Antithrombin Therapies for Acute Coronary Syndromes

1
Antithrombin Therapies for Acute Coronary
Syndromes

• Advances Advantages

2
PrevalenceCoronary Heart Disease/Angina

• CHD is the leading cause of mortality in American
  adults
• Post-MI 27 men, 44 women die within 1 year
• 84.7 who die of CHD are age 65 or older
• 13.9 million people in the U.S. have a history of
  heart attack, angina, or both
• 7.2 million Americans have angina (2.9 million
  males 4.3 million females)
• 350,000 new angina cases each year prevalence
  higher in women

From American Heart Association, 1998
3
Acute Coronary Syndrome (ACS) Defined

• Unstable angina (UA)
• MI without ST-segment elevation (suspected
  non-Q-wave MI)
• MI with ST-segment elevation
• Presence of cardiac troponin in ACS indicates a
  worse prognosis than absence of troponin

4
Unstable Angina (UA)

• Acute coronary syndrome between stable angina and
  MI
• Rapid increase in coronary stenosis, but
  incomplete occlusion
• Chest pain evident
• At rest
• On effort with change in previous pattern,
  variant
• De novo becoming severe within 1-2 months of
  starting
• Previous stable angina becoming severe
• Not associated with myocardial necrosis, but
  continuing risk of this

5
Thrombotic Process PathophysiologyPlaque
Characteristics Disruption
Thrombus
Lumen
Fibrous Cap
Lipid-Rich Core
Thinning
Fibrous Cap Disruption
6
Thrombotic Process PathophysiologyPlatelet
Activation
TxA2
Thrombin
ADP
Epinephrine
Platelet
Ruptured Plaque
Collagen Tissue Factor

• Alexander JH, Harrington RA, 1997

7
Thrombotic Process PathophysiologyPlatelet
Aggregation
Fibrinogen
VWF
VWF
GP Ib Receptor
GP IIb/IIIa Receptor
Ruptured Plaque

• Alexander JH, Harrington RA, 1997

8
Thrombotic Process PathophysiologyCoagulation
RBC
Activated Platelet
Fibrin
9
Thrombotic Process PathophysiologyThrombin
Factor Xa
Factor VII
Prothrombin

• Promotes
• Tissue factors
• Adhesive molecules
• Smooth muscle
• Leukocyte activation
• Platelet aggregation
• Release reaction

Thrombin (II)
Fibrinogen
Fibrin
10
Antiplatelet AgentsAspirin (ASA)

• Prior to aspirin for unstable angina
• death/MI 16 of patients
• death/MI/refractory angina 35 of patients
• ASA prevents platelet aggregation by blocking
  TxA2
• Introduction of ASA reduced relative risk of
  death/MI by about 35-50

11
Antiplatelet AgentsTiclopidine, Clopidogrel

• Thienopyridines inhibit ADP-dependent
  activation of GP IIb/IIIa complex
• Ticlopidine slow in producing antiplatelet
  activity, limited use
• Clopidogrel more active (than ticlopidine),
  better side effect profile
• Useful in patients hypersensitive to ASA or
  predisposed to GI bleeding

12
Antiplatelet AgentsGP IIb/IIIa Inhibitors
GP IIb/IIIa Receptor
Fibrinogen
GP IIb/IIIa Inhibitors
13
Antiplatelet AgentsGP IIb/IIIa Inhibitors (cont.)

• Monoclonal antibody  abciximab
• Natural products disintegrin familyRGD
  containing proteins (from viper venom)
• Synthetic peptides  eptifibatide
• Nonpeptide inhibitors RGD mimicstirofiban,
  lamifiban, fradafiban
• Oral agentsxemilofiban, orofiban, lefradafiban,
  sibrafiban, roxifiban

Meyer BJ, 1998
14
Antiplatelet AgentsGP IIb/IIIa Inhibitors (cont.)

