Primary percutaneous coronary intervention (p-PCI) is the first choice of treatment for patients with acute myocardial infarction (AMI), but it has a relatively high incidence of no reflow and high risk of intrastent thrombosis following catheter therapy in our clinical practice.1 Inhibiting platelet aggregation and thrombus formation rapidly and effectively is very important for these patients. Although considerable evidence supports the use of antiplatelet therapy with both of aspirin and clopidogrel,2-5 whether the addition of intravenous tirofiban to aspirin and clopidogrel is of further benefit has not been clarified, especially in patients with ST segment elevation myocardial infarction (STEMI) who received p-PCI via transradial access.6-9 Tirofiban, a rapidly acting antagonist of platelet glycoprotein (GP) IIb/IIIa receptor, inhibits platelet aggregation and thrombus formation by blocking the combination of fibrinogen with GP IIb/IIIa receptor. The safety and effectiveness of three antiplatelet agents in patients with STEMI who received p-PCI via trasradial access has rarely been reported.10,11
The present study evaluated the effect and safety of intravenous tirofiban plus aspirin and clopidogrel in STEMI patients undergone p-PCI via transradial approach.
Consecutive patients with STEMI were enrolled into this study from January 2005 to May 2007, if they: (1) had chest pain within 12 hours of onset of AMI; (2) were suitable for percutaneous revascularization; and (3) had ECG that demonstrated ≥0.1 mV ST segment elevation in 2 or more contiguous leads or documented new left bundle branch block.
Exclusion criteria were bleeding diathesis, administration of thrombolytic agents, neoplasm, recent stroke, uncontrolled hypertension, recent surgery, oral anticoagulant therapy and known contraindications to therapy with aspirin, clopidogrel, tirofiban or heparin. Written informed consent was obtained from each patient.
Among the enrolled 150 patients, 72 were in tirofiban group and 78 in placebo group. The demographics and presentations of the two groups were not significantly different (Table 1).
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Table 1. Patients' demographics and presentations of two groups
Each patient received aspirin 300 mg and clopidogrel 300 mg as they were enrolled and then randomly assigned to either tirofiban group or placebo group. Tirofiban (Wuhan Grand Pharmaceutical Group Co. Ltd., China) was given as a bolus injection of 10 µg/kg over 3 minutes and then followed by continuing intravenous 0.15 μg∙kg-1∙min-1 for 24 hours. The placebo, saline, was infused in the same way. Heparin was given as an initial bolus of 70 U per kilogram (less than 7000 U totally). If necessary, additional boluses were administered to achieve an activated clotting time about 250 seconds. Other medications, including β-blockers, nitrates and morphine, were administered at the discretion of the attending physician.
Catheterization procedures and angiographic analysis
Diagnostic coronary angiography was performed in all patients before p-PCI. PCI was not performed on lesions of less than 65% of stenosis in the artery. If intracoronary stents were placed, clopidogrel (75 mg/d) and aspirin (300 mg/d) were prescribed.
Access and systemic bleeding complications were observed and recorded according to thrombolysis in myocardial infarction (TIMI) definitions of minor and major bleeding. Occurrences of major adverse cardiovascular events (MACE) including subsequent infarction, acute heart failure, urgent revascularization and death were followed up for 6 months.
Angiographs were taken before PCI, when first crossing of occlusion segment by guide wire and immediately after PCI. Estimation of final TIMI flow grade (TFG), corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG) of the infarction related artery (IRA) were calculated offline by 2 blinded, independent observers and the values were averaged if the results were not in agreement.
Total creatine phosphokinase (CPK), CPK isoenzyme MB (CPK-MB) and troponin I levels were measured at admission and were repeated every 6 hours. ECG was also obtained at least daily. Blood platelet aggregation rate (PAR) was measured on admission and at different times (15 minutes, 30 minutes, 2 hours, 6 hours and 12 hours) after transradial p-PCI.
Left ventricular function
Left ventricular performance parameters such as left ventricular ejection fractions (LVEF), peak ejection rate (LPER), time of peak ejection rate (LTPER), peak filling rate (LPFR) and time of peak filling rate (LTPFR) were measured by equilibrium radionuclide ventriculography one week after PCI.
