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Schering-Plough Announces Results of the Early ACS Trial
Date:3/30/2009

Early Use of INTEGRILIN(R) Investigational Dosing is Not Superior to Delayed Provisional Use in Patients with High-Risk Acute Coronary Syndrome, Study Finds

KENILWORTH, N.J., March 30 /PRNewswire-FirstCall/ -- In a study presented today at the 58th annual Scientific Sessions of the American College of Cardiology and simultaneously published by The New England Journal of Medicine, researchers reported that a strategy using an upstream, investigational dose of INTEGRILIN(R) (eptifibatide) routinely in patients with Acute Coronary Syndrome (ACS), at least 12 hours prior to angiography, failed to achieve either the primary or secondary endpoints of the trial. Significantly higher rates of bleeding and transfusions also were reported.

"These results do not support the upstream use of double-bolus plus infusion eptifibatide as a routine course of treatment in ACS," said Enrico Veltri, M.D., group vice president of global clinical research, cardiovascular and metabolic disease, Schering-Plough Research Institute. "However, the results do not change what other studies have previously reported: that eptifibatide remains an integral component of therapy for appropriate patients undergoing PCI."

L. Kristin Newby, MD, associate professor of medicine at Duke Clinical Research Institute, presented the results of the nearly 9,500-patient Early Glycoprotein IIb-IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) study, which was designed to determine whether routine early use of eptifibatide would result in improved cardiovascular outcomes for patients with ACS compared to delayed provisional use. The primary efficacy endpoint was a composite of death, (re)infarction (MI), recurrent ischemia requiring urgent revascularization, or thrombotic bailout through 96 hours. The secondary endpoint was death or (re)MI at 30 days. Safety endpoints included bleeding and transfusions through 120 hours.

No statistical difference was observed between the groups in either the primary or secondary endpoints. The primary endpoint occurred in 9.3 percent of the study group (receiving double-bolus plus infusion early administration of eptifibatide 12 or more hours prior to angiography), compared with 10.0 percent of the delayed provisional group (p=0.23). At 30 days, the death or (re)MI rate for the study group was 11.2 percent compared to 12.3 percent for the delayed provisional group (p=0.079).

Significantly higher rates of bleeding were observed in the study group, with 118 patients experiencing a TIMI major bleeding event, compared to 83 in the delayed provisional group (p=0.015). Investigators reported a 7.6 percent vs. 5.1 percent rate of moderate or severe bleeding (p<0.001) in the study group as compared to the delayed provisional group, as measured by the GUSTO scale. Red blood cell transfusions occurred in 8.6 percent of patients in the study group vs. 6.7 percent of patients in the delayed provisional group (p=0.001). There were no significant differences in mortality or any serious adverse events between the two groups.

"This was a very well-treated population that demonstrates the influence of aggressive and sophisticated therapies," said Dr. Newby. "Further evaluation of the safety and efficacy data at one year should provide additional insights into the early use of eptifibatide in this patient population."

Within the trial, the single largest group was PCI patients (n=5,559). An analysis of those randomized to receive early eptifibatide showed that these patients experienced fewer primary and secondary composite events after PCI than those randomized to the delayed provisional eptifibatide strategy.

"Consistent with findings from prior trials, in this double-bolus study, NSTE ACS patients undergoing PCI experienced fewer post-PCI ischemic complications with early eptifibatide," said Robert Giugliano, MD, lead author of the EARLY ACS study, associate physician at Brigham and Women's Hospital and associate professor at Harvard Medical School.

EARLY ACS Study Design

EARLY ACS randomly allocated 9,492 patients with high-risk non-ST-segment elevation ACS to one of two strategies: early routine eptifibatide, or early placebo with delayed provisional eptifibatide commenced after angiography but pre-PCI. After randomization, patients received double-blinded early eptifibatide (180 mcg/kg intravenous double bolus [10 minutes apart] and 2.0 mcg/kg/min [1.0 mcg/kg/min if creatinine clearance <50 mL/min] infusion), or matching placebo. For bleeding, the investigator could decrease study drug infusion by one-third.

