Antithrombotics drugs Vitamin K antagonists

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Antithrombotic drugs Vitamin K
antagonists These slides were kindly
provided by AstraZeneca
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Anticoagulant drugs
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Vitamin K antagonists history

• 1930s Investigations of the haemorrhagic
  effects of spoiled sweet clover in cattle
• 1939 Link identifies the active agent,
  dicoumarol dicoumarol synthesized by Heubner
  (1940) and Lehmann (1942)
• 1941 First clinical use (short term)
• 1944 Use of dicumarol in long-term prophylaxis
  after MI
• 1948 Synthesis of warfarin as a rat poison
• 1954 Warfarin introduced in clinical practice

Sweet clover Melilotus alba
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First seventeen cases of thrombosis in the
extremities treated with dicumarol
(anti-prothrombin, AP) by Dr. J. Lehmann,
published in the Lancet, March 14, 1942
?F
Temperature
1938-41. Interest in coumarin and spoiled sweet
clover May -41. Dicumarol published in JBC by KP
Link June -41. Dicumarol synthesised at Ferrosan,
Sweden Summer -41. Studies in rabbits and a few
dogs October -41. First patient, DVT Dec -41.
First international presentation submitted, Lancet
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100
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0.75 g
0.25 g
0.5 g
80
60
Prothrombin index
40
20
0
2
4
6
8
10
12
14
Days
Effect of AP in a patient with phlegmasia alba
dolens
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Vitamin K antagonists mechanism of action
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Vitamin K antagonists mechanism of action
Gamma carboxy glutamic acid
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Vitamin K antagonists mechanism of action
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Vitamin K-dependent clotting factors

• Varying half-life (6-72 hours)
• Anticoagulant effect of vitamin K antagonists
  starts after several days

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Vitamin K antagonists pharmacokinetics

• Slow onset and offset of action. Onset of the
  anticoagulant effect is slow as existing
  functional coagulation factors (factors II, VII,
  IX and X) must first be cleared from the
  patients plasma. This takes about 3-4 days. The
  slow offset of action is due to the time required
  for synthesis of new, functional coagulation
  factors
• Early procoagulant effect because of elimination
  of the anticoagulant protein C which is
  eliminated faster as its half-life is much
  shorter. A normal haemostatic balance in man is
  maintained via two endogenous enzyme systems, the
  pro-coagulant coagulation system and the
  anti-coagulant protein C system. Both of these
  systems are indirectly inhibited by VKAs.
• Thus, there will be an initial imbalance between
  the two counteracting systems which results in a
  pro-thrombotic period of 1-2 days as the
  endogenous protein C system is downregulated
  before the anti-coagulant system is inhibited.
  The initial treatment with VKAs, such as
  warfarin, must therefore always be combined with
  heparin
• When rapid reversal is required, fresh frozen
  plasma or coagulation factor concentrates can be
  administered. Vitamin K can also be administered
  but the effect of this treatment is delayed

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Vitamin K antagonists major use

• Prevention and treatment of thromboembolic
  diseases

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Vitamin K antagonists major drawbacks

• Variable and unpredictable effect, necessitating
  regular INR monitoring and dose adjustment
• Narrow separation of antithrombotic effect and
  bleeding leads to increased risk of
  complications
• Under-anticoagulation (INRlt2.0) can lead to more
  frequent and more severe strokes and higher
  treatment costs
• Over-anticoagulation (INRgt3.0) can result in
  increased bleeding, including haemorrhagic stroke
• Slow onset and offset of action
• Numerous interactions with alcohol, foods
  containing vitamin K, with foods and drugs
  metabolised by cytochrome P450 enzymes and with
  foods and drugs which interfere with
  gastrointestinal absorption
• Concern over the safety profile of vitamin
  K-antagonist therapy is almost certainly a
  contributing factor to the current
  under-treatment with anticoagulant therapies

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Limitations of vitamin K antagonists

• Slow onset/offset Delayed action
• Unpredictable response
• Narrow separation between Requires monitoring
• anticoagulation effect and bleeding to avoid life
  threatening
• complications
• Factors influence response
• Side effects Bleeding
• Reversibility Slow
• Frequent dose changes Requires management

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Vitamin K antagonists are responsible for a
significant number of adverse drug events

• In France, 500,000 patients are treated with
  vitamin K antagonists (VKAs) each year and there
  are 17,000 hospitalisations per year for
  VKA-related bleeding events1
• Swedish Medical Products Agency (MPA) reported 52
  fatalities on warfarin in 2003, which accounted
  for 51 of all drug-related fatalities2
• In a UK study, warfarin, among individual drugs,
  was the 2nd most common cause of hospital
  admissions related to adverse drug reactions
  (ADRs)3
• A US study indicates that warfarin is among the
  top five medications based on frequency of ADRs4
• Five of the top ten most problematic drug
  interactions in the US long term care setting
  involve warfarin5

1 AFSSAPS, Dossier VKA. http//agmed.sante.gouv.fr
/htm/5/5703c.htm 2 www.mpa.se/biverkningar/biv05/
050621_bivrapport-2004.shtml 3 Pirmohamed M et
al. BMJ 200432915-19 4 Wu WK Pantaleo N.
Am J Health-Syst Pharm. 2003 60253-9 5 American
Society Consultant Pharmacists Sept 2002
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Swedish Medicinal Products Agency (MPA) reported
on 52 fatalities on warfarin in 2003
The 15 pharmaceuticals judged most related to
drug-induced fatalities.
1 Warfarin
2 www.mpa.se/biverkningar/biv05/050621_bivrapport
-2004.shtml

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Complex dosing regiment and frequent coagulation
monitoring
Starting dose Average 510 mg, based on body
weight (may be lower for elderly patients)
Initiation
Titration and INR test ? once a week until stable
(INR 2.03.0), then monitor every 2 weeks
INR out of range
Monthly INR test
Adjust dose
INR in range
Repeat INR
Maintenance
Continue monthly INR test
INR out of range
Monthly INR test until stable
Repeat dose adjustment and INR
Lackie CL et al. Ann Pharmacother 200236200-4
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Variable efficacy and bleeding
INR values of a patient on warfarin over six
months
Patient at risk of a major bleed
Patient at risk of stroke
Anticoagulation Clinic, University of Washington
Medical Center
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Adjusted odds ratios for ischaemic stroke and
intracranial bleeding Randomised trials of
antithrombotic therapy for patients with AF
International Normalised Ratio
ACC/AHA/ESC Guidelines. Circulation
20011042118-30