Bivalirudin angiomax the gold standard anticoagulant during pci
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Bivalirudin (Angiomax ® ) 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.

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Bivalirudin (Angiomax ® ) The Gold Standard Anticoagulant during PCI?

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Bivalirudin angiomax the gold standard anticoagulant during pci

Bivalirudin (Angiomax®) The Gold Standard Anticoagulant during PCI?

Carrie Oliphant, Pharm.D., BCPS

Cardiology Clinical Specialist

Methodist University Hospital


Pci procedure

PCI procedure

Thrombin Generation

Tissue Factor

Platelet Activation

Adhesion Molecules

Vessel Wall InjuryInflammation


Bivalirudin angiomax the gold standard anticoagulant during pci

Ann Pharmacother 2004;38:99-109.


Role of thrombin

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

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.


Bivalirudin angiomax the gold standard anticoagulant during pci

N Engl J Med 2005;353:1028-40.


Bivalirudin vs other dtis

Bivalirudin vs. other DTIs


Pci studies

PCI studies

  • BAT, BAT reanalysis

  • CACHE

  • REPLACE-1

  • REPLACE-2


Bivalirudin angiomax the gold standard anticoagulant during pci

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.


Bivalirudin angiomax the gold standard anticoagulant during pci

BAT

Major Bleeding

p<0.001

N Engl J Med 1995;333:764-9.


Bat reanalysis

BAT reanalysis

  • Intention to treat analysis

    • n=4312

  • Primary endpoint

    • Death, revasc., MI at 7, 90 and 180 days

Am Heart J 2001;142:952-9.


Bat reanalysis1

BAT reanalysis

  • Major bleeding

    • Bivalirudin 76 (3.5%)

    • UFH 199 (9.3%) p<0.001

Am Heart J 2001;142:952-9


Cachet

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.


Cachet1

CACHET

Am Heart J 2002;143:847-53.


Replace 1

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 11

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.


Bivalirudin angiomax the gold standard anticoagulant during pci

Am J Cardiol 2004;93:1092-1096.


Replace 2 study design

REPLACE-2: Study Design

Bivalirudin 0.75 mg/kg bolus,

1.75 mg/kg infusion with

provisional GP IIb/IIIa

6002

Urgent or elective

PCI

patients

aspirin

clopidogrel

stent

2994

abciximab

or

eptifibatide

UFH

65 units/kg

3008

JAMA 2003; 289: 853-863.


Replace 2

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

Endpoint Definitions

Death

  • Any cause

MI

  • Q wave in2 leads

  • CKMB 3 fold ULN if <48 hr PCI

  • 2 fold ULN if no revasc.

Urgent revasc

  • Precipitated by ischemia

  • Re-intervention within 24 hours

Major bleeding

  • 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

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

10.0%

9.2%

bivalirudin

7.6%

7.1%

7.0%

6.2%

4.1%

2.4%

1.4%

0.4%

0.2%

1.2%

Quadruple

composite

MI

Urgent

revasc

Triple

composite

Death

Protocol

major bleed

Outcomes – 30 days

JAMA 2003; 289: 853-863.


Hemorrhagic end points

D -43%

p < 0.001

  • -47%

  • p < 0.001

  • -33%

  • p = 0.30

  • -55%

  • p < 0.001

  • -63%

  • p < 0.001

  • -59%

  • p < 0.001

heparin + GP IIb/IIIa

Bivalirudin with provisional GP IIb/IIIa

Hemorrhagic End Points

25.8%

Major bleed

Minor bleed

TIMI

major bleed

TIMI

minor bleed

Access

site bleed

Platelets

< 100,000

JAMA 2003; 289: 853-863.


Bleeding vs other clinical trials

Bleeding vs. other clinical trials

UFH + abciximab

N=794

UFH +eptifibatide

N=1040

UFH +GPI

N=3002

Bivalirudin

N=2994

Lancet 1998;352:87-92.; Lancet 2000;356:2037-2044.


6 month ischemic end points

6 month- Ischemic end points

JAMA 2004;292:696-703.


1 year mortality

heparin+GPI

bivalirudin with provisional GPI

1-year Mortality

All patients

2.5%

Cumulative Percentage of Mortality

1.9%

p-value=0.16

Days (time from randomization)

JAMA 2004;292:696-703.


Clopidogrel in replace 2

Clopidogrel in REPLACE-2

  • Pretreatment N=5893

  • No Pretreatment N=841

*

*

*

*

*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

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


Bivalirudin angiomax the gold standard anticoagulant during pci

Meta-analysis

p<0.001

p=0.049

p=0.02

p<0.001

Death, MI, revasc., major bleeding

J Am Coll Cardiol 2005;45 Suppl A:36A.


Economic analysis drug cost

Economic analysis- Drug cost

The Medicines Company- Data on File.


Economic analysis outcomes

Economic Analysis-Outcomes

Average reduction in cost: $405 (95% CI $ 37-773, p<0.001)

J Am Coll Cardiol 2004;44:1792-1800


Drug properties

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

Half life


Inhibition of platelet aggregation

Inhibition of Platelet Aggregation

Pharmacotherapy 2002;22:97S-104S.


Fda approval

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

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

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

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

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

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

Sheath Removal

Am J Cardiol 2004;94:1417-19.


Side effects replace 2

Side Effects- REPLACE-2

Drugs 2005;65:1869-1891.


Place in therapy guidelines

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

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

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 trials1

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


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