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(Circulation. 1997;95:1145-1156.)
© 1997 American Heart Association, Inc.

Articles

Results of a Consecutive Series of Patients Receiving Only Antiplatelet Therapy After Optimized Stent Implantation

Comparison of Aspirin Alone Versus Combined Ticlopidine and Aspirin Therapy

Remo Albiero, MD; Patrick Hall, MD; Akira Itoh, MD; Simonetta Blengino, MD; Shigeru Nakamura, MD; Giovanni Martini, CCP; Massimo Ferraro, RT; Antonio Colombo, MD

Centro Cuore Columbus, Milan, Italy, and Toho University Ohashi Hospital (S.N.), Third Department of Internal Medicine, Tokyo, Japan.

Correspondence to Antonio Colombo, MD, Centro Cuore Columbus, Via M. Buonarroti 48, 20145 Milan, Italy. E-mail albire{at}chiostro.univr.it

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Previous studies have shown that stents can be inserted in coronary arteries of patients who are subsequently treated safely with antiplatelet therapy only (ticlopidine and/or aspirin) with a low incidence of stent thrombosis, provided that stent expansion is adequate and there are no other flow-limiting lesions present. However, it is unknown whether ticlopidine combined with aspirin is superior to aspirin alone in preventing stent thrombosis.

Methods and Results From March 1993 through July 1995, 801 consecutive patients assigned to receive either aspirin therapy alone (ASA, 264 patients, 348 lesions) or a combination of ticlopidine and aspirin (TIC-ASA, 537 patients, 737 lesions) after a successful stent insertion, in most accomplished with intravascular ultrasound guidance, were evaluated retrospectively. At 1 month, there was no difference in the ASA group compared with the TIC-ASA group in the rate of any stent thrombosis (1.9% versus 1.9%; P=1), subacute stent thrombosis (1.9% versus 1.3%; P=.5), cumulative major adverse clinical events (1.9% versus 2.0%; P=1), and peripheral vascular complications (0.5% versus 0.2%; P=.3). Medication side effects that required termination of antiplatelet therapy occurred only in 1.9% of patients in the TIC-ASA group (P=.04).

Conclusions At 1-month clinical follow-up, stent thrombosis and other adverse clinical outcomes were not significantly different between the ASA and TIC-ASA groups. Medication side effects occurred only in patients treated with ticlopidine. These results provide further evidence of the safety of treatment with antiplatelet therapy only after optimal stent implantation and support the efficacy of aspirin alone in preventing stent thrombosis.

Key Words: stents • ultrasonics • platelet aggregation inhibitors • coronary disease • aspirin

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Intracoronary stents have been shown to offer a valuable nonsurgical approach to the management of acute complications of failed angioplasty and to reduce restenosis compared with percutaneous transluminal coronary angioplasty in selected lesions.^{1 2 3 4} However, the need for an aggressive anticoagulation regimen to prevent stent thrombosis, together with the associated bleeding and vascular complications, has limited their clinical use. We have previously demonstrated that patients with adequate Palmaz-Schatz stent expansion, obtained with the use of high-pressure balloon dilation and confirmed by IVUS, can be treated safely with antiplatelet therapy (either ticlopidine and aspirin or aspirin alone) without anticoagulation, with significant reduction in vascular complications and hospital time and with a low stent thrombosis rate.^{5 6 7} Similarly favorable results have been reported by other investigators,^{8 9} stimulating the use of ticlopidine combined with aspirin.^{10 11 12 13 14 15 16 17 18 19} However, the superiority of ticlopidine combined with aspirin compared with aspirin alone in preventing stent thrombosis remains to be proved.^{7 20 21 22} The purpose of the present study was to retrospectively evaluate stent thrombosis rate and other adverse clinical events in a consecutive series of patients treated with aspirin alone compared with patients treated with a combination of ticlopidine and aspirin after successful optimized stent implantation.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
From March 1993 through July 1995, 1322 patients with a target lesion stenosis 70% by visual estimate in a major epicardial coronary artery associated with demonstrable ischemia underwent a coronary intervention. In 890 (67%) of these patients, an intracoronary stent implantation was attempted, with one or more stents successfully deployed in 847 patients (95%). The present study included 801 (94.6%) of these patients who, after the completion of a successful optimized stent implantation procedure, were treated with antiplatelet therapy only, without anticoagulation, using either ticlopidine and aspirin (TIC-ASA, 537 patients with 737 lesions) or aspirin alone (ASA, 264 patients with 348 lesions). Assignment to either regimen was based on physician preference (nonrandomized) in 575 patients. The remaining 226 patients included in the present study were part of a subsequent randomized trial.⁷ The reasons for exclusion of 46 eligible patients were as follows: (1) requirement of an anticoagulation therapy for other medical problems, enrollment in a stent trial that required the use of anticoagulation, or suboptimal result at the end of the procedure (40 patients); (2) treatment with an antiplatelet agent other than aspirin or ticlopidine (5 patients); and (3) inadvertent discontinuation of any antiplatelet agent after stent implantation (1 patient). Although a minority of patients underwent stent implantation without IVUS guidance, this was not an exclusion criterion for entry into the study.

