CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Lack of efficacy of clopidogrel pre-treatment in the prevention of myocardial damage after elective stent implantation
Dirk J. van der Heijden, MD*,
Iris C. D. Westendorp, MD, MSc, PhD*,
Robert K. Riezebos, MD*,
Ferdinand Kiemeneij, MD, PhD*,
Ton Slagboom, MD*,
L. Ron van der Wieken, MD* and
Gert-Jan Laarman, MD, PhD*,*
* Amsterdam Department for Intervention Cardiology (ADIC), Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
Manuscript received June 10, 2003;
revised manuscript received February 5, 2004,
accepted February 10, 2004.
* Reprint requests and correspondence: Dr. Gert-Jan Laarman, Onze Lieve Vrouwe Gasthuis, Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Postbus 95500, 1090 HM Amsterdam, The Netherlands.
g.j.laarman{at}olvg.nl
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Abstract
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OBJECTIVES: The object of this study was to determine the effect of pre-treatment with clopidogrel in patients undergoing elective stent implantation.
BACKGROUND: The treatment of patients with adenosine diphosphate receptor blockers after percutaneous coronary intervention (PCI) with stent implantation has been shown to decrease the incidence of subacute stent thrombosis. Furthermore, non-randomized studies on pre-treatment with clopidogrel among patients undergoing stent implantation have suggested a reduction in myocardial damage and clinical events. The effect of pre-treatment with clopidogrel has been studied in only a few randomized trials.
METHODS: In a randomized trial, three days of pre-treatment with clopidogrel was compared with standard post-procedural treatment in 203 patients undergoing elective stent implantation. The primary end point was a rise in troponin I or creatine kinase-MB fraction (CK-MB) serum levels at 6 to 8 and 16 to 24 h after PCI. Secondary end points were death, stroke, myocardial infarction, coronary bypass grafting, repeated PCI, and subacute stent thrombosis at one and six months after PCI.
RESULTS: No difference was found between non–pre-treated and pre-treated patients in the post-procedural elevation of troponin I (42 [43.3%] vs. 48 [51.1%], respectively, p = 0.31) or CK-MB (6 [6.3%] vs. 7 [7.4%], respectively, p = 0.78). Adjustment for possible confounding factors did not change these findings. Patient follow-up at one and six months showed no significant difference between the treatment groups in death, stroke, myocardial infarction, coronary artery bypass grafting, repeated PCI, or subacute stent thrombosis.
CONCLUSIONS: In this randomized study, no beneficial effect of pre-treatment with clopidogrel on post-procedural elevation of troponin I and CK-MB or on clinical events after one and sixth months could be demonstrated. The study suggests that among patients with stable coronary syndromes in whom coronary stent implantation is planned, pre-treatment may not be beneficial in reducing early myocardial damage.
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Abbreviations and Acronyms
| | PCI | = percutaneous coronary intervention | | CABG | = coronary artery bypass grafting | | CK-MB | = creatine kinase-MB fraction | | CREDO | = Clopidogrel for the Reduction of Events During Observation study | | CURE | = Clopidogrel in Unstable angina to prevent Recurrent Events trial | | GP | = glycoprotein | | MI | = myocardial infarction |
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Optimizing anti-platelet therapy is an important matter in developing future treatment strategies for patients undergoing percutaneous coronary intervention (PCI) with stent placement. Treatment with clopidogrel, in addition to aspirin, has been shown to decrease the risk of ischemic complications of these patients (1–3). Whether pre-treatment with this medication also decreases this risk is subject to debate.
A sub-study of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated a beneficial effect of clopidogrel among patients with unstable coronary syndromes after 30 days when clopidogrel treatment was started 3 to 10 days before PCI was performed (4–6). In the Clopidogrel for the Reduction of Events During Observation (CREDO) study, patients with stable coronary syndromes were randomized to 3 to 24 h of pre-treatment with clopidogrel or placebo, but no significant difference was found between the treatment groups after 30 days (7). The observation was made, however, that patients who received clopidogrel >6 h before PCI seemed to have a more favorable outcome. Among stable, non-diabetic patients, a smaller randomized trial found no difference in clinical events between pre-treated and non–pre-treated patients after one year (8). Whether pre-treatment with clopidogrel decreases minimal myocardial damage in stable patients has not been studied in a randomized study.
We performed a randomized study evaluating the occurrence of elevation of troponin I and creatine kinase-MB fraction (CK-MB) within 24 h after elective coronary stent implantation in patients pre-treated for three days with clopidogrel compared with patients starting clopidogrel treatment immediately after the procedure. Also, we examined the prevalence of clinical events after one and six months.
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Methods
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Study protocol.
