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J Am Coll Cardiol, 2002; 40:662-668 © 2002 by the American College of Cardiology Foundation |
* Department of Cardiology, University of Würzburg, Würzburg, Germany
Manuscript received October 16, 2001; revised manuscript received April 16, 2002, accepted May 15, 2002.
* Reprint requests and correspondence: Dr. Andreas W. Bonz, Medizinische Universitätsklinik, Josef Schneider Strasse 2, 97080 Würzburg, Germany.
a.bonz{at}medizin.uni-wuerzburg.de
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Abstract |
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BACKGROUND: No data are available yet as to whether additional administration of a GP IIb/IIIa receptor antagonist might be beneficial in patients undergoing elective PCI already pretreated with aspirin and clopidogrel.
METHODS: After bolus application of the study medication (tirofiban [T] or placebo [P]), PCI was performed followed by an 18-h continuous infusion of T/P. Primary end point of the study was incidence and amount of TnT release after elective PCI after 24 h.
RESULTS: A total of 12 h after PCI troponin release was detected in 63% of the patients receiving P and in 40% of the patients receiving T (p < 0.05), after 24 h in 69% (P) and 48% (T) (p < 0.05) and after 48 h in 74% (P) versus 58% (T) (p < 0.08) of the patients. No differences were observed regarding major bleeding, intracranial bleeding or nonhemorrhagic strokes. After nine months a reduction of combined death/myocardial infarction/target vessel revascularization could be observed in the tirofiban group ([T] 2.3% vs. [P] 13.04%, p < 0.05).
CONCLUSIONS: Troponin T release occurs after successful intervention in 74% of the patients undergoing elective PCI after 48 h even after pretreatment with aspirin and clopidogrel. The GP IIb/IIIa receptor antagonist tirofiban is able to decrease the incidence of troponin release significantly in this patient population.
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Methods |
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18 and 
81 years) had a history of stable angina and were treated by conventional PCI, which was performed as a staged procedure. All patients were pretreated with a loading dose of thienopyridine (clopidogrel, 375 mg) and aspirin (500 mg) at least one day before PCI (Fig. 1). Study medication was administered when the guidewire passed the target stenosis but before first balloon inflation/direct stent implantation. After bolus administration (10 µg/kg), continuous infusion of the study medication (0.15 µg/kg/min) was started immediately without interruption in accordance with the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trial (8). The study followed the guidelines of the revised declaration of Helsinki (10.10.75) and was accepted and approved by the Ethics Committee of the University of Würzburg.
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70% suitable for PCI. Exclusion criteria were acute coronary syndromes, subacute or acute MI. Myocardial infarction was defined as significant electrocardiogram (ECG) changes (ST-segment elevation 2 mm or ST-segment depression in combination with elevation of ischemic parameters such as elevation of CK with an MB fraction of <10%); existence and elevation of troponin T twice the upper limit; unstable angina defined as chest pain at rest within the last seven days; stenosis located in venous or arterial bypass grafts; renal insufficiency; recent peptic ulcers or a history of bleeding, thrombocytopenia or thrombolytic therapy within the previous 24 h; stroke during the past two years; severe hypertension; neoplasms; and previous or planned administration of a GP IIb/IIIa receptor antagonist. Definition of complications. Bleeding was classified as minor (prolonged bleeding after sheath removal or necessity of prolonged compression without a drop in hemoglobin more than 2 g/dl), major (hemoglobin loss of >5 g/dl or necessity of red blood cell transfusion) and severe (death, MI or early reintervention within 24 h, the development of acute coronary syndromes with characteristic temporary ECG changes, nonhemorrhagic strokes or intracranial bleeding).
