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WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bleeding

Bleeding is the most common complication encountered during INTEGRILIN therapy. Administration of INTEGRILIN is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) [see ADVERSE REACTIONS]. Most major bleeding associated with INTEGRILIN has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins).

Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents

Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT [see DOSAGE AND ADMINISTRATION].

Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)

In patients undergoing PCI, treatment with INTEGRILIN is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, INTEGRILIN infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while INTEGRILIN is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of < 45 seconds or ACT < 150 seconds be achieved. In any case, both heparin and INTEGRILIN should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of INTEGRILIN and heparin should be discontinued immediately.

Thrombocytopenia

There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with INTEGRILIN. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to < 100,000/mm³, discontinue INTEGRILIN and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate [see ADVERSE REACTIONS].

There has been no clinical experience with INTEGRILIN initiated in patients with a baseline platelet count < 100,000/mm³. If a patient with low platelet counts is receiving INTEGRILIN, their platelet count should be monitored closely.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide. There are, however, no adequate and well-controlled studies in pregnant women with INTEGRILIN. Because animal reproduction studies are not always predictive of human response, INTEGRILIN should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether eptifibatide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when INTEGRILIN is administered to a nursing mother.

Pediatric Use

Safety and effectiveness of INTEGRILIN in pediatric patients have not been studied.

Geriatric Use

The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with INTEGRILIN. The incidence of bleeding complications was higher in the elderly in both placebo and INTEGRILIN groups, and the incremental risk of INTEGRILIN-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study [see ADVERSE REACTIONS].

Renal Impairment

Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma INTEGRILIN concentrations are doubled in patients with an estimated CrCl < 50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients [see DOSAGE AND ADMINISTRATION]. The safety and efficacy of INTEGRILIN in patients dependent on dialysis has not been established.

OVERDOSE

There has been only limited experience with overdosage of INTEGRILIN. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.

Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.

From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.

CONTRAINDICATIONS

Treatment with INTEGRILIN is contraindicated in patients with:

• A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days
• Severe hypertension (systolic blood pressure > 200 mm Hg or diastolic blood pressure   > 110 mm Hg) not adequately controlled on antihypertensive therapy
• Major surgery within the preceding 6 weeks
• History of stroke within 30 days or any history of hemorrhagic stroke
• Current or planned administration of another parenteral GP IIb/IIIa inhibitor
• Dependency on renal dialysis
• Hypersensitivity to INTEGRILIN or any component of the product (hypersensitivity reactions that occurred included anaphylaxis and urticaria).

CLINICAL PHARMACOLOGY

Mechanism of Action

Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.

Pharmacodynamics

Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model).

Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, INTEGRILIN inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of INTEGRILIN was observed immediately after administration of a 180-mcg/kg intravenous bolus. Table 4 shows the effects of dosing regimens of INTEGRILIN used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 μM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.

Table 4: Platelet Inhibition and Bleeding Time

	PURSUIT 180/2*
Inhibition of platelet aggregation 15 min after bolus	84%
Inhibition of platelet aggregation at steady state	> 90%
Bleeding-time prolongation at steady state	< 5x
Inhibition of platelet aggregation 4h after infusion discontinuation	< 50%
Bleeding-time prolongation 6h after infusion discontinuation	1.4x
* 180-mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min.

The INTEGRILIN dosing regimen used in the ESPRIT study included two 180-mcg/kg bolus doses given 10 minutes apart combined with a continuous 2-mcg/kg/min infusion.

When administered alone, INTEGRILIN has no measurable effect on PT or aPTT.

There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.

Pharmacokinetics

The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4-6 hours). This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma.

Special Populations

Geriatric

Patients in clinical studies were older (range: 20-94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight ( < 50 kg) patients over 75 years of age.

Renal Impairment

In patients with moderate to severe renal insufficiency (CrCl < 50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

Hepatic Impairment

No studies have been conducted in patients with hepatic impairment.

Gender

Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.

Clinical Studies

INTEGRILIN was studied in 3 placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: UA or NSTEMI. Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a PCI. Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.

Non-ST-Segment Elevation Acute Coronary Syndrome

Non-ST-segment elevation acute coronary syndrome is defined as prolonged ( ≥ 10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and 1 mm or depression > 0.5 mm), T-wave inversion ( > 1 mm), or positive CK-MB. This definition includes “unstable angina” and “NSTEMI” but excludes MI that is associated with Q waves or greater degrees of ST-segment elevation.

PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using INTEGRILIN Therapy)

PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest ( ≥ 10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression > 0.5 mm), T-wave inversion ( > 1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine > 2 mg/dL, dependency on renal dialysis, or platelet count < 100,000/mm³.

Patients were randomized to placebo, to INTEGRILIN 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion (180/2), or to INTEGRILIN 180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the INTEGRILIN infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.

The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding.

Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%).

This was a “real world” study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion).

The majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, most commonly as an intravenous bolus of 5000 units followed by a continuous infusion of 1000 units/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 units/kg followed by a continuous infusion of 12 units/kg/h. A target aPTT of 50 to 70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an ACT of 300 to 350 seconds.

The primary endpoint of the study was the occurrence of death from any cause or new MI (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization.

Compared to placebo, INTEGRILIN administered as a 180-mcg/kg bolus followed by a 2mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events (see Table 6). The reduction in the incidence of endpoint events in patients receiving INTEGRILIN was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table 5 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.

Table 5: Clinical Events in the PURSUIT Study

Death or MI	Placebo (n=4739) n (%)	INTEGRILIN (180 mcg/kg bolus then 2 mcg/kg/min infusion) (n=4722) n (%)	p-value
3 days	359 (7.6%)	279 (5.9%)	0.001
7 days	552 (11.6%)	477 (10.1%)	0.016
30 days
Death or MI (primary endpoint)	745 (15.7%)	672 (14.2%)	0.042
Death	177 (3.7%)	165 (3.5%)
Nonfatal MI	568 (12%)	507 (10.7%)

Figure 1: Kaplan-Meier Plot of Time to Death or Myocardial Infarction Within 30 Days of Randomization in the PURSUIT Study

Treatment with INTEGRILIN prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table 6 shows the incidence of death or MI within 72 hours.

Table 6: Clinical Events (Death or MI) in the PURSUIT Study Within 72 Hours of Randomization

	Placebo	INTEGRILIN (180 mcg/kg bolus then 2 mcg/kg/min infusion)
Overall patient population	n=4739	n=4722
- At 72 hours	7.6%	5.9%
Patients undergoing early PCI	n=631	n=619
- Pre-procedure (nonfatal MI only)	5.5%	1.8%
- At 72 hours	14.4%	9%
Patients not undergoing early PCI	n=4108	n=4103
- At 72 hours	6.5%	5.4%

All of the effect of INTEGRILIN was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure.

An analysis of the results by sex suggests that women who would not routinely be expected to undergo PCI receive less benefit from INTEGRILIN (95% confidence limits for relative risk of 0.94 - 1.28) than do men (0.72 - 0.9). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRIT).

Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9% of the initial enrollment). This follow-up included 4566 patients who received INTEGRILIN at the 180/2 dose. As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with INTEGRILIN 180/2.

Percutaneous Coronary Intervention (PCI)

IMPACT II (INTEGRILIN to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)

IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT > 1.2 times control, hematocrit < 30%, platelet count < 100,000/mm³, and pregnancy.

Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:

135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of INTEGRILIN (135/0.5);

135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of INTEGRILIN (135/0.75); or

a matching placebo bolus followed by a matching placebo continuous infusion.

Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.

The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.

As shown in Table 7, each INTEGRILIN regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose INTEGRILIN group. As in the PURSUIT study, the effects of INTEGRILIN were seen early and persisted throughout the 30-day period.

Table 7: Clinical Events in the IMPACT II Study

	Placebo n (%)	INTEGRILIN (135 mcg/kg bolus then 0.5 mcg/kg/min infusion) n (%)	INTEGRILIN (135 mcg/kg bolus then 0.75 mcg/kg/min infusion) n (%)
Patients	1285	1 300	1286
Abrupt Closure	65 (5.1 %)	36 (2.8%)	43 (3.3%)
p-value   versus placebo		0.003	0.03
Death, MI, or Urgent Intervention
24 hours	123 (9.6%)	86 (6.6%)	89 (6.9%)
p-value versus placebo		0.006	0.014
48 hours	131 (10.2%)	99 (7.6%)	102 (7.9%)
p-value versus placebo		0.021	0.045
30 days (primary endpoint)	149 (11.6%)	118 (9.1%)	128 (10%)
p-value versus placebo		0.035	0.179
Death or MI
30 days	110 (8.6%)	89 (6.8%)	95 (7.4%)
p-value versus placebo		0.102	0.272
6 months	151 (11.9%)*	136 (10.6%)*	130 (10.3%)*
p-value versus placebo		0.297	0.182
* Kaplan-Meier estimate of event rate.

ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with INTEGRILIN Therapy)

The ESPRIT study was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of a saphenous vein graft or subsequent “staged” PCI, prior stent placement in the target lesion, PCI within the previous 90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT > 1.2 times control, hematocrit < 30%, platelet count < 100,000/mm³, and pregnancy.

Patient age ranged from 24 to 93 (mean 62) years, and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received a wide variety of stents. Patients were randomized either to placebo or INTEGRILIN administered as an intravenous bolus of 180 mcg/kg followed immediately by a continuous infusion of 2 mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later (180/2/180). INTEGRILIN infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least 1 dose of aspirin (162-325 mg) and 60 units/kg of heparin as a bolus (not to exceed 6000 units) if not already receiving a heparin infusion. Additional boluses of heparin (10-40 units/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.

The primary endpoint of the ESPRIT study was the composite of death, MI, urgent target vessel revascularization (UTVR), and “bailout” to open-label INTEGRILIN due to a thrombotic complication of PCI (TBO) (e.g., visible thrombus, “no reflow,” or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by a blinded Clinical Events Committee.

As shown in Table 8, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received INTEGRILIN. A treatment benefit in patients who received INTEGRILIN was seen by 48 hours and at the end of the 30-day observation period.

Table 8: Clinical Events in the ESPRIT Study

	Placebo (n=1024)	INTEGRILIN* (n=1040)	Relative Risk (95% CI)	p-value
Death, MI, UTVR, or Thrombotic “Bailout”
48 hours (primary endpoint)	108 (10.5%)	69 (6.6%)	0.629 (0.471, 0.84)	0.0015
30 days	120 (11.7%)	78 (7.5%)	0.64 (0.488, 0.84)	0.0011
Death, MI, or UTVR
48 hours	95 (9.3%)	62 (6%)	0.643 (0.472, 0.875)	0.0045
30 days (key secondary endpoint)	107 (10.4%)	71 (6.8%)	0.653 (0.49, 0.871)	0.0034
Death or MI
48 hours	94 (9.2%)	57 (5.5%)	0.597 (0.435, 0.82)	0.0013
30 days	104 (10.2%)	66 (6.3%)	0.625 (0.465, 0.84)	0.0016
*INTEGRILIN was administered as 180 mcg/kg boluses at times 0 and 10 minutes and an infusion at 2 mcg/kg/min.

The need for thrombotic “bailout” was significantly reduced with INTEGRILIN at 48 hours (2.1% for placebo, 1% for INTEGRILIN; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with INTEGRILIN was in the reduction of MI. INTEGRILIN reduced the occurrence of MI at 48 hours from 9% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days.

There was no treatment difference with respect to sex in ESPRIT. INTEGRILIN reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours.

Follow-up (12-month) mortality data were available for 2024 patients (1017 on INTEGRILIN) enrolled in the ESPRIT trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on INTEGRILIN), representing 95.2% of the initial enrollment. As shown in Table 9, the treatment effect of INTEGRILIN seen at 48 hours and 30 days appeared preserved at 6 months and 1 year. Most of the benefit was in reduction of MI.

Table 9: Clinical Events at 6 Months and 1 Year in the ESPRIT Study

	Placebo (n=1024)	INTEGRILIN (n=1040)	Hazard Ratio (95% CI)
Death, MI, or Target Vessel Revascularization
6 months	187 (18.5%)	146 (14.3%)	0.744 (0.599, 0.924)
1 year	222 (22.1%)	178 (17.5%)	0.762 (0.626, 0.929)
Death, MI
6 months	117 (11.5%)	77 (7.4%)	0.631 (0.473, 0.841)
1 year	126 (12.4%)	83 (8%)	0.63 (0.478, 0.832)

Percentages are Kaplan-Meier event rates.

PATIENT INFORMATION

Instruct patients to inform the doctor or healthcare provider about any medical conditions, medications, and allergies.