ABOUT HIT/HITTS

Heparin-induced thrombocytopenia (HIT) is an immune-mediated clinicopathological syndrome initiated by heparin therapy and associated with thrombocytopenia and the presence of antiplatelet factor 4/heparin antibodies.¹

Heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) is an immune-mediated clinicopathological syndrome initiated by heparin therapy and associated with thrombocytopenia plus venous or arterial thrombosis.¹

Patients with or at risk for HIT/HITTS undergoing PCI pose a challenge since use of heparin should be avoided. In in vitro studies, Angiomax® (bivalirudin) exhibited no cross-reactivity with heparin-induced antibodies in patients with a history of HIT/HITTS.²

ATBAT: The Anticoagulant Therapy With Bivalirudin to Assist in the Performance of Percutaneous Coronary Intervention in Patients With Heparin-Induced Thrombocytopenia (ATBAT) Study³

ANGIOMAX in HIT/HITTS patients

• Summary
• ATBAT: Trial Design
• Clinical End Points

Summary

• Ninety-eight percent of the heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) patients undergoing percutaneous coronary intervention (PCI) with ANGIOMAX had a successful procedure
• The patient population had a number of risk factors for increased risk of ischemic and bleeding complications, including a higher proportion of women than expected (50%), a majority of patients with prior myocardial infarction (MI) (70%), and 21% reported a history of HIT/HITTS
• Major bleeding occurred in 1 patient (1.9%; 95% CI, 0.04% to 10.65%) in the high-dose group, who underwent elective bypass surgery. Only 1 unit of packed red blood cells was given
• These data, in concert with the extensive experience with ANGIOMAX in PCI, led to the FDA approval for an indication for ANGIOMAX in patients with or at risk for HIT/HITTS undergoing PCI
• This study provides further evidence that ANGIOMAX overcomes the limitations of heparin in PCI, and demonstrates safe and effective management of high-risk patients—those with HIT/HITTS undergoing PCI

ATBAT: Trial Design

• ATBAT was a prospective, multicenter, open-label, single-arm study to evaluate the safety and efficacy of ANGIOMAX in patients undergoing PCI with newly diagnosed or previous HIT or HIT/HITTS. The study was conducted from July 1999 to February 2003; a total of 52 patients were recruited
• The protocol defined HIT as:
  1. A positive heparin-induced platelet aggregation or other functional assay for HIT or immunoassay for HIT antibodies. Or,
  2. As thrombocytopenia associated with heparin therapy in which the platelet count had decreased to <100x10⁹/L (decrease of >30% from the pretreatment platelet count) or to <150x10⁹/L (decrease of >40% from the pretreatment platelet count)
• The first half of the study (25 patients) used the BAT dose of 1.0 mg/kg bolus with 2.5 mg/kg/h infusion for up to 4 hours; after CACHET and REPLACE-1 were completed, the rest of the study (27 patients) was done at the REPLACE-2 dose of 0.75 mg/kg bolus followed by infusion of 1.75 mg/kg/h for the duration of the procedure or up to 4 hours postprocedure. If anticoagulation therapy was required for less than 4 hours, the ANGIOMAX dose was reduced to 0.2 mg/kg/h for up to 20 hours after PCI
• The use of concomitant medications was at the discretion of the physician, including clopidogrel, aspirin, ticlopidine, and glycoprotein (GP) IIb/IIIa inhibitors. Ten patients had concomitant GP IIb/IIIa therapy. Aspirin and clopidogrel were given to 98% and 86% of patients, respectively.

Clinical End Points

• Primary end point was the incidence of major bleeding within 48 hours of study-drug administration or until hospital discharge, whichever occurred first
• Secondary end points included event rates for components of the primary end point and the activated clotting time (ACT), activated partial thromboplastin time (aPTT), and platelet counts at baseline, pre-PCI, post-PCI, and pre-discharge

Outcomes

• No major bleeding was observed in any patients undergoing PCI. Major bleeding occurred in 1 patient (1.9%; 95% CI, 0.04% to 10.65%) in the high-dose group, who underwent elective bypass surgery. Only 1 unit of packed red blood cells was given. No bleeding source was identified, and the bleeding was defined by a drop in hemoglobin/hematocrit without hemodynamic compromise.* There were no reports of intracranial bleeding, retroperitoneal bleeding or transfusions

  *Major bleeding was defined as intracranial or retroperitoneal bleeding; bleeding resulting in hemodynamic compromise; bleeding with transfusion of >3 units of blood; or a decrease in hemoglobin of >3 g/dL or in hematocrit of >9%.

• No significant thrombocytopenia was observed and no patient had a platelet count <50 x 10⁹/L after treatment with study drug. However, after receiving ANGIOMAX and GP IIb/IIIa inhibitor, 2 patients with a diagnosis of HIT/HITTS developed moderate thrombocytopenia
• Procedural success was achieved in 98% of patients^† and clinical success in 96% of patients

  ^†Procedural success was defined as Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow after PCI and a final lesion stenosis <50%. Clinical success was defined as procedural success without death, emergency bypass surgery, or Q-wave MI as reported by investigators.

• Major cardiac events were rare. One patient in the low-dose ANGIOMAX group died ~46 hours after a clinically uncomplicated PCI from asystolic cardiac arrest without evidence of recurrent ischemia, infarction, or congestive heart failure. No patient suffered acute MI, transient ischemic attack, or stroke

ATBAT Bleeding Events

Procedural Details and Results

Safety Considerations

ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components. The most common (10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration. Please see complete prescribing information.