• Abciximab, eptifibatide, tirofiban 35,000
  patients studied in ACS and patients undergoing
  percutaneous coronary interventions
• Risk reductions in death/MI/emergency
  revascularization up to 50
• Risk reductions in death/new MI range from
  10-27
• Patients undergoing interventions and with ACS
  (when used with heparin) appear to benefit

15
Anticoagulants Indirect Thrombin
InhibitorsUnfractionated Heparin (UFH)

• Most widely used antithrombotic agent
• Disadvantages include
• Poor bioavailability
• No inhibition of clot-bound thrombin
• Dependent on antithrombin III (ATIII) cofactor
• Variable effects
• Frequent monitoring (aPTT) to ensure therapeutic
  levels
• Rebound ischemia after discontinuation
• Risk of heparin-induced thrombocytopenia (HIT)

16
AnticoagulantsIndirect Thrombin
InhibitorsLow-Molecular-Weight Heparin (LMWH)

• Fraction of standard (UFH) heparin
• Advantages over UFH
• Greater bioavailability
• No need to closely monitor
• Resistant to inhibition by activated platelets
• Lower incidence of HIT
• Enhanced anti-factor Xa activity
• Effective subcutaneous administration
• Enoxaparin, dalteparin, reviparin, nadroparin,
  fraxiparin, others
• Differ in anti-Xa/anti-IIa ratios

17
AnticoagulantsDirect Thrombin InhibitorsHirudin

• 65 amino acid protein
• Originally identified in saliva of medicinal
  leech (Hirudo medicinalis)
• Now available through recombinant DNA technology
  (lepirudin and desirudin)

18
AnticoagulantsDirect Thrombin InhibitorsHirudin-
Thrombin Binding

• Mechanisms of Thrombin Inhibition

Fibrin Binding Site
Fibrin
Fibrin
ATIII/ Heparin
Catalytic Site
Thrombin
Thrombin
Thrombin
Substrate Recognition Site
Hirudin
Rihal, Flather, Hirsh, Yusuf, 1995
19
AnticoagulantsDirect Thrombin InhibitorsHirudin
Monitoring

• Ecarin clotting time (ECT)
• Sensitive, rapid
• Linear correlation hirudin/time
• No heparin/warfarin interaction

ECT
Clotting Time
Hirudin
20
AnticoagulantsDirect Thrombin InhibitorsHirulog

• Synthetic antithrombin agent
• Not as potent as hirudin in binding to thrombin
• Investigated in an angioplasty population
• Has shown modest benefits compared to heparin,
  with lower bleeding risks
• Under investigation for acute MI

21
Therapeutic Objectives in Antithrombin
TherapyStandard Pharmacotherapy for ACS

• Mainstays for UA  UFH, LMWH, ?-blockers,
  nitrates
• Others  
• GP IIb/IIIa blockers
• Direct thrombin inhibitors (eg, hirudin),
  lipid-lowering agents, and clopidogrel
• Invasive procedures for refractory cases  IABP,
  PTCA, CABG

22
Therapeutic Objectives in Antithrombin
TherapyRationale of Antithrombin Therapy

• Objective is to prevent worse acute event or
  chronic syndrome
• Activation of thrombin is a key step in the
  pathogenesis of ACS
• Antithrombin therapy treats an acute exacerbation
  via short-term treatment
• Direct antithrombins (eg, hirudin) may be most
  effective

23
Therapeutic Objectives in Antithrombin
TherapyTreatment Effects

• Treatment effects are usually greatest in sickest
  patients
• Outcomes are usually equal in subgroups (eg,
  gender, weight)
• Interactions among multiple agents are
  unpredictable
• Combining newer therapies requires careful
  evaluation in clinical trials
• Experimental drugs may offer beneficial
  equivalence to a control agent

24
Therapeutic Objectives in Antithrombin
TherapyAcceptable Outcomes

• Prolonged survival
• Absence of critical negative events (eg, stroke,
  MI)
• Improvement in how the patient feels and
  functions
• Live longer, feel better, and/or avoid
  unpleasant experiences.

