ORIGINAL ARTICLES

Clopidogrel Treatment Before Percutaneous
Coronary Intervention Reduces Adverse Cardiac Events

Ulf Berglund, MD and Arina Richter, MD, PhD
Ulf Berglund, MD and Arina Richter, MD, PhD
The benefit of platelet inhibition during percutaneous coronary intervention (PCI) has been known for some time.1 In recent years, the interest has focused on the platelet glycoprotein IIb/IIIa inhibitors, which block the final common pathway of platelet aggregation and are the most potent of the antiplatelet drugs. Compared to the standard treatment with aspirin and heparin, the addition of the IIb/IIIa inhibitor abciximab reduced adverse cardiac events in several large PCI studies.2,3 In most institutions, however, abciximab is considered too expensive to be used on a general basis in coronary intervention. The thienopyridines (ticlopidine and clopidogrel) are another class of platelet inhibitors. They act by blocking the platelet adenosine diphosphate (ADP)-receptor4 and have shown synergistic platelet inhibition with aspirin in laboratory studies.5,6 The clinical benefit of the combination of ticlopidine and aspirin after stent implantation is well documented.7,8 Very few studies have focused on the effect of a thienopyridine compound given together with aspirin before PCI.9–11 This study aimed to evaluate the effects of a loading dose of clopidogrel in addition to aspirin given the day before the procedure in an unselected PCI population. METHODS The clopidogrel group consisted of 706 consecutive patients undergoing PCI between February and December 2000. A control group of 724 consecutive procedures was obtained from the preceding 14-month period. In both study groups, the only reason for exclusion was PCI in the setting of acute myocardial infarction (MI). All patients in the study group received 375 mg clopidogrel the day before either scheduled PCI or planned coronary angiography, which could be followed by PCI (ad hoc procedure). Clopidogrel was continued at 75 mg daily for 1 month in cases of stent implantation; otherwise, no further clopidogrel was administered. In the control group, no patient received pre-treatment with clopidogrel or ticlopidine. If a stent was implanted, a loading dose of clopidogrel was given directly after the procedure followed by clopidogrel 75 mg daily or by ticlopidine 250 mg twice daily for 1 month. All patients in both groups had chronic treatment with aspirin 75 mg daily. During the procedure, they received sublabial or intravenous nitroglycerin and heparin with a target activated clotting time of > 300 seconds (200–250 seconds in abciximab-treated patients). Abciximab was given at the operator’s discretion in high-risk PCI (Table 1). Due to medical contraindication or administrative failure, some patients in the clopidogrel group did not receive the drug. This was handled according to the intention to treat principle. CKMB mass was analyzed 6–10 hours after the procedure in all patients. If the value exceeded the upper normal limit (5 µg/L), CKMB was obtained every sixth hour until the maximum had passed. Myocardial infarction was defined as CKMB greater than twice the upper normal limit, i.e., at least 11 µg/L. Patients requiring urgent revascularization received either immediate bypass surgery because of a failed PCI or repeat PCI of the target lesion for those with severe chest pain and ischemia after the procedure. Bleeding was registered if blood transfusion was given. The study was confined to in-hospital events. All data were collected prospectively. Continuous variables were described as means (standard deviation) and tested with analysis of variance. Categorical data were expressed as absolute numbers or as percentages of non-missing observations and were analyzed by the Pearson Chi-square test. Logistic regression tested the impact of clopidogrel treatment and other factors on the composite endpoint. Statistica (Stat Soft, Tulsa, Oklahoma) was used for data analysis. Results Unstable coronary disease as an indication for PCI was more frequent, while previous myocardial infarction and stent implantation during the procedure were less common in the clopidogrel group. Otherwise, the groups were well balanced (Table 1). Compared to the control group, patients with clopidogrel pre-treatment had a lower rate of adverse cardiac events (Table 2). All factors that could influence the composite of death, myocardial infarction or urgent revascularization were entered in a logistic regression analysis. Increasing age [odds ratio, 8.0; 95% confidence interval (CI), 