Pharmacokinetic Comparison of Warfarin and Heparin

This article compares the pharmacokinetic properties of warfarin and heparin, including absorption, distribution, metabolism, and elimination. It discusses how these properties inform the clinical aspects of the drugs, such as dosing, onset/offset of effect, and patient suitability.

Running head: PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 1
Principles of Pharmacology and Therapeutics
Name of Author
Institution of Affiliation
Date of Submission

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 2
My profile drug is warfarin and its generic name is Coumadin. The relevant drug classes
based on ATC classification system of warfarin include:
B- Blood and blood forming organs
B01-Antithrombotic agents
B01A- Antithrombotic agents and
B01AA- Vitamin K antagonists
Warfarin is anticoagulant drug that is used to reduce the risk of blood clotting. It prevents blood
from forming coagulating to form a clot in sensitive organs like lungs, brain and heart. Its
indication includes
-Prophylaxis and treatment of venous thrombosis
-Prophylaxis and treatment of thromboembotic complications that are linked with cardiac valve
replacement and atrial fibrillation.
-Reduction in the risk of death as a result of stroke or systemic embolization, and recurrent
myocardial infarction.
-Heart attack

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 3
- Heparin and aspirin

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 4
A study was done to determine the effectiveness of warfarin among ischemic stroke patients
who had atrial fibrillation. Among the participants were 12000 survivors of stroke. Out of
11000, 88 % were treated with warfarin (Ahmed et al., 2010). According to the findings of
the study, patients that were treated with warfarin had more days at home than 1000
patients who had no warfarin therapy. Besides, patients that were discharged on warfarin
therapy had reduced risk of recurrent ischemic stroke. This study provides crucial evidence
that warfarin therapy is effective in treatment of ischemic stroke disease as it improved the
clinical outcomes of the participants with stroke conditions (Adam et al., 2012).
Another study was carried out to compare the efficacy and safety of warfarin therapy verses
left atrial appendage therapy in prevention of stroke in patients with atrial fibrillation.
According to the findings of the research, the efficacy of percutaneous closure of left atrial
appendage was inferior to the warfarin therapy.
A randomized study was carried out to determine the safety and efficacy drug in
comparison to dextron 40 in the prevention of venous thrombosis. The patients who were
selected in the study had a high risk for deep vein thrombosis after elective total knee
replacement. Medication f warfarin was done in a two-step approach in order to avoid any
bleeding complications. Among the participants, 53 patients were treated with warfarin and
37 treated with dextron. According to the findings of the study, measures of blood loss
indicated that there are no difference between patients that were treated with dextran with
these who were treated with warfarin. Also, the findings showed that excessive

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 5
postoperative bleeding was infrequent besides being similar in both therapy groups. The
study demonstrated that the two step approach of warfarin treatment gives highly effective
prophylaxis of postoperative venous thrombosis after knee surgery when compared to
dextron therapy (Adam et al., 2012).
Chemically heparin is a glycosaminoglycan polymer whereas warfarin is organic compound
known as 4-hydroxycoumarins. Both medication works in different ways to inhibit the
production of cofactors of blood clotting.
Warfarin is anticoagulant drug that acts by blocking the formation of clotting factors that
are dependent on vitamin K. This action decreases the ability of the body to form blood
clots. On the other hand, Heparin is anticoagulant drug which acts by binding different
proteins and enzymes thereby preventing fibrin and thrombin from working correctly in the
blood hence making the process of blood clotting and coagulation to stop (Dans et al.,
2013).
Once administered, Warfarin medication requires enough time to build a therapeutic level
in the blood whereas Heparin acts quickly thus mostly used during emergence situation to
quickly stabilize blood circulation to the body. Warfarin is supplied through injectable
intravenous, subcutaneous medication or oral tablet whereas heparin is supplied as an
injectable medication thus it can be administered through intravenous or subcutaneous route
(Dans et al., 2013).
Warfarin is mostly used anticoagulants but since human being differs in their physiological
function, its dosage differs from each individual. Patients under warfarin therapy are
supposed to take their blood tests for every 2 to 3 weeks for confirmation of their blood
thinning degree. On the other hand, heparin is commonly used in hospitals to prevent

