Administration of Intracoronary Eptifibatide During ST-Elevation Myocardial Infarction

Administration of Intracoronary Eptifibatide During ST-Elevation Myocardial Infarction Duane S. Pinto, MDa, Ajay J. Kirtane, MDa, Nicholas A. Ruocco, MDb, Albert J. Deibele, MDd, Amy Shui, BSc, Jacki Buros, BSc, Sabina A. Murphy, MPHc, and C. Michael Gibson, MS, MDa,* Distal embolization of atherothrombotic material during primary percutaneous coronary intervention (PCI) is associated with impaired myocardial perfusion, abnormal left ventricular function, and higher mortality. At high local concentrations, glycoprotein IIb/IIIa receptor antagonists have been demonstrated to promote clot disaggregation in vitro. Intracoronary administration of eptifibatide in vivo may increase local drug concentration by several orders of magnitude and promote clot disaggregation with a minimal increase in systemic drug concentrations. We hypothesized that intracoronary administration of eptifibatide before primary PCI for ST-elevation myocardial infarction would be safe and would be associated with high rates of normal myocardial perfusion. Clinical and angiographic data were pooled from patients who underwent primary PCI and received intracoronary eptifibatide as part of clinical practice. In-hospital adverse events were collected retrospectively. No deaths, urgent revascularizations, or reinfarctions were observed among the 59 patients who were treated with intracoronary eptifibatide. There were no Thrombolysis In Myocardial Infarction (TIMI) major bleeding events. Two TIMI minor bleeding events were noted. Normal TIMI myocardial perfusion grade 3 flow after PCI was noted in 54.4% of patients. No adverse events. including arrhythmias, were noted during intracoronary eptifibatide administration. In conclusion, intracoronary eptifibatide can be administered safely during primary PCI and is associated with few adverse events. Relatively high rates of normal myocardial perfusion were observed after primary PCI with adjunctive intracoronary eptifibatide. Further prospective randomized trials are warranted to evaluate the efficacy and safety of intracoronary eptifibatide. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: 1494 –1497) Spontaneous embolization of atherothrombotic debris during ST-segment elevation myocardial infarction (STEMI) can lead to microvascular obstruction and myocardial necrosis. Although primary percutaneous coronary intervention (PCI) restores normal epicardial flow in most patients, additional distal embolization can occur during the procedure. The resultant microvascular plugging and dysfunction have been associated with increased mortality.1,2 Although mechanical devices may, in theory, minimize distal embolization of atherothrombotic material, limitations include (1) embolization distally during device placement, (2) embolization of material proximally during aspiration, and (3) poor side branch protection.3,4 Thus, there remains an unmet The aBeth Israel Deaconess Medical Center, Division of Cardiology, Boston, Massachusetts; the bDivision of Cardiology, Caritas Norwood Hospital, Norwood, Massachusetts; the cPERFUSE Angiographic Core Laboratory and TIMI Study Group, Boston, Massachusetts; and the dDivision of Cardiology, Duluth Clinic, Duluth, Minnesota. Manuscript received May 5, 2005; revised manuscript received and accepted July 7, 2005. This study was supported in part by a grant from Millenium Pharmaceuticals, Inc., Cambridge, Massachusetts. *Corresponding author: Tel: 617-278-0065; fax: 888-249-5261. E-mail address: [email protected] (C.M. Gibson). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.056

need to minimize distal embolization during PCI, and pharmacologic thrombus disaggregation before instrumentation of the lesion may be useful to complement mechanical strategies. •••

Although fibrinolytic agents are effective in clot dissolution, glycoprotein IIb/IIIa receptor antagonists may enhance thrombus disaggregation at high local concentrations with a lower incidence of bleeding complications.5–9 Higher levels of platelet receptor occupancy by eptifibatide have been associated with improved myocardial perfusion in the STEMI setting.10 Highly localized intracoronary delivery of a glycoprotein IIb/IIIa receptor inhibitor may increase local concentration by several orders of magnitude and may promote high levels of receptor occupancy and, hence, clot disaggregation with minimal increase in systemic drug concentrations.11 We hypothesized that intracoronary eptifibatide administration would be feasible and safe in the STEMI setting. A retrospective analysis of angiographic and clinical outcomes among 59 patients who received intracoronary eptifibatide as part of clinical management of primary PCI www.AJConline.org

