COMPARISON OF WARFARIN AND HEPARIN

FOR THROMBOPROPHYLAXES BASED UPON

THERE SAFETY, EFFICACY AND TOLERABILITY

Noor-ul-ain (CMS#15561)
Faiza Iftikhar (CMS#8420)
Saliha Sayyab (CMS#8571)
Kalsoom Saleem (CMS#8107)

THROMBOSIS
Thrombosis is the formation of blood clot (thrombus) inside
a blood vessel, obstructing the flow of blood through the
circulatory system.

MECHANISM:
When a blood vessel is injured, body uses platelets (thrombocytes) and fibrin
to form a blood clot to prevent blood loss.
Even when vessel is not injured, blood clots may form in the body under
certain conditions.
A clot that breaks free and begin to travel around the body is known as
EMBOLUS

What is the cause of embolism

Risk factors for emboliinclude:

high blood pressure
atherosclerosis (buildup of fatty plaque in the blood vessels)
and high cholesterol.

Causes
The main causes of thrombosis are given which
lists
hypercoagulability,
endothelial cellinjury,
and disturbedblood flow

INITIATION OF BLOOD COAGULATION

Extrinsic Pathway
Tissue trauma

Intrinsic Pathway
Blood trauma/ contact with collagen
Activation of factor XII,
IX, VIII

Leakage of Tissue Factor

Ca+2, factor VII

Xa

Xa
Ca+2

Ca+2
Prothrombin activator

Prothrombin
activator

Ca+2

Prothrombin
(factor II)

Thrombin

Prothrombin
(factor II)

Thrombin

Activation of certain factors (VII, II, X and protein C and S) is

essential for coagulation. This activation requires vit K (reduced
form)

DRUGS USED FOR THROMBOSIS

Anticoagulants
Thrombolytics

WARFARIN
Pharmacological class:
Anticoagulant
Activity:
Warfarin is an anticoagulant which is used to
decrease the clotting ability of the blood and
helps prevent harmful clots from forming in
blood vessels i-e thrombosis and
thromboembolism.
Warfarin (generic , Coumadin)
Oral : 1 - 10 mg tablets

WARFARIN: MECHANISM OF ACTION

Vitamin K epoxide
WARFARIN

Vitamin K reduced

Inactive factors II,

VII, IX, and X
Proteins S and C

Active factors II,

VII, IX, and X
Proteins S and C

Prevents the reduction of vitamin K, which is essential for activation of certain factors

INDICATIONS
Prophylaxis and treatment of venous thromboembolism (deep
vein thrombosis and pulmonary embolism)

Prophylaxis and treatment of Atrial fibrillation

Valvular stenosis
Heart valve replacement
Myocardial infarction

WHY TO MONITOR WARFARIN THERAPY?

Narrow therapeutic range
Can increase risk of bleeding

CONTARINDICATIONS AND PRECAUTIONS

Hypersensitivity to warfarin
Condition with risk of hemorrhage
Hemorrhagic tendency
Inadequate laboratory techniques
Protein C & S deficiency
Vitamin K deficiency
Intramuscular injections

SIDE EFFECTS
Hemorrhage
Skin necrosis
Purple toe syndrome
Microembolization
Teratogenecity
Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.

HEPARIN
Pharmacological class:

antithrombotic/anticoagulant

Activity:
Inhibits thrombus by inhibiting the conversion of
prothrombin to thrombin and fibrinogen to fibrin,
preventing the clot formation. It does not lyse the existing
clot but prevent the clot enlargement and extension.
Heparin (generic, Liquaemin sodium)
Parenteral - 1000 - 40,000 U/ml

Mechanism of Action
HEPARIN
enhances the action of Antithrombin III (AT-III) (plasma protease
inhibitor) 1000 fold activity
antithrombin III inhibits clotting factor proteases,
Thrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexes
heparin binds to AT-III and causes a conformational change
thereby activating AT-III

MOA of
Heparin

Indications
Anticoagulant (blood thinner)
Used to treat and prevent blood clot in veins,
arteries and lungs
Used before surgeries to prevent risk of clots

CONTRAINDICATIONS
Hypersensitivity
Uncontrolled bleeding
Severe thrombocytopenia

PRECAUTIONS
Severe liver and kidney diseases
Ratinopathy (hypertensive or diabetic)
Untreated Hypertension
Ulcers
Spinal cord or brain injury
History of congenital or aquired bleeding disorders
Malignancies

Side effects
Drug induced hepatitis
Alopecia (long term use)
Rashes
Urticaria
Bleeding
Anemia
Thrombocytopenia
Hypersensitivity
Fever

Warfarin and heparin

pharmacokinetics and
pharmacodynamics

Warfarin pharmacokinetics
Warfarin sodium is a racemic mixture of the R- and Senantiomers of Warfarin. The S-enantiomer exhibits 2 to
5 times more anticoagulant activity than the Renantiomer in humans, but generally has a more rapid
clearance.