2.2–28.9; p = 0.001); no clopidogrel pre-treatment (odds ratio, 1.8; 95% CI, 1.1–2.8; p = 0.010); and abciximab treatment (odds ratio, 1.8; 95% CI, 1.1–3.2; p = 0.028) were associated with a worse outcome. The effect of clopidogrel on the composite endpoint in different subgroups is shown in Table 3. The subgroups not presented in this table had odds ratios similar to the total population. Patients without previous myocardial infarction and those with more than one lesion treated or a thrombus-containing lesion tended to benefit more from the clopidogrel pre-treatment. The loading dose of clopidogrel was well tolerated; only a few patients had temporary gastro-intestinal discomfort. In the clopidogrel group, a total of 79 patients had radial artery puncture. Those with femoral puncture had no increase in femoral complications compared to the control group (Table 4). No patient in either group had hemorrhagic stroke. One case of ischemic stroke occurred among the clopidogrel patients. Compared to the control group, the clopidogrel patients had a somewhat shorter hospital stay after the procedure (1.65 days versus 1.70 days) and a reduced need for repeat coronary angiography (1.56% versus 3.04%) and intervention (0.28% versus 1.24%). The resulting cost reductions from these factors were greater than the expense of the extra clopidogrel tablets in the clopidogrel group, also taking into account the treated patients who had only coronary angiography without intervention. The net cost benefit per patient in the clopidogrel group was SEK 447, corresponding to $40 United States currency. DISCUSSION The main finding of this study is the significant reduction of in-hospital adverse cardiac events when clopidogrel was given before PCI. In both groups, very few patients died or required urgent bypass surgery. The need for urgent repeat PCI of the target lesion and the occurrence of myocardial infarction both decreased with the clopidogrel pre-treatment (Table 2). With one exception, odds ratios in all subgroups were below 1 (Table 3), indicating a consistent benefit of clopidogrel. Most myocardial infarctions related to PCI are small, and their importance has been questioned. Even if the severity of the prognosis depends on the size of the myocardial infarction, there is evidence that small infarctions are also related to an increase in mortality.12 The greatest difference between our two groups was the incidence of large myocardial infarctions (Table 2). In a substudy of EPISTENT, treatment with ticlopidine before coronary stenting was associated with a 33% reduction of the composite of death, myocardial infarction or urgent revascularization at 30 days in the patients who did not receive abciximab. In contrast, ticlopidine had no effect in abciximab-treated patients.9 Chevalier et al. reported that ticlopidine pre-treatment decreased in-hospital adverse cardiac events by 31%.10 In these studies, however, the ticlopidine doses given before the intervention were not defined. The CURE study randomized unstable coronary patients to clopidogrel or placebo. In the subgroup undergoing PCI, clopidogrel reduced the composite of cardiovascular death, myocardial infarction or need for urgent revascularization within 30 days of the procedure by 30% compared to placebo (4.5% versus 6.4%, respectively).11 About 25% of the patients in both groups received open-label clopidogrel before the intervention. When these patients were excluded, clopidogrel reduced the composite endpoint by 42%, which is very similar to our results (Table 2). Compared to our study, the PCI-CURE trial had a longer follow-up period, which would increase the number of events. In addition, PCI-CURE did not analyze post-procedure myocardial biomarkers in all patients, which would decrease the incidence of MI. Thrombotic stent occlusion is a feared complication. The combination of aspirin and ticlopidine post-procedure has reduced the incidence of this event, but early thrombosis still occurs.8,9 In the above-mentioned study by Chevalier et al., pre-treatment with ticlopidine significantly reduced acute or subacute stent thrombosis compared to the control group (0.5% versus 1.9%, respectively).10 Compared to non-ionic contrast media, ioxaglate was reported to reduce the risk of stent thrombosis;13 this contrast agent was used in all of our patients unless contraindicated. In-hospital stent occlusion occurred in 5 cases in our control group (1.0%) and in 1 case in the clopidogrel group; this patient, however, did not receive the drug before the procedure. Thus, with