Coronary Artery Disease/Intracoronary Eptifibatide During STEMI

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Table 1 Eptifibatide dosing Integrilin Dosing Strategy

Total Intracoronary Eptifibatide Bolus Dose (mg)

Total Amount of IV and or IC Eptifibatide Administered in Bolus Form (mg)

Received IC and IV Bolus

Postprocedure IV Drip

Duration of Postprocedure IV Drip

IC 0.75 mg/ml with IV bolus (180 ␮g/kg) ⫻ 2 (n ⫽ 48)* IC 180 ␮g/kg ⫻ 2 and no IV bolus (n ⫽ 11)†

6.2 ⫾ 4 5.6 (3.4–7.9) 26.7 ⫾ 6 29.4 (19.0–32.0)

25.4 ⫾ 12 24.0 (16.9–35.9) 30.0 ⫾ 6 31.2 (26.4–33.6)

46 (96%)

37 (77%)

2 (18%)

11 (100%)

10.6 12 (12.0–12.0) 16.8 18 (17.0–18.0)

Values are means ⫾ SD/medians (interquartile ranges), numbers of patients (percentages), or means/medians (interquartile ranges). * Two patients received an IC but no IV bolus. One did not receive an IV infusion during the catheterization procedure. † Two patients received 1 IV bolus in addition to 2 IC boluses. IC ⫽ intracoronary; IV ⫽ intravenous.

for STEMI between January 2001 and March 2005 was undertaken. Two dosing regimens were employed (Table 1). At site 1, 2 standard intravenous bolus doses (each 180 ␮g/kg) were administered. Additional intracoronary eptifibatide (0.75 mg/ml) was administered as needed in 5- to 10-ml aliquots based on the angiographic appearance of the vessel (n ⫽ 48). Two patients received intracoronary boluses of eptifibatide but no intravenous bolus. Active gastrointestinal bleeding was present in 1 patient and PCI was unsuccessful in another, so eptifibatide was discontinued in the catheterization laboratory. At site 2, 2 intracoronary boluses (each 180 ␮g/kg) were administered, and in general no intravenous eptifibatide bolus was administered (n ⫽ 11). There were 2 exceptions at site 2, i.e., the 2 patients received 2 intracoronary boluses (each 180 ␮g/kg) with an additional single intravenous bolus (180 ␮g/kg). At sites 1 and 2, a maintenance intravenous eptifibatide infusion was administered in 44 of 59 patients (81%) and continued for 12 to 18 hours at the treating physician’s discretion. Coronary guiding catheters without side holes were used to administer intracoronary eptifibatide. Patients were pretreated with ⱖ325 mg of acetylsalicylic acid orally. A bolus and a maintenance dose of unfractionated heparin were administered and titrated to achieve an activated clotting time ⬎250 seconds as per the sites’ routine clinical practice. Among patients who were treated with intracoronary stent placement, a loading dose of 300 mg of clopidogrel and a maintenance dose of 75 mg/day for ⱖ4 weeks were administered after PCI. In-hospital patient outcomes were reviewed retrospectively. Major adverse cardiac events included recurrent myocardial infarction, the need for urgent revascularization, or death. The local ethics committees approved the review of patient records for the study. All analyses were performed with STATA 8.0 (STATA Corp., College Station, Texas). All continuous variable values are reported as mean ⫾ SD or median with interquartile range. Thrombolysis In Myocardial Infarction (TIMI) grade flow was assessed as previously defined at the TIMI Angiographic Core Laboratory.12 To objectively evaluate coronary flow as a continuous quantitative variable, the number of cine frames that were required for contrast to first reach

Table 2 Baseline characteristics (n ⫽ 59) Age (yrs) Men Weight (kg) Diabetes mellitus Hypertension Current smoker Hyperlipidemia* Heart rate (beats/min) Systolic blood pressure (mm Hg) Infarct-related artery Left anterior descending Left circumflex Right coronary Graft or multivessel

62 ⫾ 13 59 (52–72) 69.5% 84 ⫾ 18 83.2 (73.5–96.8) 12% 46% 61% 39% 84 ⫾ 26 82 (56–109) 131 ⫾ 20 132 (116–146) 15 (25%) 12 (20%) 29 (49%) 3 (5%)