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 6
emergence clot and mostly recommended for pregnant women when antiphospholipid
antibodies are discovered. The recommendation for heparin instead of warfarin for pregnant
women is because warfarin can harm the foetus (Björck et al., 2013).
Both warfarin and heparin are anticoagulant used to treat thrombosis and stroke. Besides
both have almost similar side effects which include bleeding, rash, headache and elevated
enzymes. Both drugs have the same indication that is treatment of stroke,
thromboembolism, transient ischemic attack and myocardial infarction.
Although Warfarin has various indications, its mechanism of action is the same with that of
heparin. Its mechanism of action for these multiple indications is antagonising the action of
vitamin K that leads to production of clotting proteins. It acts by blocking the formation of
clotting factors that are dependent on vitamin K. This action decreases the ability of the
body to form blood clots. After its action, the medication is cleared through the cytochrome
P450 enzymes found in the liver (Carlquist et al., 2013). Heparin acts by binding different
proteins and enzymes thereby preventing fibrin and thrombin from working correctly in the
blood hence making the process of blood clotting and coagulation to stop. It is metabolized
through the liver and through endothelial system. It is eliminated by reticuloendothelial
system and small fractions excreted via urine.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 7
Frequency monitoring of warfarin therapy is crucial for quality clinical outcome and for the
prevention of adverse effects caused by the medication. The initial dose for of outpatient
should be monitored for at least 2 to 3 times a week for the first 10 days of warfarin
therapy. The monitoring of the initial dose is important as it gives the prescriber whether
stable value will be achieved (Ahmed et al., 2010). The target of INR levels differs from
case to case depending on the disease being cured but most patients tend to have 2.5 to 3.5
values. More frequent testing is done until greater therapeutic range is achieved for quality
clinical outcomes. The greater therapeutic range is achieved by repeated adjustment of
warfarin dose for therapeutic response (Dans et al., 2013).
Therapeutic effect of warfarin should be monitored closely. Monitoring closely to patient
receiving under warfarin ensures safety and efficacy of the medication. Monitoring is done
through periodic blood testing which assesses the patient’s prothrombin time. The blood
testing also is used by the physician to assess the international normalized ratio. The
physician uses the laboratory parameter to monitor the ratio of PT/ INR. This ensures
standardized measurement without variations for improved clinical outcomes. INR that is
greater than 5 is understood to increase the risk of bleeding. For example, for INR that is
greater than 1.5 linked to bleeding, the physician is supposed to advice the patient to cease
warfarin or give the patient vitamin K, and assess the INR frequently until it is clinically
stable (Adam et al., 2012). Some factors that is thought to influence the INR includes drug
interaction with warfarin, changes in diet and alteration of health status like chronic renal or
hepatic impairment.
References for Question 2

