Eptifibatide

A synthetic cyclic heptapeptide glycoprotein IIb/IIIa antagonist modeled on the KGD motif of barbourin, a pygmy rattlesnake venom disintegrin; FDA-approved as Integrilin (1998) for intravenous antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention.

Also referenced as: Integrilin, Integrelin, Intrifiban, Sch 60936, Sch-60936, HS-2011

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What is Eptifibatide?

Eptifibatide is a synthetic cyclic heptapeptide (molecular weight 831.96 Da) made of six amino acids plus a mercaptopropionyl (des-amino cysteinyl) residue, closed into a ring by a disulfide bridge between that residue and a C-terminal cysteinamide. Its core is a Lys-Gly-Asp (KGD) sequence copied from barbourin, a disintegrin in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarius barbouri), which gives it selectivity for the platelet integrin glycoprotein (GP) IIb/IIIa over related integrins. Designed at COR Therapeutics and co-developed with Schering-Plough (hence the development code Sch 60936), it was approved by the FDA on May 18, 1998 as Integrilin for intravenous antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention (PCI). Eptifibatide is a hospital drug given through a vein in the coronary care unit or catheterization laboratory; it has little if any research-market presence, and it is one of the few venom-derived peptides to reach broad clinical use.

How it works

• Ligand-mimetic blockade of GP IIb/IIIa. GP IIb/IIIa (integrin αIIbβ3) is the final common pathway of platelet aggregation: once activated, it binds fibrinogen and von Willebrand factor, cross-linking platelets into a plug. Eptifibatide occupies the receptor’s ligand-binding site and reversibly prevents that binding, inhibiting aggregation in a dose- and concentration-dependent manner regardless of the agonist that activated the platelet (FDA label, clinical pharmacology section).
• KGD instead of RGD confers selectivity. Most disintegrins and integrin ligands use an Arg-Gly-Asp (RGD) motif that is recognized by many integrins. Barbourin was the first disintegrin found to carry Lys-Gly-Asp in that position, and this single substitution made it specific for GP IIb/IIIa while sparing the vitronectin receptor αvβ3 and the fibronectin receptor α5β1 (Scarborough et al., Journal of Biological Chemistry, 1991;266(15):9359–9362). Grafting KGD into a small, conformationally constrained disulfide ring and optimizing the ring size and lysyl side chain reproduced barbourin’s potency and selectivity in a seven-residue peptide (Scarborough et al., Journal of Biological Chemistry, 1993;268(2):1066–1073).
• Rapid, reversible, calcium-sensitive binding. Unlike the antibody fragment abciximab, eptifibatide binds with relatively fast off-kinetics, so platelet function recovers within hours of stopping an infusion as the peptide dissociates from the receptor. Its apparent potency is also sensitive to ionized calcium: in citrate-anticoagulated blood, where calcium is chelated, eptifibatide binds GP IIb/IIIa more tightly and inhibits aggregation more than it does in blood with physiologic calcium, which led early clinical dose selection to overestimate inhibition and was corrected in later dosing (Phillips et al., Circulation, 1997;96(5):1488–1494; Tcheng et al., American Journal of Cardiology, 2001;88(10):1097–1102, the PRIDE study).
• Pharmacokinetics. Pharmacokinetics are linear over the studied range, plasma protein binding is about 25%, and the elimination half-life is roughly 2.5 hours. In healthy subjects, renal clearance accounts for about half of total clearance, with the drug excreted in urine as unchanged eptifibatide, deamidated eptifibatide, and more polar metabolites; clearance falls by about 50% when creatinine clearance is below 50 mL/min, roughly doubling steady-state concentrations (FDA label, clinical pharmacology section).

Research status

Eptifibatide is an approved drug with a large randomized evidence base in coronary disease assembled mainly between 1995 and 2009. Its place in practice has narrowed since, as potent oral P2Y12 inhibitors and radial access reduced the need for routine intravenous GP IIb/IIIa blockade, and recent trials outside cardiology have been negative.