Patient randomization and blood sampling. The patients were randomized (tirofiban [T] vs. placebo [{P} 0.9% NaCl solution]) by an independent study nurse. Unfractionated heparin was given in a dosage of 5,000 U to 10,000 U in both groups with a target activated clotting time (ACT) of 250 s. Mean heparin dosage during PCI was 8,388 ± 228 IU (T) and 9,089 ± 308 IU (P) (p = NS). Activated coagulation time was similar in both groups (T: 242 ± 7.9 s, P: 244 ± 9.1 s) (p = NS). Blood samples for analysis of white and red blood count, CK/CK-MB, TnT, myoglobin, partial thromboplastin time and international normalized ratio were collected before PCI and 30 min (34 ± 2.2 min), 2 h (148 [2 h 28 min] ± 4.2 min), 6 h (389 [6 h 29 min] ± 7.4 min), 12 h (708 [11 h 48 min] ± 14.4 min), 24 h (1,482 [24 h 42 min] ± 20.6 min) and 48 h (3,047 [50 h 47 min] ± 68.5 min) after the procedure. Thrombocyte inhibition was measured on-line using Ultegra (Accumetrics, San Diego, California) rapid platelet function assay (RPFA) before, after bolus administration, 6 h, 12 h, 24 h and 48 h after PCI (15,16). The results of the level of platelet inhibition during PCI were analyzed by the study nurse and not forwarded to the investigating physician. Patients in this analysis were stated to be troponin-positive when exceeding the decision limit (99th percentile of the values for a reference control group) of the laboratory cutoff level of 0.009 µg/ml compared with pre-PCI levels. Troponin T was measured with TnT STAT immunoassay (ECLIA) of Roche Elecsys 2010 (Roche Diagnostics GmbH, Mannheim, Germany).
Patients. Of 109 patients enrolled, 96 patients could finally be included in the study. Patients were excluded because of technical reasons (five patients); in three patients the index stenosis was due to initial coronary spasm, and PCI was not performed; one patient was excluded due to wire-induced side-branch perforation before administration of the study medication; three patients with lesions primarily suitable for PCI preferred the option of bypass surgery due to personal conviction; and one patient had to be unblinded, and study medication had to be stopped 4 h after PCI due to nonrelevant, but continuously ongoing, nose bleeding and was counted in the intention-to-treat analysis as a bleeding patient.
Patients characteristics and baseline medication. Both groups were similar in baseline characteristics like sex, weight, size, body mass index, cardiovascular risk factors, recent MI (defined as MI >14 days before diagnostic catheterization) and medication at admission (Table 1).
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Results |
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Platelet function. All patients were on aspirin and clopidogrel before the PCI procedure. The mean platelet activation units (PAU) before the intervention was 142.6 ± 5.4 (T) versus 146.3 ± 7.2 (P). After bolus application platelet function was reduced to PAU 10.8 ± 1.4 (7.8 ± 1.0% of baseline) in the T group. The aggregation units in the P group increased up to 171.7 ± 5.6 PAU (128.5 ± 7.9%, p < 0.001 vs. T). During administration of the study drug, platelet function levels were 9.5 ± 1.2 PAU (7.0 ± 0.9%, p < 0.001 vs. P) at 6 h and 12.3 ± 2.4 PAU (9.8 ± 2.3%, p < 0.001 vs. P) at 12 h in the T group. At 48 h platelet function levels had normalized to 112.6 ± 5.9 PAU (83.3 ± 4.3%) in the T group and 129.5 ± 6.9 PAU (98.7 ± 6.3%, p = NS) in the P group (Fig. 2).
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TnT.
In both groups there was a continuous increase in TnT levels up to 48 h. There was a nonsignificant trend at all time intervals toward lower troponin levels in the T group. Troponin T increase at 48 h was 0.0291 ± 0.0094 µg/l in the T group versus 0.036 ± 0.01 µg/l in the P group referred to preprocedural levels (p = NS). At 12 h 40% of patients in the T group but 63% in the P group revealed TnT (0.01 µg/l, p < 0.05). At 24 h 48% of the T group and 69% of the P group were TnT positive (p < 0.05). At 48 h 58% of the T patients and 74% of the P patients revealed a positive TnT (p = NS) (Fig. 3). The number of a biphasic postinterventional troponin elevations were significantly higher in the P group (24%) than in the T group (8%, p < 0.05).
