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CLINICAL STUDIES

Clopidogrel as adjunctive antiplatelet therapy during coronary stenting

^a Prairie Educational and Research Cooperative, Division of Cardiology, Southern Illinois University School of Medicine, Springfield, Illinois, USA

Manuscript received April 2, 1999; revised manuscript received July 27, 1999, accepted August 27, 1999.

Reprint requests and correspondence: Dr. Gregory J. Mishkel, Prairie Cardiovascular Consultants, Ltd., P.O. Box 19420, Springfield, Illinois 62794-9420
pccl{at}fgi.net

	Abstract

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OBJECTIVES

We examined the procedural and 30-day clinical outcomes among patients receiving aspirin and either ticlopidine or clopidogrel during coronary stenting.

BACKGROUND

Ticlopidine-plus-aspirin has become standard antiplatelet therapy for the prevention of thrombotic complications after coronary stenting. Clopidogrel has a similar mechanism of action as ticlopidine, but both its efficacy and its safety as a pharmacologic adjunct to coronary stenting have not been well described.

METHODS

This single-center, prospective analysis examined the in-hospital procedural and 30-day clinical outcomes among 875 consecutive patients undergoing coronary stenting who received adjunctive aspirin and either clopidogrel (n = 514; 58.7%) or ticlopidine (n = 361; 41.3%) therapy.

RESULTS

Procedural success rates were similar among the clopidogrel- (99.6%) and ticlopidine-treated patients (99.4%). Subacute stent thrombosis (i.e., >24 h 30 days) occurred in one clopidogrel-treated (0.2%) and in one ticlopidine-treated (0.3%) patient (p = 0.99). By 30 days following the index procedure, the combined rates of death, nonfatal myocardial infarction and need for target vessel revascularization were similar among patients who received either clopidogrel (2.1%) or ticlopidine (1.4%; p = 0.57) therapy.

CONCLUSIONS

In this analysis the antiplatelet combination therapy of aspirin-plus-clopidogrel was an effective regimen for preventing thrombotic complications and major adverse cardiovascular events among a broad spectrum of patients undergoing coronary artery stenting.

Abbreviations and Acronyms   ACT = activated clotting time   AST = acute stent thrombosis   CABG = coronary artery bypass grafting   CK = creatinine kinase   GPIIb/IIIa = glycoprotein IIb/IIIa inhibitor   MACE = major adverse cardiac event   MI = myocardial infarction   PCI = percutaneous coronary intervention   SST = subacute stent thrombosis   TVR = target vessel revascularization

Attempts to suppress stent thrombosis using aggressive anticoagulant regimens unfortunately contributed to excess hemorrhagic and vascular access site complications and prolonged hospitalization (3,4). The recognition of the major contribution of platelet-mediated mechanisms to the pathogenesis of stent thrombosis led to the evaluation of the antiplatelet combination of aspirin-plus-ticlopidine, with resultant stent thrombosis rates of <1% and concomitant reduced hemorrhagic complication rates.

Ticlopidine (Ticlid^TM), a member of the thienopyridine class of antiplatelet agents, acts by blocking the platelet adenosine diphosphate receptor, interferes with the binding of von Willebrand factor to platelet receptors, and has synergistic antiplatelet activity when used in combination with aspirin (5,6). Recent reports (7,8) highlight the potential hematological toxicity (neutropenia and thrombotic thrombocytopenic purpura) associated with even brief courses of ticlopidine.

Clopidogrel (Plavix^TM), a new thienopyridine derivative with a similar mechanism of action as ticlopidine, has been shown to be an effective antiplatelet agent for patients with cardiovascular disease (9), with a favorable tolerability and safety profile. The incidence of severe neutropenia with clopidogrel is similar to that with aspirin (0.04% vs. 0.02%, respectively), and less than that reported with ticlopidine (0.08% to 2.5%) (10). Unlike ticlopidine, thrombotic thrombocytopenic purpura has not been reported with clopidogrel use. These findings have led to the proposal of clopidogrel as a potentially "safer" alternative to ticlopidine; however, the clinical efficacy and safety of the clopidogrel-plus-aspirin antiplatelet combination during coronary stenting is relatively unknown.

Thus, the purpose of this study was to compare the in-hospital and 30-day procedural and clinical outcomes among a broad spectrum of patients who received aspirin and either clopidogrel or ticlopidine as adjunctive antiplatelet therapy during coronary stenting.

	Methods

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Study population.   Demographic, procedural and outcome information of patients undergoing a PCI at the Prairie Heart Institute at St. John’s Hospital and the Heart Center at Memorial Medical Center, Springfield, Illinois, were prospectively entered into an electronic database. From this database we examined a consecutive cohort of patients undergoing elective or bail-out coronary stenting procedures over a five-month period between March 1, 1998, until July 31, 1998. Analysis was performed on all patients who received combination aspirin and either ticlopidine or clopidogrel either prior to or immediately following the index coronary stenting procedure.

