Anticoagulants

PRESENTATION ON ANTICOAGULANTS

1. Dr Anu chandran
Final year PG
Department of Pharmacology
Trivandrum medical college
Anticoagulant therapy :Anticoagulant therapy :
a look to the futurea look to the future

2. OverviewOverview
•Older anticoagulants: Warfarin ,Heparin and
LMWH
•Why we need new drugs
•Newer drugs
–Direct Thrombin Inhibitors
–Xa inhibitors
–Heparinoids
•The future

3. BALANCE BETWEEN
COAGULATION AND FIBRINOLYSIS
BLOOD REMAIN FLUID
YET CLOT
THROMBUS
FIRINOLYSIS
FLUID
BALANCE

6. NATURAL ANTICOAGULANT
•PGI 2 - Inhibit platelet
•Antithrombin III - Blocks II, X, IX,XI,XII
•Protein C - V and VIII inactivate
•Heparin sulphate - enhance anti thrombin
III

7. HEPARINHEPARIN
•Indirect thrombin inhibitor
•Called UFH
•Activates ANTI THROMBIN III
•Acts on
–Thrombin [ II A]
–Factor Xa
–XIIa, XIa, IXa (lesser extent)
•At high concentrations: Also binds to platelets and
heparin co-factor II—which inhibits thrombin

8. •Heparin made of polysaccharide chains
•AT + Heparin: conformational
•AT MORE ACCESSIBLE TO IIA AND X A
•Unique pentasaccharide sequence binds to AT
•Inactivation of Xa—Heparin doesn’t have to bind to it
•Inactivation of Thrombin--Requires heparin to bind to both AT
and itself
–Heparin must be >18 monosaccharides long to do this
–Virtually all heparin molecules are > 18

9. IV Injection
Subcutaneous
Intramuscular - Hematoma
Duration – 1 to 5 hours
Metabolised in liver
Pharmacokinetic Pharmacokinetic
characteristicscharacteristics

10. Heparin - indicationsHeparin - indications
•When immediate anticoagulation required
•Prevention and treatment of venous
thrombosis
•Pulmonary embolism
•Acute Coronary syndromes

11. Adverse effectsAdverse effects
•Increased bleeding 3%
- antidote (protamine sulfate)
•Heparin induced thrombocytopaenia
- HITs 1% up to 3 days 5% >5 days
•Osteoporosis with long term high-dose
administration 3-6mths
•Inhibit aldosterone synthesis – rarely causes ↑K+

12. LMWHsLMWHs
•Molecular Wt: 4000-5000 D
•Short polymer length
•LMWH inactivates Xa
•Ratio of anti-Xa to anti IIa activity of
3:1

14. Low Mol Weight HeparinsLow Mol Weight Heparins
•More predictable pharmacokinetics
•Lower incidence of heparin induced
thrombocytopenia
•Ease of administration s/c injection
•No need for monitoring
•Possible improvement in outcomes of acute
coronary syndromes
(Such a benefit was suggested with enoxaparin in
TIMI II B, ESSENCE, and EVET)

15. •ENOXAPARIN
•DALTEPARIN
•ARDEPARIN
•REVIPARIN
•TINZAPARIN
•NADROPARIN

16. •Fondaparinux [ Synthetic
LMWH]
Xa Inhibitor
Subcutaneous (2.5 mg)
Uses
•Prevention of post op DVT and PE in
orthopedic surgery
• MI, PCI, UA

17. Oasis 5Oasis 5
•Compared with enoxaparin, fondaparinux
substantially reduces bleeding

•Reduced bleeding that accompanies the
use of fondaparinux is associated with
lower long-term mortality and morbidity

18. COUMARINSCOUMARINS

19. CoumarinsCoumarins
Warfarin, Dicumarol
•Mechanism of action:
–Block the Vitamin K reductase there by inhibiting
synthesis of II, VII, IX and X
–Also inhibits Proteins C & S
•8-12 hour delay in action because of T1/2 of
clotting factors in plasma
•Recovery needs synthesis of new clotting factors
•Action is reversed with vitamin K

20. IndicationsIndications
Prophylaxis and treatment of
1. Venous thrombosis
2. Pulmonary embolism
3. Thromboembolic disorders
4. Atrial fibrillation with risk of embolism
5. Prophylaxis of systemic embolism post MI (LV thrombus)

21. Adverse effectsAdverse effects
•Bleeding
(risk depends on both the INR and patient factors)
•Contraindicated in pregnancy
- teratogenic effects, crosses placenta risk foetal
haemorrhage
•Warfarin induced skin necrosis
- paradoxical local thrombosis
- increased in patients with protein C or S deficiency
•"Purple toes syndrome," cholesterol microembolization
•Hepatic dysfunction

22. Why new drugs?Why new drugs?
•UFH and LMWH are inconvenient for the
outpatient setting (IV or sq only)
•UFH and LMWHs can cause HIT
–Risk 0.2% with LMWH vs. 2.6 % with UFH
–Pts with HIT still need to be anticoagulated
•Warfarin has interaction with large number of
drugs
•Warfarin needs strict monitoring with INR

