®
(Angiomax )
Bivalirudin
The Gold Standard
Anticoagulant during PCI?
Carrie Oliphant, Pharm.D., BCPS
Cardiology Clinical Specialist
Methodist University Hospital
PCI procedure
Thrombin Generation
Tissue Factor
Platelet Activation
Adhesion Molecules
Vessel Wall Injury
Inflammation
Ann Pharmacother 2004;38:99-109.
Role of Thrombin
• Conversion of fibrinogen to fibrin
– Fibrin strands trap platelets and RBCs
• Factor XIII activation
– Stabilizes fibrin clot by cross linking strands
• Activates Factor VIII and V
– Enhance production of thrombin
• Platelet activation
– Secretes tissue factors, expression of GP IIb/IIIa
receptors
Am Heart J 2005;149:S43-53.
Heparin Limitations
• Indirect inhibition of thrombin
– Cannot inhibit fibrin-bound thrombin
• Nonlinear pharmacokinetics, dose response
variability
• Causes platelet activation
• Inhibition by PF4
• Heparin:PF4 complex formation
Am Heart J 2005;149:S43-53.
N Engl J Med 2005;353:1028-40.
Bivalirudin vs. other DTIs
Drug
Bivalirudin
Lepirudin
(Refludan,
Hirudin)
Argatroban
Binding
site
Exosite-1;
active
Exosite-1;
active
Active
Type of
binding
Reversable
Irreversable
Reversable
PCI studies
•
•
•
•
BAT, BAT reanalysis
CACHE
REPLACE-1
REPLACE-2
BAT
• Unstable angina or postinfarction angina
• n=4098 (excluded 214 enrolled patients)
• Protocol (All patients: ASA 300-325 mg)
– Bivalirudin 1 mg/kg bolus, 2.5 mg/kg/hr
infusion x 4 hours, 0.2 mg/kg/hr infusion x 20
hours
– UFH 175 units/kg bolus, 15 units/kg/hr infusion
x 18-24 hours
• ACT < 350: Additional 60 units/kg bolus
N Engl J Med 1995;333:764-9.
BAT
Major Bleeding
12
9.8
10
8
Bivalirudin
UFH
6
4
3.8
2
0
p<0.001
N Engl J Med 1995;333:764-9.
BAT reanalysis
• Intention to treat analysis
– n=4312
• Primary endpoint
– Death, revasc., MI at 7, 90 and 180 days
Bivalirudin
7 days
135 (6.2%)
90 days 340 (15.7%)
180 days 496 (23%)
Heparin
169 (7.9%)
399 (18.5%)
532 (24.7%)
p value
0.039
0.012
0.153
Am Heart J 2001;142:952-9.
BAT reanalysis
• Major bleeding
– Bivalirudin 76 (3.5%)
– UFH 199 (9.3%)
p<0.001
Am Heart J 2001;142:952-9
CACHET
• Elective angioplasty or stenting
• n=268
•Abciximab 0.25 mg/kg bolus,
0.125 mcg/kg/min infusion x
12 hours.
•UFH 70 U/kg bolus,
additional boluses PRN for
ACT > 200 sec
•ASA for all patients.
•Clopidogrel x 30 days (load?)
Am Heart J 2002;143:847-53.
CACHET
Am Heart J 2002;143:847-53.
REPLACE-1
• Elective or urgent PCI
• n=1056
• Protocol (All patients: ASA, Clopidogrel)
– Bivalirudin 0.75 mg/kg bolus, 1.75 mg/kg/hr
infusion for the duration of the procedure
– UFH 60-70 units/kg bolus, adjusted to ACT of
200-300 sec
– GP IIb/IIIa inhibitors at recommended doses
• Use at the discretion of the MD
Am J Cardiol 2004;93:1092-1096.
REPLACE-1
• GPI use
– UFH 72.5% vs. Bivalirudin 71.1%
• 34% Abciximab, 30% Eptifibatide, 6% Tirofiban
• Clopidogrel use prior to procedure
– UFH 57.4% vs. Bivalirudin 54.7%
• 29% 2-48 hours before procedure
• Primary endpoint
– Composite of death, MI or repeat revasc. by
discharge or within 48 hours of randomization
Am J Cardiol 2004;93:1092-1096.
Am J Cardiol 2004;93:1092-1096.
REPLACE-2: Study Design
6002
Urgent
or
elective
PCI
patients
2994
aspirin
clopidogrel
stent
3008
Bivalirudin 0.75 mg/kg bolus,
1.75 mg/kg infusion with
provisional GP IIb/IIIa
UFH
65 units/kg
abciximab
or
eptifibatide
JAMA 2003; 289: 853-863.