adequate clopidogrel pre-treatment, there were no cases of in-hospital stent occlusion. Abciximab substantially reduced PCI complications in several studies.2,3 It was therefore somewhat surprising that abciximab was significantly associated with an increased rate of adverse events in our study. The main reason for this finding is most likely that abciximab treatment was confined to high-risk PCI patients, i.e., those with complex lesions, diabetes and/or intracoronary thrombus. Also, in a small number of patients, abciximab was given as a bail-out treatment during the procedure when a thrombotic complication had already occurred. In the above-mentioned EPISTENT substudy, there was no effect of ticlopidine pre-treatment when the patient had received abciximab9 and it has been suggested that the glycoprotein IIb/IIIa inhibitors are so potent that addition of other antiplatelets compounds does not matter. In our study, however, the benefit of clopidogrel was at least as good in abciximab-treated patients as in those without this treatment (Table 3). This finding is in accordance with the TARGET study, which randomized patients to abciximab or tirofiban before coronary stenting.14 Most patients were pre-treated with clopidogrel, which decreased the composite of death, myocardial infarction or urgent revascularization at 30 days in both the abciximab (30% reduction) and tirofiban groups (42% reduction) compared to patients without clopidogrel pre-treatment. Clopidogrel and IIb/IIIa inhibitors have different modes of action on the platelet and their combination might be clinically beneficial. The main limitation of this study is the non-randomized design. Improving technology over time might be a concern. There has been a dramatic evolution in PCI technology since the first procedure in 1977. However, during the study period (1999–2000), the improvements were rather small and there were only marginal changes in our PCI equipment; no new device was introduced. The PCI operators were the same during the two study periods, except for 2 new operators performing 9% of the procedures during the clopidogrel period. The general routines for patient management before, during and after the procedure were the same during the study and we believe that the PCI conditions during the 2 study periods were quite similar. The 2 groups were also similar regarding the baseline characteristics (Table 1); if anything, the increased rate of unstable patients would disfavor the clopidogrel group. Also, the findings in this “real world” study in an unselected population are in agreement with the randomized PCI-CURE trial. In conclusion, we found that treatment with clopidogrel in addition to aspirin before PCI was associated with a reduction of in-hospital adverse cardiac events. It was also safe and cost-saving.
References
1. Barnathan ES, Schwartz JS, Taylor L, et al. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987;76:125–134. 2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696. 3. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87–92. 4. Jarvis B, Simpson K. Clopidogrel. A review of its use in the prevention of atherothrombosis. Drugs 2000;60:347–377. 5. Moshfegh K, Redondo M, Friedgard J, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699–705. 6. Rupprecht HJ, Darius H, Borkowski U, et al. Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation. Circulation 1998;97:1046–1052. 7. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet with anticoagulant therapy after the placement of coronary artery stents. N Engl J Med 1996;334:1084–1089. 8. Lablanche JM, McFadden EP, Bonett JL, et al. Combined antiplatelet therapy with ticlopidine and aspirin. A simplified approach to intracoronary stent management. Eur Heart J 1996;17:1373–1380. 9. Steinhubl SR, Ellis SG, Wolski K, et al., for the EPISTENT Investigators. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events. Data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial. Circulation 2001;103:1403–1409. 10. Chevalier B, Glatt B, Guyon P, et al. Does preprocedural ticlopidine treatment modify the short-term outcome after coronary angioplasty? (Abstr). Eur Heart J 1999;20(Suppl):253. 11. Mehta RM, Yusuf S, Peters RJG, et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001;358:527–533. 12. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241–251. 13. Scheller B, Hennen B, Pohl A, et al. Acute and subacute stent occlusion. Risk-reduction by ionic contrast media. Eur Heart J 2001;22:385–391. 14. Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894.