Eptifibatide

Summary

Abstract

Eptifibatide (Integrilin®) is a selective inhibitor of platelet glycoprotein (GP) IIb/ IIIa receptors used as adjunctive therapy for patients undergoing percutaneous coronary intervention (PCI) and for patients with acute coronary syndromes (ACS), particularly those requiring PCI. Most economic analyses of eptifibatide have incorporated clinical and healthcare resource use data from either the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin® Therapy) study in low-to moderate-risk patients undergoing selective PCI with stent implantation or the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin® Therapy) trial in patients with ACS. Eptifibatide achieved statistically significant reductions in combined endpoints of death and ischaemic complications in both of these large multicentre clinical trials, in which patients were randomised to receive intravenous eptifibatide or placebo as adjunctive therapy to heparin and aspirin (plus a thienopyridine in ESPRIT).

In US economic analyses using ESPRIT trial data, approximately 40% and 70% of the acquisition cost of eptifibatide was offset by reduced medical resource consumption during the initial hospitalisation period and over a 1-year period, respectively. Eptifibatide was associated with a favourable cost-effectiveness ratio of $US1407 (year 2000 costs) per life-year gained (LYG) in a retrospective US cost-effectiveness analysis that incorporated data from the ESPRIT trial and modelled life expectancy using a large cardiovascular database.

Several cost-effectiveness analyses used prospectively collected data from the PURSUIT trial and modelled survival projections using similar methods. These analyses, conducted in the US, Canada and Western Europe, also showed favourable results ($US3761–$US18 774 per LYG; various years of costing). Cost-utility ratios reported in US analyses varied somewhat, but remained <$US20 000 per quality-adjusted life-year gained (1996 values) when clinical efficacy data were derived from the US cohort of PURSUIT.

Conclusion: Significant clinical benefits have been demonstrated with eptifibatide as adjunctive therapy in patients undergoing selective PCI with stent implantation in the ESPRIT trial and in patients with ACS in the PURSUIT trial. Pharmacoeconomic analyses using data from either ESPRIT or PURSUIT have demonstrated favourable cost-effectiveness ratios for both indications in various countries. ESPRIT-based results from the limited number of available economic analyses are particularly favourable. The cost-effectiveness of eptifibatide in ACS (i.e. PURSUIT-based results) may be further improved by targeting the drug for patients in whom catheterisation and PCI are planned, although further analyses are required to confirm this.

Percutaneous Coronary Intervention (PCI) and Acute Coronary Syndromes (ACS)

Percutaneous coronary intervention (PCI) refers to all forms of percutaneous mechanical revascularisation and is a relatively common intervention in patients with coronary artery disease, with more than 1 million angioplasty procedures conducted in the US each year. Acute coronary syndromes (ACS), for the purposes of this review, comprise unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI). Each year, approximately 2–2.5 million patients are hospitalised worldwide because of unstable angina or NSTEMI, and at least half of these are in the US.

In-hospital costs for patients undergoing PCI and planned stent implantation were estimated at $US10 430 per patient (without a glycoprotein [GP] IIb/IIIa receptor antagonist; year 2000 costs) in a large retrospective US cost analysis, although both higher and lower estimates of costs associated with PCI have also been reported. Total discounted 10-year medical costs were estimated at $US50 254 per patient (1997 values) in a study in 4319 patients with unstable angina who underwent an initial cardiac catheterisation at a US medical centre between 1986 and 1997. More than 40% of costs were incurred during the acute phase of therapy (which did not include GP IIb/IIIa receptor antagonists).