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 8
Adam, S. S., McDuffie, J. R., Ortel, T. L., & Williams, J. W. (2012). Comparative
effectiveness of warfarin and new oral anticoagulants for the management of atrial
fibrillation and venous thromboembolism: a systematic review. Annals of internal
medicine, 157(11), 796-807.
Ahmed, I., Gertner, E., Nelson, W. B., House, C. M., Dahiya, R., Anderson, C. P., ... & Zhu,
D. W. (2010). Continuing warfarin therapy is superior to interrupting warfarin with or
without bridging anticoagulation therapy in patients undergoing pacemaker and
defibrillator implantation. Heart Rhythm, 7(6), 745-749.
Björck, S., Palaszewski, B., Friberg, L., & Bergfeldt, L. (2013). Atrial fibrillation, stroke risk,
and warfarin therapy revisited: a population-based study. Stroke, 44(11), 3103-3108.
Carlquist, J. F., Horne, B. D., Mower, C., Park, J., Huntinghouse, J., McKinney, J. T., ... &
Anderson, J. L. (2010). An evaluation of nine genetic variants related to metabolism
and mechanism of action of warfarin as applied to stable dose prediction. Journal of
thrombosis and thrombolysis, 30(3), 358-364.
Dans, A. L., Connolly, S. J., Wallentin, L., Yang, S., Nakamya, J., Brueckmann, M., ... &
Yusuf, S. (2013). Concomitant use of antiplatelet therapy with dabigatran or warfarin
in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)
trial. Circulation, 127(5), 634-640.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 9
Question 3 (Pharmacokinetics)
Compare and contrast the key pharmacokinetic aspects of your profile drug with that of
the comparator drugs. Focus primarily on discussing how these underlying
pharmacokinetic properties inform or explain any significant clinical aspects of the effects
or use of the drugs (e.g. differences in dosing/administration, speed on onset/offset of
effect, who can use the drug). It is insufficient to simply list the pharmacokinetic values of
the drugs - your explanation and interpretation of the values is required.
Warfarin is rapidly absorbed after oral administration with nearly 100 % oral
bioavailability. It is also absorbed percutaneously with considerable interindividual
variations. It achieves its peak concentrations within 4 hours. It has small volume of
distribution which is 0.14 L per kg (Rosenberg, 2010). Also, warfarin has 99 % binding
primarily to protein albumin. After its absorption, warfarin is metabolized to stereo and
regio- selectively by the hepatic microsomal enzymes (Hawcutt et al., 2014). Regio-
warfarin is then metabolized by 3A4, 1A2 and CYP1A1 to give rise to 6-, 8- and 10-
hydroxylated metabolites whereas Stereo warfarin is further metabolized by cytochrome
P450 to give rise to 6- and 7- hydroxylated metabolites. The hydroxylated metabolites are
then conjugated and excreted through the bile or urine. Its pharmacokinetic half- life is 36
to 42 hours that is 4 days for the patient to acquire steady state concentration. The toxicity
level of warfarin therapy is LD50=374 and is understood to affect human s and other
mammals (Gomes et al., 2012).
On the other hand, Heparin administered parenterally since it is absorbed via the
gastrointestinal mucosa. It is mostly administered by the use of deep sc injection or iv
infusion. Its onset of action after administration is immediately but it can be delayed by 20
to 60 minutes. Its volume of distribution is ranges from 40 to 70 ml/ min which is
approximately the same as blood volume. Heparin has very high protein binding such as
globulins, fibrinogens and to low- density lipoproteins. It is metabolized through the liver
and through endothelial system. It is eliminated by reticuloendothelial system and small
fractions excreted via urine. The plasma half-life of heparin is 1.5 hours and its adult
clearance is 0.43ml/kg/min (Shehab et al., 2010).

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 10
References for Question 3
Felmlee, M. A., Morris, M. E., & Mager, D. E. (2012). Mechanism-based pharmacodynamic
modeling. In Computational Toxicology (pp. 583-600). Humana Press, Totowa, NJ.
Finkelman, B. S., Gage, B. F., Johnson, J. A., Brensinger, C. M., & Kimmel, S. E. (2011).
Genetic warfarin dosing: tables versus algorithms. Journal of the American College of
Cardiology, 57(5), 612-618.
Gomes, T., Mamdani, M. M., Holbrook, A. M., Paterson, J. M., & Juurlink, D. N. (2012).
Persistence with therapy among patients treated with warfarin for atrial
fibrillation. Archives of internal medicine, 172(21), 1687-1689.
Gomes, T., Mamdani, M. M., Holbrook, A. M., Paterson, J. M., Hellings, C., & Juurlink, D. N.
(2013). Rates of hemorrhage during warfarin therapy for atrial fibrillation. Cmaj, 185(2),
E121-E127.
Hawcutt, D. B., Ghani, A. A., Sutton, L., Jorgensen, A., Zhang, E., Murray, M., ... &
Pirmohamed, M. (2014). Pharmacogenetics of warfarin in a paediatric population: time in
therapeutic range, initial and stable dosing and adverse effects. The pharmacogenomics
journal, 14(6), 542.
Rosenberg, A. F., Zumberg, M., Taylor, L., LeClaire, A., & Harris, N. (2010). The use of anti-Xa
assay to monitor intravenous unfractionated heparin therapy. Journal of Pharmacy
Practice, 23(3), 210-216.
Shehab, N., Sperling, L. S., Kegler, S. R., & Budnitz, D. S. (2010). National estimates of
emergency department visits for hemorrhage-related adverse events from clopidogrel plus
aspirin and from warfarin. Archives of internal medicine, 170(21), 1926-1933.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 11

