Upstream Tirofiban Research Articles

Effect of Up-Stream Tirofiban Therapy in STEMI Patients, Who Are Not Candidates for Primary Reperfusion Strategy with Thrombolysis and Undergoing Delayed PCI: A Single Tertiary Care Centre Observational Study

Effect of Up-Stream Tirofiban Therapy in STEMI Patients, Who Are Not Candidates for Primary Reperfusion Strategy with Thrombolysis and Undergoing Delayed PCI: A Single Tertiary Care Centre Observational Study

Comparative effectiveness of upstream glycoprotein IIb/IIIa inhibitors in patients with moderate- and high-risk acute coronary syndromes: An Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) substudy

Tirofiban and eptifibatide are both small-molecule, competitive glycoprotein IIb/IIIa receptor inhibitors (GPIs) that are guideline-supported for upstream therapy in acute coronary syndromes (ACS). This study sought to compare the efficacy and safety of tirofiban and eptifibatide in patients with ACS. Within the ACUITY trial, 4,323 patients with moderate- and high-risk ACS received upstream, adjunctive GPI (tirofiban or eptifibatide) in addition to an antithrombin. Primary outcomes included 30-day rates of composite major adverse cardiac events (MACE), major bleeding (not related to coronary artery bypass grafting), and composite net adverse clinical events (NACE). The outcomes were compared based on the upstream GPI administered. There were significant differences in the baseline characteristics of patients treated with tirofiban vs eptifibatide, particularly related to country/region. In unadjusted analyses, treatment with upstream tirofiban vs eptifibatide was associated with similar rates of major bleeding (5.8% vs 6.5%, P = .39) and nonsignificantly lower rates of MACE (6.1% vs 7.6%, P = .06) and NACE (10.6% vs 12.6%, P = .06). After propensity-based multivariable adjustment, there were no significant differences between tirofiban and eptifibatide with respect to 30-day major bleeding, MACE, or NACE. Among more than 4,000 patients with moderate- and high-risk ACS treated with upstream GPI as part of an early invasive management strategy, the use of tirofiban and eptifibatide resulted in similar clinical outcomes. These data suggest equivalence of these 2 agents for upstream use, while highlighting some of the difficulties of nonrandomized comparative effectiveness analyses, specifically the difficulty in addressing geographic differences in the use of nonrandomized treatments.

Upstream tirofiban reduces reperfusion cardiac arrhythmias in patients of acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention

