Clinical and economic studies of eptifibatide in coronary stenting

Figures & data

Figure 1 Platelet activation pathway and site of action of antiplatelet agents.

Notes: Platelets are activated via several different membrane receptors, resulting in platelet adhesion and aggregation. When endothelium is injured, the subendothelium exposes von Willebrand factor that binds to GP Ib, causing platelet adhesion. Thrombin, TXA₂, and ADP bind to the thrombin receptor, TXA₂ receptor, and P2Y₁₂, respectively. This causes an increase in intracellular calcium (Ca²⁺) and a decrease in cAMP, leading to platelet contraction and GP IIb/IIIa activation. Activated GP IIb/IIIa on adjacent platelets bind to fibrinogen (final common pathway) leading to platelet aggregation and thrombus formation.
Abbreviations: AA, arachidonic acid; COX-2, cyclo-oxygenase-2; cAMP, cyclic adenosine monophosphate; ADP, adenosine diphosphate; ASA, aspirin; UFH, unfractionated heparin; LMWH, low molecular weight heparin; TXA₂, thromboxane A₂; GP, glycoprotein; vWF, von Willebrand factor; TXA₂R, thromboxane A₂ receptor.

Table 1 Basic pharmacologic characteristics of glycoprotein IIb/IIIa inhibitors

Characteristic	Eptifibatide	Abciximab	Tirofiban
Type	Synthetic cyclic heptapeptide	Fab fragment of chimeric human-murine monoclonal antibody	Synthetic nonpeptide
Molecular weight	Small molecule (832 Da)	Large molecule (47,515 Da)	Small molecule (496 Da)
Plasma half-life	2.5–2.8 hours	10–30 minutes	1.2–2 hours
Receptor binding	Seconds	Minutes	Seconds
Elimination route	Renal ~50%	Spleen	Renal 65% Biliary 25%

Table 2 Studies with eptifibatide in patients undergoing PCI in STEMI

Reference	Patients (n)	Prior antiplatelet drugs	Patient population	Study groups/dosage of eptifibatide (bolus + infusion)	Endpoints (P) = Primary endpoint	Endpoint results (eptifibatide versus placebo, P-value)	Bleeding endpoints (TIMI bleeding; eptifibatide versus placebo)
INTAMI^Citation20	102	ASA	STEMI undergoing PCI	Early eptifibatide 2×180 μg/kg + 2.0 μg/kg/min .12–24 hours Late or no eptifibatide	TIMI III patency prior to PCI (P) Death at 30 days Reinfarction at 30 days	34% versus 10.2%, P=0.01 3.8% versus 4.1%, P=0.9 5.7% versus 0.0%, P=0.09	Major: 10.6 versus 9.1%, P<0.05
TITAN-TIMI 34^Citation21	343	ASA	STEMI undergoing primary PCI	Early eptifibatide 2×180 μg/kg + 2.0 μg/kg/min Late or no eptifibatide	Pre-PCI TIMI corrected frame count (P) Death at 30 days	77.5±32.2 versus 84.3±30.7, P=0.049 4.0% versus 2.8%, P=0.76	Major: 1.7% versus 3.5%, P=NS Minor: 5.2% vs 4.2%, P=NS
ASSIST^Citation22	400	ASA, clopidogrel	STEMI undergoing primary PCI	Heparin + eptifibatide 2×180 μg/kg + 2.0 μg/kg/min ~18 hours Heparin alone	Death, reinfarction, recurrent severe ischemia at 30 days (P)	6.5% versus 5.5%, P=0.69	Major: 9.5% versus 5.5%, P=0.14 Minor: 12.9% versus 9.1%, P=0.21
HORIZONS-AMI^Citation23	3,602	ASA, clopidogrel	STEMI undergoing PCI	Heparin + planned GP IIb/IIIa inh (eptifibatide 45.6%) Bivalirudin + provisional GP IIb/IIIa inh (eptifibatide 3.2%)	Net clinical outcome and major bleeding complications (P)	12.1% versus 9.2%, P=0.005	Major: 5.0% versus 3.1%, P=0.002 Minor: 4.6% versus 2.8%, P=0.006
EVA-AMI^Citation32	427	ASA, clopidogrel	STEMI undergoing PCI	Eptifibatide: 2×180 μg/kg + 2.0 μg/kg/min .24 hours Abciximab: 0.25 mg/kg + 0.125 μg/kg/min	ST-segment resolution at 60 minutes after PCI (P) Death/MI/TVR at 30 days	13.1% versus 10.0%, P=0.34 7.5% versus 8.5%, P=0.72	Major: 4.0% versus 2.0%, P=0.27 Minor: 12.4% versus 9.0%, P=0.28