REPLACE-2
• Low risk PCI patients
– Excluded primary PCI patients
• Suggested indications for provisional GPI:
– Abrupt or side branch closure, obstructive
dissection, new or suspected thrombus,
impaired or slow coronary flow, distal
embolization, persistent residual stenosis,
unplanned stent placement, prolonged ischemia,
or other clinical instability.
JAMA 2003;289:853-863.
Endpoint Definitions
Death
2º
1º
• Any cause
• Q wave in 2 leads
• CKMB 3 fold ULN if <48 hr PCI
2 fold ULN if no revasc.
MI
Urgent
revasc
Major
bleeding
• Precipitated by ischemia
• Re-intervention within 24 hours
•
•
•
•
Intracranial or retroperitoneal
Observed bleed with fall in Hgb >3g/dL
No observed bleed with fall in Hgb >4g/dL
Transfusion 2 units PRBC or whole blood
JAMA 2003; 289: 853-863.
Antiplatelet therapy
JAMA 2003;289:853-863.
Outcomes – 30 days
p = 0.32
p = 0.40
p = 0.26
p = 0.23
p = 0.44
p < 0.001
heparin + GP IIb/IIIa
bivalirudin
10.0%
9.2%
7.1%
7.6%
7.0%
6.2%
4.1%
2.4%
1.4% 1.2%
0.4% 0.2%
Quadruple Triple
composite composite
Death
MI
Urgent Protocol
revasc major bleed
JAMA 2003; 289: 853-863.
Hemorrhagic End Points
D -43%
p < 0.001
D -47%
p < 0.001
D -33%
p = 0.30
D -55%
p < 0.001
D -63%
p < 0.001
D -59%
p < 0.001
25.7%
25.8%
heparin + GP IIb/IIIa
Bivalirudin with provisional GP IIb/IIIa
4.1%
13.6%
3.0%
2.5%
2.4%
1.7%
1.3%
0.9% 0.6%
Major bleed Minor bleed
TIMI
TIMI
major bleed minor bleed
0.8%
Access
site bleed
0.7%
Platelets
< 100,000
JAMA 2003; 289: 853-863.
Bleeding vs. other clinical trials
5%
4%
TIMI-any
TIMI-minor
TIMI-major
4.3%
4.3%
3.9%
3%
3.0%
3.0%
2.9%
2%
1.9%
1.5%
1%
1.3%
1.3%
0.9%
0.6%
0%
EPISTENT
ESPRIT
REPLACE-2
UFH + abciximab UFH +eptifibatide UFH +GPI
N=794
N=1040
N=3002
REPLACE-2
Bivalirudin
N=2994
Lancet 1998;352:87-92.; Lancet 2000;356:2037-2044.
6 month- Ischemic end points
JAMA 2004;292:696-703.
1-year Mortality
All patients
3.0
heparin+GPI
bivalirudin with provisional GPI
2.5
2.5%
2.0
Cumulative
Percentage 1.5
of Mortality
1.9%
p-value=0.16
1.0
0.5
0.0
0
60
120
180
240
300
360
Days (time from randomization)
JAMA 2004;292:696-703.
Clopidogrel in REPLACE-2
• Pretreatment N=5893
• No Pretreatment N=841
30.00%
* *
Bivalirudin-no
pretreatment
Bivalirudinpretreatment
UFH-no pretreatment
20.00%
*
10.00%
*
UFH- pretreatment
0.00%
Quad
Triple
Major
Minor
endpoint endpoint bleeding bleeding
*p=0.007 Bivalirudin pretreatment vs. no pretreatment;
*p<0.001 for Bivalirudin vs. UFH
J Am Coll Cardiol 2004;44:1194-9.
REPLACE-2 Controversies
• Study design
– Non-inferiority study
– Primary endpoint included efficacy and safety
• Ineffective drugs with better safety profile may appear
better
• Increased ACT values w/UFH (median 317
sec) vs. previous GPI trials (EPISTENT,
ESPRIT)
• Increased non-Q wave MIs, CPK MB >5-10x
Meta-analysis
p<0.001
11%
10%
9%
8%
7%
6%
5%
4%
3%
2%
1%
0%
p=0.049
p=0.02
p<0.001
10.8%
7.8%
Bivalirudin
5.8%
UFH
3.0%
2.7%
2.0%
0.1%
0.2%
Death
Revasc.
Major bleeding Quad endpoint
Death, MI, revasc.,
major bleeding
J Am Coll Cardiol 2005;45 Suppl A:36A.
