. If necessary, multiple stents were used for complete coverage of the lesion. Intravascular ultrasound was not part of the protocol and therefore not used routinely.
Immediately after the intervention, patients were randomized, and the individual score of risk criteria was assessed by the operator responsible for the procedure on the basis of the data available at the end of the procedure. This list consisted of 18 criteria (Table 1⇓), and applicable criteria were checked on a protocol. Patients with two or fewer risk criteria were stratified to the low-risk group, patients with three criteria were stratified to the intermediate-risk group, and patients with four or more criteria were stratified to the high-risk group.
This list of 18 clinical, procedural, and angiographic variables for the risk stratification protocol had been assembled through consensus of the investigators before the initiation of the ISAR Trial (Table 1⇑). These variables were based on our previous experience (LAD stent, occlusion before stent)3 or had been described by other investigators (residual stenosis, residual dissection, MLD <3.2 mm, MLD <2.8 mm, thrombus after stent).12 13 14 Other variables defined complex lesion morphology (occlusion before PTCA, Y stent, side branch in stent jail, stent overlap, passage impossible) or had previously been considered as contraindications to stenting (acute MI, thrombus before PTCA, stent in left main) or used to identify patients who were excluded from several major studies on coronary stents (ostial stent, MLD <2.8 mm, and partial Y stent, MLD <3.2 mm).4 5 8 Furthermore, we intended to identify patients with well-known risk factors for adverse events after PTCA (occlusion before PTCA, residual stenosis, slow flow after stent, residual dissection).15 16 17 These 18 factors represent risks with presumably different prognostic impact. Some factors were intentionally redundant and not independent to weigh particular risks in subsets of patients. For example, a patient with acute MI would be classified by at least three factors: acute MI, thrombus before PTCA, and occlusion before PTCA. A patient with a small target vessel (ie, luminal diameter <2.5 mm) would automatically be classified by two factors: MLD <2.8 mm and MLD <3.2 mm.
Clinical Management After the Intervention
Clinical management was identical for the three risk groups. Arterial sheaths were removed when the PTT fell to <60 seconds. Immediately after pressure bandage application, a continuous heparin infusion, titrated to a PTT of 80 to 100 seconds, was started in all patients.
In patients assigned to antiplatelet therapy, heparin was discontinued 12 hours after the intervention. Ticlopidine (250 mg BID; Tiklyd; Sanofi-Winthrop) was started immediately after the procedure. Patients assigned to anticoagulation received the coumarin derivative phenprocoumon (Marcumar; Hoffmann-La Roche), and heparin infusion was continued for 5 to 10 days until a stable level of oral anticoagulation was achieved (target international normalized ratio, 3.5 to 4.5). Ticlopidine and phenprocoumon were both administered for 4 weeks, and all patients in both groups received 100 mg aspirin BID continuously.
Per protocol, all patients remained in the hospital for ≥10 days. ECGs were recorded daily. Repeat coronary angiography was performed in patients with suspected myocardial ischemia. All surviving patients were seen on an outpatient basis at 1 month after discharge.
Definition of Events
The ISAR Trial was designed to compare the outcome of patients with two different antithrombotic regimens. The present study focuses on two end points within a 30-day follow-up: adverse cardiac events defined as death due to cardiac causes, MI, or repeat intervention of the stented vessel (aortocoronary bypass surgery or repeat PTCA), and stent vessel occlusion. All deaths were considered cardiac in nature unless autopsy results established a noncardiac cause. The diagnosis of acute MI was based on typical chest pain lasting >30 minutes, new pathological Q waves not present in the baseline ECG, or an increase in creatine kinase to twice the upper limit of normal, with a concomitant rise in the MB isoenzyme. The diagnosis of recurrent MI was also based on a >30% increase in creatine kinase above previous values. Stent vessel occlusions were angiographically differentiated as either due to thrombotic occlusion of the stented segment or due to progressive dissection in vessel segments adjacent to the stented segment.
Data and Statistical Analysis
The frequency of the 18 risk criteria differentiating the two antithrombotic regimens was compared with the use of Fisher’s exact test. Differences in the distribution of risk criteria between the three risk groups were compared with one-way ANOVA. The effect of the 18 risk criteria together with the effect of the antithrombotic regimen (ie, anticoagulant therapy as risk factor) on the incidence of adverse cardiac events and stent vessel occlusion was analyzed univariately and multivariately with the logistic model.18 The selection of factors was based on a stepwise forward procedure. Comparison of the three risk groups with respect to adverse cardiac events and stent vessel occlusion was performed with isotonic regression analysis.19 Statistical significance was assumed at P<.05.