Califf RM, 1998
25
Therapeutic Objectives in Antithrombin
TherapyEndpoint Timing

• Activation of hemostatic system may persist for
  months
• IV antithrombotic agents are mainly effective
  during infusion possibly little beyond
• 3-day (72hr) endpoint maximizes chances of
  proving an early treatment effect
• Longer secondary endpoint (30 days) serves as
  check on persistence of treatment effect

26
Clinical RCTsUFHASA vs ASA Meta-analysis

• UFHASA vs ASA for unstable angina (UA)
• 6 RCTs (randomized controlled trials) included (n
  1,353)
• Endpoint  death/MI during treatment (2-7 days)
• Result  RRR (relative risk reduction) favoring
  UFHASA 33, p 0.06
• Conclusion  patients with UA might benefit from
  UFHASA combination

Ohler, et al, 1996
27
Clinical RCTsLMWH vs Placebo

• FRISC Study
• LMWH (dalteparin) vs Placebo ASA in both
  groups
• Patients  UA or non-Q-wave MI n1,506
• Endpoint  death/MI/revascularization or IV UFH
• Results _at_6d RRR 48, p lt 0.001 (primary
  follow-up point) _at_40d RRR 21, p
  0.011 _at_150d RRR 6, p 0.28
• Conclusion  benefits were most pronounced during
  the acute phase and for higher risk patients

28
Clinical RCTsLMWH vs UFH

• ESSENCE Study
• LMWH (enoxaparin)ASA vs UFHASA
• Patients  angina at rest or non-Q-wave MI n
  3,171
• Composite triple endpoint  death/nonfatal MI/RA
• Results _at_48hr RRR 16.2, p 0.18 _at_14d RRR
  16.2, p 0.02 (primary follow-up
  point) _at_30d RRR 15, p 0.02
• Conclusion  LMWH more effective than UFH for
  reducing ischemic events

29
Clinical RCTsLMWH vs UFH

• TIMI-11B Study
• LMWH (enoxaparin) vs UFH
• Patients UA/non-Q-wave MI n 3,910
• Composite triple endpoint  death/MI/RA
• Results _at_48hr RRR 24, p 0.02 _at_14d RRR 15,
  p 0.03 (primary follow-up point) _at_43d RRR
  11.7, p 0.049
• Conclusion  strongest superiority of LMWH is
  seen early in treatment and for patients at
  greatest risk

30
Clinical RCTsLMWH vs UFH or Placebo (Short-
Long-term)

• FRIC Study
• LMWH (dalteparin) vs UFH (short-term) vs Placebo
• (longer-term) ASA all groups
• Patients  UA or non-Q-wave MI, n1,482
• Endpoint  death/MI/RA
• Dalteparin vs UFH Result _at_ 6d RRIncr 18, p
  0.33
• Dalteparin vs Placebo Result 6d 45d RRIncr
  1, p 0.96
• Conclusion  dalteparin is a safe, effective
  (equivalent) alternative for UFH.

31
Clinical RCTsHirudin vs UFH (in acute MI, both
with TPA or streptokinase)

• TIMI-9B Study
• Hirudin vs UFH both as adjunctive treatment to
  thrombolysis
• Patients  acute MI n3,002
• Endpoint  death/recurrent MI/CHF or cardiogenic
  shock
• Results  _at_ 30d RRIncr 8, p NS
• Conclusion  hirudin and UFH have equal effects
  as adjunctive therapy

32
Clinical RCTsHirudin vs UFH (w/PTCA)

• HELVETICA Study
• Hirudin vs UFH given before and after PTCA
• Patients  UA undergoing PTCA, n 1,141
• Primary endpoint  death/MI/CABG, or repeat
  intervention _at_ 30wk
• Secondary assessment  death/MI/CABG, or repeat
  intervention _at_ 96hr

33
Clinical RCTsHirudin vs UFH (w/PTCA)

• HELVETICA Study Results

(139) 36.5
Death/MI/CABG/Repeat Invervention
40.0 30.0 20.0 10.0 0.0
(125) 32.7
(121) 32.0
UFH Hirudin IV HIR IV SC
(51) 21.6
of Patients with Events (No. of Pts.)
(29) 12.3
(42) 11.0
(30) 7.9
(21) 5.6
(12) 5.3
(20) 5.2
(7) 1.8
(7) 1.8
96 hr unstable 59 0.006 236
96 hr UFH Pretreatment 63 0.007 380
96 hr 39 0.023 1,141
30 wk 2 0.61 1,141
RRR p n
34
Clinical RCTsHirudin vs UFH (w/PTCA)

