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New Data Shows Acute Heart Attack Patients Given AGGRASTAT® in?Ambulance, with Standard of Care, Significantly Improves Clinical Outcome

Early, in–ambulance treatment with antiplatelet medicine AGGRASTAT® (tirofiban HCL), in addition to the standard combined treatment of aspirin, heparin and clopidogrel, significantly improves the results of primary coronary angioplasty (PCI) in patients with ST–elevated myocardial infarction (STEMI).1 These study findings were presented today at the Annual European Society of Cardiology Congress in Munich, Germany.

Data from the combined open label and double–blind, placebo–control, multinational, "Ongoing Tirofiban in Myocardial Infarction Evaluation (On–TIME) 2" trial in 1398 randomised showed that treatment with AGGRASTAT®, a glycoprotein IIb/IIIa inhibitor, in addition to the standard triple treatment package, significantly reduced the incidence of residual ST–segment deviation versus placebo or no AGGRASTAT® after PCI in STEMI patients (3.7 ± 5.2 mm versus 4.8 ± 6.0 mm, p<0.005).1 The ST segment in the ECG is a good marker of vessel occlusion and closely linked to the outcome of the patients with myocardial infarction.

"These results are significant in that they address the two key unknowns in this area - firstly, the value of early intervention with glycoprotein IIb/IIIa inhibitors on top of the standard treatment of aspirin, heparin and clopidogrel in STEMI patients; and secondly, the most effective timing of that intervention," said Dr Arnoud van´t Hof, Department of Cardiology, Isala Klinieken, Zwolle, Netherlands and principal investigator. "The data from On–TIME 2 shows the importance of diagnosing STEMI at the earliest possible point in the cascade of events that lead to a heart attack, thereby allowing for the initiation of anti–thrombotic and triple antiplatelet therapy including AGGRASTAT® , as early as the ambulance setting, thereby fully optimising the outcome for the patient."

The data from the double–blind placebo control trial was published recently in The Lancet, with an accompanying commentary from independent expert, Dr Gilles Montalescot, Institute of Cardiology Pitié–Salpêtrière Hospital, stating, "On–TIME 2 tells us more than the benefit of AGGRASTAT® in pre–PCI. The study reveals that high–dose clopidogrel is not effective enough and confirms the need for fast and strong platelet inhibition."2

On–TIME 2 is the first–ever study to investigate the efficacy and safety of AGGRASTAT® , which belongs to the glycoprotein IIb/IIIa inhibitors (GPI) class of anticlotting medicines, in STEMI patients in the pre–hospital setting.1

The data showed:

  • A significant reduction in the percentage of patients with more than 3 mm residual ST–segment deviation one hour post–PCI in the AGGRASTAT® group versus placebo (38.7 percent versus 45.0 percent, respectively; p=0.024 [primary endpoint]).1
  • A median of 60 minutes pre–PCI administration of AGGRASTAT® in the ambulance or referral centre setting significantly reduced cumulative ST–segment deviation before PCI, compared to placebo (11.4 ± 9.4 mm versus 12.4 ± 9.4 mm, p=0.020).1
  • One hour after PCI, cumulative ST–segment deviation as a continuous variable was also reduced with early AGGRASTAT® administration (3.7 ± 5.2 mm versus 4.8 ± 6.0 mm, p<0.005) in the no AGGRASTAT® or placebo group.1

"Adding early AGGRASTAT® to our current standard of care in primary PCI for AMI not only provides us with an efficacious treatment option, but also a safe one. The combined endpoint of death, recurrent myocardial infarction (MI) or urgent target vessel revascularization (uTVR), was reduced without a significant increase in bleeding," said Professor Christian Hamm, Department of Cardiology, Kerckhoff–Klinik GmbH, Bad Nauheim, Germany and co–principal investigator. Study results showed that:

  • More patients had aborted myocardial infarction, defined as the absence of a rise in Creatin Kinase (CK) in patients pre–treated with AGGRASTAT® (14 % versus 10%, p=0.04)
  • The combined incidence of death, re–infarction or uTVR, and thrombotic bailout were significantly reduced in the AGGRASTAT® group versus placebo or no AGGRASTAT® (5.8 percent versus 8.6 percent, respectively; p=0.043).1
  • Early intervention with AGGRASTAT® did not result in a significant increase of major bleeding when compared to placebo or no AGGRASTAT® (3.4 percent versus 2.9 percent, respectively; p=0.580).1
  • The net clinical outcome was greater in the AGGRASTAT® group compared to placebo or no AGGRASTAT®, showing a lower combined incidence of major adverse cardiac events (MACE), stroke or major bleeding (8.0% vs. 11.6% for AGGRASTAT® and placebo/no AGGRASTAT® group respectively, p=0.024).1

Professor Hamm continued, "Our finding that routine pre–hospital initiation of AGGRASTAT® improved ST–segment resolution and clinical outcome after PCI, emphasises that early and intensive platelet aggregation inhibition is mandated in patients with STEMI undergoing PCI."

"We are pleased to announce these new data which reinforce the potential benefits of AGGRASTAT® in this critically ill patient population," said John Vavricka, President and Chief Executive Officer of Iroko Pharmaceuticals. "Iroko is committed to furthering its clinical research in this area, and exploring AGGRASTAT®´s potential as an early intervention strategy for patients with acute myocardial infarction."