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 12
Warfarin is mostly utilized to treat blood clots. The drug has various adverse effects that
can lead to harm or death if not avoided. One of the potential side effects of warfarin that I
believe the physician should know is severe bleeding.
It is of important for the physician to be aware of this adverse effect since it is one of the
most common complications. The complication can contribute to morbidity, medical related
ED visits and increased health care expenditures. With the knowledge of excessive bleeding
that may happen as a result of warfarin, the doctor will try to avoid the adverse effects by
considering the patients history before to determine whether the patient may be affected by
bleeding. The physician may avoid this by considering the intensity of anticoagulation, the
age of the patient, whether the patient has the history of renal failure or cerebrovascular
diseases and whether the patient has history of gastrointestinal bleeding or history of recent
trauma or recent surgery. Patients with more risk factors will be considered to have higher
chances of having bleeding thus the doctor will have to consider comparator drugs rather
than warfarin.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 13
The basis of adverse effects that results from warfarin medication is that warfarin has ability to
interact with other medications. Other drugs such as herbal medicines, naproxen, ibuprofen and
vitamin alter the effectiveness of warfarin. This results in an INR that is either too high or low as
these drugs are understood to enhance anticoagulant effects of warfarin thereby increasing the
likelihood of adverse effects such as bleeding.
Warfarin also interacts with alcohol and various foods resulting to adverse effects. Alcohol intake
affects how the body metabolizes warfarin therapy. Even if the INR remain within the set range,
alcohol is known to cause antiplatelet effect which increases the risk of major bleeding.
This results to antiplatelet effects which increases the risk of bleeding. Furthermore, some diets
mostly containing vitamin K such as lettuce, spinach and broccoli is known to affect the
effectiveness of warfarin. Eating diets rich in vitamin K is understood to lower the INR and PT
thereby making warfarin therapy to be ineffective which significantly increases the risk of blood
clots. Therefore, if a patient is under warfarin therapy, he or she is supposed to avoid alcohol,
other drugs and be put under diet control which is aimed at preventing or reducing risks of
adverse effect of warfarin.
Various research studies on patients having adverse effects of warfarin in different settings
have been reported. Most of these cases are as a result of warfarin’s narrow therapeutic
index, its predisposition to drug and food interactions and its ability to cause haemorrhage.
A recent study found out that warfarin can interact with anti- diabetes drugs thereby causing
serious hypoglymic effects. Among the participants were older people who were treated
with sulfonylurea and glimepiride. According to the study, warfarin was linked with a 22

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 14
% increase in hospitals admission and emergence visits. The study noted that emergence
visits in hospitals was very rare for hypoglycaemia but were common for falls.
Furthermore, the adverse effect was pronounced when warfarin drug was administered. The
concurrent use of glimepiride together with warfarin was linked with hospital admissions
with many being altered consciousness and fall related fractures. Another study which is
similar to this one involved 465918 patients who had diabetes. The study found out that 80
% of these diabetic patients who were using anti-diabetes drugs together with warfarin were
hospitalized with hypoglycaemia effects.
The main aim of warfarin medication is to reduce the clotting tendency of blood. Hence, its
effect must be monitored carefully to reduce its adverse effect. The physician is supposed
to monitor the adverse effect of warfarin by carefully testing the blood. The dosage of
warfarin is adjusted based on the results of the blood test as this keeps the clotting time
within a target range.
During monitoring, the blood test is used to measure the time it takes for blood to clot
which in this case is referred to as protime (PT) and reported by the physician as the
International Normalized Ratio (INR). The INR values obtained can then be compared with
the PT results acquired from different laboratories. It is of crucial important to monitor for
the prescriber to monitor INR twice a week as this ensures the level of warfarin therapy
remains at effective therapy range. If the INR is found to be too low then the blood clots
will not be prevented and if it is too high then there is an increased risk of serious bleeding.
This remains the main reason why these under warfarin therapy should have their blood
tested frequently to maintain it’s effective for quality clinical outcome (Carlquist et al.,
2012).

