Managing Venous Thromboembolism: pentasaccharides lessons of reducing sugars

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Managing Venous Thromboembolismpentasaccharides
lessons of reducing sugars
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Outline

• Evidence for current standard therapy in VTE
• Role of synthetic pentasaccharides
• Treatment in 2010

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Clinical evaluation of unfractionated heparin
1924 Masson Intravenous use in 33
volunteers 1937 Crafoord Reduction of
thrombosis in surgical patients 1939
Jorpes First proper clinical evaluation 1960
Barrit Jordan Treatment of pulmonary embolism
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Antithrombotic treatment in venous thromboembolism

• Patients with symptomatic pulmonary embolism, a
  randomized comparison
• Recruitment stopped prematurely

N fatal PE non fatal PE Untreated 19 5
(26) 5 (26) Treated 16 0 0
Barrit Jordan, Lancet 1960
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Unfractioned heparin in the treatment of venous
thromboembolism

• Initial full dose heparin is absolutely required
• (Brandjes et al., N Eng J Med 93)
• Adequate plasma concentrations early reduce risk
  of recurrence (Ginsberg, N Eng J Med 96)
• Long term (10 days) as effective as short term (5
  days) heparinisation (Gallus et al., Lancet 86
  Hull et al., N Eng J Med 87)

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(No Transcript)
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LMWH versus UFH in the treatment of acute venous
thromboembolism

• Total 29 comparative studies
• 15 excluded dose finding duplicate reports
  inability to extract clinical data adjusted dose
  LMWH
• 14 studies analyzed for incidence recurrent VTE,
  major bleeding and mortality (n4754)

van Den Belt AG, Prins MH, Lensing AW, et al.
Fixed dose subcutaneous LMWH versus adjusted dose
unfractionated heparin for venous
thromboembolism. The Cochrane Library, issue 4,
2002.
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LMWH versus UFH

• LMWH UFH OR 95 CI
• Recurrent VTE 86/1998 113/2021 0.75 0.55-1.01
• 4.3 5.6
• Major hemorrhage 30/2353 51/2401 0.60 0.39-0.93
• 1.3 2.1
• Mortality 135/2108 172/2137 0.78 0.62-0.99
• 6.4 8.0

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Symptomatic venous thromboembolism at the end of
treatment in trials comparing low-molecular-weight
heparin (LMWH) with unfractionated heparin (UFH)
for the treatment of acute pulmonary embolism
Quinlan DJ et al, Ann of Int Med 2004140175-183
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Recurrent Symptomatic Venous Thromboembolism and
Death at 3 months

• Outcome LMWH UFH Odds Ratio
• Recipients Recipients (95 CI)
• Any VTE 30/988 (3.0) 39/895 (4.4) 0.68
  (0.42-1.09)
• DVT 15/891 (1.7) 19/792 (2.4) 0.64
  (0.33-1.25)
• PE 16/891 (1.8) 20/792 (2.5) 0.78
  (0.41-1.47)
• Major bleeding 14/1023 (1.4) 21/928 (2.3) 0.67
  (0.36-1.27)
• All-cause
• Mortality 46/988 (4.7) 55/895 (6.1) 0.77
  (0.52-1.15)
• Quinlan D.J. et al,
• Ann Intern Med 2004140175-183

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LMWH drug of choice in the treatment of venous
thromboembolism
Easier to use Less thrombocytopenia No
laboratory monitoring
Similar efficacy Superior safety Out of hospital
Cost-effective
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Treatment of Venous Thromboembolism 2004(ACCP)

• Initial 5-10 days LMWH (or UFH)
• Secondary prophylaxis with vitamin K antagonists
  6-12 months

