Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 2.
Table 2: Major Hematologic Outcomes REPLACE-2 Study (Safety Population)
| Angiomax with “provisional” GPI1 ( n=2914) |
HEPARIN + GPI (n=2987) |
p-value | |
| Protocol defined major hemorrhage2 (%) | 2.30% | 4.00% | < 0.001 |
| Protocol defined minor hemorrhage3 (%) | 13.60% | 25.80% | < 0.001 |
| TIMI defined bleeding4 | |||
| -Major | 0.60% | 0.90% | 0.259 |
| -Minor | 1.30% | 2.9 | < 0.001 |
| Non-access site bleeding | |||
| -Retroperitoneal bleeding | 0.20% | 0.50% | 0.069 |
| -Intracranial bleeding | < 0.1% | 0.10% | 1 |
| Access site bleeding | |||
| -Sheath site bleeding | 0.90% | 2.40% | < 0.001 |
| Thrombocytopenia5 | |||
| <100,000 | 0.70% | 1.70% | < 0.001 |
| <50,000 | 0.30% | 0.60% | 0.039 |
| Transfusions | |||
| -RBC | 1.30% | 1.90% | 0.08 |
| -Platelets | 0.30% | 0.60% | 0.095 |
| 1GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group 2Defined as the occurence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥ 2 units of blood/blood products, a fall in hemoglobin > 4g/dL, whether of not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin > 3g/Dl 3Defined as observed bleeding that does not meet the criteria for major hemorrhage 4TIMI major bleeding is defined as intracranial, or a fall in adjusted Hgb > 5g/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 5If < 100,000 and > 25% reduction from baseline, or < 50,000 |
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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 3. The incidence of major bleeding was lower in the Angiomax group than in the heparin group.
Table 3: Major Bleeding and Transfusions in BAT Trial (all patients) 1
| Angiomax N=2161 |
Heparin N=2151 |
|
| No. (%) Patients with Major hemorrhage2 | 79 (3.7) | 199 (9.3) |
| -with ≥ 3 g/dL fall in Hgb | 41 (1.9) | 124 (5.8) |
| -with ≥ 5 g/dL fall in Hgb | 14 (0.6) | 47 (2.2) |
| -retroperitoneal bleeding | 5 (0.2) | 15 (0.7) |
| -intracranial bleeding | 1 ( < 0.1) | 2 (0.1) |
| Required transfusions | 43 (2.0) | 123 (5.7) |
| 1No monitoring of ACT (or PTT) was done after a target ACT was achieved. 2Major hemorrhage was defined as the occurence 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. |
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In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.
Other Adverse Reactions
Adverse reactions, other than bleeding, observed in clinical trials were similar between the Angiomax treated patients and the control groups.
Adverse reactions (related adverse events ) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.
Table 4 : Most frequent ( ≥ 0.2%) treatment-related adverse events (reactions) (through 30 days) in the REPLACE-2 Safety population
| Angiomax with “provisional” GPI1 (N = 2914) |
Heparin+GPI (N = 2987) |
|||
| n | (%) | n | (%) | |
| Patients with at least one treatment-related AE | 78 | (2.7) | 115 | (3.9) |
| Thrombocytopenia | 9 | (0.3) | 30 | (1) |
| Nausea | 15 | (0.5) | 7 | (0.2) |
| Hypotension | 7 | (0.2) | 11 | (0.4) |
| Angina pectoris | 5 | (0.2) | 12 | (0.4) |
| Headache | 6 | (0.2) | 5 | (0.2) |
| Injection site pain | 3 | (0.1) | 8 | (0.3) |
| Nausea and vomiting | 2 | (0.1) | 6 | (0.2) |
| Vomiting | 3 | (0.1) | 5 | (0.2) |
| Note: A patient could have more than one event in any category. Abbreviation: AE = adverse event. | ||||
Table 5: Adverse Events Other Than Bleeding Occurring In ≥ 5% Of Patients In Either Treatment Group In BAT Trial
| EVENT | Treatment Group | |
| ANGIOMAX N=2161 |
HEPARIN N=2151 |
|
| Number of Patients (%) | ||
| CARDIOVASCULAR | ||
| Hypotension | 262 (12) | 371 (17) |
| Hypertension | 135 (6) | 115 (5) |
| Bradycardia | 118 (5) | 164 (8) |
| GASTROINTESTINAL | ||
| Nausea | 318 (15) | 347 (16) |
| Vomiting | 138 (6) | 169 (8) |
| Dyspepsia | 100 (5) | 111 (5) |
| GENITOURINARY | ||
| Urinary retention | 89 (4) | 98 (5) |
| MISCELLANEOUS | ||
| Back pain | 916 (42) | 944 (44) |
| Pain | 330 (15) | 358 (17) |
| Headache | 264 (12) | 225 (10) |
| Injection site pain | 174 (8) | 274 (13) |
| Insomnia | 142 (7) | 139 (6) |
| Pelvic pain | 130 (6) | 169 (8) |
| Anxiety | 127 (6) | 140 (7) |
| Abdominal pain | 103 (5) | 104 (5) |
| Fever | 103 (5) | 108 (5) |
| Nervousness | 102 (5) | 87 (4) |
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 BAT trial, there was no causality assessment for adverse events.
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.
Postmarketing Experience
Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postapproval use of Angiomax: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.