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 15
There are several approaches that can be taken to reverse the adverse effect of warfarin.
These pharmacological strategies includes the omission of the warfarin therapy,
administration of intravenous or oral dose of vitamin K , use of 3 or 4 factor Prothrombin
complex concentrate and administration of fresh frozen plasma. Other management
strategies for reversal of adverse effects caused by warfarin therapy include the
administration of factor eight inhibitor bypassing activity and recombinant factor viia.
The fate of clinical situation must be first evaluated to check the patient’ INR and find out
whether there is a major bleeding or not. The evaluation is important since it determines the
best approach to use in reversing of the adverse effects of warfarin (Felmlee, Morri &
Mager, 2012).
For a patient who is at high risk of bleeding, oral vitamin K should be given in concert with
the omission of warfarin therapy. This is because warfarin acts as competitive inhibitor of
VKOR with a significant decrease in the activity of vitamin K- dependent coagulation
factors. Administration of vitamin K is understood to overpower the anticoagulation
systems which in turn activate the endogenous coagulation factor (Rhea & Molinaro, 2011).
The adverse effect of warfarin and heparin are the same since they both are anticoagulant. The
most serious side effects include bleeding which can be experienced either in internal organs such
as kidney, lungs and brain. Other adverse effects include bloating, diarrhea, jaundice and pain in

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 16
the toes in case of warfarin and mild pain, redness in the injection site in case of heparin. Some
patients receiving heparin may experience confusion, swelling and trouble in breathing. Warfarin
interacts with many foods, drugs and alcohol resulting to serious adverse effects thus in most
cases it is avoided (Björck et al., 2013). Also, heparin is recommended to prevent emergence clot
for pregnant women when antiphospholipid antibodies are discovered. In this case, heparin is
used instead of warfarin because warfarin can harm the baby in the womb (Douketis, 2011).
References for question 4
Björck, S., Palaszewski, B., Friberg, L., & Bergfeldt, L. (2013). Atrial fibrillation, stroke risk, and
warfarin therapy revisited: a population-based study. Stroke, 44(11), 3103-3108.
Carlquist, J. F., Horne, B. D., Mower, C., Park, J., Huntinghouse, J., McKinney, J. T., ... &
Anderson, J. L. (2010). An evaluation of nine genetic variants related to metabolism and
mechanism of action of warfarin as applied to stable dose prediction. Journal of
thrombosis and thrombolysis, 30(3), 358-364.
Dans, A. L., Connolly, S. J., Wallentin, L., Yang, S., Nakamya, J., Brueckmann, M., ... & Yusuf,
S. (2013). Concomitant use of antiplatelet therapy with dabigatran or warfarin in the
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)
trial. Circulation, 127(5), 634-640.
Douketis, J. D. (2011). Perioperative management of patients who are receiving warfarin therapy:
an evidence-based and practical approach. Blood, 117(19), 5044-5049.
Felmlee, M. A., Morris, M. E., & Mager, D. E. (2012). Mechanism-based pharmacodynamic
modeling. In Computational Toxicology (pp. 583-600). Humana Press, Totowa, NJ.
Rhea, J. M., & Molinaro, R. J. (2011). Direct thrombin inhibitors: clinical uses, mechanism of
action, and laboratory measurement. Med Lab Obs, 43, 20-22.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 17

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 18

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 19

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 20

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 21

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 22
There is a wider inter –individual variability that significantly influences the efficacy of warfarin
therapy. One of these causes is genetic factors that involved variation in CYP4F2, VKORC1 and
VKORC1 genes which are clustered on chromosome.