After angiography but pre-PCI, investigators could request a PCI study drug kit (to ensure eptifibatide was used during PCI while maintaining the original blind) containing bolus treatment (either eptifibatide or placebo) opposite to the randomized treatment assignment. Following kit administration, an open-label eptifibatide infusion was continued for 18-24 hours post-procedure. If provisional study drug was not administered pre-PCI, the initial infusion was continued unchanged for 18-24 hours post-PCI. If a thrombotic complication occurred after the wire crossed the lesion, investigators could request a bailout PCI kit containing bolus therapy opposite to initial treatment assignment.

For patients undergoing PCI, infusion duration was less than or equal to 96 hours (longer infusions were permitted to ensure a minimum 18-hour infusion post-PCI). In patients undergoing coronary artery bypass graft (CABG) surgery, the infusion continued until 2 hours preoperative (maximum 120 hours). Patients without revascularization received an infusion of less than or equal to 96 hours.

Aspirin (162-325 mg orally or 150-500 mg intravenously) was required upon enrollment, followed by greater than or equal to 75 mg daily thereafter. Thienopyridine was substituted in aspirin-intolerant patients. The protocol mandated either weight-based unfractionated heparin or weight- and renal-adjusted enoxaparin by investigator choice. After a study amendment, bivalirudin and fondaparinux were allowed as concomitant baseline antithrombotic therapies. If early clopidogrel was used, the recommended loading dose was 300 mg. A 600 mg loading dose was permitted peri-PCI if no prior loading dose had been administered. The recommended clopidogrel maintenance dose was 75 mg daily.

The primary efficacy endpoint was a composite of all-cause mortality, (re)MI, recurrent ischemia requiring urgent revascularization, or thrombotic bailout through 96 hours. The key secondary efficacy endpoint was 30-day death or (re)MI. Safety endpoints included rates of hemorrhage, transfusion, surgical re-exploration, stroke, thrombocytopenia, and serious adverse events through 120 hours. Bleeding was measured according to the TIMI and GUSTO bleeding scales.

About INTEGRILIN(R) (eptifibatide) Injection

INTEGRILIN is indicated for the treatment of patients with acute coronary syndrome (unstable angina/non-ST-segment-elevation myocardial infarction), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI). It is also indicated in the United States for the treatment of patients undergoing PCI, including those undergoing intracoronary stenting.

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 greater than 200 mm Hg or diastolic blood pressure greater than 110 mm Hg) not adequately controlled on antihypertensive therapy; major surgery within the preceding six 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; or known hypersensitivity to any component of the product.

In patients undergoing PCI, INTEGRILIN is associated with an increase in major and minor bleeding at the site of arterial sheath placement; special care should be employed to minimize the risk of bleeding among these patients; if bleeding cannot be controlled with pressure, infusion of INTEGRILIN and concomitant heparin should be stopped immediately; because INTEGRILIN inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, NSAIDs, and dipyridamole; use with other GP IIb-IIIa inhibitors should be avoided; INTEGRILIN is cleared in part by the kidney, and its plasma concentrations are doubled in patients with renal disease (CrCl <50 mL/min); therefore, the infusion dose of INTEGRILIN needs to be reduced to 1mcg/kg/min in these patients; INTEGRILIN is contraindicated in patients who are dependent upon renal dialysis (please see dosing guidelines); caution should be exercised when administering INTEGRILIN to patients with a platelet count <100,000/mm3. Bleeding is the most common complication encountered during INTEGRILIN therapy. The majority of excess major bleeding events were localized at the femoral artery access site. Oropharyngeal, genitourinary, gastrointestinal and retroperitoneal bleeding were also seen more commonly with INTEGRILIN compared to placebo.

Full prescribing information for INTEGRILIN (eptifibatide) is available at www.schering-plough.com.

About Schering-Plough

Schering-Plough (NYSE: SGP) is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription, animal health and consumer health care products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.

SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release contains certain "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to potential of INTEGRILIN and further actions under the clinical trials. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 1A. "Risk Factors" in the 2008 10-K, filed February 27, 2009.


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