High-Dose Tirofiban Administered as Bolus-Only during
Percutaneous Coronary Intervention

Inhibition of platelet glycoprotein IIb/IIIa receptors during percutaneous coronary intervention (PCI) using tirofiban, eptifibatide and abciximab has been associated with improved outcomes.¹ The only head-to-head comparison to these agents was provided by the “do Tirofiban And Reopro Give similar Efficacy outcomes Trial (TARGET)”, in which patients were randomized to tirofiban or abciximab.² In this study tirofiban offered less protection from major ischemic events compared to abciximab. However, the dose of tirofiban used in the TARGET trial (bolus of 10 μg/kg followed by an infusion of 0.15 μg/kg per minute for 18–24 hours) is now perceived as having been inadequate to fully inhibit platelet function. Specifically, studies conducted after the TARGET trial showed that the extent of platelet inhibition 15–60 minutes post bolus of tirofiban dose used in that trial was suboptimal (61–66%) compared to > 90% platelet inhibition by abciximab.³ Furthermore, additional subsequent studies done with higher doses of tirofiban (25 μg/kg bolus dose with the same infusion dose) showed that the average inhibition of platelets could be increased to > 90%.⁴
Based on the demonstration that a 25 μg/kg bolus dose is associated with high levels of platelet inhibition, the full-time faculty at our institution adopted this dose for patients undergoing PCI. Furthermore, it has been our routine practice to administer glycoprotein IIb/IIIa inhibitors (GPI) using a bolus-only strategy during PCI.^5–8 In our previous report, the eptifibatide bolus-only group had a significantly lower inhospital composite endpoint of death, myocardial infarction, revascularization and bleeding complications compared to the abciximab bolus-only group, predominantly secondary to the fewer bleeding complications.⁶ We now present a retrospective analysis of the in-hospital outcomes of the first 292 patients who underwent PCI with this high-dose tirofiban bolus-only regimen compared to our previously-reported eptifibatide bolus-only group.