Absorption
Warfarin is essentially completely absorbed after oral
administration, with peak concentration generally attained
within the first 4 hours.

Distribution
Warfarin distributes into a relatively small apparent volume of
distribution of about 0.14 L/kg.
A distribution phase lasting 6 to 12 hours is distinguishable after
rapid intravenous or oral administration of an aqueous solution.
Approximately 99% of the drug is bound to plasma proteins.
http://www.drugs.com/pro/warfarin.html

Metabolism
The elimination of Warfarin is almost entirely by metabolism.
Warfarin is stereoselectively metabolized by hepatic
cytochrome P-450 (CYP450) microsomal enzymes to
inactive hydroxylated metabolites (predominant route)
Patients with one or more variant CYP2C9 alleles have
decreased S-Warfarin clearance

http://www.drugs.com/pro/warfarin.html

Excretion
The terminal half-life of Warfarin after a single dose is
approximately 1 week; however, the effective half-life ranges
from 20 to 60 hours, with a mean of about 40 hours.
The clearance of R-Warfarin is generally half that of SWarfarin,
thus as the volumes of distribution are similar,
the half-life of R-Warfarin is longer than that of S-Warfarin.
http://www.drugs.com/pro/warfarin.html

 The half-life of R-Warfarin ranges from 37 to 89 hours,

that of S-Warfarin ranges from 21 to 43 hours. up to 92%
of the orally administered dose is recovered in urine.
Very little Warfarin is excreted unchanged in urine.
Urinary excretion is in the form of metabolites.

Warfarin pharmacodynamics
An anticoagulation effect generally occurs within 24
hours after Warfarin administration.
However, peak anticoagulant effect may be delayed
72 to 96 hours.
The duration of action of a single dose of racemic
Warfarin is 2 to 5 days.
The effects of Warfarin sodium may become more
pronounced as effects of daily maintenance doses
overlap.

Pharmacodynamics of warfarin
Warfarin is administered clinically as a racemic mixture
of 2 enantiomer, r and s warfarin
The disposition and action of the enantiomers are
qualitatively similar but quantitatively quite different
For most purposes the racemic mixture cab be
considered as a single drug
The dose effect relat ionship
For most drugs the relationship between dose and effect
can be conventiently considered in 2 parts
The dose concentration relationship and the
concentration effect relationship

A 3rd step is required to describe the extent and time

course of changes in clotting factor concentration refered
to as the prothrombin complex
This step has been called physiological effect
relationship
Concentration bound or unboumd
The study of plasma protein binding and warfarin and its
interaction with other drugs has provided an insight into
the significance of ppb for many clinical useful drugs

Heparin pharmacokinetics

Absorption
Not effective orally
When given intra muscularly it may cause hematoma
Normally given iv and sc
Metabolism
Heparin is metabolized by heparinase in the liver
Elimination
Average half life is 1to 5hr and is dose dependent
excreted in urine
20-50 % is excreted unchanged.

Comparison of warfarin and heparin

pharmacokinetics and pharmacodynamics
Absorption

Heparin
Parental only

Warfarin
oral

Vol of distribution

Plasma vol (0.07l/kg)

7.6-13.9l

Hepatic metabolism and uptake

by reticulo endothelial system
also by thrombin and other
clotting factors

hepatic

elimination

50-90min

36-42hr

Protein binding

Bound to antithrombin 3 and

other serine proteases

99.4% bound to albumin

Plasma concentration

0.2-0.4uml

1.5 mg/l

Side effect

Bleeding
thrombocytopenia

Bleeding skin necrosis

Drug interaction

Metabolism/ clearance

Need of thromboprophylatic
system
Patient related
Active cancer or cancer treatment
Age > 60
Dehydration
Known thrombophilias
Obesity (BMI >30 kg/m2)
One or more significant medical comorbidities (e.g. heart disease; metabolic,endocrine or respiratory
pathologies; acute infectious diseases; inflammatory conditions)
Personal history or first-degree relative with a history of VTE
Use of hormone replacement therapy (HRT)
Use of oestrogen-containing contraceptive therapy
Varicose veins with phlebitis
Pregnancy or < 6 weeks post partum (see obstetric section for specific risk factors)

