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CLINICAL STUDY: ACUTE CORONARY SYNDROMES/INFARCTION

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction

Results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic urial

Robert P. Giugliano, MD, SM, FACC^*,*, Matthew T. Roe, MD, MHS, FACC, Robert A. Harrington, MD, FACC, C. Michael Gibson, MS, MD, FACC^*, Uwe Zeymer, MD, Frans Van de Werf, MD, PhD^||, Kenneth W. Baran, MD, FACC^¶, Hans-Peter Hobbach, MD^#, Lynn H. Woodlief, MS, Karen L. Hannan, BA, Sally Greenberg, PhD^**, Joanne Miller, BS^**, Michael M. Kitt, MD^**, John Strony, MD, FACC, Carolyn H. McCabe, BS^*, Eugene Braunwald, MD, FACC^*, Robert M. Califf, MD, FACC the INTEGRITI Investigators

^* TIMI Study Group, Boston, Massachusetts, USA
Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Duke Clinical Research Institute, Durham, North Carolina, USA
Klinikum Kassel, Kassel, Germany
^|| Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium
^¶ St. Paul Heart Clinic, St. Paul, Minnesota, USA
^# St. Marienkrankenhaus Siegen, Siegen, Germany
^** Millennium Pharmaceuticals, Inc., South San Francisco, California, USA
Schering Plough Research Institute, Kenilworth, New Jersey, USA

Manuscript received July 15, 2002; revised manuscript received October 25, 2002, accepted November 11, 2002.

^* Reprint requests and correspondence: Dr. Robert P. Giugliano, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston, Massachusetts 02115, USA.
rgiugliano{at}partners.org

OBJECTIVES: The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI).

BACKGROUND: Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established.

METHODS: Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 µg/kg bolus, 2 µg/kg/min infusion, and 180 µg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min.

RESULTS: In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively.

CONCLUSIONS: Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

Abbreviations and Acronyms   aPTT   activated partial thromboplastin time   CABG   coronary artery bypass graft surgery   cTFC   corrected Thrombolysis In Myocardial Infarction frame count   ICH   intracranial hemorrhage   INTEGRITI   Integrilin and Tenecteplase in Acute Myocardial Infarction trial   MI   myocardial infarction   PCI   percutaneous coronary intervention   STEMI   ST-elevation myocardial infarction   TIMI   Thrombolysis In Myocardial Infarction   TMPG   Thrombolysis In Myocardial Infarction myocardial perfusion grade   TNK   tenecteplase

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