Methods
Study cohort. This is a retrospective study of 876 patients, of which 292 consecutive patients underwent PCI with a high-dose tirofiban bolus-only regimen from December 2004 to August 2005, and 584 consecutive patients who underwent PCI with an eptifibatide bolus-only regimen from January 2003 to August 2004 at a single institution. The hospital’s institutional review board approved the study. Demographic, periprocedural and laboratory data are collected by reviewing charts and hospital records. The in-hospital events and the length of stay are also recorded. Patients with ST-segment elevation myocardial infarction (STEMI) were not given this novel dosing and were excluded from the study. All patients were loaded with aspirin 325 mg and clopidogrel 300–600 mg just prior to PCI. All patients received an initial bolus of intravenous 40 units/kg of unfractionated heparin (UFH) plus either high-dose tirofiban (25 μg/kg) bolus or eptifibatide (180 μg/kg x 2) bolus at the beginning of the intervention. Tirofiban was administered at a concentration of 250 μg/ml via a peripheral intravenous catheter. The tirofiban dose was reduced to half (12.5 μg/kg) in patients with end-stage renal disease (ESRD), as recommended by the manufacturer. UFH was administered as a supplemental boluses if required to achieve a target activated clotting time (ACT) of at least 200 seconds. ACT was measured by using the Hemochron^® device (ITC Technidyne Corp, Edison, New Jersey). Coronary interventional procedures were performed according to standard techniques via a femoral approach. Femoral vascular closure devices (Angio-Seal [St. Jude Medical, Minnetonka, Minnesota] or Perclose [Perclose Inc., Redwood City, California]) were used unless contraindicated. Serial monitoring of cardiac biomarkers was performed every 8 hours for 24 hours after PCI, and hemoglobin levels were measured every 24 hours until the patient was discharged. All patients were discharged on aspirin and clopidogrel.
Sample collection and measurement of platelet function. As per our standard catheterization laboratory protocol for patients receiving GPI, all operators were encouraged to monitor baseline and post-tirofiban bolus platelet activity using the rapid platelet function assay (RPFA) expressed in platelet activation units (PAU) with the Ultegra device (Accumetrics, San Diego, California). This monitoring is performed to ensure that the medication was successfully administered and that an effective inhibition of platelet function had been achieved prior to PCI. Additional PAU measurements were performed usually either at the end of the procedure, just prior to the deployment of an arterial closure device, or several hours after the procedure at the time of sheath removal at the discretion of the operator. All the PAU data available in the charts were collected. The samples were drawn from the standard femoral arterial sheaths. Percentage of platelet inhibition was calculated using the equation: 100 - (PAU at time t)/(PAU baseline) x 100.
Definitions. Post-PCI myocardial infarction (MI) was defined according to the thrombolysis in myocardial infarction (TIMI) criteria.⁹ A new MI was defined by biochemical or electrocardiographic criteria: the MB isoform of creatinine kinase (CK-MB) at least 3 times the upper limit of the normal range in at least 1 blood sample, or the finding of abnormal Qwaves in 2 or more contiguous leads. For patients with recent MI who had an elevated CK-MB level before the procedure, a value > 3 times the upper limit of normal and at least 50% above the baseline value was required to meet the definition.
Bleeding was defined according to the Randomized Evaluation in the PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) criteria.¹⁰Major bleeding was defined as either any intracranial, intraocular, or retroperitoneal or clinically overt bleeding with a drop of hemoglobin by 3 g/dl, or any drop of hemoglobin by 4 g/dl, or the transfusion of 2 or more units of packed red blood cells. Minor bleeding was defined as clinically overt bleeding not meeting the above criteria. We chose to define and compare our bleeding complications using the REPLACE-2 trial rather than TIMI definitions because REPLACE-2 definitions are more sensitive and this trial has reported the lowest rates of bleeding in the context of modern PCI. Thrombocytopenia was defined as a fall in the platelet count < 100,000/μl, or a decrease by 25% below baseline values in the event the initial platelet count was < 100,000/μl. Patients were considered to have ESRD if they were dependent on chronic dialysis. The composite endpoint was defined as the sum of in-hospital death, target vessel revascularization, MI and bleeding.
Statistical analysis. Continuous variables are presented as mean ± standard deviation (SD). Categorical variables are presented as percentages. The chi-square test was used to compare the differences between categorical variables. The independent samples t-test was used to compare between continuous variables with normal distribution, and the Mann-Whitney test was used to compare continuous variables without a normal distribution. Adjustment for baseline risk factors and procedural characteristics was done using logistic regression analysis. Baseline and procedural characteristics significantly different between the two groups (p < 0.05) were used as covariates in the logistic regression analysis. The covariates used were body mass index (BMI), history of coronary artery disease (CAD), smoking, use of ACE-inhibitors, statins, left anterior descending artery (LAD) intervention, multivessel intervention, peak ACT and successful PCI. A p-value < 0.05 was considered significant. All statistical analyses were performed utilizing SPSS software version 15.0 (SPSS, Chicago, Illinois). Microsoft Excel software was used to construct the graphs.

Results

Baseline characteristics. A total of 876 patients underwent PCI with high-dose tirofiban (n = 292) or eptifibatide (n = 584) bolus-only regimens during the study period. Baseline characteristics and procedural data are shown in Tables 1 and 2, respectively. Most of our patients were African-American (83%) and had a high prevalence of hypertension, diabetes and coronary artery disease. The patients in the eptifibatide group had a significantly higher mean BMI (28 kg/ m² in tirofiban vs. 30 kg/m² in eptifibatide), a greater number of patients with smoking history (19.5% in tirofiban vs. 33% in eptifibatide) and previously documented CAD (50% in tirofiban vs. 73% in eptifibatide). A greater number of patients in the eptifibatide group were given ACE-inhibitors (63% in tirofiban vs. 70% in eptifibatide) and statins (75% in tirofiban vs. 85% in eptifibatide) during hospitalization compared to those in the tirofiban group. The peak mean ACT was significantly higher in the eptifibatide group compared to the tirofiban group (281.5 seconds in tirofiban vs. 284 seconds in eptifibatide; p = 0.03). More patients in the tirofiban group underwent multivessel intervention (4% in tirofiban vs. 1.5% in eptifibatide), and more patients in the eptifibatide group underwent a successful PCI (98% in tirofiban vs. 99.5% in eptifibatide) compared to the tirofiban group. Closure devices were used in 41% of patients receiving tirofiban. The mean duration of the procedure was 27 ± 15 minutes. For tirofiban-treated patients, the mean duration from the time of tirofiban administration to sheath removal was 145 ± 71 minutes in patients who did not receive closure devices.

