Eptifibatide
C68-22, intrifiban, eptifibatide acetate, barbourin analogue
Eptifibatide is a small cyclic peptide that blocks the glycoprotein IIb/IIIa receptor on platelets, the final common step in platelet aggregation. Its active fragment was copied from barbourin, a protein in the venom of the south-eastern pygmy rattlesnake. It is a licensed intravenous antiplatelet drug used in acute coronary syndromes and during coronary stenting.
Mechanism
Eptifibatide is a reversible, competitive antagonist of platelet glycoprotein IIb/IIIa, the integrin αIIbβ3. This receptor is the final common pathway of platelet aggregation: once platelets are activated by any agonist (thrombin, ADP, thromboxane A2, collagen), αIIbβ3 changes conformation and binds fibrinogen and von Willebrand factor, which then cross-bridge adjacent platelets into an aggregate. Blocking the receptor prevents aggregation regardless of which agonist triggered activation, which is why glycoprotein IIb/IIIa inhibitors produce a more complete antiplatelet effect than aspirin or a P2Y12 inhibitor alone.
The design origin is unusual and worth stating precisely. Most snake venom disintegrins present an Arg-Gly-Asp (RGD) motif that binds several integrins indiscriminately, including the vitronectin receptor αvβ3 on endothelium. Barbourin, from Sistrurus miliarius barbouri, instead presents Lys-Gly-Asp (KGD), and the substitution of lysine for arginine confers marked selectivity for αIIbβ3. Eptifibatide is a synthetic cyclic heptapeptide built around that KGD pharmacophore, with homoarginine in place of lysine and a disulfide-closed ring formed between a mercaptopropionyl group and a C-terminal cysteinamide. The cyclisation resists proteolysis; the small size and lack of protein backbone mean it is non-immunogenic, unlike the chimeric antibody fragment abciximab. Binding is rapidly reversible, so platelet function recovers within about four to eight hours of stopping the infusion. Roughly half of clearance is renal.
What the research shows
PURSUIT, the largest trial, randomised 10,948 patients with acute coronary syndrome without persistent ST elevation to eptifibatide or placebo. The primary endpoint of death or non-fatal myocardial infarction at 30 days fell from 15.7% to 14.2%, a 1.5 percentage point absolute reduction (p=0.04). The benefit appeared within 96 hours and persisted to 30 days; bleeding complications were more frequent with eptifibatide but haemorrhagic stroke was not increased. IMPACT-II, in 4,010 patients undergoing percutaneous coronary intervention across 82 US centres, found a 30-day composite endpoint of 9.2% with the lower-dose regimen versus 11.4% with placebo, which did not reach significance by intention-to-treat (p=0.063) though it did in the treated-patient analysis (9.1% versus 11.6%, p=0.035); the investigators concluded the doses tested sat at the low end of the efficacy-response curve. ESPRIT, using a higher double-bolus regimen in 2,064 patients undergoing planned coronary stenting, was stopped early for efficacy: the 48-hour composite endpoint fell from 10.5% to 6.6% (p=0.0015), at the cost of more major bleeding (1.3% versus 0.4%).
The important negative result is EARLY ACS. In 9,492 patients with high-risk non-ST-elevation acute coronary syndrome, routine early eptifibatide started at least 12 hours before angiography was compared with delayed provisional use after angiography. The primary composite endpoint was 9.3% versus 10.0%, not significant (odds ratio 0.92, p=0.23), and 30-day death or myocardial infarction was 11.2% versus 12.3%, also not significant, while early administration significantly increased non-life-threatening bleeding and red-cell transfusion. This trial, combined with the arrival of potent oral P2Y12 inhibitors, is the main reason glycoprotein IIb/IIIa inhibitors have retreated to a bail-out role for large thrombus burden or no-reflow during intervention rather than routine upstream use.
Evidence assessment
High-quality evidence
Eptifibatide is licensed in the UK, EU and US on the basis of multiple large randomised placebo-controlled trials (PURSUIT alone enrolled 10,948 patients), and it appears in acute coronary syndrome guidelines, albeit in an increasingly narrow bail-out role. All four cited trials were verified against PubMed with matching titles, PMIDs, DOIs, years, journals, sample sizes and effect estimates. The evidence is unequivocally strong in quality. Its clinical position has nonetheless contracted substantially since the trials were run, because modern oral P2Y12 inhibitors and radial-access techniques have absorbed much of the benefit while eptifibatide retains its bleeding cost; EARLY ACS specifically showed that routine early administration is not beneficial.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II Preclinical only
The 30-day composite endpoint was 9.2% with the 135/0.5 eptifibatide regimen versus 11.4% with placebo, not significant by intention-to-treat (p=0.063), significant in the treated-patient analysis (9.1% versus 11.6%, p=0.035). The authors judged the doses tested to be at the low end of the efficacy-response curve.
Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes Preclinical only
Death or non-fatal myocardial infarction at 30 days fell from 15.7% with placebo to 14.2% with eptifibatide (absolute reduction 1.5 percentage points, p=0.04). Benefit emerged by 96 hours and persisted to 30 days; bleeding was more frequent but haemorrhagic stroke was not increased.
Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial Preclinical only
Stopped early for efficacy. The 48-hour composite of death, myocardial infarction, urgent target vessel revascularisation or thrombotic bailout fell from 10.5% to 6.6% (p=0.0015) and the 30-day endpoint from 10.5% to 6.8% (p=0.0034). Major bleeding was higher with eptifibatide (1.3% versus 0.4%).
Early versus delayed, provisional eptifibatide in acute coronary syndromes Preclinical only
Negative result. The primary composite endpoint was 9.3% with early versus 10.0% with delayed provisional eptifibatide (odds ratio 0.92, 95% CI 0.80-1.06, p=0.23); 30-day death or myocardial infarction was 11.2% versus 12.3%, also not significant. Early administration significantly increased non-life-threatening bleeding and red-cell transfusion. Delayed provisional use was the preferable strategy.
Safety
Bleeding is the principal adverse effect and is dose- and duration-dependent, most commonly at the vascular access site. Rates rise when eptifibatide is combined with heparin and dual oral antiplatelet therapy, and the EARLY ACS result shows that adding it earlier adds bleeding without adding benefit. Renal impairment increases exposure and bleeding risk, and the drug is generally avoided in severe renal failure and in dialysis patients.
Acute profound thrombocytopenia (platelet counts sometimes falling below 20,000/µL within hours of first exposure) is a recognised, uncommon but potentially serious reaction, and platelet counts are monitored. Unlike abciximab, eptifibatide has not been shown to provoke an antibody response even after repeated administration, based on immunogenicity sampling reported during the clinical development programme. Hypotension is reported. It is contraindicated in the presence of active bleeding, recent major surgery or stroke, severe uncontrolled hypertension and severe renal failure. This is an intravenous hospital medicine given under continuous clinical and laboratory monitoring; it has no legitimate use outside that setting.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Prescription-only medicine (POM), hospital use. Licensed by the MHRA for the prevention of early myocardial infarction in adults with unstable angina or non-Q-wave myocardial infarction, used with aspirin and unfractionated heparin. Originally authorised centrally in the EU in July 1999; generic eptifibatide products are now available. |
| United States | FDA-approved (May 1998) for the treatment of acute coronary syndrome, including patients managed medically and those undergoing percutaneous coronary intervention. Multiple generic intravenous formulations are approved. |
| WADA (sport) | Not listed on the WADA Prohibited List. Antiplatelet agents are not prohibited in or out of competition. |
Questions
Rattlesnake venoms contain disintegrins, small proteins that block integrin receptors and stop prey blood from clotting. Most use an Arg-Gly-Asp motif that binds many integrins non-selectively. Barbourin, from the south-eastern pygmy rattlesnake, uniquely uses Lys-Gly-Asp instead, and that single substitution makes it highly selective for the platelet receptor αIIbβ3 over the endothelial vitronectin receptor. Eptifibatide is a synthetic cyclic peptide built around that selective motif rather than an extract of venom.
Much less than in the late 1990s. EARLY ACS showed routine early administration adds bleeding without adding benefit, and potent oral P2Y12 inhibitors such as ticagrelor and prasugrel now provide much of the antiplatelet effect that glycoprotein IIb/IIIa inhibitors used to supply. Current guidelines position eptifibatide mainly as a bail-out agent during percutaneous coronary intervention (for large thrombus burden, slow flow or no-reflow) rather than as routine upstream therapy.
Rapidly. Binding to the receptor is competitive and reversible, and the plasma half-life is about 2.5 hours, so platelet aggregation typically recovers to more than half of baseline within about four hours of stopping the infusion. That fast offset is one advantage over abciximab, whose antiplatelet effect persists for days.
No antibody response has been detected in immunogenicity sampling during the clinical development programme, even after repeated administration. It is a seven-residue cyclic peptide rather than a chimeric antibody fragment, so it presents essentially no epitope for an immune response. It can nonetheless cause acute profound thrombocytopenia through a non-immunogenic mechanism, so platelet counts are monitored during treatment.