About HIT/HITTS

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

Diagnosis and impact: Under-recognized risk⁴

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

Impact of HITTS¹

• Associated with morbidity and mortality
• The risk of thrombosis in HIT patients is 35-75%
• Most common of thrombotic events are venous thromboembolism (DVT and PE).
• Arterial thrombosis most often manifests as an acutely ischemic lower limb due to occlusion of large limb arteries or the distal aorta.
• Thrombosis can lead to amputation and death
  • 20% limb amputation
  • 20-30% death

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 (n=51) (n/N=52) 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
• 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 Design³

• ATBAT was conducted prospectively 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)
• ATBAT Dosing:³
  1. Open-label use of IV ANGIOMAX (bolus followed by infusion – duration of procedure and/or up to 4 hours)
  2. ANGIOMAX was to be given > 5 minutes before the PCI as a 1 mg/kg intravenous bolus and continued as a 2.5 mg/kg/hour infusion for 4 hours (BAT dose group).
  3. In January 2002, the ANGIOMAX dosing was changed to a 0.75 mg/kg bolus and 1.75 mg/kg/hour infusion during PCI and for up to 4 hours after PCI.
  4. If the attending physician determined that the patient required anticoagulant therapy for > 4 hours, then the ANGIOMAX dose was reduced to 0.2 mg/kg/hour for up to 20 hours after PCI.
• The use of concomitant medications was allowed and included clopidogrel, aspirin, ticlopidine, and glycoprotein (GP) IIb/IIIa inhibitors.
  1. 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

Baseline Characteristics³

Clinical Outcomes³

• 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

Data are presented as n/n (%) unless otherwise noted * Not mutually exclusive † Sum of packed red cells and whole blood units ‡ Two patients were enrolled a second time (as per original protocol) For this analysis only their first enrollment information was used.

Procedural Details and Results

* Not mutually exclusive. Data are presented as number (%) or n/n (%). PCI = percutaneous coronary intervention. LAD = left anterior descending artery. RCA = right coronary artery. TIMI = Thrombolysis in Myocardial Infarction.