Economic analysis- Drug cost
Heparin + GPI
Bivalirudin
Cost
n
Total cost n
Total cost
$10 2896
$28,960 0
$0
$395
0
$0 2994 $1,182,630
$1350 1290 $1,741,500 106
$143,100
$600 1606
$963,600 111
$66,600
$2,734,060
$1,392,330
$909
$465
Drug
Heparin
Bivalirudin
Abciximab
Eptifibatide
Total
Average per
patient
Patient savings
> $400
The Medicines Company- Data on File.
Economic Analysis-Outcomes
Average
reduction in
cost: $405
(95% CI $ 37773, p<0.001)
J Am Coll Cardiol 2004;44:1792-1800
Drug Properties
• Synthetic compound based on the structure of
hirudin
• Onset of action: 2 minutes
• Predictable response
• Clearance
– Proteolytic cleavage and renal elimination (< 20%)
• No antidote for rapid reversal
Drugs 2005;65(13): 1869-1891.
Half life
Renal function
(GFR, ml/min)
Mild renal impairment-normal
renal function (> 60 ml/min)
Moderate renal impairment
(30-59 ml/min)
Severe renal impairment
(10-29 ml/min)
Dialysis-dependent patients
Half life
(min)
25
34
57
210
Inhibition of Platelet Aggregation
Pharmacotherapy 2002;22:97S-104S.
FDA approval
• PCI with provisional GPI
– Only studied in patients also receiving aspirin
• Patients with HIT/HITTS or at risk of
HIT/HITTS undergoing PCI
The Medicines Company. Angiomax: prescribing information. www.angiomax.com
Preparation
• 250 mg vial
– Add 5 ml sterile water for
reconstitution
• Add to D5W or 0.9% NS
– Final concentration 5 mg/ml
• Standard 250 mg/50 ml
Conversion from
Heparin/LMWH to Bivalirudin
• UFH
– Wait 30 minutes after discontinuation
• LMWH
– Wait 8 hours after last LMWH dose
Pharmacotherapy 2002;22:105S-111S.
Dosing
• Bolus 0.75 mg/kg
– Five minutes after bolus given, measure ACT
• If ACT<225, give additional 0.3 mg/kg bolus
• Infusion
– Normal to mild renal impairment: 1.75 mg/kg/hr
– Severe renal impairment (GFR 10-29 ml/min):
1 mg/kg/hr
– Dialysis dependent: 0.25 mg/kg/hr
The Medicines Company. Angiomax: prescribing information. www.angiomax.com
Indications for Provisional GPI
•
•
•
•
•
•
•
•
•
Decreased TIMI flow (0-2) or slow reflow
Dissection with decreased flow
New or suspected thrombus
Persistent residual stenosis
Distal embolization
Unplanned stent; suboptimal stenting
Side branch closure; abrupt closure
Clinical instability
Prolonged ischemia
www.angiomax.com
ACT monitoring
REPLACE-2
Bivalirudin
Median ACT:358
UFH
Median ACT:317
Pharmacotherapy 2002;22(8):1007-1018.; JAMA 2003;289:853-863.
Sheath Removal
Am J Cardiol 2004;94:1417-19.
Side Effects- REPLACE-2
Drugs 2005;65:1869-1891.
Place in Therapy- Guidelines
• ACC/AHA
– Class IIa- reasonable alternative to UFH + GPI
in low risk patients.
– Class I- replace UFH in patients with HIT.
• ESC
– Class IIa- replace UFH or LMWHs to reduce
bleeding complications.
– Class I- replace UFH or LMWHs in patients
with HIT.
www.acc.org; Eur Heart J 2005;26:804-47.
Methodist University
• ~ 100 PCI procedures/month
• July 2005-January 2006
– Bivalirudin used in 532 cases
– ~90% of PCI cases
– Bivalirudin + GPI: 8.1%
Ongoing Clinical Trials
• ACUITY (n=13,800)- ACS (NSTEMI)
– Bivalirudin + GPI vs. Bivalirudin + provisional GPI
vs. UFH or LMWH + GPI
– 1° endpoint-death, MI, revasc., major bleeding
– GPI subgroup upstream vs. PCI
• BIAMI (n=300)
– Bivalirudin during primary PCI for STEMI
• ISAR-REACT 3 (n=3000)
– Bivalirudin + Clopidogrel 600 mg vs. UFH +
Clopidogrel 600 mg in PCI
www.clinicaltrials.gov
Ongoing Clinical Trials
• EVOLUTION (n=300)
– Bivalirudin vs. UFH + protamine during
CABG.
• CHOOSE (n=100)
– Bivalirudin vs. UFH + protamine during CABG
in patients with HIT.
www.clinicaltrials.gov