Abbreviations: STEMI, ST-segment elevation myocardial infarction; TIMI, thrombosis in myocardial infarction; NS, not statistically significant; PCI, percutaneous coronary intervention; ASA, aspirin; inh, inhibitor; MI, myocardial infarction; TVR, target vessel revascularization; GP, glycoprotein.

Table 3 Studies with eptifibatide in patients with ACS and stable CAD undergoing PCI

References	Patients (n)	Prior antiplatelet drugs	Patient population	Study groups/dosage of eptifibatide (bolus + infusion/duration)	Endpoints (P) = primary endpoint	Endpoint results (eptifibatide versus placebo, P-value)	Bleeding endpoints (TIMI bleeding) (eptifibatide versus placebo)
IMPACT-II^Citation16	4,010	ASA	Elective, urgent, and emergent PCI	Eptifibatide 135 μg/kg + 0.5 μg/kg/min for 20–24 hours Eptifibatide 135 μg/kg + 0.75 μg/kg/min 20–24 hours Placebo	Death, MI, urgent, or emergency repeat coronary revascularization (P)	9,2% versus 9.9% versus 11.4% P=0.063 (135/0.5) P=0.22 (135/0.75)	Major: 5.1% versus 5.2% versus 4.8%
PURSUIT^Citation25	10,948	ASA	ACS (PCI in 11.2%)	Eptifibatide 180 μg/kg + 2.0 μg/kg/min Placebo	Death or nonfatal MI at 30 days (P)	14.2% versus 15.7%, P=0.04 11.6% versus 16.7%, P=0.010a	Major: 3.0% versus 1.3%, P<0.001 Minor: 11.1% versus 4.7%, P<0.001
ESPRIT^Citation27	2,064	ASA, clopidogrel	Elective PCI and ACS (13%)	Eptifibatide 2×180 μg/kg + 2.0 μg/kg/min 18–24 hours Placebo	Death, MI, urgent TVR and bailout eptifibatide use at 30 days	6.6% versus 10.5%, P=0.001	Major: 1.3% versus 0.4%, P=0.027 Minor: 2.8% versus 1.7%, P=NS
EARLY ACS^Citation42	9,492	ASA, clopidogrel	ACS undergoing invasive strategy (PCI in 59%)	Early eptifibatide: 2×180 μg/kg + 2.0 μg/kg/min ≥12 hours Placebo + delayed, provisional use of eptifibatide	Death, MI, recurrent ischemia requiring urgent revascularization or bailout eptifibatide at 96 hours (P) Death or MI at 30 days	9.3% versus 10.0%, P=0.23 11.2% versus 12.3%, P=0.079	Major: 2.6% versus 1.8%, P=0.015 Minor: 3.6% versus 1.7%, P<0.001
ACUITY^Citation29	9,207	ASA, clopidogrel	Moderate to high risk ACS undergoing invasive strategy (PCI in 56.1%)	Routine upstream GP IIb/IIIa inh (eptifibatide in 61.5%) Deferred GP IIb/IIIa inh for PCI only Bivalirudin alone	Death, MI, or unplanned revascularization at 30 days (P)	7.1% versus 7.9%, P^NI=0.044 P^sup=0.13	Major bleeding, non-CABG related: 6.1% versus 4.9%, P<0.001
REPLACE-2^Citation30	6,010	ASA, thienopyridine	Urgent or elective PCI	Heparin + planned GP IIb/IIIa inh (eptifibatide in 53.4%) Bivalirudin + provisional GP IIb/IIIa inh (7.2% use)	Death, MI, urgent repeat revascularization or inhospital major bleeding at 30 days (P)	10.0% versus 9.2%, P=0.32	Major bleeding: 4.1% versus 2.4%, P<0.001
PROTECT-TIMI 30^Citation31	857	ASA, clopidogrel	Moderate to high-risk ACS undergoing PCI	Heparin + eptifibatide (2×180 μg/kg + 2.0 μg/kg/min 18–24 hours) Bivalirudin + provisional eptifibatide	Post-PCI coronary flow reserve (P) Death or MI at 48 hours	1.33 versus 1.43, versus 0.036 8.8% versus 6.6%, P=0.246	Major: 0.7% versus 0.0%, P=0.308 Minor: 2.5% versus 0.4%, P=0.027
BRIEF-PCI^Citation38	624	ASA, clopidogrel (65.7%–70.8%)	Stable angina, ACS, or recent STEMI who underwent successful PCI	Eptifibatide 2×180 μg/kg + 2.0 μg/kg/min 18 hours Eptifibatide 2×180 μg/kg + 2.0 μg/kg/min <2 hours	Troponin-I >0.26 μg/L (P) Death, MI, or urgent TVR	28.3% versus 30.1%, P^NI<0.012 4.5% versus 4.8%, P=1.0	Major: 4.2% versus 1.0%, P=0.02 Minor: 21.2% versus 17.6%, P=0.31