“Open the artery in time” has become the dogma in treating ST-elevation myocardial infarction (STEMI) since the 1990s. It has been a consensus that the more patent the infarct-related artery (IRA), the better the clinical outcomes [ 1 Simes R.J. Topol E.J. Holmes Jr., D.R. et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation. 1995; 91: 1923-1928 Crossref PubMed Scopus (463) Google Scholar , 2 Anderson J.L. Karagounis L.A. Califf R.M. Meta-analysis of five reported studies on the relation of early coronary patency grades with mortality and outcomes after acute myocardial infarction. Am J Cardiol. 1996; 78: 1-8 Abstract Full Text PDF PubMed Scopus (160) Google Scholar ]. In addition, the strategies of reperfusion, referring to intravenous thrombolytics and primary percutaneous coronary interventions (pPCI), have been proved to differ among themselves in acute success of reperfusion and long-term outcomes. The pPCI is better in restoring the coronary blood flow and renders less complications than thrombolytic therapy [ 3 Zijlstra F. de Boer M.J. Hoorntje J.C.A. Reiffers S. Reiber J.H. Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med. 1993; 328: 680-684 Crossref PubMed Scopus (1177) Google Scholar , 4 Zeymer U. Schroder R. Machnig T. Neuhaus K.L. Primary percutaneous transluminal coronary angioplasty accelerates early myocardial reperfusion compared to thrombolytic therapy in patients with acute myocardial infarction. Am Heart J. 2003; 146: 686-691 Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar ]. As the platelet plays the central role in triggering the acute thrombotic mechanism in STEMI, the complete inhibition of the platelet function, from adhesion, activation to aggregation, has been the focus of current optimal anti-platelet therapy. The standard dual anti-platelet therapy (DAT), consisting of aspirin and clopidogrel, exerts its function to counteract the platelet activation. The inadequacy and negligence to inhibiting platelet aggregation at the time of pPCI were proved to result in more major adverse cardiovascular events (MACE), especially in patients of clopidogrel resistance [ [5] Matetzky S. Shenkman B. Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004; 109: 3171-3175 Crossref PubMed Scopus (1282) Google Scholar ]. It is also said “the lower the platelet reactivity, the less the myocardial necrosis and the better the clinical outcomes [ [6] Campo G. Valgimigli M. Gemmati D. et al. Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention. Insights into the STRATEGY Study. J Am Coll Cardiol. 2006; 48: 2178-2185 Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar ].” In order to further block the platelet aggregation, adding a glycoprotein IIb/IIIa (GP IIb/IIIa) antagonist, thus formulating the triple anti-platelet therapy, has been recommended for high risk non-ST-elevation acute coronary syndromes (NSTEACS) [ [7] Bassand J.P. Hamm C.W. Ardissino D. et al. Task force for diagnosis and treatment of non ST elevation acute coronary syndromes. Eur Heart J. 2007; 28: 1598-1660 Crossref PubMed Scopus (49) Google Scholar ]. GP IIb/IIIa antagonist, especially tirofiban, could be adopted as one of the background therapy in dealing with NSTEACS [ [8] Hsin H.T. Li A.H. Yeih D.F. et al. Two-year follow-up of tirofiban-based management of non-ST-elevation acute coronary syndrome — a single center study. Acta Cardiol Sin. 2010; 26: 19-27 Google Scholar ]. On the other hand, peri-PCI abciximab has been demonstrated to significantly improve reperfusion in the infarct region and clinical outcomes of patients with STEMI undergoing pPCI, which has been regarded as class IIa recommendation since 2004 [ 9 Van de Werf F. Ardissino D. Betriu A. et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003; 24: 28-66 Crossref PubMed Scopus (1491) Google Scholar , 10 Antman E.M. Anbe D.T. Armstrong P.W. et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004; 44: E1-E211 Abstract Full Text PDF PubMed Google Scholar ]. However, the role of tirofiban is rather obscure. The efficacy and timing to administer tirofiban in STEMI are still on debate.

Benefit of standard versus low-dose tirofiban for percutaneous coronary intervention in very elderly patients with high-risk acute coronary syndrome

This study aimed to compare the efficacy and safety between standard and low-dose tirofiban in the treatment of elderly high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients who underwent percutaneous coronary intervention (PCI). Ninety-four very elderly (>or=80 years) high-risk patients with NSTE-ACS were randomly assigned to the standard or the low-dose group. Upstream tirofiban was administered intravenously with a bolus dose of 0.4 microg x kg(-1) x min(-1) over a period of 30 min after the diagnosis had been confirmed, and was followed by a 36-48 h infusion of 0.10 microg x kg(-1) x min(-1) or 0.075 microg x kg(-1) x min(-1). PCI was performed within 24 h of admission. Platelet aggregation inhibition and thrombolysis in myocardial infarction (TIMI) grade flow were assessed. The major adverse cardiac events (MACEs), including death, myocardial infarction, recurrent angina and urgent target-vessel revascularization (TVR), were documented at 7 d, 30 d, and 6 months, and bleeding events were recorded at 7 d. Although a significantly higher inhibition of platelet aggregation was observed in the standard-dose group (P<0.05), angiographic PCI success was similar between the two groups (P>0.05). The rate of MACEs was not significantly different at 7 days (2.1% vs 4.4%, P=0.61), 30 days (6.3% vs 8.7%, P=0.71) and 6 months (14.6% vs 17.4%, P=0.71). Major bleeding events were significantly higher in the standard-dose group (10.4% vs 0.0%, P=0.03). In very elderly high-risk patients with NSTE-ACS undergoing PCI, low-dose tirofiban offered about the same level of protection from major ischemic events that standard doses did, with less associated bleeding.