SAS 6.12 Software was used for statistical analysis. All continuous variables were presented as mean ± standard deviation (SD) and analyzed by Student's t test. Categorical variables were presented as percentage and analyzed by chi-square test or Fisher's exact test. P value less than 0.05 was considered statistically significant.
Analyses of effectiveness
Angiographic analysis showed a statistical significance in initial TIMI grade 0 and 1 flow (Table 2).
The percentage of TFG 0 was significantly lower before PCI and when first crossing of guide wire, while the percentage of TFG 3 of IRA was significantly higher in tirofiban group than those in placebo group. Five cases in tirofiban group did not need stenting because the thrombus was completely dissolved without obvious stenosis of IRA when the guide wire crossed through occluded segment. The percentage of TFG 3 after PCI was significantly higher, while the final CTFC was significantly fewer. The incidence of no reflow phenomenon was significantly lower and the percentage of final TMPG 3 was significantly higher in the tirofiban group than that in the placebo group (Table 2, Figure 1).
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Table 2. Procedural findings (n (%))
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Figure 1. Impacts of tirofiban on TFG before PCI when the guide wire first crossing and after PCI. TIMI: thrombolysis in myocardial infarction; PCI: percutaneous coronary intervention. *P<0.01 and #P<0.05 compared with the palcebo group.
The mean value of peak CPK-MB in the tirofiban group was significantly lower ((210.50±91.40) U/L vs (294.78±69.88) U/L, P <0.001), while the Left ventricular performance parameters were improved much more than those in the placebo group 1 week after PCI (Table 3).
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Table 3. Cardiac function between the two groups one week after PCI
The value of PAR was significantly decreased as soon as 15 minutes after tirofiban infusion. Figure 2 shows the changes of PAR at different times in the two groups.
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Figure 2. Changes of platelet aggregation rate at different time in the two groups. *P <0.01 compared with the placebo group.
No statistical difference was noted between the two groups with regard to bleeding complications (Table 4). The clinical outcomes revealed a significantly lower incidence of MACE (death, recurrent myocardial infarction, serious heart failure or arrhythmia) in the tirofiban group.
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Table 4. Complications and outcomes of p-PCI (n (%))
The patients with STEMI are always facing the risk of thrombosis, whose coronary angiogram often indicates heavy thrombus burden. The microthrombi and desquamated atheromatous plaques caused by mechanical intervention often lead to distant microcirculatory embolism, platelet activation and release of vascular active factors, which result in microvascular slow reflow (or no reflow) phenomenon and decrease of myocardial reperfusion. These are all closely related to the recovery of cardiac performance and clinical prognosis.12-14 Therapy with aspirin and clopidogrel is beneficial for these patients,2-5 but the variability in responses to clopidogrel and aspirin is associated with different clinical outcomes.15 It is possible that, at higher dose of clopidogrel, any benefit in terms of efficacy may be offset by an increased incidence of adverse events, particularly local access bleeding complications.16 So, whether the addition of a third intravenous antiplatelet agent, such as tirofiban that take effect rapidly, is of further benefit has been investigated in recent trials.
In the intracoronay stenting and antithrombotic regimen: rapid early action for coronary treatment (ISAR-REACT) study,17 2159 patients on clopidogrel and aspirin received randomly a bolus of abciximab or placebo before undergoing planned PCI. ISAR-REACT revealed no decrease in ischaemic complications by adding abciximab to therapy. Furthermore, although the incidence of bleeding in both study groups was low, abciximab was associated with a higher rate of thrombocytopenia (1% vs 0%, P=0.002) and an increased need for blood transfusion (2% vs 1%, P=0.007). A recently published meta-analysis18 also indicated that treatment with GP IIb/IIIa inhibitors in the setting of PCI significantly reduced the rates of 30 days' mortality, myocardial infarction and repeating revascularization procedures. These beneficial effects were achieved at an increased risk of thrombocytopenia and minor, but not major, bleeding.