Stent Implantation Procedure
Patients received aspirin 325 mg and calcium channel antagonists before stent deployment. A bolus of 10 000 U heparin was given after sheath insertion with a repeat bolus of 5000 U given as needed to maintain the activated clotting time >250 seconds. Patients were not given dextran or dipyridamole (Persantine) before, during, or after the stent procedure. Ticlopidine was not administered before the stent procedure. Six different types of stents were used during the course of this study: the Palmaz-Schatz stent (Johnson and Johnson Interventional Systems Co), the Gianturco-Roubin stent (Cook Cardiology, Cook, Inc), the Wiktor stent (Medtronic, Inc), the Micro stent (Applied Vascular Engineering), the Wallstent (Schneider Inc), and the Cordis stent (Cordis Corp). After balloon predilation, stents were delivered according to standard guidelines. The majority of the Palmaz-Schatz stents that were deployed were bare stents that were deployed by use of previously described techniques.^{5 23} After deployment of all stents, further dilations were performed with noncompliant balloons (for the Palmaz-Schatz stent and the Wallstent) or minimally compliant balloons (for all coiled stents). A final angiographic result with <10% residual diameter stenosis by visual estimate was considered acceptable. In the patients in whom IVUS was performed, all subsequent treatment decisions were based on the ultrasound results in conjunction with angiographic assessment. Indications for stenting and their definitions were as previously reported.^{5 7} Stent deployment performed for acute or threatened closure was considered bailout stent implantation. The use of >1 stent per lesion or per patient was considered multiple stents. Each stent was counted as one stent, except that the short Palmaz-Schatz stents and the 4- or 8-mm Micro stents were counted as half stents.

IVUS Equipment and Measurements
After stent implantation, 86% of stented coronary arteries underwent IVUS evaluation. Imaging was performed with the use of a 3.9F monorail system with a 25-MHz transducer–tipped catheter (Interpret Catheter, InterTherapy/CVIS) or a 2.9F or 3.5F monorail system with a 25-MHz transducer–tipped catheter (Cardiovascular Imaging System). Validation of quantitative measurements, pathological correlation with ultrasound measurements, and intraobserver and interobserver reproducibilities have been reported previously.^{5 24 25} Images were obtained with a manual or automated pullback system. Data were stored on 0.5-in Super VHS videotape. Measurement sites and criteria for optimized stent expansion were as previously reported.^{5 26 27}

Angiographic Analysis
Coronary angiograms were analyzed without knowledge of the IVUS data by experienced angiographers not involved in the stenting procedure. Patients received intracoronary nitroglycerin before baseline and final angiograms to achieve maximal vasodilation. Lesions were measured in matching views as previously reported^{7 28 29} and were characterized according to the modified American College of Cardiology–American Heart Association score.³⁰ A long lesion was defined as a single continuous narrowing extending for a length >15 mm. The presence of any thrombus was defined as a filling defect seen in multiple projections surrounded by contrast in the absence of calcification.