Clinical benefits of adjunctive tirofiban therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

There is continued debate as to whether a combined reperfusion regimen with platelet glycoprotein IIb/IIIa inhibitor-tirofiban provides additional benefit in optimal myocardial reperfusion for patients with acute ST-segment elevation myocardial infarction (STEMI). This study was conducted to investigate the clinical benefits of adjunctive tirofiban therapy combined with primary percutaneous coronary intervention (PCI) in patients with STEMI. One hundred and seventy-two consecutive patients with STEMI presented within 12 h of symptoms were randomly allocated to primary PCI combined with early (upstream group, n=57) or late administration of tirofiban (downstream group, n=57) or primary PCI treatment alone (control group, n=58). Clinical characteristics, angiographic findings, and in-hospital outcomes were compared between groups, as well as left ventricular ejection fraction (LVEF) and major adverse cardiac events (MACE, including death, reinfarction and target vessel revascularization) at 30-day and 6-month clinical follow-up. Despite comparable baseline clinical features among three groups, angiographic and procedural characteristics and outcomes differed significantly between patients receiving tirofiban treatment and controls, with respect to preprocedural (upstream: 28.1%, downstream: 7.0%, control: 5.2%, P<0.001) and postprocedural thrombolysis in myocardial infarction (TIMI) grade 3 flow of infarct-related artery (98.2, 94.7, 86.2%, P=0.03), TIMI myocardial perfusion grade 3 (75.4, 70.2, 53.4%, P=0.03), corrected TIMI frame count (20.4+/-5.0, 23.1+/-5.3, 32.2+/-6.7, P<0.001), resolution of the sum of ST-segment elevation (6.16+/-1.21, 6.02+/-1.09, 4.53+/-2.65 mm, P<0.001), peak value of creatine kinase-MB (218.0+/-72.5, 224.2+/-69.4, 255.3+/-77.0 ng/ml, P=0.02) and troponin I (76.0+/-21.5, 79.8+/-18.7, 86.4+/-11.0 ng/ml, P=0.007), and average hospital stay (10.6+/-5.4, 12.6+/-4.7, 14.5+/-6.5 days, P=0.001). The MACE rate at 30 days (3.5, 5.3, 15.5%, P=0.04) was reduced and LVEF (0.51+/-0.07, 0.50+/-0.07, 0.47+/-0.08, P=0.008) was higher in upstream and downstream groups than in controls. At 6-month follow-up, the MACE rate was not significantly different among groups (7.0, 8.8, 17.2%, P=0.17), but LVEF in upstream and downstream groups was significantly improved (0.59+/-0.06, 0.57+/-0.07, 0.54+/-0.07, P<0.001). Subgroup analysis demonstrated a statistically significant difference between upstream and downstream groups in preprocedural TIMI grade 3 flow (P=0.003) and postprocedural corrected TIMI frame count (P=0.007), which resulted in a shortened hospital stay (P=0.04), reduction of MACE rate at 30-day and 6-month follow-up by 34 and 20%, respectively. Multivariate logistic analysis revealed that age more than 65 years [odds ratio (OR)=3.42, P<0.01], tirofiban therapy (OR=0.56, P<0.05) and LVEF less than 0.5 during hospitalization (OR=2.56, P<0.01) were major independent predictors of MACE at 6-month clinical follow-up. No significant difference in hemorrhagic complications among three groups was noted (upstream: 10.5%, downstream: 12.3%, control: 6.9%, P=0.61). This prospective study indicates that adjunctive tirofiban therapy for patients with STEMI who undergo primary PCI can significantly improve reperfusion level in the infarct area, clinical outcomes at 30-day and 6-month follow-up, especially with upstream tirofiban therapy, and is safe.

