1. RYAN J PUNAMBOLAM MD FRCPC
NEUROLOGY
ARHCC
!
May 21 2014
h AF, dabigatran 150 mg is taken twice daily
od. A reduced dose of 75 mg is recommended
reatinine clearance (CrCl) is 15 to 30 mL/
ated with the Cockcroft–Gault formula using
ht (see Table 1). Clearance is primarily renal,
substrate of permeability glycoprotein (P-gp).
atran with P-gp inducers (such as rifampin)
d. The combination of renal impairment and
as a greater tendency to achieve undesirable
hen compared with each factor separately.12–14,26
th moderate renal impairment (a CrCl of 30–50
hemodialysis can be considered for revers
bleeding.27–30
Clinical Trials and Efficacy
In the Randomized Evaluation of Long-Te
Therapy trial (RE-LY), patients older than 6
AF received blinded doses of dabigatran 110
daily to establish non-inferiority versus unb
ed warfarin. Study participants (n = 18,133
up to 2 years (Table 3).31–35
Two independen
were blinded to treatment assignments confi

2. Disclosures
• Speaker Fees from Bayer, Sanofi-Aventis,
Allergan,Tribute Pharmaceuticals,
Boehringer-Ingelheim

4. relative burden of stroke compared with heart disease contrib-
utes to substantial societal costs since each stroke is associated
with upward of 10 times the cost of myocardial infarction.16
Onthebasisofcurrentdemographicandpopulation-levelvascu-
lar risk factor trends, current projections are for an unprecedented
50% increase in stroke incidence in China during the next 20
years.17
Although demographic changes do account for some of the
Conclusions
Stroke is the second leading cause of death worldwide. In the
ongoing global epidemic of cardiovascular disease, stroke has
emerged as a major cause of preventable death and morbidity, par-
ticularly in the developing world where stroke is the predominant
subtype of vascular disease. Demographic and vascular risk factor
trends suggest that there will be an even greater burden of disease
Figure 1. The Global Stroke-Belt. Relative mortality rate from stroke compared with ischemic heart disease, 2004 (based on WHO Global
Burden of Disease data).15
S123
Burden of Stroke in the United States
tinues to present a significant public health challenge
ted States. Stroke is a leading cause of adult disabil-
thnic and geographic disparities in stroke incidence
mes have remained stubbornly persistent,2
and the
er of deaths from stroke is projected to increase in
g decades as the population ages.3
However, there is
n for optimism. During the last 40 years, there has
0% decline in the age-adjusted mortality rate from
he United States,4
and stroke has recently moved
ior position as the third leading cause of death to
e fourth leading cause of death overall.5
h there are multiple factors to help to explain this
ovements in blood pressure control at the population
kely to be playing a major role. During the last few
ach successive national health survey has recorded
ents in population systolic blood pressure and
on control. For example, the median systolic blood
mong aged 60 to 74 years in 1960–1962 was ≈150
subsequent surveys, the median systolic blood pres-
onsistently declined and by the 1988–1991 National
Nutrition Examination Survey III, the median sys-
pressure had decreased to 130 mmHg.6
ments in blood pressure have been particularly pro-
mong those with very high blood pressure, which
isproportionately higher risk for stroke. For instance,
ame period, the 90th percentile for systolic blood pres-
sed from >190 mmHg to <160 mmHg.6
This pattern
d hypertension control has also been demonstrated in
-income countries, which have experienced a 42%
stroke incidence overall during the past 40 years.7
Ongoing Global Epidemic of Stroke
lobal prospective, the outlook for stroke is quite dis-
conventional wisdom is that heart disease and stroke
ly diseases of the developed world, although in point
t of the burden of cardiovascular disease and stroke is
ountries in the developing world.8,9
Stroke continues to
nd leading cause of death worldwide (second only to
ular disease) and accounts for ≈1 in 10 deaths or 5.7
ths a year.10
This mortality burden has come with a
doubling of the stroke incidence in low- and middle-
untries with incidence rates that commonly surpass the
incidence rates seen in most high-income countries.7
So not only
is the overall disease burden of stroke higher in the developing
world but stroke also accounts for a greater relative proportion of
total deaths in low- and middle-income countries as well.