23. Categories of new drugsCategories of new drugs
–Direct Thrombin Inhibitors:
–Indirect Thrombin inhibitors
–Heparinoids:

24. THROMBIN INHIBITORSTHROMBIN INHIBITORS
•PARENTERAL
•Lepirudin
•Bivalirudin
•Desirudin
•Argatroban
•Danaparoid
•Drotrecogin alpha
•ORAL
•Dabigatran
•Rivaroxiban
•Apixaban

25. VIIa
Xa
IXa
XIa
XIIa
Direct Thrombin inhibitionDirect Thrombin inhibition
Tissue
factor
Factor IIa
(thrombin)
THROMBIN INHIBITORS
[parenteral]
II
×

26. LEPIRUDINLEPIRUDIN
•Recombinant form of hirudin
•Use = HIT ,Thromboembolic disease, Acute
coronary syndromes
•Intravenous administration
•APTT monitoring
•Side effects
–Haemorrage
–ANTIBODIES

27. •BIVALIRUDIN - pci
•DESIRUDIN - dvt
•ARGATROBAN - hit
•DANAPAROID - post op dvt
• hit
•DRONTRECOGIN
•Human recombinant activated protein c
•Inhibit Va VIIIa
•Short half life
•Anticoagulant and severe sepsis

28. Fibrinogen Fibrin
Common Pathway
Thrombin
Xa
Prothrombin
Clot
Xa
Blocker
Apixaban
Rivaroxaban
Dabigatran
New Oral Agents

29. Rivaroxaban
•Direct, specific, competitive
factor Xa inhibitor
•Rapid onset within 2-4 hours
•High bioavailability of >80%
•Metabolized via the CYP3A4,
CYP211, and P-gp transport
mechanisms
•Renal and fecal elimination
Perzborn et al., J Thromb Haemost 2005.
Kubitza et al., J Clin Pharmacol 2007.
Xarelto
®

30. Rivaroxaban Dosage and Administration
Approved Dosage Forms 10, 15, & 20 mg tablets
Nonvalvular Atrial Fibrillation Dosing
Normal Renal Function
(CrCl > 50 ml/min)
20 mg once daily*
Moderate Renal Impairment
(CrCl 15 – 50 ml/min)
15 mg once daily*
Severe Renal Impairment
(CrCl < 15 ml/min)
Avoid use
Prophylaxis of DVT
10 mg once daily with or without food

31. ROCKET-AF:
Purpose: Compare rivaroxaban with warfarin for the
prevention of stroke in nonvalvular atrial fibrillation
(AF)
Intervention:
Rivaroxaban 20 mg daily
or
Warfarin (Target INR 2.5)

32. ROCKET-AF:
Clinical Trial Outcomes
•Efficacy
–Rivaroxaban: non-inferior to warfarin
•Safety
–Similar rates of bleeding and adverse events
–Less ICH and fatal bleeding with rivaroxaban
•Conclusion
–Rivaroxaban is a potential alternative to warfarin for
moderate or high risk AF patients

33. Rivaroxaban: FDA Status
•XareltoÒ trade name (Janssen pharma)
•For the prevention of DVT/PE after orthopedic
surgery:
•For the prevention of stroke in patients with atrial
fibrillation:
–FDA advisory committee voted to approve (Sept. 2011)

34. Apixaban
•Direct, reversible FXa
inhibitor
•Rapid onset, peak within 3
hrs
•Bioavailability of 51-85%
•Long half life, slightly longer
in elderly (15 hrs)
•Multiple elimination pathways
–25% renal
–75% biliary
•Metabolism via CYP3A4,
SULT1AA pathways
Perzborn et al., J Thromb Haemost 2005.
Kubitza et al., J Clin Pharmacol 2007.
EliquisÒ

35. ARISTOTLE: Study Outcomes
•Treatment with apixaban as compared to warfarin
in patients with AF (n>18,000) and at least one
additional risk factor for stroke:
–Reduces stroke and systemic embolism by 21%
(p=0.01)
–Reduces major bleeding by 31% (p<0.001)
–Reduces mortality by 11% (p=0.047)
–Consistent effects across all major subgroups
–Fewer drug discontinuations on apixaban than on
warfarin, consistent with good tolerability
Granger CB, et al. NEJM 2011;365: Aug 28

36. Apixaban: FDA Status
•EliquisÒ trade name
•For the prevention of DVT/PE after orthopedic
surgery:
–No FDA approval yet
–Apixaban approved in the EU
•For the prevention of stroke in patients with
non valvular atrial fibrillation:
–US FDA recommendation Dec 2012

37. Dabigatran Etexilate
•Specific, competitive, reversible univalent
thrombin inhibitor
•Pro-drug converted to active form
•Rapid onset within 2 hours
•Low bioavailability, 3.5-5%
•Low protein binding
•Half life 12-17 hours
•Renal clearance as glucuronic acid
conjugate: 85%
•Metabolized by esterase catalyzed
hydrolysis and P-gp transport
mechanisms
Perzborn et al., J Thromb Haemost 2005.
Kubitza et al., J Clin Pharmacol 2007.
Pradaxa
®