The more recent ISAR-REACT 2 trial extended the concept of triple therapy to 2022 higher risk patients presenting with non-STEMI and undergoing PCI within 48 hours.19 Again, patients received abciximab or placebo, along with standard heparin, aspirin and clopidogrel, but this time a significant 25% risk reduction was found in the triple antiplatelet therapy group (P=0.03). The incidence of death or myocardial infarction was 8.6% in the triple antiplatelet therapy group and 11.5% in the placebo group (P=0.003) and there was no significant difference in major bleeding complications.
ELISA 2 study also favoured the addition of a GP IIb/IIIa inhibitor to aspirin and clopidogrel.20 This study evaluated the effects of triple therapy on enzymatic infarct size, angiographic measurements, rates of death and MI in 328 patients with non-ST segments elevation acute coronary syndrome. The results showed a small, non-significant reduction in enzymatic infarct size, measured by reduced concentrations of lactate dehydrogenase and creatine kinase and an improved vessel flow rate as measured by TFG. There was also a reduced rate of death and myocardial infarction in the triple therapy group compared with the aspirin and clopidogrel treatment group (46% vs 57%, P=0.05).
Martiez et al21 found that GP IIb/IIIa antagonist improved TFG by 11%, rate of TMPG 3 by 18% and the incidence of MACE 30 days later was lowered by 13.7% in patients after p-PCI.
On the other hand, Yip et al9 reported that GP IIb/IIIa antagonist did not reduce the thrombus burden and did not improve the 30-day prognosis in STEMI patients receiving p-PCI. Yeh et al10 also reported negative results that tirofiban did not improve immediate reperfusion rate in STEMI patients or lower the 6-month infarction and death rates after p-PCI. The clinical guidelines of AHA/ESC also put the application of tirofiban in acute STEMI as IIb indication (evidence level C).
Unlike abciximab, tirofiban is a non-peptide GP IIb/IIIa receptor antagonist, which was not manufactured in China until recently. There is little data about its use, especially in p-PCI via transradial access in China.
Our study indicated that tirofiban plus aspirin and clopidogrel improved TFG before PCI, when guide wire first passing through, which even resulted in self-recanalization of the occluded coronary artery and thus avoided implantation of stent in the cases without serious stenosis lesion. Tirofiban plus aspirin and clopidogrel also improved TIMI flow after implantation of stent and reduced the incidence of slow reflow phenomenon. It also has been reported that intravenous tirofiban in combination with half normal dose of tissue type plasminogen activator completely dissolved intracoronary embolic thrombi secondary to mitral valve prosthesis.22 These results strongly indicate that intravenous administration of tirofiban played a role of loosening intracoronary thrombus, then improving TMPG. The triple antiplatelet treatment enhanced also myocardial microcirculation, which, in turn, resulted in the early repair of injured myocardium. The lowered CPK-MB and improved left ventricular function in our study were in accordance with the reduction of myocardial infarction size and incidence of MACE. Tirofiban administration was beneficial to the early improvement of myocardial reperfusion and the early protection of cardiac performance. Using cTn-I, cTn-T and CK-MB as markers, Okmen et al23 also found that tirofiban reduced the incidence of minor myocardial injury, which decreased long-term cardiac events after PCI.
Data concerning the relationship of the time course and antiplatelet effect of intravenous tirofiban in Chinese were few until recently.24 Our study showed PAR was inhibited approximately by 50% at about 15 minutes after administration of tirofiban and maintained during the whole observation period, which indicated that addition of tirofiban to aspirin and clopidogrel had a faster and stronger effect on inhibiting blood platelet aggregation than that without tirofiban. The treatment with triple antiplatelet agents may improve TFG before PCI, when the crossing of guide wire and after implantation of stent. Not only did it help prevent thrombus formation during the operation, but also facilitated the repatency of the IRA, so that it increased the success rate and shortened the duration of the p-PCI procedure.25
Although GP IIb/IIIa inhibitors are recommended for patients with unstable angina and non-STEMI who undergo PCI, the ACC/AHA guidelines did not specify the optimal timing for their use. Tricoci et al26 compared patients' characteristics and clinical outcomes in 30 830 patients with non-STEMI included in the CRUSADE (January 2001 to December 2004) who underwent PCI with upstream (>1 hour before PCI) or periprocedural use of GP IIb/IIIa inhibitors. Overall, ischemic outcomes were similar between the two groups. However, Bolognese et al27 found that upstream tirofiban is associated with improved tissue level perfusion and attenuated myocardial damage. So, clinical trials are needed to solve the controversy over optimal timing of GP IIb/IIIa inhibitor administration.