In-hospital outcomes. The in-hospital outcomes are summarized in Table 3 and hemorrhagic endpoints and other vascular complications in Table 4. There were noin-hospital deaths or target vessel revascularizations in our study group. The composite endpoint of in-hospital death, target vessel revascularization, MI and bleeding complications was 5.5% in the tirofiban group and 5.3% in the eptifibatide group (p = 0.79). Seven patients (1.5%) had bleeding complications (0.7% major and 0.9% minor) in the eptifibatide group, while 6 patients (2%) had bleeding complications (0.3% major and 1.7% minor; p = 0.55). Only 1% of patients in the tirofiban group and 0.5% of patients in the eptifibatide group had thrombocytopenia (p = 0.34). One patient in the eptifibatide group developed acute thrombosis of a right aorto-femoral bypass graft and underwent surgical thrombectomy. A total of 3 patients (2 in the eptifibatide group and 1 in the tirofiban group) developed pseudo-aneurysm of the femoral artery at the puncture site diagnosed by Doppler and were managed conservatively.

We performed a subgroup analysis on patients with acute coronary syndrome (ACS) versus patients undergoing PCI for stable CAD among those who received high-dose tirofiban bolus-only during PCI (Table 5). Except for usage of beta-blockers during the periprocedural period, all the other baseline and procedural characteristics were similar between the two groups. Over 85% of patients with ACS were given beta-blockers while only 73% of patients with stable CAD were given beta-blockers periprocedurally (p = 0.013). After adjustment for beta-blocker usage using logistic regression analysis, there was a trend towards higher post-PCI MI in the ACS group (5.4% in ACS group vs. 1.5 % in the non-ACS group; p = 0.08).
Platelet inhibition. The time course of platelet inhibition after the high-dose tirofiban bolus in all patients and in patients with ESRD who received half the bolus dose are summarized in Figures 2 and 3, respectively. Because this is a retrospective study, we do not have PAU values for all patients at all time points. The most commonly measured PAUs were at baseline prior to administration of the bolus dose (n = 236), post bolus approximately 3–15 minutes after the bolus dose (n = 184), at the end of procedure approximately 20 to 40 minutes after the bolus dose (n = 106), and in patients not receiving a closure device prior to sheath removal between approximately 120–180 minutes (n = 23). In those cases where the PAU values were obtained, the mean percent platelet inhibition as measured by PAU values was 94% between 3–15 minutes after the bolus dose, 92% at the end of the procedure (between 20–40 minutes), and 74% at the time of sheath removal between 2–3 hours. In patients with ESRD, the mean maximum platelet inhibition achieved at the end of the procedure was 93%; this value dropped to 76% at the time of sheath removal (between 2–3 hours).