The frequencies of the 18 risk criteria are listed in Table 2⇓, with the two antithrombotic regimens differentiated. Eight individual criteria occurred in <10% of patients, eight others were applicable to >20% of patients, and only two were applicable to >40%. There were no significant differences in the frequency of any risk criteria between the two treatment groups.
The risk stratification protocol identified 165 patients with two or fewer risk criteria who were stratified to the low-risk group, 148 patients with three criteria composed the intermediate-risk group, and 204 patients with four or more criteria were part of the high-risk group. The frequency of the individual risk criteria in the three risk groups is illustrated in Table 3⇓.
Table 4⇓ summarizes the rates of adverse cardiac events. In a comparison of the three groups, there is a striking difference in cardiac event rates: while 15 events occurred in the high-risk group, there were 5 events in the intermediate-risk group and none in the low-risk group. This significant trend was seen in the rates of MI, repeat intervention, and stent vessel occlusion.
Tables 5⇓ and 6⇓ summarize the data and results from logistic regression analysis for the risk for adverse cardiac events and stent vessel occlusion. To account for the pivotal role of antithrombotic therapy for adverse cardiac events,11 anticoagulation was included as an additional variable for the analysis.
Logistic regression analysis for adverse cardiac events in Table 5⇑ identified five variables as independent risk factors for cardiac events (in the order of level of significance): large residual dissection, residual dissection, anticoagulation therapy, thrombus before PTCA, and LAD stent. All five risk factors were applicable to only 1 of 497 patients without any adverse cardiac event (0.2%). At least one of these five factors was applicable to 359 patients: 177 with anticoagulant therapy (68.1%) and 182 with antiplatelet therapy (70.8%; P=.56).
The analysis for stent vessel occlusion is illustrated in Table 6⇑; the identified independent risk factors were residual dissection, anticoagulation therapy, MLD <3.2 mm, and thrombus before PTCA. All four risk criteria were applicable to none of 501 patients without stent vessel occlusion. At least one of these three factors was applicable to 418 patients: 214 with anticoagulant therapy (82.3%) and 204 with antiplatelet therapy (79.4%; P=.46).
The Figure⇓ illustrates the rates of adverse cardiac events and stent vessel occlusion in the three risk groups differentiating the two antithrombotic regimens. With a very low incidence of events in the intermediate- and low-risk groups, there is no significant difference between the two regimens in these groups. However, in the high-risk group, there is a significant benefit for patients with antiplatelet therapy with respect to adverse cardiac events and stent vessel occlusion. The differences between the three risk groups are further contrasted by the subset of patients with thrombotic occlusion of the stent (Table 5⇑)—all 13 patients had anticoagulation therapy; 11 were in the high-risk group, 2 in the intermediate-risk group, and none in the low-risk group.
In the present study, we observed three main findings. First, the described prospective risk stratification protocol can help to identify patients at risk for adverse cardiac events. Second, the risk for adverse cardiac events is mainly confined to patients stratified to the high-risk group. Although this group congregated patients with acute coronary syndromes, complex procedures, and suboptimal final results, the rate of adverse cardiac events is comparable to that of previous reports in patients with stable angina and noncomplex lesions. Third, in a comparison of the incidence of events with anticoagulant versus antiplatelet therapy, patients in the high-risk group had the most benefit from antiplatelet therapy.
Patients in the ISAR Trial encompassed the entire spectrum of symptomatic coronary artery disease, even patients who had been excluded from several previous trials, such as patients with acute MI, with long lesions requiring the placement of several stents, or with technically complex lesions due to main stem, ostial, or bifurcational stenoses.4 5 11 Because the protocol of the study was designed to exclude only patients with specific indications or contraindications for any of the antithrombotic drugs and patients in cardiogenic shock, the rationale of the risk stratification protocol was to identify in particular these above-mentioned high-risk patients as well as patients in whom the final result was considered suboptimal due to residual dissections, impairment of large side branches, small final luminal diameter within the stent, or similar situations. Table 4⇑ illustrates well that our risk stratification protocol was highly successful in identifying patients at risk: three fourths of adverse cardiac events occurred in the high-risk group, one fourth occurred in the intermediate-risk group, and none occurred in the low-risk group.
The observed high incidence of adverse cardiac events in the high-risk group is, however, confined to patients with anticoagulation, ie, there is a particular benefit for patients with antiplatelet therapy in the high-risk group, with an 85% decrease in adverse cardiac events and an abolishment of stent vessel occlusion (from 11.5% to 0%). Because adverse cardiac event rates are very low in the intermediate- and low-risk groups, the sample sizes in the ISAR Trial are too small to allow detection of differences effected by the antithrombotic regimens in these risk groups.