Postprocedure Medication Protocol
After a successful optimized result was achieved, no further heparin was administered and sheaths were removed in 4 to 6 hours. When procedures were performed in the evening, heparin was infused overnight and the sheaths were removed the following morning. Patients were treated either with a combination of ticlopidine 250 mg BID for 1 month and long-term aspirin 325 mg/d or long-term aspirin alone 325 mg/d.

Events and Follow-up
Death, emergency bypass surgery, elective bypass surgery, myocardial infarction (Q wave or non–Q wave), emergency repeat intervention (bailout stenting or repeat angioplasty), or vascular complications were considered major clinical events and were defined as previously reported.⁷ Acute thrombosis events were defined as angiographically documented occlusion with TIMI grade 0 flow at the stent site occurring within 24 hours of the stent procedure. Subacute thrombosis events were angiographically documented occlusions with TIMI grade 0 flow at the stent site occurring >24 hours after the stent procedure. Unexplained sudden death that occurred in the first month after a stent implantation procedure was considered a stent thrombosis event. Medication side effects were also recorded. The following "classic" risk factors³¹ for stent thrombosis were evaluated in patients who sustained stent thrombosis in both groups: (1) vessel diameter <3 mm; (2) final poststent inflation pressure <14 atm; (3) the presence of significant disease or dissection distal to the stent; (4) incomplete stent expansion by angiography or IVUS; (5) filling defects inside or adjacent to the stent; (6) final TIMI flow grade <3; (7) minimal final CSA <8 mm² by IVUS; (8) bailout stenting; (9) stent in the LAD; and (10) multiple stents in the same vessel. After a successful procedure, patients were generally discharged from the hospital within 1 to 2 days. Clinical follow-up was performed by telephone contact of all patients within 1 to 4 months of hospital discharge.

Statistics
The primary clinical analysis consisted of a comparison between the two study groups of the major clinical events and medication side effects at 1-month follow-up. Normally distributed data are expressed as the mean±SD. Not normally distributed data are expressed as a median with a range of values. Comparisons between continuous variables were performed by use of the two-tailed Student's t test. Comparisons of discrete variables were made by ² analysis. Differences were considered statistically significant at P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Patient Characteristics
The present study included 801 patients who received either aspirin alone (ASA, n=264) or a combination of ticlopidine and aspirin (TIC-ASA, n=537) after a successful optimized stent implantation. The percentage of patients who had diabetes in the ASA group was lower than in the TIC-ASA group (7% versus 14%; P=.003). Otherwise, there were no significant differences in the baseline characteristics of the two groups (Table 1). As shown in Table 2, the ASA group had a lower rate of LAD stent implantation (42% versus 55%, respectively) and a higher rate of right coronary artery stent implantation (37% versus 25%). Furthermore, in the ASA group versus the TIC-ASA group, the rate of long (>15 mm) lesions (14% versus 8%; P=.006) and the rate of total occlusions (12% versus 8%, P=.04) were higher. The indication for stenting and the type and number of stents that were deployed were not significantly different between the two groups (Table 3). There was a similar rate of lesions undergoing IVUS-guided stent placement in the ASA and TIC-ASA groups (87% versus 85%; P=.5). The rate of lesions in which only Palmaz-Schatz stents were deployed was lower in the ASA group than in the TIC-ASA group (59% versus 72%; P=.0001).

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Characteristics

View this table: [in this window] [in a new window]   Table 2. Angiographic Characteristics

View this table: [in this window] [in a new window]   Table 3. Stent Implantation Procedure Characteristics

Clinical Outcome After Stenting
Major clinical events occurred in 5 patients in the ASA group and in 11 patients in the TIC-ASA group (1.9% versus 2.0%; P>.99), with no difference in the incidence of death, emergency bypass surgery, repeat intervention, and myocardial infarction (non–Q wave and Q wave), as shown in Table 4. In the ASA group, all events were related to stent thrombosis. In the TIC-ASA group, there was one short-term event that was not a stent thrombosis event. This occurred in a patient who was readmitted to the hospital 20 days after an LAD stent implantation for recurrent exertional angina. The patient underwent coronary artery bypass surgery after angiography revealed a nonocclusive left main dissection and a patent stent site with no evidence of thrombus. Acute stent thrombosis occurred in 3 patients in the TIC-ASA group 2, 4, and 12 hours after the stent implantation procedure, respectively, whereas no acute stent thrombosis occurred in the ASA group (P=.3). Subacute stent thrombosis occurred in 5 patients in the ASA group and in 7 patients in the TIC-ASA group (1.9% versus 1.3%; P=.5) between 3 and 27 days after stent implantation. Stent thrombosis events were angiographically documented in all patients except 1 in the ASA group who had a witnessed sudden death 20 days after stenting. The death occurred without prodromic chest pain and in the absence of antecedent history of ventricular arrhythmias.