Coronary procedures and adjunctive antiplatelet therapy.   Before balloon dilation, a heparin bolus was administered to achieve an activated clotting time (ACT) of >200 and >300 s among patients who did and did not receive glycoprotein IIb/IIIa inhibitor (GPIIb/IIIa) antagonists, respectively. Subsequent coronary artery stenting was performed using current Food and Drug Administration-approved stents. Following stent implantation, high-pressure (12 atmospheres) balloon inflation and use of larger balloon sizes were routinely performed with the goal of achieving a post-stent balloon-to-vessel ratio of 1.0 to 1.2:1. Use of intravascular ultrasound following stent implantation was not routine. The use of pre- and intra-procedural intracoronary nitroglycerin, postprocedural use of heparin, and the adjunctive use of platelet GPIIb/IIIa inhibitors were left to the discretion of the individual operators.

All patients received pretreatment with oral aspirin (325 mg) prior to the procedure and continued daily thereafter. Patients received either oral ticlopidine (250 mg twice daily) or oral clopidogrel (75 mg once daily) at the discretion of the operator. A loading dose of either drug was not used, and therapy was either initiated the night before or the day of the index procedure and continued for two to four weeks following the procedure.

Vascular access sheaths were generally 8F, and were removed following a successful procedure once the ACT was 160 to 180 s. Manual groin compression was used to achieve vascular hemostasis in all patients.

Study end points and definitions.   Procedural success was defined as all lesions dilated and stented with an angiographic residual stenosis <10% by visual estimate. Acute stent thrombosis (AST) was defined as the occurrence of stent thrombosis 24 h after the index procedure. Subacute stent thrombosis (SST) was defined as stent closure >24 h and 1 month following stent implantation.

A major adverse cardiac event (MACE) was defined as any one of the following: a) myocardial infarction (Q-wave or non–Q-wave); b) need for urgent repeat target vessel revascularization (TVR); or c) cardiovascular death that occurred during the period of hospitalization through one month following the index coronary procedure.

Postprocedural myocardial infarction (MI) was defined as the occurrence of typical ischemic chest pain of greater than 30 min duration with a creatine kinase (CK) elevation of >2.5 times the upper limit of normal with an associated increase in the MB fraction. There was no routine protocol for acquisition of postprocedure CKs. All postprocedural cardiac enzymes were obtained only for suspected recurrent myocardial ischemia, manifested by recurrent postprocedural chest pain, hemodynamic instability, or new electrocardiographic changes of ischemia.

Urgent TVR was defined as a repeat PCI or coronary artery bypass grafting (CABG) of the index stented artery due to presumed recurrent ischemia manifested by recurrent angina, arrhythmias or hemodynamic compromise.

Hemorrhagic complications were defined as a) clinically evident bleeding from a vascular access site, gastrointestinal or genitourinary site, and which resulted in a drop in hemoglobin >4 g/dl or which required a blood-product transfusion or surgical/ultrasound guided repair; b) retroperitoneal hemorrhage; or c) hemorrhagic stroke.

Length of hospitalization was assessed from the day of the procedure until the day of hospital discharge. All end points were assessed at hospital discharge and 30 days following the index procedure and independently adjudicated by investigators blinded to the antiplatelet therapy received. All events were recorded through chart review, hospital readmission data, follow-up patient questionnaires and telephone calls.

Statistical analysis.   Chi-square test and the Fischer exact test were used for analysis of categorical variables when appropriate, and the Student t-testing was used for analysis of continuous variables. Confidence intervals (95%) were determined when appropriate for each proportion. Multivariate logistic regression analysis was performed to determine significance of variables related to 30-day MACE. Variables of the model included a) use of clopidogrel or ticlopidine; b) clinical presentation; c) anticoagulant/thrombolytic therapy; d) adjunctive administration of GPIIb/IIIa inhibitors; e) ejection fraction <40%; f) prior history of MI, CABG or PTCA; g) vein graft stenting; h) number of diseased vessels; i) gender; j) age >65; k) hypertension; l) lipid status; and m) smoking history. Statistical analysis was performed using SPSS software (SPSS Institute).

	Results

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Baseline demographics and clinical characteristics.   Between March 1 and July 31, 1998, a total of 875 patients underwent coronary stenting, of whom 514 (58.7%) received clopidogrel-plus-aspirin and 361 (41.3%) received ticlopidine-plus-aspirin. Of the 875 total patients, 576 (65.8%) received their antiplatelet therapy prior to the index stent procedure, usually the night before or the morning of the intervention. Of the 514 who received clopidogrel, 361 (70.2%) were pretreated, and 215 of 361 (59.6%) ticlopidine-treated patients were pretreated. The remaining patients received their thienopyridene after a successful procedure.