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 23

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 24
I choose the VKORC1 and CYP2C9 genotypes because they are most important known
genes that are determinant of warfarin dosage therapy. It is understood that warfarin targets
an enzyme that is involved in vitamin K recycling known as VKORC1. A variation in
VKORC1 which is very common among individuals is linked with an increased sensitivity
to warfarin therapy leading to a lower warfarin dose requirement (Maddox, et al., 2013).
Warfarin medication is metabolized by CYP2C9 enzyme and the variation of the enzyme
among individuals that is CYP2C9*2 and CYP2C9*3 are linked with the lower dose
requirement. This lower requirement of warfarin dosage as a result of genetic variant
comprises the efficacy of warfarin therapy (Hohnloser, et al., 2012).
CYP2C9 is a microsomal enzyme which is partially responsible for the breakdown of warfarin
therapy. Mutated CYP2C9 leads to reduced rate of warfarin metabolism thus a longer half-life.
As a result, this increases the risk of haemorrhage with a normal dose of coumarin. VKOR is
responsible in reduction of vitamin K to its active form. It leads to activation of vitamin K-
dependent clotting factors (Amitrano et al., 2010). Mutated VKOR results to insufficient levels of
reduced vitamin K and other vitamin K dependent clotting factors. The addition of warfarin
therapy would compound this deficiency thereby leading to patient’s risk of internal bleeding also
known as haemorrhaging. Furthermore a mutation in the factor IX propeptide lead to extreme low
levels of factor IX during warfarin medication. This in turn results to an increased risk of
bleeding and other adverse effects of warfarin therapy (Monagle, et al., 2012).

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 25
Warfarin is commonly used oral anticoagulant. It shows wide interindividual variations in
dose requirement. A study was carried out to determine interaction of individual genotype
and warfarin response. According to this research, knowledge on individual genotype and
warfarin response plays a key role in optimization of warfarin efficacy. The study found out
that CYPP2C9, VKORC1 enzymes influences the warfarin dosage. The study also found
out that there is a weak effect of CYP4F2 and the presence of CYP2C9*2 and CYP2C9*3
variant alleles led to decreased enzyme activity which was linked to decreased warfarin
dosage
Considering the genetic variant of CYP2C9 AND VKOR1 is crucial when describing
warfarin drug. This is important as it help the prescriber to know the right warfarin dosage
for its therapeutic outcome. There are warfarin dosage algorithms which are sensitive to
variant in CYP2C9 and VKOR1 that combine genetic information (Lee & Klein, 2013).
Furthermore, when the prescriber finds out the person has mutated VKOR, the physician
may prescribe other anticoagulant drugs that can fit the patient as Mutated VKOR results to
insufficient levels of reduced vitamin K and other vitamin K dependent clotting factors.
Prescribing other anticoagulant medication is crucial as the addition of warfarin therapy

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 26
would compound this deficiency thereby leading to patient’s risk of internal bleeding also
known as haemorrhaging (Hohnloser, et al., 2012).
References for question 5
Amitrano, L., Guardascione, M. A., Menchise, A., Martino, R., Scaglione, M., Giovine,
S., ... & Balzano, A. (2010). Safety and efficacy of anticoagulation therapy with low
molecular weight heparin for portal vein thrombosis in patients with liver
cirrhosis. Journal of clinical gastroenterology, 44(6), 448-451.
Björck, S., Palaszewski, B., Friberg, L., & Bergfeldt, L. (2013). Atrial fibrillation, stroke
risk, and warfarin therapy revisited: a population-based study. Stroke, 44(11), 3103-
3108.
Hohnloser, S. H., Oldgren, J., Yang, S., Wallentin, L., Ezekowitz, M., Reilly, P., ... &
Connolly, S. J. (2012). Myocardial ischemic events in patients with atrial fibrillation
treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-
Term Anticoagulation Therapy) trial. Circulation, 125(5), 669-676.
Lee, M. T. M., & Klein, T. E. (2013). Pharmacogenetics of warfarin: challenges and
opportunities. Journal of human genetics, 58(6), 334.
Maddox, W., Kay, G. N., Yamada, T., Osorio, J., Doppalapudi, H., Plumb & McElderry, H.
T. (2013). Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation
during atrial fibrillation ablation. Journal of cardiovascular
electrophysiology, 24(8), 861-865.
Monagle, P., Chan, A. K., Goldenberg, N. A., Ichord, R. N., Journeycake, J. M., Nowak-
Göttl, U., & Vesely, S. K. (2012). Antithrombotic therapy in neonates and children:
antithrombotic therapy and prevention of thrombosis: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2), e737S-

PRINCIPLES OF PHARMACOLOGY AND THERAPEUTICS 27
e801S.