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Death/MI/urgent vessel revascularization. After 30 days one patient of the P group was readmitted to the hospital due to stent occlusion and consecutive MI, and no event was regarded in the T group. After nine months one patient of the T group (2.3%) and five patients of the P group were readmitted because of MI or need for bypass surgery; one additional patient died (13.04%; p < 0.05; Fig. 4).
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Discussion |
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Pretreatment with aspirin and clopidogrel. Platelet inhibition with aspirin and clopidogrel is cumulatively effective and significantly reduces subacute stent thrombosis and mortality in acute coronary syndromes (1–3). In the TOPSTAR trial, all patients were pretreated with a combination of aspirin and clopidogrel. The reduced amount of myonecrosis, as demonstrated by the lack of TnT release is, therefore, a beneficial effect of GP IIb/IIIa antagonism, which occurs on top of the pretreatment therapy and platelet inhibition level with aspirin and clopidogrel.
Platelet inhibition with aspirin, clopidogrel and tirofiban. The (AU-Assessing Ultegra) Multicenter Study (GOLD) trial (16) could demonstrate a clear correlation between the level of platelet inhibition, as measured with the Ultegra RPFA assay (15–17), and major adverse cardiac events. The authors concluded that a level of at least 90% inhibition is necessary to reduce events in PCI. Besides a possible confoundation of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) IV study by patients without unstable angina but with positive troponin (e.g., patients with heart failure), another reason contributing to the negative outcome (18) might partly be related to an inhomogenous level of inhibition of the platelets over the time of administration with the GP IIb/IIIa inhibitor abciximab as demonstrated by Chew and Molitero (19). This effect has not been observed with the small molecules eptifibatide or tirofiban (17). In the TOPSTAR trial, tirofiban was chosen as GP IIb/IIIa antagonist because of its temporary efficacy to allow the observation of postinhibitional effects up to 48 h. The levels of inhibition measured with the Ultegra RPFA system were over 90% at the time intervals after bolus application and after 6 h and 12 h infusion of tirofiban (Fig. 2) and was referred to an already reduced baseline level due to the administration of the fixed combination of aspirin and clopidogrel before PCI. The activation of platelets by unfractionated heparin, as observed in the P group, is a well-known phenomenon (20).
Correlation between troponin/CK-MB and outcome. Release of CK-MB mass or TnT or TnI is a strong indicator of myocardial damage (21,22). However, to detect minor myocardial injury, cardiac TnT has been shown to be superior to CK and its MB fraction (23,24). Furthermore, the amount of TnT or I or MB mass of CK release is correlated with the amount of necrotic myocardial cells and infarct size. In a meta-analysis of the C7E3 AntiPlatelet Therapy in Unstable Refractory Angina (CAPTURE), Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) and Evaluation in PTCA to Improve Long-term Outcome with abciximab Glycoprotein IIa/IIIb Blockade (EPILOG) trials (25), a correlation between modest elevation of cardiac enzyme and an impaired late outcome was found. Mild to moderate periprocedural elevation of CK-MB is related to an increased subsequent MI and mortality (26). Even small CK elevation after elective PTCA was associated with increased late cardiac mortality (27). It was demonstrated that CK-MB (>5%) can be increased in up to 26% of patients after "uncomplicated" coronary interventions (28,29). Regarding the recently published redefinition of MI by the Joint Commission of the European Society of Cardiology/American College of Cardiology Committee, even modest elevation of cardiac parameters have to be classified as an MI (30). However, the reduced secondary end point death/MI/TVR in the T group after nine months further supports these observations.
