GP IIbIIIa Inhibitors in LowRisk Percutaneous Intervention: Is There a Need for AntiThrombin Therapy

1
GP IIb-IIIa Inhibitors in Low-Risk Percutaneous
Intervention Is There a Need for Anti-Thrombin
Therapy?Scott J. Denardo, M.D.1 no
conflictsKeith E. Davis, M.D.1 no
conflictsJames E. Tcheng, M.D.2 conflict of
interestMillennium, Schering-Plough1FirstHealt
h of Carolinas/Moore Regional Hospital,Pinehurst,
North Carolina 2Duke University Medical Center,
Durham, North Carolina
2
Introduction

• The purpose of adjunctive pharmacotherapy during
  percutaneous coronary intervention (PCI) is to
  prevent thrombosis-mediated ischemic
  complications.
• Adjunctive pharmacotherapy during PCI has
  historically consisted of anti-thrombin therapy
  using unfractionated heparin, and anti-platelet
  therapy using a variety of anti-platelet agents.

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Thrombosis Platelets and the Coagulation System
Intrinsic System
Extrinsic System
XII
Injury
XIIa
Surface contact
XI
IX
Tissue Thromboplastin VII
XIa
IXa VIII Ca
Platelet membrane
X
Xa V Ca
Platelet membrane
Prothrombinase complex
Fibrinogen
Prothrombin
Thrombin
Stabili- zation
Fibrin
XIIIa
Stein et al. J Am Coll Cardiol. 198914813836.
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Introduction

• Potential problems of using unfractionated
  heparin during PCI
• effectiveness never definitively proven...
• activate platelets
• induce other pro-thrombotic activities
• increase bleeding complications
• cause thrombocytopenia
• never approved by FDA in PCI indication .

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Introduction

• Efficacy and safety of minimal dose (lt1,000
  Units) unfractionated heparin with abciximab in
  PCI
• 500 consecutive patients undergoing emergent,
  urgent or elective PCI involving stent deployment
  or high speed rotational atherectomy
  (03/97-09/99)
• Adjunctive pharmacotherapy aspirin
  clopidogrel or ticlopidine
• Primary success 99.8
• 24 hr MACE 0
• Non-Q wave MI 1.6
• Bleeding complications major, 0.2 minor,
  3.6
• Thrombocytopenia 2.2
• 30 day MACE 0.2

Denardo et al. Am J Cardiol. 2003911-5
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Hypothesis

• In elective, low-risk PCI, adjunctive
  pharmacotherapy confined to an anti-platelet
  regimen composed of aspirin, clopidogrel and
  eptifibatide, without unfractionated heparin or
  other anti-thrombin agent, would be efficacious
  and safe.

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Methods

• Study design prospective, observational,
  single-center registry (05/00 - 12/02)
• Study population 350 consecutive outpatient PCI
  cases
• PCI stent deployment cutting balloon
  atherotomy conventional balloon angioplasty
  high speed rotational atherectomy
• Adjunctive pharmacotherapy
• aspirin (325 mg po QAM) started ? 4 days pre-PCI
• clopidogrel (75 mg po QAM) started ? 4 days
  pre-PCI
• eptifibatide (double bolus of 180 µg/kg,
  continuous infusion of 2.0 µg/kg/min for 24 hrs)
  started immediately pre-PCI
• no unfractionated heparin nor other anti-thrombin
  agent

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Methods

• Study end-points
• MACE death, Q wave myocardial infarction, or
  target vessel revascularization
• Non-Q wave myocardial infarction
• Myocardial infarction determined based on
  serial EKGs and serum CK/MB pre-, post- and
  16-24hrs after PCI defined as any elevation of
  CK and CK-MB above normal range
• Bleeding complications major and minor (TIMI
  criteria), thrombocytopenia
• Timing of assessments
• MACE, non-Q wave myocardial infarction 24hrs,
  30days
• Bleeding complications, thrombocytopenia 3,
  24hrs

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Results Baseline demographic, clinical and
procedural characteristics of 350 study patients

• Age 63.8 yrs (? 9.4) Specific PCI
• Male sex 216 (61.7) Stent deployment 178
  (50.9)
• Risk factors Cutting balloon 73 (20.9)
• HTN 313 (89.4) Conventional balloon 61 (17.4)
• DM 109 (31.1) Rotational atherectomy 38
  (10.9)
• ?Lipids 275 (78.6) Native coronary artery 338
  (96.6)
• Cigarette smoker 221 (63.1) De novo lesion 289
  (82.6)
• Indication Multivessel 44 (12.6)
• Accelerating angina 266 (76.0) Stenosis
  severity 81.1 (? 9.5)
• Progressive SOB 84 (24.0) LVEF 54.6 (? 7.9)

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Results Primary success and ischemic
complications (24 hr)

• Outcome Number () Max CK/MB
• Primary success 350 (100.0)
• Ischemic complication 6 (1.7)
• Death 0
• Q wave MI 0
• Non-Q wave MI 6 (1.7) 421/38.0
• Stent deployment (N178) 3 (2.4) 421/38.0
• Cutting balloon (N73) 1 (1.4) 469/12.2
• Conventional balloon (N61) 1 (1.6) 261/9.6
• Rotational atherectomy (N38) 0 -/-
• Coronary artery bypass grafting 0

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Results Angiographic complications and
subsequent non-Q wave myocardial infarction

• Complication Number () non-Q wave MI ()
• Thrombus (significant) 5 (1.4) 2 (40)
• Thrombus (limited) 3 (0.9) 0
• Loss of side branch 11 (3.1) 2 (18)
• (?0.5mm)
• Loss of side branch 12 (3.4) 0
• (?0.5mm)
• No-reflow 2 (0.6) 0
• p?0.001 vs. pts. without significant thrombus
• p0.090 vs. pts. without loss of side branch
  ?0.5mm

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Results Bleeding complications and
thrombocytopenia (24 hr)

• Outcome Number ()
• Bleeding complications 1 (0.3)
• TIMI Major 0
• TIMI Minor 1 (0.3)
• Transfusion PRBC 0
• Pseudoaneurysm 1 (0.3)
• Thrombocytopenia (lt100K) 2 (0.6)
• Profound (lt20K) 0

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Results Major Adverse Clinical Events (30
days)
Outcome Number () MACE 1 (0.4) Death 1
(0.4) MI (Q wave) 0 (0.0) Revascularization 0
(0.0)
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Acute and 30 Day Results Current Study and
Representative Clinical Trials

• Outcome Trial Percent
• 24hr MACE current study 0
• REPLACE-2 -
• TARGET (non-ACS) 0.7
• ESPRIT 3.9
• 24hr major bleeding current study 0
• REPLACE-2 0.6
• TARGET (non-ACS) 0.8
• ESPRIT 0.7
• 30day MACE current study 0.3
• REPLACE-2 3.2
• TARGET (non-ACS) 6.1
• ESPRIT 6.8
• includes non Q-wave MI with CK-MB gt 10 x control

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Conclusions

• In elective, low-risk PCI, adjunctive
  pharmacotherapy confined to the anti-platelet
  regimen composed of aspirin, clopidogrel and
  eptifibatide, without unfractionated heparin or
  other anti-thrombin agents, appears efficacious
  and safe.
• If results of this pilot study are confirmed by a
  large, randomized clinical trial, then a change
  in pharmacotherapy during elective, low-risk PCI
  may occur that involves an exclusion of
  anti-thrombin therapy.