Between August 2000 and March 2002, 203 patients were enrolled at our hospital and scheduled to undergo elective PCI with stent implantation. Patients were randomized into two groups. In the control group the loading dose of 300 mg clopidogrel was administered immediately after coronary stent implantation; the second group underwent pre-treatment with 300 mg of clopidogrel three days before coronary stent implantation followed by 75 mg once daily. Both groups were treated with clopidogrel 75 mg once daily for four weeks after the coronary intervention in combination with aspirin 100 mg once daily for at least six months.
During diagnostic angiography, angiographic characteristics were recorded. The procedure was routinely performed by radial artery puncture, unless contraindicated. At the beginning of each procedure, a bolus of 10,000 IU of heparin was given intravenously, and for every additional hour of the procedure a further bolus of 5,000 U was administered. Overnight heparin infusion and post-procedural usage of glycoprotein (GP) IIb/IIIa inhibitors were at the physician's discretion.
Blood samples were taken at baseline, 6 to 8 h, and 16 to 24 h after PCI. Clinical events such as death, coronary artery bypass grafting (CABG), repeated PCI, myocardial infarction (MI), stroke, and access site bleeding were assessed. The follow-up took place in the outpatient clinic or by means of telephone interview after one and six months. Follow-up was completed in 99.5% of the cases.
The physicians were blinded to patient drug assignment both during stent implantation and during the assessment of follow-up data. All patients gave informed consent. The study was approved by the medical ethical committee of our institution.
Patients.
Patients were excluded from enrollment in cases of primary intervention for acute MI or other emergency procedures, elevated baseline troponin I or CK-MB levels, known intolerance of clopidogrel or aspirin, long-term use of non-steroidal anti-inflammatory drugs, planned peri-procedural treatment with GP IIb/IIIa inhibitors, or known thrombocytopenia.
End point definitions.
The primary end point evaluated was a rise in levels of troponin or CK-MB at 6 to 8 h or 16 to 24 h after PCI. Enzyme rise was defined as end point when troponin  0.2 µmol/l or CK-MB 16 mmol/l.
Secondary end points were death, stroke, MI, CABG, repeated PCI, and subacute stent thrombosis at one and six months. In addition, access site complications and acute vessel closure within 24 h after PCI were assessed. A composite end point was defined as death, stroke, MI, CABG, repeated PCI, or subacute stent thrombosis at six months.
Statistical methods.
All patients randomized to the two study arms were included in the analysis. Baseline characteristics between the pre-treated and the non–pre-treated group were compared by means of the chi-square test for proportions and Student t test for continuous variables. Proportions of patients with elevated levels of troponin or CK-MB after 6 to 8 h and 16 to 24 h were compared between the two study groups using the chi-square test. Analyses were repeated with additional adjustments for age, hypercholesterolemia, previous MI, and the presence of diabetes by way of logistic regression analysis. Secondary end points and the composite end point were compared using the chi-square test. An alpha value of 0.05 was considered statistically significant. All analyses were performed with SPSS statistical software (SPSS Inc., Chicago, Illinois).
The reduction of risk of procedure-related myocardial damage, defined as a rise in enzyme levels by pre-treatment with ticlopidine, was found in a previous study (9) to be 24%. Assuming a comparable effect of clopidogrel (10,11) and an incidence of a rise of enzymes in 29% (9) of patients, with a significance level of 0.05 and power of 0.9, a minimum of 90 patients in each group would have been necessary to detect a statistically significant difference between groups. Accounting for losses of follow-up, we included 10 additional patients in each group.
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Results
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Of the 203 patients randomized, nine patients did not undergo coronary stent implantation, because of different reasons (no significant lesion, unable to cross the lesion with the wire) or because they withdrew their informed consent. We followed these patients according to the intention-to-treat principle.
Baseline and angiographical characteristics in the two groups are presented in Tables 1 and 2. The difference in hypercholesterolemia was statistically significant (p = 0.04). A history of MI and current smoking were slightly more prevalent in the non–pre-treated group, but only the difference in a history of MI was statistically significant (p = 0.01). There was no difference between the study groups in angiographic characteristics or anginal class using the Canadian Cardiovascular Society classification.
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Table 1 Baseline Clinical Characteristics of Patients in the Two Treatment Arms Before Percutaneous Coronary Intervention
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Table 2 Baseline Angiographical Characteristics of Patients in the Two Treatment Arms Before and During Percutaneous Coronary Intervention
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No significant difference was found in troponin I level rise at 24 h above the clinically relevant level of 0.2 µmol/l: a rise in troponin was found in 42 (43.3%) non–pre-treated patients versus 48 (51.1%) pre-treated patients (p = 0.31). The distribution of serum troponin I levels are shown in Figure 1. Analyses were repeated using a troponin I cut-off level of 0.5 µmol/l, which did not change the results. Also, no significant difference between non–pre-treated and pre-treated patients could be observed in the percentage of patients with a CK-MB elevation above 16 mmol/l (Table 3). Analyses were repeated with adjustment for important baseline variables, which did not change our findings. We performed a sub-group analysis on patients with a type C lesion, but also in this sub-group, no differences were observed between pre-treated and non–pre-treated patients.