View this table: [in this window] [in a new window]   Table 4. Frequency of Primary Clinical and Angiographic Events at 1-Month Clinical Follow-up

Analysis of Patients With Subacute Stent Thrombosis
Tables 5 and 6 show demographic data and study results of the patients who suffered subacute stent thrombosis in the ASA (s-ASA, n=5) and TIC-ASA (s-TIC-ASA, n=7) groups. In every patient in both groups, there was a stent thrombosis–related major clinical event, either myocardial infarction in 9 patients or death in 3 patients. In the s-ASA group compared with the s-TIC-ASA group, there was a trend for a lower number of 10 of the classic risk factors for stent thrombosis (2.6±1.5 versus 4.0±1.4; median, 2 versus 4; range, 1 to 5 versus 2 to 6; P=.14). The different distribution of risk factors between the two groups is shown in Table 7.

View this table: [in this window] [in a new window]   Table 5. Demographic Data and Study Results of the 5 Patients in the s-ASA Group

View this table: [in this window] [in a new window]   Table 6. Demographic Data and Study Results of the 7 Patients in the s-TIC-ASA Group

View this table: [in this window] [in a new window]   Table 7. Distribution of 10 Classic Risk Factors for Subacute Stent Thrombosis in the 12 Patients in Whom the Event Occurred

Vascular Complications and Side Effects
Peripheral vascular complications occurred in 2 patients in the ASA group and in 1 patient in the TIC-ASA group (0.8% versus 0.2%; P=.3). Side effects requiring discontinuation of ticlopidine occurred in 10 patients in the TIC-ASA group, whereas none of the patients in the ASA group had to stop the treatment (1.9% versus 0%; P=.04). The reasons for stopping ticlopidine were leucopenia in 3 patients (0.6%), skin rash in 5 (0.9%), and gastritis in 2 (0.4%). One patient with leucopenia developed an absolute white cell count of <500/mm³ complicated by sepsis requiring hospitalization and treatment with broad-spectrum intravenous antibiotics for 2 weeks.

Angiographic and IVUS Analysis
Angiographic data were obtained in all lesions (Table 8). The baseline and final reference vessel diameters were similar in the ASA and TIC-ASA groups. The baseline MLD was smaller with a higher %DS in the ASA group than in the TIC-ASA group (MLD, 0.87±0.52 versus 0.95±0.54 mm, P=.02; %DS, 72±17% versus 69±18%, P=.005). At baseline, the lesions were longer in the ASA group than in the TIC-ASA group (11.4±7.6 versus 9.8±7.4 mm; P=.001). The final MLD was also smaller with a higher %DS in the ASA group than in the TIC-ASA group (MLD, 3.09±0.51 versus 3.23±0.56 mm, P=.0001; %DS, 0±13% versus -5±15%, P=.0001). Final balloon size and balloon-artery ratio were smaller in the ASA group than in the TIC-ASA group (balloon size, 3.42±0.46 versus 3.67±0.51 mm, P=.0001; balloon-artery ratio, 1.08±0.16 versus 1.18±0.19, P=.0001). Final quantitative IVUS measurements were performed on 303 of the ASA lesions and 630 of the TIC-ASA lesions (87% versus 85%; P=.5), as shown in Table 9. At the stent site in the ASA group, the final CSA was smaller and the percentage of plaque area was higher than in the TIC-ASA group (CSA, 7.5±2.3 versus 8.0±2.6 mm², P=.02; percentage of plaque area, 41±14% versus 36±16%, P=.0001). The lumen, vessel, and percentage of plaque area measurements at the distal and proximal reference vessel sites were otherwise similar in the two groups.