Discussion
The current study suggests that high-dose tirofiban bolusonly during PCI appears safe and compares favorably with eptifibatide bolus-only during PCI.
Previously-reported studies on platelet function inhibition after administration of GPI during PCI showed that a 25 μg/kg bolus dose of tirofiban was associated with much higher levels of platelet inhibition compared to the 10 μg/kg bolus dose.^4,11 In a study by Danzi et al, the mean level of platelet inhibition 10 minutes after a 0.25 mg/kg bolus of abciximab, 2 boluses of 180 μg/kg of eptifibatide administered 10 minutes apart, and a 25 μg/kg bolus of tirofiban was 86 ± 9% for abciximab, 92 ± 6% for eptifibatide and 95 ± 5% for tirofiban (p < 0.001).¹¹ Platelet inhibition ≥ 95% 10 minutes after the bolus dose was achieved in 29% of the patients treated with abciximab, 44%of those receiving eptifibatide and 68% of those receiving tirofiban.¹¹ Ernst et al showed similar results with high-dose tirofiban and abciximab.¹² The amount of platelet inhibition post bolus in our study is similar to previous reports.^11,12 Our study is unique in that we avoided an infusion of tirofiban post bolus. This strategy was associated with a high level of platelet inhibition that was sustained until the end of the procedure (92%), and which persisted to a significant degree at the time of sheath removal (74%) several hours later. This apparently persistent antiplatelet effect may in part explain the low rate of complications seen in this study.
Approximately half of the patients in our study were elective cases that could potentially have undergone PCI without GPI. The ISAR-REACT study (Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment) evaluated the efficacy of abciximab in patients preloaded with 600 mg of clopidogrel undergoing elective PCI. This study showed that adding abciximab did not provide any additional benefit against ischemic events, but was associated with nonsignificant increased bleeding complications and significant profound thrombocytopenia.¹³ The patients undergoing PCI in ISAR-REACT trial were low- to intermediate-risk patients undergoing elective PCI, and all patients were preloaded with 600 mg of clopidogrel at least 2 hours before the procedure. However, in many clinical settings, it is not possible to load patients with clopidogrel 2 hours prior to the procedure. Most patients in the United States are loaded with clopidogrel once the decision is made to proceed with PCI after coronary angiography, as higher bleeding complications were reported in patients receiving aspirin and clopidogrel prior to coronary artery bypass surgery.¹⁴ It is possible that the need for loading the patients with clopidogrel 2 hours prior to the procedure can be overcome by administering tirofiban as a high-dose bolus just prior to the PCI. Also Bonz et al showed the release of troponin post PCI in patients undergoing elective PCI could be reduced by high-dose tirofiban compared to placebo.¹⁵
The subgroup analysis on patients with ACS and stable CAD undergoing elective PCI showed that there is almost a 4- fold increase in the rate of post-PCI MI in patients with ACS compared to patients without ACS. However, the actual incidence of post-PCI MI in patients with ACS in our study (5.4%) compares favorably with the in-hospital post-PCI MI rates reported in the heparin plus GPI arm (6.3%) and bivalirudin ± GPI arm (7.2%) of REPLACE-2, which had approximately 44% and 43% ACS patients, respectively.¹⁶ These findings suggest that if the efficacy of a high-dose tirofiban bolus-only strategy were to be evaluated in a randomized, prospective study, it would be appropriate to compare the outcomes of high-dose tirofiban bolus-only versus high-dose tirofiban bolus plus infusion in a population of ACS patients.
Despite using a higher dose of tirofiban, our study group did not have increased bleeding complications. Our sample size is not large enough to make a definitive statement regarding the bleeding rates in patients given high-dose tirofiban in comparison to other GPIs. Our results are in agreement with the results reported by Danzi et al on high-dose tirofiban 25 μg/kg bolus dose followed by 0.15 μg/kg/minute infusion versus standard dosing of abciximab.¹⁷ In contrast, the report by Gunasekara et al showed a slightly higher bleeding rate requiring blood transfusion in the high-dose tirofiban arm.¹⁷ However, it is our practice to use bolus-only strategy (i.e., no infusion), which could explain our low rate of bleeding.^5–8 The incidence of thrombocytopenia in the tirofiban group was 1%, which is similar to the previously-reported studies.^17,18
With respect to patients with ESRD, our study demonstrates two intriguing findings. First, the use of a half-bolus dose (12.5 μg/kg) of tirofiban achieved a similar degree of platelet inhibition in ESRD as compared with patients without ESRD. (Mean peak platelet inhibition was 93% in ESRDvs. 94% in patients without ESRD; p = 0.19). Second, although the numbers are very small, it appears that the recovery of platelet function in ESRD patients occurs at a rate not dissimilar from patients without ESRD (mean platelet inhibition at 2–3 hours post bolus was 76% in ESRD patients vs. 74% in patients without ESRD; p = 0.47). These observations are consistent with previous reports that tirofiban has a partial (40–70%) renal clearance mechanism;¹⁹ thus, under certain clinical scenarios, up to 60% of its plasma clearance may be due to nonrenal mechanisms.