Our risk stratification protocol comprised 18 different clinical, angiographic, and procedural variables. As illustrated in Table 2⇑, there was no significant difference between the frequencies of individual risk factors in the two regimen groups, as well as the distribution of the three risk groups. Furthermore, the average number of any applicable risk factors was identical in the two groups (3.2 criteria per patient). Regarding the significant factors identified by logistic regression analysis, there was a small but insignificant trend that suggested a bias against antiplatelet therapy in the number of patients in whom any of the five factors significant for adverse cardiac events was applicable and an insignificant trend for a bias against anticoagulant therapy in the analysis of stent vessel occlusion. These analyses together suggest that in the ISAR Trial, there is no relevant bias in the distribution of risk factors between the two antithrombotic regimen groups.
Although only nine applied to >10% of patients, logistic regression analysis was able to identify several variables to be predictive of adverse cardiac events as well as stent vessel occlusion, independent of the significant effect of the antithrombotic regimen as previously reported.11 Taking into account the very low rate of stent vessel occlusion and, in particular, the abolishment of thrombotic stent occlusion with antiplatelet therapy, this analysis indicates that there is a particular benefit from antiplatelet therapy for patients with thrombi at the beginning of a PTCA procedure, for patients with vessels <3.2 mm, and, most notably, for patients with residual dissections that could not be covered by the stent (Table 6⇑). For adverse cardiac events, this benefit is extended to patients with target lesions in the LAD, and the significance of a residual coronary dissection is further emphasized (Table 5⇑).
The study population encompasses patients who were part of the ISAR Trial. The sample size was calculated to detect differences in clinical outcome between patients with two antithrombotic regimens after coronary stent placement. With the low incidence of adverse events in patients with antiplatelet therapy and in all patients in the low-risk group, a larger cohort of patients is necessary for a comprehensive analysis of risk factors in these subgroups. A larger study with antiplatelet therapy alone is currently under way to detect the small differences in this group of patients.
This analysis included 18 factors composing a subjective, inhomogeneous, and limited list of clinical, procedural, and angiographic variables. This list had been assembled through consensus of the investigators prior to the initiation of the ISAR Trial to stratify all patients. This list of risk factors is by far not comprehensive, and a retrospective risk analysis would require assessment of numerous additional factors. However, our analysis is based on a prospective risk stratification that has to take into account potential limitations and subjectivity.
Neither bleeding complications nor discontinuation of anticoagulant therapy was part of our prospective protocol. These factors have been associated with subsequent thrombotic stent vessel occlusion.3 20 However, such an association has not been verified in the ISAR Trial: only 2 of 16 patients with stent vessel occlusion had bleeding complications before this event, and only 1 of 24 patients in whom anticoagulant therapy had been discontinued due to bleeding or vascular complications subsequently had stent vessel occlusion.11
The results of this study validate our prospective risk stratification protocol after coronary stent placement, as it can help to identify patients at risk for adverse cardiac events and stent vessel occlusion. This protocol distinguished patients at high risk according to clinical, angiographic, or procedural data, identifying patients with acute ischemic syndromes, with complex lesions, complicated stenting procedures, or suboptimal results after stent placement. Independent risk factors for adverse events were residual dissection after stent placement, thrombus in target lesion before PTCA, target lesion in LAD, and MLD within the stented segment <3.2 mm. The previously reported results from the ISAR Trial have illustrated the significant benefit from antiplatelet therapy in comparison with anticoagulation.11 The data of the present study demonstrate that patients in the high-risk group have the highest benefit from subsequent antiplatelet therapy with aspirin plus ticlopidine. With the assumption that patients do not have a particular indication for anticoagulant therapy (ie, for prosthetic heart valves), these data suggest that there is no subgroup of patients with an indication for anticoagulation after coronary stent placement. Therefore, combined antiplatelet therapy is not a less effective or less reliable therapy after coronary stent placement, indicated only after optimal stent deployment and expansion; it is in fact the therapy of choice, in particular for patients with acute ischemic syndromes or suboptimal final results.
Selected Abbreviations and Acronyms
|PTT||=||partial thromboplastin time|
|ISAR Trial||=||Intracoronary Stenting and Antithrombotic Regimen Trial|
|MLD||=||minimal luminal diameter|
|PTCA||=||percutaneous transluminal coronary angioplasty|
We thank E.M. Zitzmann-Roth, MD; A. Novosel, BSc; and R. Ahlers, BSc; for their assistance in preparation of the data. We especially thank F.J. Neumann, MD; E. Alt, MD; C. Schmitt, MD; and G. Richardt, MD; who performed many of the stent procedures, for their careful assessment of the risk stratification protocol.
- Received September 16, 1996.
- Revision received November 14, 1996.
- Accepted November 22, 1996.
- Copyright © 1997 by American Heart Association
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