Safety and Bleeding Rates
Significantly Less Major and Minor Bleeding Consistent Across Angiomax®
(bivalirudin) Trials1-4
Major Bleeding1-5
Minor Bleeding1,3
* IN Randomized Evaluation of PCI Linking ANGIOMAX to Reduced Clinical Events (REPLACE-2):
93% of ANGIOMAX patients received ANGIOMAX monotherapy.1
†IN THE Acute Catheterization and Urgent Intervention Triage StrategY
(ACUITY) ANGIOMAX-ALONE GROUP: 91% of percutaneous coronary intervention (PCI) patients
received ANGIOMAX monotherapy.2
Heparin(s) = unfractionated heparin (UFH) or enoxaparin
‡ ANGIOMAX monotherapy = ANGIOMAX monotherapy with glycoprotein
(GP) IIb/IIIa reserved for severe breakthrough ischemia and procedural complications
during PCI2
¶ In Harmonizing Outcomes with Revascularization and Stents in Acute
Myocardial Infarction Study (HORIZONS AMI): 93% of ANGIOMAX patients received ANGIOMAX
monotherapy.4
§ Important Bleeding Definitions
To learn more about these studies, visit REPLACE-2, ACUITY PCI and
HORIZONS AMI clinical outcomes sections.
Significantly Reduced Bleeding Complications1,3
- With ANGIOMAX, significantly more patients will go home from percutaneous coronary
intervention (PCI) without bleeding complications1
- Sheaths can be removed 2 hours after ANGIOMAX discontinuation in most patients,
reducing access-site complications||7-9
|| Sheath removal has not been studied in dialysis-dependent patients.
Follow standard hospital protocol for this population.
* IN REPLACE-2: 93% of ANGIOMAX patients received ANGIOMAX monotherapy.1
†IN THE ACUITY ANGIOMAX-ALONE GROUP: 91% of PCI patients received
ANGIOMAX monotherapy.2
Important Bleeding Definitions1,2,4,10
Major Bleed
Defined in REPLACE-2 as intracranial, intraocular, retroperitoneal, or bleeding; transfusion
of 2 or more units of blood/blood products; a fall in hemoglobin of >4 g/dL, whether
or not bleeding site was identified; clinically overt blood loss (spontaneous or
nonspontaneous) with a fall in hemoglobin of >3 g/dL.1
Defined in ACUITY as non-coronary artery bypass grafting (non-CABG) intracranial,
retroperitoneal, or intraocular bleeding; access-site hemorrhage requiring intervention;
≥5-cm diameter hematoma; reduction in hemoglobin concentration of ≥4 g/dL
without an overt source of bleeding, reduction in hemoglobin concentration of ≥3
g/dL with an overt source of bleeding, reoperation for bleeding; use of any blood-product
transfusion.2
Thrombolysis in Myocardial Infarction trial (TIMI)-defined as intracranial bleeding
or bleeding associated with a hemoglobin decrease of >5 g/dL (or a hematocrit decrease
of 15%).10
Defined in HORIZONS AMI as non-CABG intracranial, intraocular, or retroperitoneal
bleeding; access-site hemorrhage requiring intervention or resulting in a ≥5
cm diameter hematoma; reduction in hemoglobin concentration of ≥4 g/dL without
or ≥3 g/dL with an overt bleeding source; reoperation for bleeding; or blood
product transfusion.4
Minor Bleed1,2,10
Defined in REPLACE-2 as observed bleeding that did not meet the criteria for a major
bleed.1
Defined in ACUITY as all bleeding other than clinically significant bleeding.2
TIMI-defined as bleeding that was spontaneous and observed as gross hematuria or
hematemesis; or observed blood loss (spontaneous or nonspontaneous) with a decrease
in hemoglobin of >3 g/dL (or a hematocrit decrease
of ≥10%); or a decrease in
hemoglobin of >4 g/dL (or a hematocrit decrease of 12%) with no identifiable bleeding
site.10
Adverse Events
Adverse events observed in clinical trials were similar between patients treated
with ANGIOMAX and the control groups.11 In the REPLACE-2 trial, similar
adverse events were reported with similar frequencies in both treatment groups and
were typical of events seen in most PCI trials. The most frequent treatment-emergent
events for ANGIOMAX with "provisional" GP IIb/IIIa vs heparin plus GP IIb/IIIa were
back pain, angina pectoris, pain, hypotension, and nausea.
