Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI).

Eptifibatide, an Older Therapeutic Peptide with New Indications

Eptifibatide (also known as Integrilin, Intrifiban, SB-1, or Sch-60936; DrugBank accession number: DB00063) is a heptapeptide derived from a disintegrin protein in the rattlesnake venom. It reversibly inhibits the GPIIb/IIIa, preventing platelet aggregation and activation. Eptifibatide belongs functionally to the GPIIb/IIIa inhibitors (GPI) and, with respect to its structure and origin, to the family of disintegrin proteins. This section briefly presents the pharmacological basis of eptifibatide classification. The United States Food and Drug Administration (FDA) has already approved numerous snake venom-derived drugs, including Integrilin (eptifibatide), Captopril (enalapril), Aggrastat (tirofiban), Reptilase (batroxobin), and Exanta (ximelagatran). In addition, many medications are now at the preclinical and clinical stages of testing for therapeutic use. It was derived by determining the minimum active sequence (MAS) of this component of snake venom. A minimum active sequence (MAS) is the shortest amino acid sequence derived from an endogenous peptide, still retaining its potency or binding affinity to its target. The process of truncation is used to remove biologically redundant amino acid residues from the protein. The endogenous peptides are “trimmed” in such a way as to reach a more economical protein size that can be widely synthesized without compromising its effect on biological targets. The cys-rich endogenous disintegrin protein from snake venom contains 73 amino acids, and a length of seven amino acids was achieved for eptifibatide by the process of truncation. The small size of the peptide explains its low immunogenicity, which is an essential factor in repetitive administration and the use of the drug on patients with an unknown history.[1]

Moreover, in developing eptifibatide, researchers had to overcome the drawbacks of peptide drugs, especially their low in vivo stability and membrane impermeability. Since the direct action of eptifibatide is thought to be limited only to the extracellular domain of GPIIb/IIIa on platelets, the drawback of membrane impermeability was eliminated. To increase the stability of eptifibatide, the peptide was cyclized using a disulfide bridge between the captopropionyl residue (des-amino-cysteinyl) and the cysteine. The cyclic structure increases the bioavailability of the drug and its resistance to plasma proteases. Besides these modifications, the peptide undergoes guanylation at the Lys side chain and deamination at the N-terminus (among other modifications), giving it a highly potent therapeutic value. The pharmacokinetics of peptides are characterized by their typically short half-life in the bloodstream, which results from cleavage by proteases and peptidases. A short elimination half-life for endogenous peptides is desirable for regulating their concentrations and function. The eptifibatide plasma elimination half-life is 2.5 h. Peptides have a molecular weight between 1 and 10 kDa; therefore, the primary absorption process is diffusion-driven uptake into blood. On the other hand, eptifibatide has a molecular weight of 800 D. The volume of distribution for eptifibatide is 0.2 to 0.3 L/kg.

A meta-analysis by Karathanos et al. in 2019 showed that routine use of GPIs in patients with STEMI was associated with reduced mortality, which was probably the consequence of a reduction in recurrent ischemic events. Despite the promising result, it should be noted that these results are largely based on studies before dual antiplatelet therapy with prasugrel/ticagrelor was routinely used, as is the case today. Although less convincing, eptifibatide can also improve myocardial perfusion in STEMI, as shown in the TITAN-TIMI 34 trial. Nevertheless, more recent studies have shown that prehospital administration of GPI in STEMI has not shown benefits and even increases the bleeding risk compared to routine use in a catheterization laboratory. Although eptifibatide has not been tested in a randomized trial, the European Society of Cardiology guidelines (ESC) suggest it as bail-out therapy in high-risk patients (slow flow or no flow with occlusion of the stent, high thrombus burden, etc.) but not as a routine drug for primary PCI.

Eptifibatide in Patients with Acute Coronary Syndromes

Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein Ilb/IIIa Receptor with Integrilin? Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/ IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI (STEMI).[2]

According to retrospective cost analyses conducted in the US using ESPRIT trial data, approximately 40% and 70% of the acquisition cost of eptifibatide was offset by the reduced medical resource consumption during the in-hospital period and over a 1-year period, respectively. Moreover, in a Canadian study, eptifibatide plus stenting was dominant over stenting alone in terms of cost and outcome in patients requiring PCI.In a prospective, randomised, double-blind trial in patients undergoing PCI, median total in-hospital costs were significantly lower in eptifibatide than in abciximab recipients. The between-group difference in cost was largely attributable to the higher acquisition costs within the abciximab-treated group.Prospectively conducted cost-effectiveness analyses (US, Canada and Western Europe) based on data from the PURSUIT trial were similar and favourable for eptifibatide as an adjunct to standard care relative to standard care alone ($US3761-18 774 per life-year gained; various years of costing).Eptifibatide was effective as adjunctive treatment in patients with low- to moderate-risk coronary artery disease undergoing PCI with intended intracoronary stent placement, in the large (n = 2064) ESPRIT trial. Eptifibatide achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. Adjuvant eptifibatide therapy provides significant long-term benefit (up to 12 months), with most of the benefit occurring within the first 48 hours.

In the large (n = 10 948) PURSUIT trial, eptifibatide was effective in patients with NSTE ACS (patients received standard care, including aspirin and unfrac-tionated heparin). Eptifibatide was associated with a significantly lower incidence of death or MI at 30 days than placebo, with the benefit evident early during drug treatment. Limited data suggest that early administration of eptifibatide in the emergency room before primary PCI or administration of eptifibatide in combination with fibrinolytics improves surrogate markers of reperfusion in patients with STEMI (off-label indication). Bleeding was a commonly reported adverse event; major bleeding occurred more frequently with eptifibatide than placebo in the PURSUIT (11% vs 9%) and ESPRIT (1% vs <1%) trials. Most major bleeding episodes occurred at the site of vascular access. Major intracranial bleeds, stroke or profound thrombocytopenia rarely occurred during eptifibatide treatment. Overall, the combination of eptifibatide plus enoxaparin sodium was associated with a similar tolerability profile to that of eptifibatide plus unfractionated heparin in patients with NSTE ACS.

References

[1]Tonin G, Klen J. Eptifibatide, an Older Therapeutic Peptide with New Indications: From Clinical Pharmacology to Everyday Clinical Practice. Int J Mol Sci. 2023 Mar 13;24(6):5446

[2]Curran MP, Keating GM. Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention. Drugs. 2005;65(14):2009-35.