• IMPACT. Tcheng et al. (1995), Circulation 91(8):2151–2157: the first randomized placebo-controlled trial (then called Integrelin) in elective coronary intervention, which established dose-dependent inhibition of platelet aggregation and a trend toward fewer ischemic events.
• IMPACT-II. IMPACT-II Investigators (1997), Lancet 349(9063):1422–1428: 4,010 patients undergoing elective, urgent, or emergency PCI at 82 US centers randomized to placebo or one of two eptifibatide regimens. The 30-day composite of death, MI, or urgent revascularization was 11.4% with placebo versus 9.2% with the lower-dose regimen, a difference that did not reach significance on intention-to-treat analysis (P = 0.063), and 9.9% with the higher dose (P = 0.22). Major bleeding and transfusion were not increased. The authors concluded the doses sat at the low end of the efficacy curve, an effect now attributed to the citrate artifact described above.
• PURSUIT. PURSUIT Trial Investigators (1998), N Engl J Med 339(7):436–443: 10,948 patients with unstable angina or NSTEMI enrolled internationally between November 1995 and January 1997 and randomized to eptifibatide or placebo on top of standard care. Death or nonfatal MI at 30 days was 14.2% with eptifibatide versus 15.7% with placebo (1.5 percentage point absolute reduction, P = 0.04), apparent by 96 hours and consistent in most subgroups except women. Bleeding was more common with eptifibatide without an increase in hemorrhagic stroke. This trial supported the acute coronary syndrome indication.
• PRIDE and the double-bolus regimen. Tcheng et al. (2001), American Journal of Cardiology 88(10):1097–1102, and Gilchrist et al. (2001), Circulation 104(4):406–411, showed that single-bolus regimens lost platelet inhibition transiently in the first hour before steady state, and pharmacokinetic modeling in the 39-patient Gilchrist study pointed to a higher double bolus ten minutes apart with a higher infusion rate as the way to hold inhibition above 90% throughout; that regimen was the one tested in ESPRIT.
• ESPRIT. ESPRIT Investigators (2000), Lancet 356(9247):2037–2044: 2,064 patients scheduled for coronary stenting randomized to double-bolus eptifibatide plus infusion or placebo. The 48-hour composite of death, MI, urgent target-vessel revascularization, or bailout GP IIb/IIIa therapy fell from 10.5% to 6.6% (P = 0.0015), the 30-day composite from 10.5% to 6.8% (P = 0.0034), and the trial was stopped early for efficacy. Major bleeding was 1.3% versus 0.4% (P = 0.027). The benefit was sustained at six months and one year in follow-up reports.
• EARLY ACS. Giugliano et al. (2009), N Engl J Med 360(21):2176–2190 (NCT00089895): 9,492 high-risk NSTE-ACS patients assigned to an invasive strategy were randomized to routine early eptifibatide (12 or more hours before angiography) or placebo with provisional eptifibatide after angiography. The 96-hour primary composite was 9.3% versus 10.0% (P = 0.23) and 30-day death or MI was 11.2% versus 12.3% (P = 0.08), while early eptifibatide significantly increased bleeding and red-cell transfusion. The trial did not support routine upstream use, and practice shifted toward provisional use in the catheterization laboratory.
• EVA-AMI. Zeymer et al. (2010), Journal of the American College of Cardiology 56(6):463–469 (NCT00426751): in 427 STEMI patients undergoing primary PCI, complete ST-segment resolution at 60 minutes was 62.6% with double-bolus eptifibatide versus 56.3% with abciximab, meeting non-inferiority. At six months the combined endpoint of death, reinfarction, or target-vessel revascularization was 10.6% versus 10.9% (P = 0.90) and mortality 6.2% versus 4.5% (P = 0.50), with fewer reinfarctions after eptifibatide (0.4% versus 3.5%, P = 0.03).
• Stroke. After the phase 2 CLEAR-ER trial (Pancioli et al., Stroke, 2013;44(9):2381–2387; NCT00894803), MOST (Adeoye et al., N Engl J Med, 2024;391(9):810–820; NCT03735979) randomized 514 patients treated with intravenous thrombolysis within three hours of stroke onset to adjunctive argatroban, eptifibatide, or placebo. Neither active arm met its efficacy threshold, and 90-day mortality was higher with eptifibatide (12%) than placebo (8%). A Chinese phase 3 trial after thrombolysis in the extended time window (NCT07347626) was registered as not yet recruiting in January 2026, and no randomized trial has established rescue use during mechanical thrombectomy.
• Other investigational uses. Small pilot studies in septic shock (NCT02204852), acute sickle cell pain crises (NCT00834899), and intracoronary bolus delivery during PCI were reported without changing the label.
• Regulatory history. Integrilin (NDA 020718, now held by Merck) was approved May 18, 1998 for acute coronary syndromes and PCI, with the PCI indication resting on IMPACT-II and ESPRIT; the label was most recently revised February 28, 2021. Drugs@FDA lists the brand presentations as discontinued, while generic eptifibatide injection from about ten labelers remains on DailyMed. In the European Union the Integrilin authorization was withdrawn effective January 1, 2026 at the holder’s request, and generic eptifibatide remains authorized there.

Common dosage forms

Eptifibatide is supplied only as a sterile, clear, colorless solution for intravenous use in a hospital setting. The reference product and its generics come in single-dose vials: a 10 mL vial containing 20 mg (2 mg/mL), and 100 mL vials containing 75 mg (0.75 mg/mL) or 200 mg (2 mg/mL). Vials are stored refrigerated and protected from light, and may be held at room temperature for up to two months. There is no oral, subcutaneous, intramuscular, or nasal presentation, and eptifibatide has little if any research-market presence.

Key considerations

• Regulatory status. The FDA Approved status reflects Integrilin’s May 18, 1998 approval. The molecule is now supplied almost entirely as generic injection for acute coronary syndromes and PCI, and its use in any other setting is off-label.
• Bleeding is the dominant risk. The label lists bleeding as the most common complication, with most major bleeds at the arterial access site or from the gastrointestinal or genitourinary tract, and the label contraindicates active or recent bleeding, recent stroke or major surgery, uncontrolled hypertension and dialysis dependence. There is no reversal agent; the short half-life is the practical mitigation.
• Acute, profound thrombocytopenia. The label carries a warning for acute profound thrombocytopenia, both immune-mediated and non-immune. Drug-dependent IgG antibodies that recognize GP IIb/IIIa only when occupied by eptifibatide have been identified in affected patients, including some with no prior exposure (Bougie et al., Blood, 2002;100(6):2071–2076), and the same mechanism occurs with tirofiban, so a reaction to one agent does not rule out reactions to the others.
• Evidence is older than current practice. PURSUIT, ESPRIT, and IMPACT-II predate routine use of ticagrelor, prasugrel, and radial access, so the absolute benefit in contemporary patients is smaller and less certain than the historical trials suggest, and current practice reserves GP IIb/IIIa inhibitors largely for bailout or high-thrombus situations during PCI.
• Naming. “Eptifibatide,” “Integrilin,” the earlier name “intrifiban,” and the development codes Sch 60936 and HS-2011 all refer to the same heptapeptide. It is distinct from the other parenteral GP IIb/IIIa inhibitors, tirofiban (a non-peptide small molecule) and abciximab (a chimeric antibody fragment).