38. RE-LY STUDYRE-LY STUDY
•Comparing 2 blinded doses of dabigatran
etexilate (110 mg B.I.D. [D110] AND 150 mg
B.I.D. [D150]) with open-label, adjusted-dose
warfarin aiming for a target international
normalized ratio (INR) of 2.0 to 3.0

39. RE-LY: Study Outcomes
Efficacy
•Both doses of dabigatran were non-inferior to warfarin on the
primary endpoint
–reduction of the incidence of stroke including hemorrhagic and
systemic embolism; p<0.001
•Dabigatran 150 mg BID was superior to warfarin on the primary
endpoint by 34%
–p<0.001
Safety
•No significant difference in the rate of major bleeding for dabigatran
150 mg BID compared to warfarin
–3.11 vs 3.36 % / yr; p=0.31
•Rate of major bleeding with dabigatran 110 mg BID (2.71%/yr) was
20% lower compared to warfarin; p=0.003

40. RE-LY: MORTALITY REDUCTION
DABIGATRAN VS WARFARIN
•Lower death rate with dabigatran:
–Vascular death
2.69% vs 2.43 and 2.28%* (p=0.04 for 150 mg)
–All cause death
4.13% vs 3.75 and 3.64% (p=0.05 for 150 mg)
Connolly SJ, et al. NEJM 2009;361: 1139-1151

41. RE-LY: BLEEDING
DABIGATRAN VS WARFARIN
•More bleeding with warfarin:
–Life-threatening bleeding
1.8% vs 1.2 and 1.5% (p<0.001, 0.04)
–Intracranial bleeding
0.7% vs 0.2 and 0.3% (p<0.001, <0.001)
–Major plus minor bleeding
18.2% vs 14.6 and 16.4% (p<0.001, 0.002)
Connolly SJ, et al. NEJM 2009; 361:1139-1151

42. RE-LY Trial
•Dabigatran superior to warfarin for stroke
prevention
–Equivalent rates of major bleeding
•By August 2011 dabigatran prescribed to
250,000 U.S. atrial fibrillation patients

43. Dabigatran: FDA Status
•PradaxaÒ trade name
•For the prevention of DVT/PE after orthopedic
surgery:
–FDA approval pending
–Pradaxa approved in EU and Canada
•For the prevention of stroke in patients with
non-valvular atrial fibrillation (SPAF):
–Pradaxa 150 mg BID FDA approved (Oct. 2010)
–Pradaxa approved in EU, Canada and Japan

44. Dabigatran: FDA Approved Dosing
•150 mg BID for AF
–150 mg for CrCl >30 mL / min
– 75 mg for CrCl 15-30 mL / min

45. Dabigatran: Not Without Issues
1.No anticoagulant effect if missed dose
•2% discontinuation rate due to GI distress
•Cost of drug ($240/mo vs $4/mo for warfarin)
1.No test to assess anticoagulation
2.Difficult to modulate dose
3.Bleeding in the elderly and renal impaired patients
(5 dabigatran related deaths in Japan)
4.Drug interactions
5.No specific antidote
6.0.2% increase in myocardial infarction
7.‘Real world’ untested populations

46. New OACs: ‘Real Life’
Experience
•Populations not studied in the clinical trials:
–Elderly, pediatrics, pregnant
–Heparin compromised (e.g., HIT)
–Acute vs non-acute VTE
–Chronically ill

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Onset Slow Rapid
Dosing Variable Fixed
Indications Same Same
Food effect Yes No
Drug interactions Yes Yes
Monitoring Yes No
Half-life Long Short
Antidote Yes No
Comparison of
NEW ORAL ANTICOAGULANTS
with WARFARIN

48. •Razaxaban
–Oral drug
–Inhibitor of factor Xa without requiring AT
–In phase II trials
•DX-9065a
–Xa inhibitor; also in phase II trials;
•Potential targets being developed
–TF/fVIIa
•Recombinant tissue factor inhibitor (FTPI)
•Other specific TF/fVIIa or fVIIa inhibitors being developed
–Recombinant Activated protein c
•In phase III trials—inactivates Va and VIIIa
Future possible drugs

49. Future possible drugs
•Aptamers:
–Single stranded nucleic acids that fold into
specific 3D structures which bind and inhibit a
protein target
–Anti factor VIIa, IXa, and thrombin aptamers
have been developed
–Should be nonimmunogenic—small and
similar to endogenous molecules
–Possible use in HIT

50. Conclusions
1.New anticoagulants are now clinically
available and additional drugs are being
developed.
2.The new oral anticoagulants rivaroxaban,
dabigatran and apixaban, though costly, will
provide more options for the management of
VTE; however, these drugs are not superior to
the standard of care.
3.For VTE prevention, heparins and warfarin will
remain the standard of care for some time,
especially in medical patients.

51. Conclusions
4.For atrial fibrillation (SPAF) the new oral
anticoagulants appear to have a superior
safety and efficacy profile.
5.Additional clinical trials are needed to
determine the merit of these drugs beyond the
‘clinical trial’ populations, and to address
unanswered questions.
6.Warfarin’s low cost, efficacy, and track record
will prolong its life. Its use may decrease but it
will remain for years to come.