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Figure 1 Scatter plot showing the distribution of highest troponin values of patients in the two treatment regimes.
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Acute vessel closure within 24 h occurred once in the non–pre-treated group. In 3 of the 203 patients, access site complications occurred: twice in the pre-treated and once in the non–pre-treated group. None of these patients needed blood transfusions or vascular surgery. No other hemorrhagic complications were observed during the study period.
Follow-up at one and six months did not reveal a significant difference between the two treatment groups concerning death, stroke, MI, CABG, repeated PCI, subacute stent thrombosis, or a composite of these end points (Table 4).
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Table 4 Effect of Pre-Treatment on Outcome Events at One and Six Months and the Composite End Point After Six Months
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Discussion
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The present study is one of the first randomized comparisons of pre-treatment with clopidogrel versus conventional treatment initiated after elective coronary stent implantation. No difference between non–pre-treated and pre-treated patients in the occurrence of elevation of troponin I or CK-MB levels was observed. Adjustment for possible confounding factors did not alter these findings. We did not detect any difference in clinical events.
Elevation of cardiac markers after PCI is associated with worse long-term outcome (12–14). We chose the rise in enzyme levels as the primary end point in the study because the power of the study is markedly increased compared with analyzing clinical events. Compared with other studies examining minimal myocardial damage after elective PCI, we found a slightly higher percentage of patients with a rise in troponin I levels (14). On the other hand, the frequency of the rise in CK-MB levels was similar to other publications (12), although some CK-MB elevation might have remained undetected because of the sampling window.
Few studies have focused on the effect of pre-treatment with clopidogrel in patients undergoing stent implantation. In a retrospective study by Steinhubl et al. (9), pre-treatment of patients with ticlopidine three days before coronary stent implantation was associated with a large reduction in post-procedural cardiac enzyme rise. The PCI-CURE study showed a large reduction of MI and urgent revascularization in patients pre-treated with clopidogrel. In contrast to our group, the study cohort consisted of patients with unstable coronary syndromes. In another recent study of Berglund et al. (13), clopidogrel treatment before coronary stent implantation reduced the incidence of a composite of death, MI, and urgent revascularization by 41% compared with a historical control group of patients treated in the preceding period. Like the aforementioned study, this study was not randomized and also focused on patients with unstable coronary syndromes. A sub-study of the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes (TARGET) trial, mainly consisting of unstable patients, did reveal a benefit in clinical outcome for pre-treated patients. However, the choice for pre-treatment was left at the discretion of the interventional cardiologists (4–6,9,15,16).
The CREDO study, a randomized study of 2,116 patients with stable angina pectoris, did not detect a significant difference between patients pre-treated with clopidogrel or placebo between 3 and 24 h before PCI; an 18.5% risk reduction did not reach statistical significance (p = 0.23). However, a better clinical outcome in patients pre-treated for more than 6 h before PCI was observed. The results of our study do not confirm hypotheses generated from earlier retrospective, non-randomized studies of beneficial pre-treatment with clopidogrel. Mann et al. (8) also could not detect a benefit in clinical outcome among stable patients without insulin-requiring diabetes undergoing elective stent implantation. Recently, the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) study was published, which studied the additional effect of a GP IIb/IIIa inhibitor in addition to pre-treatment with clopidogrel in patients with stable coronary syndromes. No beneficial effect was observed in patients treated with abciximab compared with placebo. According to the authors, pre-treatment with clopidogrel prevented an additive anti-platelet effect of abciximab, although all patients received pre-treatment with clopidogrel (7,8,17).
The effect of pre-treatment with clopidogrel is thought to be the result of earlier blockage of platelet aggregation and thus better prevention of peri-procedural thrombus formation. We were unable to support this mechanism in elective stent implantation among patients with stable angina pectoris. Blocking platelet aggregation in stable and thus less thrombogenic patients may be the reason that we could not detect any protective action of pre-treatment with clopidogrel in patients undergoing elective stent implantation. Some studies (7,8) do support this finding in detecting no benefit of pre-treatment in stable patients, although recent data seem to contradict this (17). However, optimizing anti-platelet therapy before PCI in patients with acute coronary syndromes remains of great importance (4,15,16).
In our patient population we did not detect a decrease in myocardial damage in patients pre-treated with clopidogrel three days before elective stent implantation. It is likely that pre-treatment with clopidogrel in this group of patients is not beneficial. However, the sample size of this study was small, and larger randomized clinical trials may be necessary to verify our results.
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Abstract
Methods