Continuous variables are reported as mean ⫾ SD median (interquartile range), percentage of patients or number of arteries (percentage). * Hyperlipidemia was defined as cholesterol levels ⬎250 mg/dl, triglyceride levels ⬎150 mg/dl, or use of lipid-lowering drugs.

standardized distal coronary landmarks in the infarct-related artery (TIMI frame count) was measured using a frame counter on a cine viewer.13 TIMI myocardial perfusion grade was used to assess tissue level perfusion.14 TIMI myocardial perfusion grade was previously defined as grade 0 (no angiographic blush), grade 1 (stain or prolonged persistence of dye on next contrast injection), grade 2 (dye bright at the end of injection, gone by next injection), and grade 3 (normal ground glass appearance of blush). A single observer (AJK) reviewed all flow and perfusion data. Patients’ baseline characteristics are listed in Table 2. Angiographically apparent thrombus was noted in ⬎80% of cases. More than 70% of arteries had a closed artery (TIMI grade 0/1 flow) before PCI. TIMI grade 3 flow was noted in ⬎90% of patients after PCI. Normal TIMI myocardial perfusion grade 3 flow was present in 54.4% of patients after PCI. Mean corrected TIMI frame count after PCI was 28 ⫾ 15 (median 24, interquartile range 20 to 33). There were no in-hospital deaths, reinfarctions, or TIMI major bleeding events. Two episodes in 2 patients met TIMI

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criteria for minor bleeding. One bleeding event occurred 24 hours after PCI in a 93-year-old patient whose calculated creatinine clearance was 16.4 ml/min. The patient received a maintenance infusion of intravenous eptifibatide that was not adjusted for renal insufficiency. Mean creatinine clearance value was 91.0 ⫾ 5 ml/min among patients who did not bleed compared with 40.0 ⫾ 24 ml/min in the 2 patients who bled (p ⫽ 0.059). In 1 patient, aspirin and clopidogrel were withheld as a result of gastrointestinal bleeding, and subacute stent thrombosis subsequently developed, which necessitated the index cardiac catheterization. It is important to note that gastrointestinal bleeding was present in this patient on presentation to the cardiac catheterization laboratory. Six units of packed red blood cells was transfused before cardiac catheterization and before intracoronary eptifibatide administration, and 2 U of packed red blood cells were then transfused after PCI. Aspirin, clopidogrel, and intracoronary eptifibatide, but not intravenous eptifibatide, were administered during the procedure. Because ongoing bleeding was present before intracoronary eptifibatide administration, this patient was excluded from the bleeding analysis. No arrhythmias were noted during or immediately after administration of intracoronary eptifibatide. Subsequent reperfusion arrhythmias occurred in ⬃30% of patients, and most commonly were bradycardia (n ⫽ 11) or atrial fibrillation (n ⫽ 3) during reperfusion of the right coronary artery, ventricular tachycardia (n ⫽ 1), and accelerated idioventricular rhythm (n ⫽ 6). •••

This study extends previous observations with regard to intracoronary administration of glycoprotein IIb/IIIa receptor antagonists and demonstrates that eptifibatide can be safely administered by the intracoronary route during primary PCI for STEMI. Restoration of epicardial flow, normal myocardial perfusion, and complete ST-segment resolution has been associated with higher levels of platelet glycoprotein IIb/IIIa receptor occupancy during STEMI.10 Intracoronary administration of eptifibatide may greatly increase local drug concentration at the site of the occlusive thrombus, promote high levels of IIb/IIIa receptor occupancy and thrombus disaggregation, and minimize systemic drug concentration.11 The relatively high levels of normal myocardial perfusion seen in the present study suggest that intracoronary eptifibatide may be an efficacious strategy to preserve microvascular perfusion during STEMI. Normal myocardial perfusion after PCI was observed in ⬎50% of patients in the present study, and this compares favorably with other primary PCI studies.15–17 Similar improvements in myocardial perfusion have been observed with the intracoronary route of administration of abciximab: improvements in ST-segment resolution (86.4% vs 52.2%, p ⬍0.030), TIMI frame count (20.4 ⫾ 7.2 vs 26.0 ⫾ 10.8, p ⫽ 0.048), and TIMI myocardial perfusion grade (grade 2/3, 95.5% vs 65%,