Clinical Profile of Eptifibatide

GP IIb/IIIa receptor antagonists such as eptifibatide inhibit the final common pathway for platelet aggregation. Therefore, these drugs can play an important role in preventing thrombus formation in coronary arteries, including that caused by mechanical disruption of an atherosclerotic plaque (e.g. during PCI) or via chemically mediated activation of platelet GP IIb/IIIa receptors (e.g. by thromboxane A2 or adenosine diphosphate). Eptifibatide is a selective GP IIb/IIIa receptor antagonist indicated for patients with coronary artery disease who require selective (nonurgent) or urgent PCI and for those with ACS (many of whom require urgent PCI). The drug is administered intravenously and is used as an adjunct to therapy with heparin and aspirin (acetylsalicylic acid).

The clinical efficacy of eptifibatide in patients with low- to moderate-risk coronary artery disease undergoing selective PCI with stent implantation was demonstrated in the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin® Therapy) trial. The study excluded higher-risk patients such as those with ongoing chest pain. Patients were randomised to receive eptifibatide (n = 1040) or placebo (n = 1024), in addition to heparin, aspirin and a thienopyridine (clopidogrel or ticlopidine). Eptifibatide was administered as a bolus of 180 μg/kg followed immediately by a continuous infusion of 2 μg/kg/min (for 18–24 hours or until discharge from hospital, whichever occurred first), and a second bolus dose of 180 ug/kg administered 10 minutes after the first bolus. Results of the primary efficacy analysis showed that, at 48 hours after randomisation, 6.6% of eptifibatide recipients and 10.5% of placebo recipients (p = 0.0015) had either died, experienced a myocardial infarction, underwent urgent target vessel revascularisation (UTVR), or required open-label eptifibatide because of thrombotic complications. An important secondary combined endpoint of death, myocardial infarction and UTVR at 30 days was similarly reduced with eptifibatide versus placebo (6.8% vs 10.5%, p = 0.0034).

The clinical efficacy of eptifibatide in patients with ACS was demonstrated in the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin® Therapy) trial. In this large, double-blind, multicentre study, analysis of efficacy included 9461 patients who were randomised to receive eptifibatide (180 μg/kg bolus followed by a continuous infusion of 2 μg/kg/min until hospital discharge for up to a duration of 72 hours, or up to 96 hours in those who underwent PCI) or placebo. A large majority of patients received concomitant heparin and aspirin, although such therapy was not mandated in this trial. For the primary endpoint of death or myocardial infarction at 30 days after randomisation, eptifibatide was associated with a significant benefit compared with placebo (14.2% vs 15.7% of patients, p = 0.04), and this effect was observed early during therapy. Approximately 13% of patients required early PCI within 72 hours of randomisation, and eptifibatide appeared to be particularly beneficial for this subgroup. However, results of subgroup analyses with inadequate statistical power must be interpreted with caution.

The most important adverse events associated with eptifibatide are major and minor bleeding (including the need for transfusion). In general, the incidence of bleeding and the need for transfusion was greater with eptifibatide than placebo in large multicentre trials. However, the incidence of bleeding complications varied widely between the studies, possibly because of differences in risk factors and eptifibatide dosage protocols. Stroke was reported in 0.7% of eptifibatide recipients and a similar proportion of placebo recipients (0.8%) in the PURSUIT study. Stroke was rare in the ESPRIT trial and haemorrhagic stroke was rare in both multicentre studies.

Pharmacoeconomic Analyses of Eptifibatide

In Patients Undergoing PCI: Prospective economic analyses of the ESPRIT trial in patients undergoing selective PCI with stent implantation have not been conducted. However, a detailed retrospective cost analysis and a briefly reported cost-effectiveness analysis have been conducted in the US using actual medical resource consumption from the ESPRIT study where possible.

Results of the US cost analysis showed that total medical costs associated with the initial hospitalisation were 2.8% higher among eptifibatide than placebo recipients ($US10 722 vs $US10 430 per patient; p < 0.001) [year 2000 costs]. Approximately 40% of the $US495 per patient acquisition cost of eptifibatide was offset by reduced medical resource consumption during the index hospitalisation.