In January of 2008, Iroko Pharmaceuticals acquired all non–US commercial rights to AGGRASTAT® (tirofiban HCl) from Merck & Co., Inc.

On–TIME 2 Study (Ongoing Tirofiban in Myocardial Infarction Evaluation 2 Trial) 1

The European study was conducted at high–volume PCI centers in Germany, Belgium and the Netherlands. The trial consisted of two consecutive phases:

  • Phase 1 (414 patients): an open labelled run where patients were randomised to receive either AGGRASTAT® (25 µg/kg bolus and 0.15 µg/kg/min maintenance infusion) or no AGGRASTAT®.
  • Phase 2 (984 patients): a double–blind, placebo controlled run with patients randomised to receive treatment with AGGRASTAT® (25 µg/kg bolus and 0.15 µg/kg/min maintenance infusion) or placebo infusion.

In the ambulance, all patients also received a bolus of unfractioned heparin (5000 IU) and aspirin intravenously, as well as 600 mg of clopidogrel orally. Following this, AGGRASTAT® or placebo was injected, followed by an infusion of AGGRASTAT® or placebo. Before PCI, activated clotting time was assessed once; if it was <250 seconds, an additional bolus of 2500 IU of unfractioned heparin was administered.

The study´s primary end point evaluated the benefit of pre–hospital initiation of high bolus tirofiban, administered in addition to aspirin, heparin and clopidogrel, on the extent of residual ST–segment deviation (defined as percentage of patients with >3 mm deviation of ST segment) at one hour after PCI. The key secondary endpoint of the pooled analysis for the open label and double–blind phase was the incidence of MACE: major adverse cardiac events (death, re–infarction, urgent target vessel revascularization) at 30 days follow up. Additionally, major bleeding, as measured by the Thrombolysis in Myocardial Infarction (TIMI) criteria, was also assessed.

AGGRASTAT® is not currently approved for use in STEMI patients or as adjunctive therapy in patients undergoing percutaneous coronary intervention (PCI).

About AGGRASTAT

AGGRASTAT®, a glycoprotein IIb/IIIa inhibitor, is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non–Q–wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes. Patients most likely to benefit from AGGRASTAT® treatment are those at high risk of developing myocardial infarction within the first 3–4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA.

In most patients, AGGRASTAT® should be administered intravenously, at an initial rate of 0.4 mcg/kg/min for 30 minutes and then continued at 0.1 mcg/kg/min. For complete information, please refer to the product´s prescribing information. AGGRASTAT® is intended for use with acetylsalicylic acid and unfractionated heparin.

AGGRASTAT® (tirofiban hydrochloride) is contraindicated in patients with known hypersensitivity to any component of the product; active internal bleeding or a history of bleeding diathesis within the previous 30 days; or a history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm. Other contraindications to AGGRASTAT® include: a history of thrombocytopenia following prior exposure to AGGRASTAT®; history of stroke within 30 days or any history of hemorrhagic stroke; major surgical procedure or severe physical trauma within the previous month; or history, symptoms, or findings suggestive of aortic dissection. AGGRASTAT® is also contraindicated in patients with: severe hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg); concomitant use of another parenteral GP IIb/IIIa inhibitor; or acute pericarditis.

Bleeding is the most common complication encountered during therapy with AGGRASTAT®. Administration of AGGRASTAT® is associated with an increase in bleeding events classified as both major and minor bleeding events, by criteria developed by the Thrombolysis in Myocardial Infarction Study group (TIMI). Most major bleeding associated with AGGRASTAT® occurs at the arterial access site for cardiac catheterization. Fatal bleedings have been reported. AGGRASTAT® should be used with caution in patients with platelet count <150,000/mm3, in patients with hemorrhagic retinopathy, and in chronic hemodialysis patients. Because AGGRASTAT® inhibits platelet aggregation; caution should be employed when it is used with other drugs that affect hemostasis. The safety of AGGRASTAT® when used in combination with thrombolytic agents has not been established. During therapy with AGGRASTAT®, patients should be monitored for potential bleeding. When bleeding cannot be controlled with pressure, infusion of AGGRASTAT® and heparin should be discontinued.

The following additional adverse reactions have been reported in post– marketing experience: bleeding, intracranial bleeding, retroperitoneal bleeding, hemopericardium, and pulmonary (alveolar) hemorrhage. Fatal bleedings have been reported; body as a whole: acute and/or severe decreases in platelet counts which may be associated with chills, low grade fever, or bleeding complications; hypersensitivity; rash and/or hives.

Please refer to the specific Prescribing Information for your country for complete warnings and precautions.

About Iroko

Iroko is a pharmaceutical company focused on acquiring, developing, and maximizing the potential of currently marketed pharmaceutical products on a worldwide basis. Iroko applies concentrated selling and marketing efforts and product life cycle management strategies focused on developing new and relevant formulations and indications that benefit patient health. For more information, visit www.iroko.com.

About Merck

Merck & Co., Inc. is a global research–driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far–reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not–for–profit service.

References

1 Van´t Hof A, ten Berg J, Heestermans T, Dill T et al. Prehospital initiation of tirofiban in patients with ST–elevation myocardial infarction undergoing primary angioplasty (On–TIME 2): a multicentre, double–blind, randomised controlled trial. Presented at ESC 31 August 2008

2 Montalescot G. Mechanical reperfusion: treat well, treat on time too. The Lancet; 372:509–10

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