Facilitated PCI by combination fibrinolysis or upstream tirofiban in acute ST-segment elevation myocardial infarction: Results of the Alteplase and Tirofiban in Acute Myocardial Infarction (ATAMI) trial

Direct percutaneous coronary intervention is the generally accepted superior strategy in acute ST-segment myocardial infarction. The concept of facilitating PCI in order to overcome delay by door-to-balloon time or transport is nevertheless of interest. Combination fibrinolysis guarantees higher rates of open infarct-related vessels and reduced reocclusion but without reduction of mortality. After a pilot trial of facilitated PCI by combination fibrinolysis in 39 patients with excellent efficacy and high safety we prospectively randomised 151 patients (96 males, mean age 67.4 ± 8.7 years) to combination fibrinolysis with 50 mg alteplase and tirofiban and 162 patients (103 males, mean age 65.6 ± 9.4 years) to upstream tirofiban before invasive approach including PCI. TIMI 2 or 3 flow of infarct-related vessel before intervention as the primary endpoint and 30-day mortality, bleeding complication and angiographic proven stent thrombosis as secondary endpoints were assessed. 160 matched patients with acute PCI and provisional abciximab served as a control group. Results TIMI 2 or 3 flow in the infarct-related vessel could be demonstrated in 87% in the combination fibrinolysis group, in 42% in the upstream tirofiban group ( p < 0.0001) and 29% in the control group. 30-day mortality was 0.7% versus 5.5% ( p < 0.02) and 6.3% in the control group. No differences could be assessed in severe or moderate (1.3% vs 1.2% vs 1.2%) and mild bleeding complications (2% vs 1.9% vs 2.5%). Stent thrombosis occurred in none of the patients with combination fibrinolysis, in 2 patients (1.5%) in the upstream tirofiban group and in 7 cases (4.4%) in the control group. Conclusions Combination fibrinolysis before PCI leads to significantly higher TIMI flow rates of the infarct-related vessel without increase in 30-day mortality or in bleeding complications. This strategy needs to be further investigated in larger trials and could optimise acute myocardial infarction management even without 24-h service of catheter laboratories.

Routine upstream versus selective down stream use of tirofiban in non-ST elevation myocardial infarction patients scheduled for early invasive therapy; a randomized comparison

Despite their proven beneficial effects and inclusion in the guidelines, glycoprotein (GP) IIb/IIIA blockers are underused in daily practice in patients with non ST-segment elevation acute coronary syndrome (NSTE ACS). This study combines the data from two randomized controlled trials, comparing routine upstream versus selective down stream use of tirofiban in patients with NSTE ACS. Inclusion criteria for both studies (ELISA-1 and 2) were angina pectoris, with ST depression >1 mm and or a positive cardiac biomarkers. All patients were scheduled for coronary angiography. The primary and secondary end points for both studies were enzymatic infarct size (LDHQ48) and initial TIMI flow of the culprit lesion respectively. From August 2000 to January 2005, 273 patients were randomized to routine upstream tirofiban and 275 patients to selective down stream use of tirofiban. Selective down stream tirofiban was used in 55 patients (20%). Patients in the upstream group more often had a patent culprit lesion (65% vs. 50%, P=0.003) and a significantly smaller enzymatic infarct size, LDHQ48 median (25-75%): 125 (55-309) vs. 189 (68-504) IU/l, P=0.006 as compared to the selective down stream group. Subgroup analysis showed that routine upstream tirofiban was particularly effective in males, patients with a positive troponin on admission and in those not pretreated with clopidogrel. Routine upstream GP IIb/IIIa is mainly effective in patients with elevated troponin on admission and those not pretreated with clopidogrel. Large scale randomized trials are needed to evaluate the effect of GP IIb/IIIa blockers on top of clopidogrel pretreatment on major adverse cardiac events.

Randomized Comparison of Upstream Tirofiban Versus Downstream High Bolus Dose Tirofiban or Abciximab on Tissue-Level Perfusion and Troponin Release in High-Risk Acute Coronary Syndromes Treated With Percutaneous Coronary Interventions: The EVEREST Trial