• HELVETICA Study Conclusions
• Hirudin associated with early, significant
  reductions in cardiac events
• Hirudin and UFH treatment groups similar by
  7-month follow-up
• No significant differences between groups in
  major or minor bleeding

35
Clinical RCTs Hirudin vs UFH

• GUSTO-2B
• Hirudin (Hir) vs Unfractionated Heparin (UFH)
• Patients  ACS with or without ST-segment
  elevation n12,142
• Primary endpoint  death/nonfatal MI
• Results_at_24hr (Hir 1.3 vs UFH 2.1), RRR 38,
  p 0.001_at_48hr (Hir 2.3 vs UFH 3.1), RRR 26,
  p 0.001_at_30d (Hir 8.9 vs UFH 9.8), RRR 9, p
  0.06 (primary follow-up point)
• Conclusion  hirudin provided an early,
  significant advantage over UFH

36
Clinical RCTsHirudin vs UFH

• OASIS-1 Pilot Study
• Hirudin (Hir medium or low dose) vs UFH
• Patients  UA or acute MI w/o ST-segment
  elevation, n909
• Dosing  72hr UFH 5000 U bolus 1000 to 1200
  U/h Med Dose Hir 0.40 mg/kg bolus 0.15
  mg/kg/h Low Dose Hir 0.20 mg/kg bolus 0.10
  mg/kg/h
• Primary outcome  death/new MI/refractory angina
• Secondary outcome  death/new MI/refractory or
  severe angina

37
Clinical RCTsHirudin vs UFH

• OASIS-1 Pilot Study (cont.)
• Results  _at_ 7 daysPrimary outcome  death/new
  MI/refractory angina Med Dose Hir (Hir 3.0 vs
  UFH 6.5), RRR 54, p 0.047 Low Dose Hir (Hir
  4.4 vs UFH 6.5), RRR 32, p 0.267Secondary
  outcome  death/new MI/refractory or severe
  angina Med Dose Hir (Hir 9.4 vs UFH 15.6), RRR
  40, p 0.02 Low Dose Hir (Hir 12.5 vs UFH
  15.6), RRR 20, p 0.27
• Hirudin vs UFH differences persisted up to 180
  days
• Conclusion  medium dose hirudin appears superior
  to lower dose hirudin or heparin

38
Clinical RCTsHirudin vs UFH

• OASIS-2 Study
• Hirudin vs UFH (ASA recommended for all
  patients)
• Patients ACS w/o ST-segment elevation, n
  10,141
• Dosing 72hr UFH 5000 U bolus 15
  U/kg/h Hirudin 0.40 mg/kg bolus 0.15 mg/kg/h
• Primary endpoint  CVD/MI _at_ 7 days
• Secondary endpoint  CVD/MI/RA _at_ 7 days
• Effects also examined _at_ 72 hr 35 days

39
Clinical RCTsHirudin vs UFH
OASIS-2 Study (cont.) Primary Endpoint Results
7.7
CVDeath/new MI n 10,141
6.8
UFH Hirudin
4.2
of Patients with Events
3.6
2.6
2.0
72h 24 0.039
7 days 16 0.077
35 days 13 0.06
RRR p
40
Clinical RCTsHirudin vs UFH
OASIS-2 Study (cont.) Secondary Endpoint
Results
CVDeath/new MI/Refractory Angina    n 10,141
7.0 6.0 5.0 4.0 3.0 2.0 1.00.0
6.7
5.6
UFH Hirudin
4.0
of Patients with Events
3.2
72h 22 0.019
7 days 18 0.0125
RRR p
41
Clinical RCTsHirudin vs UFH

• OASIS-2 Study (cont.) Other Outcomes
• Any Cardiac Intervention _at_ 7d (Hir 6.9 vs UFH
  8.1), RRR 16, p 0.016
• Heart failure after first 24hr (Hir 1.8 vs
  UFH 2.6), RRR 30, p 0.006
• Similar cardiac mortality _at_ 7d 1.4 hirudin vs
  1.5 UFH
• Drug dosage adjustments 50 hirudin vs 88 UFH