The US cost-effectiveness analysis, which examined the incremental costs and benefits of eptifibatide as an adjunct to standard therapy versus standard therapy alone, used 1-year follow-up data from the ESPRIT study and modelled life expectancy using the Duke Cardiovascular Database. In addition to basic life-expectancy projections, the effect of a nonfatal myocardial infarction on subsequent survival was also incorporated into the model. Results showed that the mean incremental cost of eptifibatide was $US146 per patient ($US12 844 vs $US12 697; year 2000 costs) and life expectancy (discounted at 3%) was projected to increase by 0.104 years, thus providing a favourable cost-effectiveness ratio of $US1407 per life-year gained (LYG). (Minor calculation discrepancies are presumably due to rounding.) Approximately 70% of the acquisition cost of eptifibatide was therefore offset by reduced medical resource consumption during the first year. Cost-effectiveness ratios remained below $US2275 per LYG in the sensitivity analysis, even when the prognostic significance of a nonfatal myocardial infarction was eliminated. In addition, a Canadian cost-effectiveness analysis using data from ESPRIT and a hospital cost database reported that eptifibatide was dominant over standard therapy (i.e. less costly and more effective); however, further details are lacking in this brief report.

A number of retrospective and prospective economic analyses have been conducted comparing eptifibatide with abciximab as adjunctive therapy in patients undergoing PCI. Study methodology was not uniform across these analyses, all of which were conducted in the US. In general, results showed that eptifibatide was associated with lower acquisition costs and similar or lower total medical costs or charges per patient, while clinical outcomes appeared to be similar between the two GP IIb/IIIa receptor antagonists.

Two prospectively conducted comparisons have been performed. In a randomised trial in 320 patients undergoing selective PCI, total inpatient costs were the primary endpoint. Median total in-hospital costs per patient (1999/2000 values) were $US7207 with eptifibatide compared with $US8268 for abciximab (p < 0.01), and clinical efficacy was deemed to be similar between treatment groups. The difference in total medical costs was primarily because of the lower acquisition cost for eptifibatide versus abciximab. The other prospective study was not randomised and did not include a formal economic analysis per se. Nevertheless, the acquisition cost of eptifibatide was lower than that of abciximab and there was little difference between groups in terms of major cost drivers (e.g. length of hospital stay, major adverse cardiovascular events) when used in patients undergoing PCI for a variety of indications.

Analyses in Patients with ACS: A number of pharmacoeconomic analyses of eptifibatide in ACS (with or without PCI) have been conducted prospectively using data from the PURSUIT trial. In these analyses, medical resource consumption data were collected for the US, Canadian, Western European and other specific cohorts of the PURSUIT trial, and unit costs for the geographical region of interest were then applied to determine total medical costs per patient. In all of these studies, the acquisition cost of eptifibatide was at least partly offset by a reduced need for medical intervention. Total medical costs, measured over a 6-month period in the majority of analyses, were 1.1–6.8% higher among eptifibatide than placebo recipients, although UK-specific resource consumption was lower in the eptifibatide group.

Several of the studies were cost-effectiveness analyses, in which long-term survival was estimated using modelled projections made from 6-month results of the PURSUIT trial, in most cases for the cohort of patients from the particular geographical region of the economic substudy. Cost-effectiveness ratios, which reflected incremental costs and benefits of eptifibatide as an adjunct to standard therapy versus standard therapy alone, were favourable for eptifibatide and ranged from approximately $US3761–$US18 774 per LYG (various years of costing). Values not reported in US dollars were converted using mid-year exchange rates for the year of costing or, if not provided, for the year of study publication. One US analysis also reported a cost-utility ratio of $US19 693 per quality-adjusted life-year (QALY) gained (1996 costs), although a somewhat less favourable cost-utility ratio ($US42 469 per QALY; year of costing not provided) was reported by other US investigators who used clinical results of the entire study population of PURSUIT (rather than the more favourable results of the US cohort) to estimate long-term survival.