 Admission related
Significantly reduced mobility relative to normal state for 3 days
Total anaesthetic + surgical time > 90 minutes
Surgery involving pelvis or lower limb and total anaesthetic +
surgical time > 60 minutes
Acute surgical admission with inflammatory or intra-abdominal
condition
Surgery with significant reduction in mobility
Hip or knee replacement
Hip fracture
Bariatric Surgery
Critical care admission

Conditions in which warfarin and

heparin prescribed

Warfarin sodium tablets are indicated for:

Prophylaxis and treatment of venous thrombosis and

its extension, pulmonary embolism (PE).
Prophylaxis and treatment of thromboembolic
complications associated with atrial fibrillation (AF)
and/or cardiac valve replacement.
Reduction in the risk of death, recurrent myocardial
infarction (MI), and thromboembolic events such as
stroke or systemic embolization after myocardial
infarction.

Heparin
is the drug of choice for the initial therapy of deep venous
thrombosis, pulmonary embolism, and acute arterial
occlusion.
After an acute myocardial infarction (with or without
thrombolysis) the initial anticoagulation is done with heparin, even
though the value of the drug is not clearly defined.
Its use for unstable angina pectoris needs to be researched
further;
heparin also serves for the prevention of thromboses in
surgery with extracorporeal circulation and in hemodialysis, as well
as for the maintenance of open venous catheters.

Comparison of Heparin
and Warfarin

Comparison-Efficacy
Warfarin is preferred in VTE in cancer patients
Main problem-achieving therapeutic drug levels (vomiting,
drug interactions, malnutrition, liver dysfunction)
Bleeding-Maintain INR (2 consecutive days)
Delayed onset

Heparin-lower risk of ADRS

Heparin is preferred based on its ease of administration and
more anticoagulant effect
Lab for PTT
Quick onset

Efficacy
LMWH (Datleparin) Superior efficacy to warfarin(patients with cancer and VTE)
without increasing the risk of bleeding
Improved response rates and survival in patients with lung
cancer

Safety
Bleeding is the serious acute complication of heparin
therapy.
A further serious complication is the syndrome of
thrombocytopenia with arterial thromboemboli
and haemorrhage which occurs in about 2 3% of
patients who receive heparin for a week or more.
Bleeding is also the commonest side effects of
warfarin
Long-term warfarin therapy is the mainstay of treatment
for cancer patients who develop VTE, several studies

Safety
Greater proportion of time spent on heparin but with a lower
intensity of anticoagulation (ie, 0.2 anti-X aU/mL) provided a
significantly reduced hazard of VTE recurrence.
In contrast, the proportion of time spent
on the currently
recommended intensity of heparin anticoagulation was not
significantly associated with fewer events
The duration of overlapping heparin and warfarin therapy was
not a predictor of VTE recurrence
A higher proportion of time on warfarin with an INR 2.0 was
associated with a significantly reduced hazard of VTE recurrence

Safety
Heparin should be substituted prior to conception and
continued throughout the first trimester, after which
warfarin should replace heparin, as continued exposure
to heparin may cause osteoporosis.
Hence, as warfarin is teratogenic, heparin is
preferred as the anticoagulant during pregnancy.

Safety
A higher mean daily prothrombin time/INR on warfarin is
associated with a significantly increased hazard of major
bleeding, the hazard is not significantly increased for proportion of
time on warfarin with an INR 2.0.
Immediate daily prothrombin time/INR is more relevant to a
warfarin-associated bleeding complication than the cumulative
time on warfarin with an INR 2.0.
Initiating heparin and warfarin concurrently and stopping the heparin
when the INR is 2.0 regardless of the duration of overlapping
heparin and warfarin therapy appears to be as effective as the
recommended 4-5 days of heparin/warfarin overlap. The duration of
heparin exposure likely will be shortened, reducing the risk of heparininduced thrombocytopenia

Tolerability
A recent study by Vargas-Hitoset al.[47]shed light on the
use of low molecular weight heparin (LMWH) as a well
tolerated and effective alternative to warfarin
therapy.
LMWH therapy was administered for an average of 36
months and resulted in the absence of recurrent
thrombosis in 87% of patients.