42
Clinical RCTsHirudin vs UFH
OASIS-2 Study (cont.) 35-Day Event Curves
0.08 0.06 0.04 0.02 0.0
CVD/MI Days 1 to 35
Cumulative Hazard Rates
Heparin Hirudin
0 10 20
30 Days
of Follow-up
OASIS-2, 1999
43
Clinical RCTsHirudin vs UFH

• OASIS-2 Study (cont.) Safety Outcomes 7 Days
• Hirudin (Hir) vs Unfractionated Heparin (UFH)
  bleeding episodes ( patients) Major
  Bleeds (Hir 59 vs UFH 34), p 0.01 Minor
  Bleeds (Hir 338 vs UFH 227), p lt 0.01
• Strokes equivalent (14 in each group)
• Life-threatening bleeds  equivalent (20 in each
  group)

44
Clinical RCTsHirudin vs UFH

• OASIS-1 OASIS-2 Combined Analysis
• Hirudin (Hir) vs Unfractionated Heparin (UFH) _at_
  7 days CVD/MI (Hir 3.5 vs UFH 4.3), RRR 19,
  p 0.039 CVD/MI/RA (Hir 5.4 vs UFH 6.7), RRR
  20, p 0.005 Interventions (Hir 6.8 vs UFH
  8.2), RRR 17, p 0.009
• Hirudin vs UFH _at_ 35 days CVD/MI (Hir 6.7 vs
  UFH 7.7), RRR 14, p 0.04

45
Clinical RCTsHirudin vs UFH

• OASIS-1, OASIS-2, TIMI-9B, GUSTO-2B Combined
  Analysis

1168
CVD/MI n 26,000
1074
763
649
Heparin Hirudin
Proportion of Patients with Event ()
470
373
lt 72hr lt 7d
lt 35d 22
16 10 0.0004
0.002
0.016
RRR p
OASIS-2, 1999
46
Conclusions

• Advances in Antithrombotic Agents
• Newer agents offer improved outcomes for patients
  with ACS
• Absolute risk reductions appear greatest in early
  stages and in higher risk patients
• More potent agents may increase bleeding risks
  patient selection and treatment timing are
  important
• Antithrombotic therapy, without further
  interventions, may offer long-term benefits
• Patients undergoing revascularization procedures
  also may benefit

47
Conclusions (cont.)

• Antiplatelet Agents ASA GP IIb/IIIa Blockers
• ASA in treating ACS reduces relative risks of
  CVD/MI by 35-50
• GP IIb/IIIa blockers offer benefits in
• CVD/MI/emergency revascularization RRR up to 50
• CVD/MI RRR 10 to 27
• Patients undergoing PTCA also have benefited from
  GP IIb/IIIa inhibitors
• Patients with acute MI may benefit from GP
  IIb/IIIa inhibition thrombolysis

48
Conclusions (cont.)

• Anticoagulants Indirect Antithrombins
• UFH LMWH
• Antithrombin therapy treats acute exacerbation
  via short-term treatment
• UFHASA better than placebo or ASA alone in
  reducing CVD/MI/RA
• LMWH has clinical advantages over UFH, and is a
  useful agent early in treatment

49
Conclusions (cont.)

• Anticoagulants Direct Antithrombin - Hirudin
• Studied internationally in 29,000 patients
• Neutralizes clot-bound and soluble fibrin no
  allergic reactions (lack of HIT)
• In acute MI, hirudin and UFH have equivalent
  effects as adjunctive therapy to thrombolysis
• In PTCA, hirudin is associated with fewer cardiac
  events compared to UFH
• In ACS, hirudin is superior to UFH
• CVD/MI RRR 14 24
• CVD/MI/RA RRR 19 22

50
Conclusions (cont.)

• Summary
• Direct thrombin inhibition offers benefits over
  indirect thrombin inhibition for ACS
• Hirudin appears to be a safe, superior
  alternative to UFH
• Longer treatment durations need to be assessed
  for possible long-term benefits
• Combining a thrombin-specific inhibitor (eg,
  hirudin) with a GP IIb/IIIa blocker may be an
  even more effective antithrombotic therapy for ACS