Bleeding:

In 6010 patients undergoing PCI treated in the REPLACE-2 trial, Angiomax patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 4.

Table 4. Major Hematologic Outcomes REPLACE-2 Study (Safety Population)

¹ GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group.

²Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of †2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/dL.

³ Defined as observed bleeding that does not meet the criteria for major hemorrhage.

⁴ TIMI major bleeding is defined as: intracranial, or a fall in adjusted Hgb >5 g/dL or Hct of >15%; TIMI minor bleeding is defined as a fall in adjusted Hgb of 3 to <5 g/dL or a fall in adjusted Hct of 9 to <15%, with a bleeding site such as hematuria, hematemesis, hematomas, retroperitoneal bleeding or a decrease in Hgb of >4 g/dL with no bleeding site.

⁵ If <100,000 and >25% reduction from baseline, or <50,000.

In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax to heparin, Angiomax patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 5. The incidence of major bleeding was lower in the Angiomax group than in the heparin group.

Table 5. Major Bleeding and Transfusions in BAT Trial: All Patients¹

¹ No monitoring of ACT (or PTT) was done after a target ACT was achieved.

²Major hemorrhage was defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin †3 g/dL or leading to a transfusion of †2 units of blood. This table includes data from the entire hospitalization period.

In the AT-BAT study, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography, 9 patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed moderate thrombocytopenia.

Other Adverse Events:

Adverse events observed in clinical trials are similar between the Angiomax-treated patients and the control groups. Adverse events seen are those typical of PCI trials, see Tables 6 and 7.

Table 6. Adverse Events Other Than Bleeding Occurring In † 5% Of Patients In Either Treatment Group In BAT Trial

Serious, non-bleeding adverse events were experienced in 2% of 2161 Angiomax-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between Angiomax- and heparin-treated patients. These events are listed by body system: Body as a Whole: fever, infection, sepsis; Cardiovascular: hypotension, syncope, vascular anomaly, ventricular fibrillation; Nervous: cerebral ischemia, confusion, facial paralysis; Respiratory: lung edema; Urogenital: kidney failure, oliguria.

In the double-blind, randomized REPLACE-2 trial comparing Angiomax with provisional GPI to Heparin plus GPI described above similar adverse events were reported in both treatment groups:

Table 7. Adverse Events Other Than Bleeding Occurring in †2% of Patients in Either Treatment Group in REPLACE-2

In the AT-BAT study, 1patient died during a bradycardic episode 46 hours after a successful PCI, another patient required surgical revascularization, and 1 patient experienced no reflow requiring a temporary intra-aortic balloon. Two of the fifty-one patients with a diagnosis of HIT/HITTS developed thrombocytopenia after receiving bivalirudin and GPIs.

Post-marketing Events:

The following events have been reported: fatal bleeding; hypersensitivity and allergic reactions including very rare reports of anaphylaxis; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.

Angiomax does not exhibit binding to plasma proteins (other than thrombin) or red blood cells.

In clinical trials in patients undergoing PTCA/PCI, co-administration of Angiomax with heparin, warfarin, thrombolytics or glycoprotein IIb/IIIa inhibitors was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications. There is no experience with co-administration of Angiomax and plasma expanders such as dextran. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.

Immunogenicity/Re-exposure:

In in vitro studies, Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.

Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.

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