View this table: [in this window] [in a new window]   Table 8. Comparison of Baseline and Final Quantitative Angiography Results

View this table: [in this window] [in a new window]   Table 9. Comparison of Quantitative IVUS Results

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The incidence of stent thrombosis for the combined 801-patient cohort treated only with antiplatelets was 1.9%, a reflection of the relatively infrequent occurrence of this early angiographic complication after optimized stent implantation. This result provides further support for the concept that anticoagulation can be safely withheld when adequate stent expansion is achieved and flow is optimized in the stented and adjacent inflow and outflow segments. The study further demonstrated no significant difference in the total and subacute stent thrombosis rates between the ASA and the TIC-ASA groups. Although it is a nonrandomized trial and there is a difference in the number of patients in each group, the study represents the largest comparison in efficacy and safety between aspirin therapy alone and a combination of ticlopidine and aspirin after optimized stent implantation. In a smaller randomized study⁷ performed in Milan on 226 patients (who are included in the present study), the rate of stent thrombosis was 2.9% in the 103 patients treated with aspirin alone and 0.8% in the 123 patients treated with ticlopidine and aspirin, a statistically insignificant difference (P=.2). These results have been confirmed by the MUSIC Study investigators.²¹ In the 133 patients treated only with aspirin 100 mg/d after optimal placement of a single Palmaz-Schatz stent accomplished with IVUS guidance in de novo coronary lesions, a single case of stent thrombosis was reported at 1-month follow-up. The very low incidence of stent thrombosis in the MUSIC Study probably also results from its inclusion criteria, with enrollment of patients at very low risk for stent thrombosis. Similar outcomes have not been achieved in a recent nonrandomized comparative study²⁰ in 342 patients after native coronary artery stenting with the Cook stent. Treatment with the combination of ticlopidine 500 mg/d and aspirin 650 mg/d (n=296) was superior to aspirin 650 mg/d alone (n=46) in preventing stent thrombosis and death, which were significantly lower at 1-month follow-up in the combined ticlopidine and aspirin group than in the aspirin-only group (stent thrombosis, 0.7% versus 6.6%, P=.02; death, 0.3% versus 4.4%, P=.05, respectively). It is noteworthy that in that study, stent implantation was performed without IVUS guidance and the number of patients in the aspirin group was rather small. Despite the lack of comparative information from large randomized trials, there are numerous reports that seem to support a possible additional benefit from the use of ticlopidine after stenting.^{5 7 9 10 11 12 13 14 15 16 17 18 19} Morice et al¹⁸ reported the results of the French registry on coronary stenting without coumadin or IVUS guidance using only ticlopidine and aspirin in 1156 patients. In that registry, there was a 1.6% incidence of stent thrombosis and a bleeding or vascular complication rate of 0.6%.¹⁸ The preliminary results of the MUST trial³² showed a stent thrombosis rate of 1.2% in 260 patients treated with Palmaz-Schatz stent implantation without IVUS guidance in native arteries of 3 mm diameter who were subsequently managed with low doses of two antiplatelet agents (ticlopidine 250 mg/d for 1 month and aspirin 100 mg/d). In the TASTE Study,³³ the stent thrombosis rate in 545 consecutive patients treated with ticlopidine 500 mg/d and aspirin 200 mg/d was 0% after elective stenting compared with 5.4% in patients with bailout stents and 1.8% in patients with suboptimal percutaneous transluminal coronary angioplasty results. At the 1-month follow-up in the RAPS study,⁴¹ no acute or subacute stent thrombosis was reported in 43 patients with 57 lesions after Palmaz-Schatz stent implantation performed with IVUS guidance in 2.5-mm-diameter native coronary vessels; these patients were treated with combined ticlopidine 500 mg/d and aspirin 325 mg/d. That study confirms the safety and efficacy of antiplatelet therapy alone in patients with one established risk factor for stent thrombosis.

