Effect of Eptifibatide on Coronary Flow Reserve Following Coronary Stent Implantation (An ESPRIT Substudy) C. Michael Gibson, MS, MD, David J. Cohen, MD, MSc, Eric A. Cohen, MD, Henry K. Lui, MD, Sabina A. Murphy, MPH, Susan J. Marble, RN, MS, Michael Kitt, MD, Todd Lorenz, MD, and James E. Tcheng, MD, for the ESPRIT Study Group P ercutaneous coronary intervention with stenting improves epicardial large vessel lumen diameters but can be detrimental to the microcirculation as a result of either downstream embolization or vaso- spasm. Coronary flow reserve (CFR) is a measure- ment of the capacity of blood flow that is augmented in response to adenosine (hyperemic flow) and is a valuable tool in assessing the integrity of the micro- vasculature after stent placement. We hypothesized that patients treated with eptifibatide in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with In- tegrilin Therapy (ESPRIT) trial 1 would have im- proved CFR after elective stent placement compared with patients receiving placebo. Furthermore, we hy- pothesized that tissue level perfusion would be im- proved with eptifibatide therapy, and we assessed the kinetics of myocardial perfusion using digital subtrac- tion angiography. ••• The ESPRIT trial was a double-blind, multicenter, randomized, parallel group, placebo-controlled trial of planned, nonemergency stenting of native coronary arteries in 2,064 patients. 1 Patients were allocated in a 1:1 ratio between eptifibatide and placebo immedi- ately before planned percutaneous coronary stent im- plantation. Eptifibatide was administered as a 180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 to 24 hours, with a second 180 g/kg bolus given 10 minutes after the first. An angiographic substudy was conducted at 3 sites that enrolled 65 patients to assess CFR and myocardial perfusion at the comple- tion of the intervention. The Corrected Thrombolysis In Myocardial Infarc- tion (TIMI) Frame Count (CTFC), the number of cine frames required for contrast to first reach standardized distal coronary landmarks in the culprit artery, was measured using a frame counter on a cine viewer. 2,3 After stenting, patients received intracoronary adeno- sine (24 to 36 g in the left anterior descending artery and left circumflex artery; 18 to 24 g in the right coronary artery). The CTFC was assessed after stent- ing and 15 seconds after adenosine administration in the primary culprit lesion by the angiographic core laboratory, which was blinded to treatment assign- ment. CFR was calculated as the ratio of preadenosine CTFC divided by postadenosine CTFC, which has been validated in the literature as highly correlated with Doppler-derived CFR (r = 0.88, p 0.0001). 4 To quantitate the kinetics of dye entry into the myocardium, digital subtraction angiography was used. Digital subtraction angiography was performed at end-diastole by aligning cine frame images before dye filled the myocardium with the frame in which dye first reached its peak brightness. The spine, ribs, diaphragm, and the epicardial artery were then sub- tracted. A representative region of the myocardium was sampled that was free of overlap by epicardial arterial branches to determine the increase in the gray- scale brightness of the myocardium. The circumfer- ence of the myocardial blush was measured using a handheld planimeter (Fowler, Inc., Medford, Massa- chusetts). The frame count divided by the number of frames per second was used to measure the time elapsed during angiography to quantitate the rate of increase in the growth (centimeters per second) and brightness (gray per second) of myocardial blush. The digital subtraction angiographic reserve was calcu- lated as the relative improvement in the rate of in- crease in brightness after adenosine: after adenosine (gray per second) divided by after stenting (gray per second). Blush was also assessed visually using the TIMI myocardial perfusion grade. 5 The size (centime- ters) and brightness of the myocardium (gray) were multiplied together to yield gray centimeters per sec- ond as a simultaneous index, integrating brightness and size of myocardial perfusion. Analyses were performed using Stata statistical software version 6.0. 6 Variables were compared using the Fisher’s exact test or chi-square test for categorical data and the Student’s t test for continuous variables. Variables known to impact the CTFC (culprit location and reference diameter) and myocardial blush were adjusted for in multivariate models. 5,7 There was no difference between patients who received placebo and those on eptifibatide with respect to baseline and postintervention angiographic charac- teristics (Table 1). CFR was greater among patients who received eptifibatide than patients on placebo (1.78  0.95, n = 16 vs 1.28  0.40, n = 27; p = From the Cardiovascular Division, Department of Medicine, the Uni- versity of California San Francisco, San Francisco, California; The Beth Israel Deaconess Medical Center, Boston, Massachusetts; Sun- nybrook Health Science Center, Toronto, Ontario, Canada; Jackson/ Madison County General Hospital, Jackson, Tennessee; COR Thera- peutics, San Francisco, California; and Duke Clinical Research Insti- tute, Durham, North Carolina. This study was supported in part by a grant from Cor Therapeutics, Inc., South San Francisco, California. Dr. Gibson’s address is: Chief of Interventional Cardiology, University of California San Francisco, 3333 California Street, Suite 430, San Francisco, California 94118. E-mail: mgibson@perfuse.org. Manu- script received October 25, 2000; revised manuscript received and accepted January 5, 2001. 1293 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matter The American Journal of Cardiology Vol. 87 June 1, 2001 PII S0002-9149(01)01524-7