We aimed to compare the effects of upstream tirofiban versus downstream high-dose bolus (HDB) tirofiban and abciximab on tissue level perfusion and troponin I release in high-risk non-ST-segment elevation acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Optimal timing and dosage of glycoprotein IIb/IIIa inhibitors for ACS remain to be explored. We randomized 93 high-risk ACS patients undergoing PCI to receive upstream (in the coronary care unit) tirofiban, downstream (just prior to PCI) HDB tirofiban, and downstream abciximab. We evaluated the effects of the three drug regimens on tissue-level perfusion using the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count, the TIMI myocardial perfusion grade (TMPG), and intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI and after cardiac troponin I (cTnI). The TMPG 0/1 perfusion was significantly less frequent with upstream tirofiban compared with HDB tirofiban and abciximab both before (28.1% vs. 66.7% vs. 71%, respectively; p = 0.0009) and after PCI (6.2% vs. 20% vs. 35.5%, respectively; p = 0.015). Upstream tirofiban was also associated with a significantly higher MCE score index (0.88 +/- 0.18 vs. 0.77 +/- 0.32 vs. 0.71 +/- 0.30, respectively; p < 0.05). Post-procedural cTnI elevation was significantly less frequent among patients in the upstream tirofiban group compared with the HDB tirofiban and abciximab groups (9.4% vs. 30% vs. 38.7%, respectively; p = 0.018). The cTnI levels after PCI were significantly lower with upstream tirofiban compared with HDB tirofiban (3.8 +/- 4.1 vs. 7.2 +/- 12; p = 0.015) and abciximab (3.8 +/- 4.1 vs. 9 +/- 13.8; p = 0.0002) Among high-risk non-ST-segment-elevation ACS patients treated with an early invasive strategy, upstream tirofiban is associated with improved tissue-level perfusion and attenuated myocardial damage.

Effects of tirofiban plus clopidogrel versus clopidogrel plus provisional abciximab on biomarkers of myocardial necrosis in patients with non–ST-elevation acute coronary syndromes treated with early aggressive approach. Results of the CLOpidogrel, upstream TIrofiban, in cath Lab Downstream Abciximab (CLOTILDA) study

In non-ST-elevation acute coronary syndromes (NSTE-ACS), a strong correlation between adverse clinical events and peak values of myocardial necrosis markers has been found. In this study, we evaluated whether the adjunctive treatment with upstream tirofiban reduces the peak levels of cardiac troponin I and creatine kinase-MB (CK-MB) fraction in patients with NSTE-ACS undergoing early invasive strategy and pretreated with aspirin, heparin, and clopidogrel. A total of 300 patients were randomized to receive tirofiban (group 1) or not (group 2). Serial marker samples were collected before and after coronary angiography in all cases and after percutaneous coronary intervention (PCI) when performed. Between the 2 groups, no differences were observed in clinical and angiographic findings. Percutaneous coronary intervention was globally performed in 198 patients (66%). Of 99 group 2 patients, 26 (26%) received abciximab just before PCI. No significant differences between the 2 groups were observed with regard to cardiac troponin I and CK-MB values at admission and at 6, 12, and 24 hours thereafter; peak values before coronary angiography; and peak values of index event. In addition, the cumulative biomarkers release of the index event was similar between the 2 groups. Major bleeding rate was 2% in group 1 and 1% in group 2 (P = not significant). Composite incidence of death, myocardial infarction, or rehospitalization for ACS at 30 days was 9% in group 1 and 10% in group 2. In patients with NSTE-ACS undergoing early invasive strategy, the adjunctive administration of upstream tirofiban did not reduce the peak values and the cumulative release of myocardial necrosis markers, compared with aspirin, heparin, and clopidogrel given on admission and associated with selective use of abciximab just before PCI.

Tirofiban in acute coronary syndromes

Acute coronary syndromes represent a major health problem in terms of incidence and mortality. Intracoronary platelet-rich thrombi may develop in response to plaque rupture, and are involved in the pathogenesis of all acute coronary syndromes. The glycoprotein IIb/IIIa receptor, a platelet surface integrin, plays a key role in platelet aggregation once it has been activated by specific ligands. The development of glycoprotein IIb/IIIa inhibitors has revolutionized the management of acute coronary syndromes. Tirofiban is one of three parenteral glycoprotein IIb/IIIa inhibitors in clinical use, and many trials have demonstrated its clinical efficacy and low rate of adverse effects in patients with non-ST-segment elevation acute coronary syndrome. This article reviews the data concerning its use in the clinical settings of acute coronary syndromes and percutaneous coronary angioplasty, and discusses its benefits in different treatment strategies and in association with other drugs. In particular, the role of early, upstream tirofiban coupled with early aggressive revascularization in the management of high-risk non-ST-segment elevation acute coronary syndromes is emphasized.