Clinical, Procedural, Angiographic, and IVUS Characteristics
In the present study, the patient groups were relatively well matched from a clinical perspective. Some procedural, angiographic, and IVUS data were significantly different in the two groups. It cannot be ruled out that the lower rate of LAD stenting in the ASA group compared with the TIC-ASA group is a reflection of physician preference to assign patients with successful LAD stent implantation to the TIC-ASA group during the initial experience of treatment with aspirin alone. The lower rate of lesions in which only Palmaz-Schatz stents were implanted in the ASA group may have resulted from the tendency to use other types of stents as experience progressed and aspirin-only therapy was evaluated. The differences in the baseline MLD and %DS between the two groups may be the result of a higher rate of baseline angiographic occlusions in the ASA group. The significant smaller final angiographic MLD, higher %DS, and smaller final CSA as assessed by IVUS may be a consequence of the use of smaller final balloons and of a lower balloon-to-artery ratio in the ASA group than in the TIC-ASA group (balloon size, 3.42±0.46 versus 3.67±0.51 mm, P=.0001; balloon-to-artery ratio, 1.08±0.16 versus 1.18±0.19, P=.0001). These differences are in part a reflection of adaptations to stent-implantation technique that have occurred since the initial experience with stent implantation without subsequent anticoagulation. The early experience primarily involved Palmaz-Schatz stents with postdilations performed with oversized balloons and postprocedure treatment exclusively with ticlopidine and aspirin. As understanding and experience progressed, postdilations were performed with more appropriately sized balloons, and poststent treatment with aspirin alone was evaluated.

The lack of a difference in the stent thrombosis rate between the groups might theoretically be influenced by the above-mentioned significant differences detected among the groups if their effects were imbalanced. In the present study, such an imbalance has not been noted. In particular, the differences that might have enhanced the protective effect on stent thrombosis of the combined antiplatelets in the TIC-ASA group (the more favorable stent expansion, the lower rate of long lesions and total occlusions, and the higher rate of only Palmaz-Schatz stent implantations) were equilibrated by the opposite effects associated with the higher rates of LAD stenting and diabetes in this group compared with the ASA group.

Subacute Stent Thrombosis
The subacute stent thrombosis event rate is a better reflection of the efficacy of the two antiplatelet regimens than the total incidence of stent thrombosis, which includes acute stent thrombosis events that occurred before the therapeutic effect of ticlopidine was complete. The subacute stent thrombosis rate was not significantly higher in the ASA group despite the theoretically lower potency of the aspirin-only regimen. Nevertheless, it could be reasoned that aspirin alone is less protective than a combined antiplatelet regimen. There was a trend for a lower number of the classic risk factors for subacute stent thrombosis in patients in the ASA group versus those in the TIC-ASA group who suffered such an event (2.6±1.5 versus 4.0±1.4 risk factors; median, 2 versus 4; range, 1 to 5 versus 2 to 6; P=.144), with an absence of filling defects indicative of thrombus, no TIMI flow grade <3, and no bailout stent procedures performed in the patients who suffered the event on aspirin. There was not a statistically higher prevalence of the bailout indication for stenting in the patients who suffered subacute stent thrombosis compared with those in whom the event did not occur (3 [25%] of 12 patients versus 77 [9.8%] of 789 patients; P=.20). Moreover, when there was a bailout indication for stenting, the subacute stent thrombosis rate was not significantly different between the TIC-ASA and the ASA groups (3 [5.9%] of 51 patients versus 0 [0%] of 29 patients; P=.47). Another interesting observation was that stent underexpansion, as reflected by a residual intrastent %DS>30% by quantitative coronary assessment, was present in 3 patients (1 in the s-ASA group and 2 in the s-TIC-ASA group); these were the only patients with subacute stent thrombosis who underwent stent implantation without IVUS guidance. This trend was not seen in the AVID study of 136 patients treated only with antiplatelet agents (ticlopidine 500 mg/d and aspirin 325 mg/d),³⁵ in which there was no difference in stent thrombosis rate at 1-month follow-up between the group randomized to stent placement directed by angiography and the group in which stent placement was directed by IVUS (2.9% versus 1.5%; P=NS). Two patients in the s-TIC-ASA group (patients 11 and 12) deserve further comment. In patient 11, two peripheral Wallstents (4.5x40 mm) and a half renal Palmaz-Schatz stent were implanted in the LAD. The presence of a distal dissection after reopening on the day of stent thrombosis required deployment of two Gianturco-Roubin stents. In this patient, the fact that a distal dissection was not initially recognized and the calculated length of the stented vessel was 91.5 mm by pullback of IVUS probably constituted important risk factors for subacute stent thrombosis that would be difficult to overcome by pharmacological therapy. Patient 12 was treated with a rotablator for two calcific lesions in the diagonal branch before stent placement that were dilated with a 3.5-mm balloon at 18 and 20 atm. The day of stent thrombosis, the vessel was reopened and stent dilation performed with a 3.5-mm balloon at 12 atm and a 4.0-mm balloon at 14 atm. By IVUS, minimal in-stent CSAs of 4.0 and 4.9 mm² were measured, respectively. IVUS showed a very hard fibrocalcific plaque at the tightest point of the stent. It was decided to implant a short Palmaz-Schatz stent inside the prior Palmaz-Schatz stent in this patient, a choice that significantly improved luminal area to a final CSA of 6.1 mm², suggesting that acute stent recoil or incomplete expansion was probably a concurrent cause for subacute stent thrombosis.