Intensive antiplatelet and anticoagulation therapy might increase the bleeding complications during p-PCI via transfemoral approach.28 Recently, the transradial access has been increasingly employed in patients with AMI.6,29 In our study, all the patients underwent p-PCI via transradial artery access without difference of the bleeding complications between the two groups. It was also reported that early discharge was feasible for these patients.30,31 All the above indicated the advantages of transradial artery access over transfemoral artery access during intensive antiplatelet therapy with tirofiban.
Yang et al32 found that tirofiban reduced the myocardial necrosis size induced by reperfusion in AMI animals, increased NO concentration, improved mRNA expression of NOS precursor and endothelial NOS in the reperfusion region of infarcted myocardium, these benefits were not found in routine antiplatelet therapy with aspirin and clopidogrel. Warnholtz et al33 evaluated the acute effect of tirofiban on endothelial function of arterial conductance vessels in patients undergoing PCI. Endothelial function was examined by ultrasonographic measurement of flow mediated vasodilation (FMD) of the brachial artery. Thirty-three patients received 10 µg/kg of tirofiban, whereas 33 patients who did not receive tirofiban served as the control group. Tirofiban significantly improved FMD, but nitroglycerine induced dilation remained unaltered in response to PCI. In another group of 11 patients with coronary artery disease, FMD did not change after coronary angiography without PCI. Therefore, endothelial dysfunction in forearm conductance vessels induced by PCI can be reversed by tirofiban, which indicated that tirofiban improves vascular endothelial function. This, in some ways, may be helpful to explain the improvement of coronary microcirculation (TFG and TMPG) in our study.
In conclusion, tirofiban infusion, combined with aspirin and clopidogrel, in STEMI patients with p-PCI via transradial artery access, can quickly inhibit platelet aggregation, loosen occlusive thrombus of related infarction artery, improve myocardial reperfusion, reduce the incidence of MACE. PCI via transradial artery access in patients with STEMI has many advantages in decreasing various complications of bleeding and vessel injury, especially for patients undergoing intensive therapy with tirofiban infusion in addition to aspirin and clopidogrel antiplatelet agents.
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20. Rasoul S, Ottervanger JP, de Boer MJ, Miedema K, Hoorntje JC, Gosselink M, et al. A comprison of dual cf triple antiplatelet therapy in patients with nonST segment elevation acute coronary syndrome: results of the ELIAS-2 trial. Eur Heart J 2006; 27: 1401-1407.[PubMed]
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30. Fu XH, Ma N, Liu J, Wu WL, Li SQ, Jiang YF, et al. A comparative study on transradial vs. transfemoral artery access for primary percutaneous coronary intervention in patients with acute myocardial infarction. Chin J Cardiol (Chin) 2003; 31: 573-577.
31. Dirksen MT, Ronner E, Laarman GJ, van Heerebeek L, Slagboom T, van der Wieken LR, et al. Early discharge is feasible following primary percutaneous coronary intervention with transradial stent implantation under platelet GP Iib/IIIa receptor blockade. Results of the AGGRASTENT Trial. J Invasive Cardiol 2005; 17: 512-517.[PubMed]
32. Yang YJ, Zhao JL, You SJ, Wu YJ, Jing ZC, Yang WX, et al. Different effects of tirofiban and aspirin plus clopidogrel on myocardial no-flow in a mini-swine model of acute myocardial infarction and reperfusion. Heart 2006; 93: 1131-1137.[PubMed]
33. Warnholtz A, Ostad MA, Heitzer T, Goldmann BU, Nowak G, Munzel T. Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 2005; 95: 20-23.[PubMed]