Additional Findings
During the 6-month study period,
minor hemorrhage occurred in 9 patients from the warfarin
group and in 5 patients from the enoxaparin group
Eighteen patients randomly assigned to warfarin (24%)
experienced 1 or more episodes of thrombocytopenia
compared with 16 patients randomly assigned to
enoxaparin (32.4%)
There
was
no
episode
of
heparin-induced
thrombocytopenia in either group.

Toxicity/Mortality
During the 3-month study treatment period,
17 patients (22.7%) receiving warfarin died compared with 8
patients (11.3%) receiving enoxaparin
Death- 9 in the warfarin group and 5 in the enoxaparin
group
Bleeding- 6 patients (all in the warfarin group), to sepsis in 4
patients, and to aspiration pneumonia in 1 patient.
At the end of the 3-month follow-up period, progression of the
underlying cancer was observed in 10 patients receiving
warfarin (13.3%) and in 12 patients receiving enoxaparin
(16.9%).

R
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Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotics: indications and management. Edinburgh: SIGN; 2012. (SIGN publication no. 129).
[August 2012]. Available from URL: http://www.sign.ac.uk

Rivaroxaban, DABIGATRAN ETEXILATE

Rivaroxaban and dabigatran

novel oral agents which are direct inhibitors of factor Xa and thrombin respectively
oral route
no requirement for monitoring.
half life eight hours for rivaroxaban (12 hours in older patients).
less susceptible to drug interactions than VKAs and serious bleeding
rivaroxaban was compared to warfarin in patients with AF at increased risk of stroke. For
the primary outcome of stroke or systemic embolism there were 1.7% per year in the
rivaroxaban group and 2.2% per year in the warfarin group
Rivaroxaban is also accepted for the treatment of DVT and prevention of recurrent DVT
and pulmonary embolism

Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med
2011;365(10):883-91.

Dabigatran etexilate
Dabigatran etexilate is a prodrug
converted to the active direct thrombin inhibitor dabigatran by hydrolysis in the intestinal wall
and liver.
It is mainly (80%) eliminated by the renal route and consequently there is a risk of accumulation
in severe renal impairment
Half life 13 hours for dabigatran etexilate
Dabigatran etexilate, rivaroxaban and apixaban are licensed for use in hip and knee
replacement surgery and for the prevention of VTE(venous thromboembolism ) in the UK

Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of
international normalised ratio control for stroke prevention in atrial fibrillation: An analysis of the RE-LY trial. Lancet 2010;376(9745):975-83.

Dabigatran etexilate can be considered as an alternative to warfarin in the management of

patients with atrial fibrillation with one or more risk factors for stroke.

orally active direct thrombin inhibitor dabigatran etexilate was compared to warfarin in
subjects with AF and at increased risk of stroke. At a dabigatran dose of 110 mg twice
daily, efficacy in prevention of vascular events was comparable to warfarin but major
bleeding was less frequent (2.87% versus 3.57%).
At a dose of 150 mg twice daily, stroke and systemic embolism occurred significantly
less frequently than with warfarin (1.11% per year versus 1.69% per year
Warfarin is not better than, dabigatran in terms of stroke risk reduction and bleeding
events.

Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older
and younger patients with atrial fibrillation: An analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation
2011;123(21):2363-72.

Fondaparinux
synthetic pentasaccharide
Like heparins, it is an indirect inhibitor requiring antithrombin for its
effect
selectively inhibits factor Xa, with no activity against thrombin
It has a longer half-life than LMWHs of around 17 hours which is an
important consideration when planning invasive procedures

Giangrande PL. Fondaparinux (arixtra): A new anticoagulant. Int J Clin Pract 2002;56(8):615-7

As for LMWH, the dose of fondaparinux is weight adjusted and routine monitoring of
prophylactic
therapeutic doses is not required
Fondaparinux is renally excreted
therefore should be used with caution in patients with moderate renal impairment
(creatinine clearance 30-50 ml/min) avoided in patients with severe renal impairment
(creatinine clearance <30ml/min)

Jazkallahu Khair!