Bivalirudin Angiomax The Gold Standard Anticoagulant during PCI

1
Bivalirudin (Angiomax) The Gold Standard
Anticoagulant during PCI?

• Carrie Oliphant, Pharm.D., BCPS
• Cardiology Clinical Specialist
• Methodist University Hospital

2
PCI procedure
Thrombin Generation
Tissue Factor
Platelet Activation
Adhesion Molecules
Vessel Wall InjuryInflammation
3
Ann Pharmacother 20043899-109.
4
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 2005149S43-53.
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Heparin Limitations

• Indirect inhibition of thrombin
• Cannot inhibit fibrin-bound thrombin
• Nonlinear pharmacokinetics, dose response
  variability
• Causes platelet activation
• Inhibition by PF4
• HeparinPF4 complex formation

Am Heart J 2005149S43-53.
6
N Engl J Med 20053531028-40.
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Bivalirudin vs. other DTIs
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PCI studies

• BAT, BAT reanalysis
• CACHE
• REPLACE-1
• REPLACE-2

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BAT

• Unstable angina or postinfarction angina
• n4098 (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 lt 350 Additional 60 units/kg bolus

N Engl J Med 1995333764-9.
10
BAT
Major Bleeding
plt0.001
N Engl J Med 1995333764-9.
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BAT reanalysis

• Intention to treat analysis
• n4312
• Primary endpoint
• Death, revasc., MI at 7, 90 and 180 days

Am Heart J 2001142952-9.
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BAT reanalysis

• Major bleeding
• Bivalirudin 76 (3.5)
• UFH 199 (9.3) plt0.001

Am Heart J 2001142952-9
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CACHET

• Elective angioplasty or stenting
• n268

• 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
  gt 200 sec
• ASA for all patients.
• Clopidogrel x 30 days (load?)

Am Heart J 2002143847-53.
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CACHET
Am Heart J 2002143847-53.
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REPLACE-1

• Elective or urgent PCI
• n1056
• 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 2004931092-1096.
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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 2004931092-1096.
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Am J Cardiol 2004931092-1096.
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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.
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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 2003289853-863.
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Endpoint Definitions
Death

• Any cause

MI

• Q wave in ?2 leads
• CKMB ?3 fold ULN if lt48 hr PCI
• ?2 fold ULN if no revasc.

2º
1º
Urgent revasc

• Precipitated by ischemia
• Re-intervention within 24 hours

Major bleeding

• Intracranial or retroperitoneal
• Observed bleed with fall in Hgb gt3g/dL
• No observed bleed with fall in Hgb gt4g/dL
• Transfusion ?2 units PRBC or whole blood

JAMA 2003 289 853-863.
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Antiplatelet therapy
JAMA 2003289853-863.
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Outcomes 30 days
JAMA 2003 289 853-863.
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Hemorrhagic End Points
25.8
Major bleed
Minor bleed
TIMI major bleed
TIMI minor bleed
Access site bleed
Platelets lt 100,000
JAMA 2003 289 853-863.
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Bleeding vs. other clinical trials
UFH abciximab N794
UFH eptifibatide N1040
UFH GPI N3002
Bivalirudin N2994
Lancet 199835287-92. Lancet 20003562037-2044.
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6 month- Ischemic end points
JAMA 2004292696-703.
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1-year Mortality
All patients
2.5
Cumulative Percentage of Mortality
1.9
p-value0.16
Days (time from randomization)

JAMA 2004292696-703.
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Clopidogrel in REPLACE-2

• Pretreatment N5893
• No Pretreatment N841

p0.007 Bivalirudin pretreatment vs. no
pretreatment plt0.001 for Bivalirudin vs. UFH
J Am Coll Cardiol 2004441194-9.
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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 gt5-10x

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Meta-analysis
plt0.001
p0.049
p0.02
plt0.001
Death, MI, revasc., major bleeding
J Am Coll Cardiol 200545 Suppl A36A.
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Economic analysis- Drug cost
The Medicines Company- Data on File.
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Economic Analysis-Outcomes
Average reduction in cost 405 (95 CI 37-773,
plt0.001)
J Am Coll Cardiol 2004441792-1800
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Drug Properties

• Synthetic compound based on the structure of
  hirudin
• Onset of action 2 minutes
• Predictable response
• Clearance
• Proteolytic cleavage and renal elimination (lt
  20)
• No antidote for rapid reversal

Drugs 200565(13) 1869-1891.
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Half life
34
Inhibition of Platelet Aggregation
Pharmacotherapy 20022297S-104S.
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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
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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

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Conversion from Heparin/LMWH to Bivalirudin

• UFH
• Wait 30 minutes after discontinuation
• LMWH
• Wait 8 hours after last LMWH dose

Pharmacotherapy 200222105S-111S.
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Dosing

• Bolus 0.75 mg/kg
• Five minutes after bolus given, measure ACT
• If ACTlt225, 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
39
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
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ACT monitoring
REPLACE-2 Bivalirudin Median ACT358 UFH
Median ACT317
Pharmacotherapy 200222(8)1007-1018. JAMA
2003289853-863.
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Sheath Removal
Am J Cardiol 2004941417-19.
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Side Effects- REPLACE-2
Drugs 2005651869-1891.
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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 200526804-47.
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Methodist University

• 100 PCI procedures/month
• July 2005-January 2006
• Bivalirudin used in 532 cases
• 90 of PCI cases
• Bivalirudin GPI 8.1

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Ongoing Clinical Trials

• ACUITY (n13,800)- 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 (n300)
• Bivalirudin during primary PCI for STEMI
• ISAR-REACT 3 (n3000)
• Bivalirudin Clopidogrel 600 mg vs. UFH
  Clopidogrel 600 mg in PCI

www.clinicaltrials.gov
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Ongoing Clinical Trials

• EVOLUTION (n300)
• Bivalirudin vs. UFH protamine during CABG.
• CHOOSE (n100)
• Bivalirudin vs. UFH protamine during CABG in
  patients with HIT.

www.clinicaltrials.gov