Note:

a In patients who underwent early PCI.

Abbreviations: CAD, coronary artery disease; ACS, acute coronary syndrome; TIMI, thrombosis in myocardial infarction; NS, not statistically significant; PCI, percutaneous coronary intervention; ASA, aspirin; inh, inhibitor; MI, myocardial infarction, TVR, target vessel revascularization; GP, glycoprotein; NI, noninferiority; sup, superiority; STEMI, ST-segment elevation myocardial infarction; CABG, coronary artery bypass graft.

Table 4 American College of Cardiology/American Heart Association guidelines (modified) for use of eptifibatide in patients undergoing PCI

STEMI
Class IIaa	It is reasonable to begin treatment with double-bolus eptifibatided at the time of primary PCI (with or without stenting or clopidogrel pretreatment) in selected patients with STEMI who are receiving UFH.
Class IIbb	It may be reasonable to administer eptifibatide in the precatheterization laboratory setting (eg, ambulance, ED) to patients with STEMI for whom primary PCI is intended.d
UA/NSTEMI
Class Ic	In UA/STEMI patients with high-risk features (eg, elevated troponin level) not treated with bivalirudin and not adequately pretreated with clopidogrel, it is useful at the time of PCI to administer eptifibatide in patients treated with UFH.e
Class IIaa	In high-risk patients treated with UFH and adequately pretreated with clopidogrel, it is reasonable at the time of PCI to administer eptifibatide.d
Class III: No benefit	Eptifibatide should not be administered to patients in whom PCI is not planned.e
Stable CAD
Class IIaa	In patients undergoing elective PCI treated with UFH and not pretreated with clopidogrel, it is reasonable to administer eptifibatide.d
Class IIbb	In patients undergoing elective PCI with stent implantation treated with UFH and adequately pretreated with clopidogrel, it might be reasonable to use eptifibatide.d

Notes:

a Recommendation that procedure or treatment is useful/effective

b recommendation in favor of treatment or procedure being useful/effective

c recommendation’s usefulness/efficacy less well established

d data derived from a single randomized trial or nonrandomized studies

e data derived from multiple randomized clinical trials or meta-analysis.

Abbreviations: PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UFH, unfractionated heparin; ED, emergency department; UA, unstable angina; NSTEMI, non ST-segment elevation myocardial infarction; CAD, coronary artery disease.

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