Peripheral Vascular Complications and Medication Side Effects
The low incidence of peripheral vascular complications that occurred is a reflection of one of the primary advantages of performing stent implantation without subsequent anticoagulation. There was no significant difference in the incidence of vascular complications between the two groups. Side effects were significantly higher in the TIC-ASA group than in the ASA group. The most important side effect of ticlopidine is bone marrow suppression, which manifests as leucopenia and disappears typically within 4 to 21 days after stopping the medication.^{36 37} Severe leucopenia with absolute neutrophil counts <500/mm³ occurred in one patient in the group treated with ticlopidine. This patient had to be hospitalized and required treatment of a life-threatening infection with intravenous antibiotics. Compared with the reported incidence of leucopenia (from 2% to 2.5%),^{36 38} we had a lower incidence of leucopenia (0.6%), probably related to the short duration of ticlopidine treatment. Because the ticlopidine-treatment group also included aspirin, it is possible that some of the side effects in that group were due to the combination of the two antiplatelet therapies. The use of ticlopidine alone, however, may not always be feasible because of the long half-life of the medication and the need to start treatment several days before the procedure so the full antiplatelet effect can be reached at the time of stent implantation.³⁹ The results of the present study and results from a previous experience without anticoagulation illustrate that the risk of leucopenia is not abolished and should be considered in the risk/benefit assessment.⁵

Mechanisms of Action of Ticlopidine and Aspirin
Aspirin exerts its effect of reducing thrombotic events by blocking the formation of thromboxane A₂, a powerful mediator of platelet degranulation, through the permanent inactivation of the cyclooxygenase enzyme. Ticlopidine has effects on platelet activities that are distinctly different from those of aspirin. The primary action of ticlopidine is to irreversibly block the binding of fibrinogen to platelets, an effect that appears to be 85% effective in inhibiting platelet aggregation, the final common pathway to the formation of thrombus.^{39 40} This effect is not associated with a conformational change in the glycoprotein IIb/IIIa receptor or an alteration of the platelet membrane, and the specific mechanism has not yet been elucidated.³⁸ Whether the combination of ticlopidine and aspirin provides a synergistic effect to reduce platelet activation and aggregation is unknown. The potential for such a synergistic effect is appealing given the difference in the principal mechanism of action of the two drugs and the incomplete effects of both agents in preventing platelet aggregation and thrombus formation.