There was a significant difference in the utilization of the two drugs (p < 0.001) by coronary interventionalists. Of the 14 interventionalists who contributed patients during this time period, 11 used the combination of clopidogrel-plus-aspirin in over half their cases, while 3 interventionalists used ticlopidine-plus-aspirin in over 50% of their cases (Fig. 1).

View larger version (15K): [in this window] [in a new window]   Figure 1 Frequency of use of clopidogrel among interventionalists during the study period, March 1, 1998, through July 31, 1998 (N = 14 interventionalists).

In-hospital and 30-day clinical outcomes.   One-month telephone follow-up was completed on 96.2% of the discharged clopidogrel-treated and 94.5% of the ticlopidine-treated patients (Table 3). There was no difference (p = 0.15) in the average length of stay after coronary stenting between patients treated with clopidogrel (2.2 ± 1.1 days) and those with ticlopidine (2.5 ± 4.3 days).

Subacute stent thrombosis occurred in two patients (0.2%); one clopidogrel-treated (0.2%) at 12 days’ post-stenting and one ticlopidine-treated (0.3%) patient at 20 days’ post-stenting (p = 0.99).

There were seven in-hospital deaths (0.8%), which occurred in similar proportions of patients in the two groups. Of the five deaths occurring among the clopidogrel-treated patients (0.9%), one was related to complications resulting from SST, three were related to complications of their presenting acute MI, and one died from surgical complications related to a severe vascular access site hemorrhagic event. Two deaths occurred among the ticlopidine-treated patients (0.6%). One resulted from a hemorrhagic stroke after stenting, having received intravenous fibrinolytic therapy, followed by the procedural administration of abciximab and low molecular weight heparin following PCI. The second death resulted from a primary ventricular arrhythmia.

As shown in Table 3, there were no significant differences observed between the clopidogrel- and ticlopidine-treated patients in the 30-day combined end point (2.1% vs. 1.4%, p = 0.57), emergent CABG (0.4% vs. 0.3%, p = 0.76), repeat PCI (0.2% vs. 0%, p = 0.99), nonfatal MI (1% vs. 0.6%, p = 0.21) or death (0.9% vs. 0.6%, p = 0.54), respectively. To eliminate the possibility that the bias inherent in each interventionalist prescribing in a nonrandomized fashion, a statistical analysis of each operator’s success and complication rate was completed. There was no difference in the odds ratio of either procedural success or adverse events for any of the 14 interventionalists.

Side effects/hemorrhagic complications.   There was no difference between the clopidogrel- or ticlopidine-treated patients with respect to the frequency of skin rashes (1.2% vs. 0.8%, p = 0.95), or bruising or minor bleeding (0.4% vs. 0.3%, p = 0.72), respectively. No patient reported significant nausea, vomiting or diarrhea or had adverse hematologic changes requiring cessation of therapy (Table 4).

Impact of platelet GPIIb/IIIa antagonists on clinical outcome.   Adjunctive GPIIb/IIIa inhibitors were utilized in 85.9% of cases with a diagnosis of an MI, 73.3% of cases with a diagnosis of unstable angina, and 58.4% of cases with a diagnosis of stable angina. By multivariate analysis, the only independent predictors of the 30-day composite end point were a) age >65 years (p = 0.041, odds ratio [OR] = 3.31) and b) acute MI presentation (p = 0.001, OR = 6.00). There was no difference in the 30-day MACE rates among patients receiving clopidogrel or ticlopidine regardless of the use of adjunctive GPIIb/IIIa receptor antagonists.

	Discussion

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This study examined the clinical efficacy of two antiplatelet regimens, clopidogrel or ticlopidine in combination with aspirin, among a wide variety of patients undergoing coronary stenting. Data collection started at the time of the clinical release of clopidogrel. Importantly, these observational data reflect procedural and 30-day outcomes utilizing contemporary clinical interventional practices employed during coronary stenting by a diverse group of interventionalists. This included standard procedural techniques of routine high-pressure balloon stent deployment and utilization of adjunct platelet GPIIb/IIIa receptor antagonists. In addition, a broad spectrum of coronary artery disease patients were included in this analysis, with approximately two-thirds of the population presenting with unstable angina, 8% presenting with an acute MI, and 10% having received thrombolytic therapy during their initial hospital presentation.

We observed no significant differences in the procedural success rates, length of hospital stay, and the incidence of acute or subacute stent thrombosis among this broad spectrum of patients undergoing coronary stent procedures, who received either clopidogrel or ticlopidine as adjunct antiplatelet therapy. The 30-day composite end point (MACE) of death, MI, or TVR, and hemorrhagic complications were also observed in similar proportions of clopidogrel- and ticlopidine-treated patients.