p ⬍0.031) were demonstrated in a small randomized comparison of abciximab administered downstream of the occlusion (intracoronary) versus the intravenous route.15 In this study, final infarct size was significantly smaller and increased left ventricular ejection fraction at 1 month was significantly greater among patients who were treated with the intracoronary regimen (p ⫽ 0.013). In other nonrandomized observational studies, intracoronary administration of abciximab has also been associated with greater improvements in angiographic thrombus burden and improved clinical outcomes compared with intravenous administration of abciximab.5,6,11,15 Intracoronary eptifibatide administration was not associated with high rates of bleeding, arrhythmia, or treatment delay. Eptifibatide is supplied in a vehicle that contains 5.25 mg/ml of citric acid and sodium hydroxide to adjust the pH to 5.35.18 Despite this acidic pH, there were no adverse events during intracoronary administration. Development of a buffer solution to achieve a more physiologic pH may be advisable before further evaluation of intracoronary administration. Eptifibatide contains no other agents such as arginine (a known coronary vasodilator) to provide additional drug stability. Eptifibatide is predominantly renally cleared; therefore, avoidance of first-pass hepatic metabolism with intracoronary administration does not increase systemic eptifibatide concentrations. In contrast, fibrinolytic agents are cleared in part by hepatic metabolism, and avoidance of this first-pass metabolism by the intracoronary route of administration may yield higher systemic concentrations than ordinarily anticipated.18 Because of the renal clearance of eptifibatide, careful attention to the adjustment of eptifibatide dosing based on creatinine clearance is necessary. The creatinine clearance of the 2 patients who sustained TIMI minor bleeding tended to be lower, and 1 bleeding event occurred in a patient whose eptifibatide infusion was not appropriately adjusted for a decreased creatinine clearance. This study is an observational, retrospective analysis and thus should be viewed as generating a hypothesis. Outcomes could have been influenced by identified and unidentified confounding factors. Although favorable rates of normal myocardial perfusion were observed in this study, due to the absence of a control group, further prospective data are required to draw more substantial conclusions regarding the relative efficacy of intracoronary eptifibatide. Nevertheless, this evaluation demonstrates the safety of intracoronary administration of eptifibatide and provides the impetus for further randomized comparisons of combined mechanical and intracoronary pharmacologic strategies to improve outcomes among patients who have STEMI. 1. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570 –580. 2. Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, McCabe CH, Van de Werf F, Braunwald E. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–130.

Coronary Artery Disease/Intracoronary Eptifibatide During STEMI 3. Stone GW, Webb J, Cox DA, Brodie BR, Qureshi M, Kalynych A, Turco M, Schultheiss HP, Dulas D, Rutherford BD, et al, for the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial. JAMA 2005;293:1063–1072. 4. Rheolytic thrombectomy in patients with acute MI did not result in a reduction in myocardial infarct size. www.theheart.org (heartwire news), September 27, 2004. Available at: http://www.theheart.org/ viewarticle.do?primarykey⫽215255. Accessed July 7, 2005. 5. Bartorelli AL, Trabattoni D, Galli S, Grancini L, Cozzi S, Ravagnani P. Successful dissolution of occlusive coronary thrombus with local administration of abciximab during PTCA. Catheter Cardiovasc Interv 1999;48:211–213. 6. Thuraisingham S, Tan KH. Dissolution of thrombus formed during direct coronary angioplasty with a single 10 mg intracoronary bolus dose of abciximab. Int J Clin Pract 1999;53:604 – 607. 7. Zhao XQ, Theroux P, Snapinn SM, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non–Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation 1999;100: 1609 –1615. 8. Moser M, Bertram U, Peter K, Bode C, Ruef J. Abciximab, eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates. J Cardiovasc Pharmacol 2003;41:586 –592. 9. Marciniak SJ Jr, Mascelli MA, Furman MI, Michelson AD, Jakubowski JA, Jordan RE, Marchese PJ, Frelinger AL. An additional mechanism of action of abciximab: dispersal of newly formed platelet aggregates. Thromb Haemost 2002;87:1020 –1025. 10. Gibson CM, Jennings LK, Murphy SA, Lorenz DP, Giugliano RP, Harrington RA, Cholera S, Krishnan R, Califf RM, Braunwald E, for the INTEGRITI Study Group. Association between platelet receptor occupancy after eptifibatide (Integrilin) therapy and patency, myocardial

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