Limitations and Conclusion
This study is retrospective and the selection of high-dose tirofiban or eptifibatide was at the discretion of the operators. Therefore, selection bias or any unknown biases cannot be excluded. The groups differed in certain baseline and procedural characteristics, which were adjusted using statistical analysis. The sample size is not large enough to assess the bleeding complication rate in the tirofiban versus eptifibatide groups, and there were no deaths and no target vessel revascularization events. We included only in-hospital outcomes; 30-day and longer-term follow-up data were not available. Finally, PAU monitoring data were collected inconsistently at different time points as a function of the clinical scenario. Despite these limitations, these data suggests that a tirofiban high-dose bolus-only regimen achieves significant antiplatelet effect that persists to the end of the procedure and is effective in preventing ischemic events post PCI without increasing the rate of bleeding complications.

References

1. Kong DF, Hasselblad V, Harrington RA, et al. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003;92:651–655.
2. TARGET investigators. 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;334:1888–1894.
3. Kabbani SS, Aggarwal A, Terrien EF, et al. Suboptimal early inhibition of platelets by treatment with tirofiban: Implications for coronary interventions. Am J Cardiol 2002;89:647–650.
4. Schneider DJ, Herrmann HC, Lakkis N, et al. Increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after greater bolus doses of tirofiban. Am J Cardiol 2003;91:334–336.
5. Marmur JD, Mitre CA, Barnathan E, et al. Benefit of bolus-only platelet glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: Insights from the very early outcomes in the EPIC trial. Am Heart J 2006;152:876–881.
6. Marmur JD, Poludasu S, Agarwal A, et al. Bolus-only platelet glycoprotein IIb-IIIa inhibition during percutaneous coronary intervention. J Invasive Cardiol 2006;18:521–526.
7. Fischell TA, Attia T, Rane S, et al. High-dose, single-bolus eptifibatide: A safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions. J Invasive Cardiol 2006;18:487–491.
8. Bertrand OF, De Larochelliere R, Rodes-Cabau J, et al. Early discharge after transradial stenting of coronary arteries study investigators. A randomized study comparing same-day home discharge and abciximab bolus only to overnight hospitalization and abciximab bolus and infusion after transradial coronary stent implantation. Circulation 2006;114:2636–2643.
9. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991; 115: 256– 265.
10. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289: 853– 863.
11. Danzi GB, Capuano C, Sesana M, et al. Variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein IIb/IIIa receptor blockers in patients undergoing a high-risk percutaneous coronary intervention. Am J Cardiol 2006; 97: 489– 493.
12. Ernst NM, Suryapranata H, Miedema K, et al. Achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004; l44: 1187– 1193.
13. Kastrati A, Mehilli J, Schuhlen H, et al. for the Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective percutaneous coronary int ervention aft er pret reatment with clopidogr el. N Engl J Med 2004; 350: 232– 238.
14. Hongo RH, Ley J, Dick SE, et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002; 40: 231– 237.
15. Bonz AW, Lengenfelder B, Strotmann J, et al. Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial). J Am Coll Cardiol 2002; 40: 662– 668.
16. Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for percutaneous coronary intervention: Results from the REPLACE-2 trial. J Am Coll Cardiol 2004; 44: 1792– 1800.
17. Danzi GB, Sesana M, Capuano C, et al. Downstream administration of a highdose tirofiban bolus in high-risk patients with unstable angina undergoing early percutaneous coronary intervention. Int J Cardiol 2006; 107: 241– 246.
18. Gunasekara AP, Walters DL, Aroney CN. Comparison of abciximab with “highdose” tirofiban in patients undergoing percutaneous coronary intervention. Int J Cardiol 2006;109:16-20.
19. Conde ID, Kleiman NS. Patient-Specific antiplatelet therapy. J Thromb Thrombolysiss 2004;17:63-77.