Role of combination antiplatelet therapy following coronary stenting.   A major development in coronary stenting has been the recognition that aggressive anticoagulant therapy is not necessary to prevent stent thrombosis, but only contributes to excess hemorrhagic and vascular access site complications. Combination antiplatelet therapy utilizing aspirin-plus-ticlopidine and current stent deployment techniques have been shown to be superior to conventional oral anticoagulation strategies and aspirin alone in reducing stent thrombosis (11–15).

Observational data from three separate institutions have provided suggestive data that the combination of clopidogrel-plus-aspirin is effective in preventing stent thrombosis and MACE following coronary stenting (16–18). On the basis of reported observations of over a thousand patients in these three studies, the rates of SST (0.2% to 1.4%) and 30-day combined rates of death, MI and TVR (0.8% to 1.6%) among patients undergoing coronary stenting who received clopidogrel-plus-aspirin were highly favorable and appeared similar to the historical rates for patients who had received ticlopidine-plus-aspirin. Furthermore, the combined efficacy results from these analyses are consistent with experimental animal models demonstrating the efficacy of clopidogrel and aspirin as an effective antiplatelet combination for the prevention of stent thrombosis (19,20).

Recent studies have demonstrated that pretreatment of coronary-stent patients with ticlopidine and aspirin is necessary to enhance drug efficacy and to reduce the rates of adverse postprocedural ischemic complications (21,22). The three ASTs in our study occurred in individuals who had received pretreatment only with aspirin but had not yet received their first dose of a thienopyridine. Both the ISAR and STARS trials initiated therapy with a thienopyridine after completion of the angioplasty.

Only two patients experienced SST (0.23%); one clopidogrel-treated patient (0.2%) occurring 12 days’ postprocedure, and one ticlopidine-treated patient (0.3%) occurring 20 days’ postprocedure. Both patients were receiving their respective antiplatelet agent at the time of the thrombotic event. The overall and individual drug rates of SST are comparable to previously published reports of SST (0.2% to 0.8%) in which patients received ticlopidine-plus-aspirin (11–13) and of the previously described clopidogrel observational reports (0.2% to 1.4%).

Study limitations.   Although the present study was nonrandomized, the large treatment groups were well matched for procedural and baseline demographics and operator outcomes, thereby limiting the potential for selection bias. The limitations of all observational data do, however, apply to this present study. Given the low rate of MACE, the ability to ascertain with statistical certainty the equivalence of these two groups would require approximately 4,500 patients per group (alpha = 0.05, beta = 0.02, probability of adverse event = 0.01).

There was no routine collection of postprocedural cardiac enzymes, hemoglobin or white blood cell counts during the course of therapy through 30 days, producing an underrepresentation of postprocedural myocardial infarcts and limiting the ability to detect potential differences in hematologic toxicity between the two drugs. However, given the similar procedural variables between the two treatment groups (i.e., stented length, number of stents, among others) the true incidence of postprocedural non–Q-wave myocardial infarcts would likewise be expected to be similar between the two drug groups.

The ability to distinguish the true hematologic differences between the two thienopyridine drugs may have been potentially affected by the relatively high use of GPIIb/IIIa inhibitors in both groups. However, the use of GPIIb/IIIa inhibition as an adjunct to coronary stenting does represent the current state-of-the-art treatment (23).

Conclusions.   The present study suggests that the combination adjunct therapy of clopidogrel and aspirin is an effective antithrombotic regimen in preventing SST and MACE after coronary stenting. Furthermore, clopidogrel is associated with excellent clinical tolerability and low rates of hemorrhagic complications.

Despite the high-risk baseline demographics and the high utilization of platelet GPIIb/IIIa receptor antagonists in our patient population, these findings appear comparable to previous randomized coronary-stent studies utilizing the combination of aspirin and ticlopidine with respect to stent thrombosis and bleeding complications.

These findings complement prior studies suggesting the importance of procedural pretreatment with thienopyridines to attenuate platelet function during coronary stenting. The randomized CLASSICS trial will report on the safety and efficacy of two dosing regimens of clopidogrel in combination with aspirin relative to the combination of ticlopidine with aspirin.

	Acknowledgments

 
The authors wish to acknowledge the invaluable skills of the research nurses, Janiece Trokey, RN, and Paula Hargrove, RN, for their contribution in the collection of the data. We also wish to acknowledge the participation of the interventional cardiologists at Prairie Cardiovascular Consultants, and the catheterization laboratory staff at both St. John’s Hospital and Memorial Medical Center.

	Footnotes

 
This study was supported by an unrestricted educational grant from Bristol-Myers Squibb and Sanofi Pharmaceuticals.

	References

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