Role of microembolization and temporary vessel occlusion during PCI. The increase of ischemic parameters after PCI might partially be related to inflation-induced temporary vessel occlusion during PCI (31). However, this might contribute to the high baseline values of troponin-positive patients after 12 h but is unlikely to be responsible for the significant differences between the two treatment groups, as all interventional parameters were the same in both groups (Table 2). Mechanical manipulation during PTCA or stent implantation can lead to embolization of debris or calcified plaque material or exposure of thrombogeneous material at intravascular sites. Furthermore, PCI procedures activate the expression of GP IIb/IIIa receptor on the platelet surface (32) and may lead to formation of microthrombi. The debris can embolize or impede the microcirculation by secondary thrombus formation and was reported in patients with acute coronary syndromes or degenerated saphenous vein grafts (33) but was believed to be uncommon in routine PCI procedures (34,35). Surprisingly, 74% in the P group of the TOPSTAR trial developed positive troponin within the first 48 h after PCI. This might explain the impaired coronary flow reserve, which has been described by Hermann (36), after elective coronary stenting. The significant reduction of troponin release by 23% within 12 h and 21% within 24 h after PCI in those patients receiving tirofiban leads to three conclusions: 1) microembolization during coronary interventions can be reduced by administration of the GP IIb/IIIa receptor antagonist tirofiban; 2) a large amount of microembolization may be either refractory to GP IIb/IIIa inhibition, as shown by 40% of patients being troponin-positive, even after successful and effective inhibition of platelet aggregation, or may be due to temporary PCI-induced vessel occlusion; and 3) after cessation of antiaggregational therapy, 10% of the patients in the T group became troponin-positive between 24 h and 48 h, indicating late microembolization after cessation of aggressive platelet inhibition. After 48 h the difference between both groups lost statistical significance, which might be due to the relative small number of patients in the two arms of the study, due to late platelet aggregation after cessation of "aggressive" antiplatelet therapy or a "rebound phenomenon" in terms of platelet GP IIb/IIIa receptor activation. Unlike the expected drop of troponin after 24 h, TnT levels further increased up to 48 h, indicating prolonged impairment of myocardial perfusion. A possible explanation could be a continuous, ongoing, stent-derived microembolization leading to repetitive release of microemboli with obstruction of microvessels.
Study limitations.
Administration of tirofiban was started shortly before the PCI procedure. Administration starting earlier or longer might have further improved the results obtained by GP IIb/IIIa receptor-inhibition. Regarding the results of Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18, an ACT of <250 s in combination with tirofiban might be associated with poorer clinical outcome in the respective patient population (7). However, the TOPSTAR trial was designed and finished before the data were available; a higher peri-interventional ACT might have improved the results. The high incidence of positive TnT patients might be the result of a low cutoff point in measuring troponin levels. According to the recommendations of the Joint Commission of the European Society of Cardiology and American College of Cardiology, patients were considered troponin-positive when reaching a cutoff in the laboratory test of 0.01 µg/l and were stated to be troponin-positive when troponin exceeded the cutoff point only once during the time interval after PCI up to 48 h. However, these multiple measurements performed in the TOPSTAR trial demonstrated the importance of various time intervals in order to estimate the time course of ischemic events after percutaneous intervention.
Clopidogrel pretreatment was performed with 375 mg at least one day before PCI. Higher dosages of clopidogrel might have decreased the amount of troponin release by stronger baseline inhibition of platelet function in both groups. The follow-up of this study included nine months postinterventional data. However, compared with the Enhanced Suppression of Platelet Receptor IIb/IIIa using Integrilin Therapy (ESPRIT) trial (37), the rate of mortality and TVR was 13.04% in the P group versus 2.3% in the T group for up to nine months, which underlines the low-risk patient collective of the study and might, furthermore, be a result of the combination pretreatment of aspirin and clopidogrel before PCI.
Conclusions. Additional temporary peri- and postprocedural administration of the GP IIb/IIIa receptor antagonist tirofiban leads to a reduced incidence of postinterventional troponin release in elective, nonacute PCI in patients pretreated with aspirin and clopidogrel. Larger studies are warranted to evaluate the benefits of this therapeutic regimen in terms of long-term mortality, MI, rehospitalization, myocardial salvage and economic aspects in this "low-risk" patient population, representing the vast majority of patients undergoing PCI.
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Footnotes |
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