Changing Clinical Perspectives
Although the results of this study indicate that there is no significant gain in clinical efficacy by combining ticlopidine with aspirin therapy, it is noteworthy that compared with the s-TIC-ASA group, the s-ASA group showed a trend for a lower number of the classic risk factors for stent thrombosis and a trend for a higher number of patients with fewer than three risk factors (60% versus 14%; P=.29), suggesting that aspirin alone could be less protective than the combined antiplatelet regimen in preventing subacute stent thrombosis. A provocative interpretation of these findings could be that patients with few risk factors for subacute stent thrombosis who nevertheless suffered the event could represent a subpopulation that does not respond to aspirin. Until the results of the ongoing prospective randomized trial of aspirin, aspirin plus warfarin, and aspirin plus ticlopidine (Stent Anti-Thrombotic Regimen Study)²² are known, it seems reasonable to recommend the following antiplatelet regimens for the prevention of subacute stent thrombosis: (1) aspirin therapy alone when only one or two risk factors are present and (2) ticlopidine with aspirin therapy when more than two risk factors are present. The occurrence of stent thrombosis in patients who received the combined antiplatelet therapy suggests that in the presence of a suboptimal result or multiple risk factors for stent thrombosis, this combination is not fully protective. In these circumstances, it is doubtful whether anticoagulant therapy is more protective, as suggested by a recent randomized trial⁴² in which anticoagulant therapy compared with antiplatelet therapy was associated with a higher incidence of thrombotic occlusion of the stented vessel at 1-month follow-up (5.4% versus 0.8%; P=.004). Future refinement in stent design with more predictable lesion coverage and stent coating may further reduce stent thrombosis even in settings not considered ideal at the present time. Preliminary experience from the Benestent II Pilot Study suggests that stents with covalently bound heparin may provide an additive measure of security in consistently reducing stent thrombosis.⁴³

Study Limitations
There are several limitations to the present study. The study was not randomized, and there were some baseline differences between the patients in the two groups. The study, however, does represent a large and nonselected experience from a single center that provides some insight into the efficacy and safety of stent implantation with either ticlopidine and aspirin or aspirin therapy alone in a setting of stent optimization, with the majority of the stent implantation procedures performed with IVUS guidance. It cannot be determined from the present study whether the ultrasound guidance had an equilibrating effect that minimized the differences in efficacy of the two antiplatelet regimens. Results of the French registry¹⁸ and preliminary results of the AVID study³⁵ suggest that IVUS guidance may not be necessary in the majority of patients.

Conclusions
The results of the present study provide further evidence of the safety of treatment with antiplatelet therapy only after optimal stent implantation and support the safety and efficacy of aspirin therapy alone. Further evidence from a prospective randomized trial that is now in progress²² may be necessary before definitive recommendations can be made as to the superiority of combined ticlopidine and aspirin compared with aspirin therapy alone in the prevention of stent thrombosis. Until then, it is reasonable to limit aspirin monotherapy to those patients who have no more than two of the classic risk factors for stent thrombosis after optimal stent implantation.

	Selected Abbreviations and Acronyms

 

%DS = percent diameter stenosis ASA = treatment with aspirin only CSA = cross-sectional area IVUS = intravascular ultrasound LAD = left anterior descending coronary artery MLD = minimum lumen diameter s-ASA = patients who suffered subacute stent thrombosis in the aspirin-only treatment group s-TIC-ASA = patients who suffered subacute stent thrombosis in the ticlopidine-plus-aspirin treatment group TIC-ASA = treatment with ticlopidine plus aspirin TIMI = Thrombolysis In Myocardial Infarction

Received May 21, 1996; revision received November 13, 1996; accepted November 14, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

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12. Colombo A, Maiello L, Nakamura S, Hall P, Blengino S, Finci L, Martini G. Preliminary experience of coronary stenting with the Micro^TM. Circulation. 1994;90(part 2):I-124. Abstract.
    
13. Russo RJ, Schatz RA, Sklar MA, Johnson AD, Tobis JM, Teirstein PS. Ultrasound guided coronary stent placement without prolonged systemic anticoagulation. J Am Coll Cardiol. 1995;25:50A. Abstract.
    
14. Blasini R, Mudra H, Schulen H, Regar E, Klauss V, Zitzman E, Paloncy R, Neller P, Neumann FJ, Richardt G, Schmitt C, Schomig A. Intravascular ultrasound guided optimized emergency coronary Palmaz-Schatz stent placement without post procedural systemic anticoagulation. J Am Coll Cardiol. 1995;25:197A. Abstract.
    
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