Update of Novel Anticoagulants

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Update of Novel Anticoagulants

• Geoffrey L. Uy

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Historical Perspective

• Coumadin
• Karl Paul Link discovers dicoumarol 1930s
• Coumadin enters into clinical use 1950s
• Heparin
• MacLean Howell isolate heparin 1918
• Heparin first used in vascular surgery 1930s
• LMWH approved for use in US 1993
• Direct Thrombin Inhibitors
• Hirudin 1894
• Refludan 1998
• Argatroban 2000
• Bivalirudin 2000

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Targets of New Inhibitors
TFPI NAPc2 FVIIai
Tissue Factor-VIIa
X
IX
IXa
APC
VIIIa
Fondiparinux Idraparinux
Xa Va
Hirudin Bivalirudin Argatroban Ximelagatran
Thrombin
Prothrombin
Fibrinogen
Fibrin
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Fondaparinux (Arixtra)
Extrinsic pathway
Intrinsic pathway
Antithrombin
Xa
Xa
ATIII
ATIII
ATIII
Fondaparinux
IIa
II
Fibrinogen
Fibrin clot
Platelets
IIA
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Pharmacokinetics

• Bioavailability 100
• Maximum concentration is achieved in 2 hours and
  steady state in 3 hours
• Half-life is 17-22 hours
• Majority of dose is excreted unchanged in urine

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Fondaparinux for DVT Prophylaxis
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Matisse DVT and PE Trials
? 5 days Fondaparinux 7.5 mg qd Warfarin (INR
2-3)
Patients with DVT
R
Double-blind
? 5 days SC enoxaparin 1 mg/kg bid Warfarin
(INR 2-3)
5 mg if body weight lt 50 kg 10 mg if body
weight gt 100 kg
90 7 Days
? 5 days Fondaparinux 7.5 mg qd Warfarin (INR
2-3)
Patients with PE DVT
R
Open-Label


? 5 days IV UFH (aPTT 1.5-2.5) Warfarin (INR
2-3)
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Matisse DVT

? 3.5
0
1.5
-1.8
-0.15
Fondaparinux - LMWH (95 CI )
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Matisse PE
Fondaparinux (N 1103)
UFH (N 1110)
Fatal PE
16 (1.5 ) 15
(1.4 ) Non-fatal PE or DVT
26 (2.4 ) 41 (3.6
) Total symptomatic recurrent VTE
42 (3.8 ) 56 (5.0 )

? 3.5
0
0.5
-3.0
-1.2
Fondaparinux - UFH (95 CI )
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Bleeding Risk
Matisse DVT
Fondaparinux
1.1
2.6
LMWH
1.2
3.0

0
2
4
6
8
Matisse PE
Fondaparinux
1.3
3.2
UFH
5.2
1.1

0
2
4
6
8
Major bleed
Clinically relevant non-major bleed
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Conclusions

• Alternative agent for LMWH for prophylaxis or
  initial treatment of venous thromboembolism
• Treatment of HIT
• No true antidote although Factor VIIa may be of
  benefit
• Ongoing trials with Idraparinux

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Direct Thrombin Inhibitors
IIa
Heparin binding site
IIa
Hirudin
Catalytic site
IIa
Argatroban Melagatran
Substrate Recognition Site
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Ximelagatran

• First oral direct thrombin inhibitor
• Prodrug of melagatran
• Well absorbed from GI tract Peak absorption in
  15-30 minutes
• Peak levels in 2-3 hours
• Not protein bound
• Half-life 3-4 hours
• Eliminated via kidneys

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Efficacy and Safety of the Oral Direct Thrombin
Inhibitor Ximelagatran Compared with Current
Standard Therapy for Acute, Symptomatic Deep Vein
Thrombosis, with or without Pulmonary Embolism
The THRIVE Treatment Study.
2,489 patients with DVT 37 w/ PE
Ximelagatran 32 mg po bid
N 1240
R
Double-blinded, double-dummy, sham INR
N 1249
Enoxaparin 1 mg/kg bid X 5 days Followed by
warfarin (INR 2.0-3.0)
6 Months
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Results

• Event Ximelagatran Enoxaparin Absolute diff
• n () Coumadin (95 CI)____
  
• Recurrent VTE (ITT) 26 (2.1) 24 (2.0) 0.2
  (-1.01.3)
• Recurrent VTE (OT) 23 (2.0) 17 (1.5) 0.5
  (-0.6 1.6)
• Major bleeding 14 (1.3) 26 (2.2) -1.0
  (-2.11.0)
• Recurrent VTE and/or 37 (3.2) 43
  (3.7) -0.5 (-2.01.0)
• Major bleeding (OT)
• All-cause mortality (ITT) 28 (2.3) 42
  (3.4) -1.1 (-2.4 0.2)
• All-cause mortality (OT) 7 (0.7) 10
  (0.9) -0.2 (-1.0 0.5)

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Stroke Prevention Using an Oral Thrombin
Inhibitor in Atrial Fibrillation (SPORTIF III)

• 7329 patients from 23 nations with nonvalvular
  atrial fibrillation
• Fixed-dose ximelagatran, 36 mg twice/day,
  compared to dose-adjusted warfarin, target INR
  2.0-3.0
• Open label design

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SPORTIF V

• 3922 patients from 409 US and Canadian sites with
  nonvalvular atrial fibrillation and one other
  stroke risk factor
• Fixed-dose ximelagatran, 36 mg twice/day,
  compared to dose-adjusted warfarin, target INR
  2.0-3.0
• Randomized, double-blinded, double-dummy, using
  sham INR

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Results
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Liver Toxicity

• Incidence of elevated ALT gt 3 X ULN
• THRIVE III
• 6.4 in Ximelagatran group
• 1.2 in placebo
• THRIVE IV
• 9.6 in Ximelagatran group
• 2.0 in Enoxaparin/warfarin group
• SPORTIF V
• 6.0 in Ximelagatran group
• 0.8 in Warfarin group
• One patient death from GI bleed during tx of
  hepatitis

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Liver Toxicity
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Conclusions

• Impressive results for oral anticoagulant
• Does not require monitoring of anticoagulation
• Real world effects may be better than warfarin
• Trend toward more thromboembolic events with
  ximelagatran in SPORTIF V
• Unclear significance of LFT abnormalities

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How much is it going to cost?

ENOXAPARIN 40 MG 27.89 FONDAPARINUX 2.5 MG
41.29 WARFARIN 5 MG 0.43 XIMELAGATRAN
????