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New Anticoagulants
Drug
Coagulationcascade
TFPINAPc2
Initiation
TF/VIIa
IX
X
IXa
Fondaparinux Idraparinux Razaxaban BAY-597939 YM-
150
VIIIa
Xa
Propagation
Va
II
Thrombin activity
IIa
Ximelagatran Dabigatran
Fibrinogen
Fibrin
Adapted with permission from Weitz I, Hirsh J.
Chest. 200111995S-107S.
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Pentasaccharidestailor made
OCH3
OCH3
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Pentasaccharide A targeted mechanism of action
Extrinsic pathway
Intrinsic pathway
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1
2
Xa
Xa
ATIII
ATIII
ATIII
Org31540/ SR90107A
IIa
II
Fibrinogen
Fibrin clot
Olson ST, et al. J Biol Chem. 199226712528-12538
.
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Clinical Development of Fondaparinux
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MATISSE Studies
Background
Current standard initial therapy in DVT and PE
are body weight-adjusted LMWH (bid/od) SC and
continuous, dose-adjusted UFH IV
Objective
To document that a fixed SC dose of od
fondaparinux is at least as effective and equally
safe as current initial therapy (upper limit
noninferiority margin for efficacy 3.5)
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MATISSE Study Designs
?5 days IV UFH (aPTT 1.5-2.5) OAC (INR 2-3)
Patients with PE DVT
R
Open-label
?5 days 7.5-mg fondaparinux SC OAC (INR 2-3)
Patients with DVT
Double-blind
R
?5 days SC enoxaparin (1 mg/kg bid) OAC (INR
2-3)
5 mg if body weight lt50 kg 10 mg if body
weight gt100 kg
90 7 days

• Primary Efficacy Outcome (3 months)
• Fatal PE/unexplained death
• Recurrent symptomatic nonfatal PE or DVT

• Principal Safety Outcome (initial treatment)
• Major bleed
• Clinically relevant nonmajor bleed

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Baseline Characteristics
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Primary Efficacy Outcome
1. The Matisse Investigators. N Engl J Med.
20033491695-1702. 2. The Matisse
Investigators. Ann of Intern Med. June 1, 2004
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Principal Safety OutcomeInitial Treatment
MATISSE PE1
Fondaparinux
4.5
1.3
3.2
6.3
UFH
1.1
5.2

0
2
4
6
8
Major bleed
Clinically relevant nonmajor bleed
MATISSE DVT2
Fondaparinux
3.7
1.1
2.6
LMWH
1.2
3.0

0
2
4
6
8
1. The Matisse Investigators. N Engl J Med.
20033491695-1702. 2. The Matisse
Investigators. Ann of Intern Med. June 1, 2004
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Out-of-Hospital Treatment
Fondaparinux
UFH
MATISSE PE1

• Home treatment
• (any dose)

0
15

MATISSE DVT2
Double-dummy medication

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• Home treatment
• (any dose)

1. The Matisse Investigators. N Engl J Med.
20033491695-1702. 2. The Matisse
Investigators. Ann of Intern Med. June 1, 2004
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Conclusions

• Fondaparinux is at least as effective and equally
  safe as UFH for the initial treatment of PE and
  as LMWH for the initial treatment of DVT
• The fondaparinux regimen is a once-daily SC
  injection without body weight adaptation and
  offers a uniform approach for DVT and PE patients
• Will allow for simplified treatment at home

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Pentasaccharidestailor made
OCH3
OCH3
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Fondaparinux Idraparinux

• 100 bioavailability via the subcutaneous route
• No metabolites and excreted mainly in the urine
• Linear, dose-dependent pharmacokinetic profile
• Peak concentration (Cmax) reached in 13 hours
• No significant binding to other blood, plasma or
  endothelial proteins

• Once-daily administration

• Once-weekly administration

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Clinical evaluation

• Idraparinux
• Persist, dose finding in symptomatic DVT
• Amadeus in atrial fibrillation
• van Gogh program

• Fondaparinux
• 5 studies in prophylaxis in orthopedic surgery
• Matisse DVT/PE in symptomatic patients
• Michelangelo program in Acute Coronary Syndromes
  (UA/NSTEMI and STEMI)

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New Anticoagulants
Drug
Coagulationcascade
TFPINAPc2
Initiation
TF/VIIa
IX
X
IXa
Fondaparinux Idraparinux Razaxaban BAY-597939 YM-
150
VIIIa
Xa
Propagation
Va
II
Thrombin activity
IIa
Ximelagatran Dabigatran
Fibrinogen
Fibrin
Adapted with permission from Weitz I, Hirsh J.
Chest. 200111995S-107S.
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Treatment in 2010

• Vitamin K antagonists and heparins will have
  disappeared
• No distinction between initial and longterm
  therapy
• Great majority of patients treated out of
  hospital
• Mainly oral (or longacting s.c.) compounds
• Better stratification for who should be treated
  longterm