REPLACE-2 Treatment-Emergent Adverse Events Other Than Bleeding Occurring in ≥2%
of Patients in Either Treatment Group (Safety Population)
|
Event
|
ANGIOMAX with
Provisional GPI
n=2914
n(%)
|
Heparin + GPI
n=2987
n(%)
|
|
Cardiovascular
|
|
|
|
Hypotension
|
91 (3.1)
|
120 (4.0)
|
|
Angina Pectoris
|
155 (5.3)
|
156 (5.2)
|
|
Gastrointestinal
|
|
|
|
Nausea
|
86 (3.0)
|
96 (3.2)
|
|
Miscellaneous |
|
|
|
Back pain
|
268 (9.2)
|
263 (8.8)
|
|
Pain |
98 (3.4)
|
72 (2.4)
|
|
Chest Pain
|
68 (2.3)
|
69 (2.3)
|
|
Headache |
75 (2.6)
|
83 (2.8)
|
|
Injection site pain
|
80 (2.7)
|
80 (2.7)
|
In the Bivalirudin and Angioplasty Trial (BAT), 82% of patients (n=2161) treated
with ANGIOMAX and 83% of heparin-treated patients (n=2161) experienced at least
one treatment-emergent adverse event. The most frequent treatment-emergent events
for ANGIOMAX vs heparin were back pain, pain, nausea, headache, and hypotension.11
BAT Adverse Events Occurring in ≥5% of Patients in Either Treatment Group
|
Event
|
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%)
|
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.
1Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional
glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa
blockade during percutaneous coronary intervention: REPLACE-2 randomized trial.
JAMA. 2003;289:853-863.
2Stone GW, McLaurin BT, Cox DA, et al; for the ACUITY Investigators.
Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-2216.
3Stone GW, White HD, Ohman EM, et al; for the Acute Catheterization and
Urgent Intervention Triage strategy (ACUITY) trial investigators. Bivalirudin in
patients with acute coronary syndromes undergoing percutaneous coronary intervention.
Lancet. 2007;369:907-919.
4Stone GW, Witzenbichler B, Guagliumi G, et al; for the HORIZONS AMI
trial investigators. Bivalirudin during primary PCI in acute myocardial infarction.
N Engl J Med. 2008;358:2218-2230.
5Supplement to: Stone GW, McLaurin BT, Cox DA, et al; for the ACUITY
Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med.
2006;355:2203-2216. Available at:http://content.nejm.org. Accessed December 6, 2006.
6Watson K, Seybert AL, Saul MI, et al. Comparison of patient outcomes
with bivalirudin versus unfractionated heparin in percutaneous coronary intervention.
Pharmacotherapy. 2007;27:647-656.
7Mehta S, Yebara SM, Ibrahim M, Reyes M, Galli A. Cedars Medical Center’s
experience: early ambulation post PCI with use of direct thrombin inhibitor, bivalirudin.
Cath Lab Digest. 2004;12:1-4.
8Minutello RM, Wong SC, Chou ET, et al. Angiomax facilitates early sheath
removal after coronary angioplasty: the AFRICA Study. (abstract 340). Presented
at: 15th Transcatheter Cardiovascular Therapeutics Meeting; Washington, DC, 2003.
9Schussler JM, Cameron CS, Anwar A, et al. Effect of bivalirudin on length
of stay in the recovery area after percutaneous coronary intervention compared with
heparin alone, heparin + abciximab, or heparin + eptifibatide. Am J Cardiol.
2004;94:1417-1419.
10Rao AK, Pratt C, Berke A, et al; for the TIMI Investigators. Thrombolysis
in myocardial infarction (TIMI) trial—phase I: hemorrhagic manifestations and changes
in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant
tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1-11.
11ANGIOMAX Prescribing Information. The Medicines Company; Parsippany,
NJ, December 6, 2005.