There is substantial variation in the distribution of stroke burden
by geographic region and by country—the level that may be most
relevant for policy and program development. These regional and
national hot spots constitute a global stroke belt that parallels the
well-documented geographic variations of stroke burden within
the stroke belt of the southeastern United States.11
The burden of
stroke is particularly high in Eastern Europe, North Asia, Central
Africa, and the South Pacific with a 10-fold difference in stroke
mortality and morbidity rates between the most affected and least
affected countries.12
For example, Russia’s standardized stroke
mortality rate is 251 per 100000 compared with a rate of 32 per
100000 in the United States.10
The pattern is quite similar for dis-
ability adjusted life year loss rates—a measure of overall disease
burden that takes into account both years of potential life lost from
premature deaths and long-term disability from stroke.12
Once again, the reasons for this geographic variation in the
burden of stroke globally are quite complex. However, national
income has emerged as a particularly strong predictor of stroke
burden.12
The association between lower national income per
capita and higher burden of stroke persists even after adjustment
for national measures of typical cardiovascular risk factors,
such as physical inactivity, hypertension, diabetes mellitus,
tobacco use, alcohol use, and dyslipidemia.12
The strong
association of stroke with national income is consistent with an
overall shift from communicable diseases to noncommunicable
diseases, such as heart disease and stroke, with rising income
in what has been termed the epidemiological transition.13
Infection, nutrition, and perinatal disease accounted for 34%
of deaths in 1990 but are projected to account for just 15%
of total deaths in 2020.14
In contrast, the proportion of deaths
from cardiovascular diseases, including stroke, is projected to
increase from 28% to 34% during that same period.14
A similar geographic pattern is also seen for the burden of
ischemic heart disease worldwide which is not surprising given
that these 2 forms of vascular disease have overlapping ath-
erosclerotic disease mechanisms and have major modifiable
risk factors in common. But although ischemic heart disease
is the predominant form of vascular disease burden overall,
stroke is the predominant form of vascular disease for many
Temporal and Geographic Trends in the Global
Stroke Epidemic
Anthony S. Kim, MD, MAS; S. Claiborne Johnston, MD, PhD
November 6, 2012; accepted April 4, 2013.
Departments of Neurology (A.S.K., S.C.J.) and Epidemiology and Biostatistics (S.C.J.), University of California, San Francisco, CA.
dence to Anthony S. Kim, MD, MAS, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Room
rancisco, CA 94158. E-mail akim@ucsf.edu
013;44[suppl 1]:S123-S125.)
merican Heart Association, Inc.
available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.000067
The Current State and Future of StrokeS124 Stroke June 2013
lower income countries.15
For example, ischemic heart disease
mortality rates are slightly higher than stroke mortality rates in
North America, Western and Northern Europe, and Australia.15
In contrast, stroke mortality rates are substantially higher than
ischemic heart disease mortality rates in much of Africa and
Asia (Figure 1). In South Korea and China, for example, 17%
to 18% of all deaths are from stroke compared with just 6%
to 8% for ischemic heart disease. This concentration of stroke
burden in low-income countries and in Asia and Africa sug-
gests that a targeted approach for addressing stroke in the
developing world may be warranted.10
The Case of China
In this global epidemic, the recent experience of China is
deserving of special attention. Not only is China an outlier in
terms of its substantial absolute stroke burden but also China
is an outlier in terms of its high relative burden of stroke com-
pared with ischemic heart disease.15
The sobering projections
of stroke incidence for the coming decades provide a case
study of the current challenges in addressing this epidemic.
Stroke is the leading cause of death in China with an esti-
mated 2.5 million incident strokes and 1.6 million deaths from
stroke each year.16
As previously described, stroke is the pre-
dominant form of vascular disease in China. The stroke mortal-
ity rate far exceeds the ischemic heart disease mortality rate in
a pattern that is shared by many low- and middle-income coun-
tries.15
Hemorrhagic strokes also make up a larger proportion
of incident strokes as well.17
In fact, the incidence of hemor-
rhagic stroke alone exceeds the incidence of myocardial infarc-
tion. This pattern of hemorrhage stroke subtypes and a higher
relative burden of stroke compared with heart disease contrib-
utes to substantial societal costs since each stroke is associated
with upward of 10 times the cost of myocardial infarction.16
Onthebasisofcurrentdemographicandpopulation-levelvascu-
lar risk factor trends, current projections are for an unprecedented
50% increase in stroke incidence in China during the next 20
years.17
Although demographic changes do account for some of the
expected increases in coronary artery disease and stroke incidence,
trends in virtually all the major vascular risk factors, including
systolic blood pressure, cholesterol, diabetes mellitus, and smok-
ing, are unfavorable and will account for a substantial proportion
of the expected excess burden of stroke moving forward.17
Mean
population body mass index has been increasing for decades; mean
cholesterol, mean systolic blood pressure, and mean blood glucose
have been steadily increasing since the early 1990s (Figure 2); and
the prevalence of smoking has remained persistently high during
the past 20 years.18
In contrast, the United States and Japan have
seen steady improvements in population-level measures of choles-
terol, systolic blood pressure, and smoking prevalence, although
obesity and mean body mass index, as well as mean serum glucose
continue to trend upward.18
Limitations
As we move forward to meet these challenges, the limited avail-
ability of high-quality epidemiological data on stroke and the
challenge of integrating heterogeneous data sources will con-
tinue to make an accurate transnational picture of the global
stroke epidemic a challenging task. Country-level analyses do
not take into account the joint distribution of risk factors in
important subnational groupings (e.g., by region or by urban/
rural area) and may be subject to the ecological fallacy, whereby
an inference made at the population level is falsely assumed
to apply at the individual level. However, together as a whole,
available data do provide a hint of the magnitude and scope of
the challenge and will help to inform public health priorities and
policy planning moving forward.
Conclusions
Stroke is the second leading cause of death worldwide. In the
ongoing global epidemic of cardiovascular disease, stroke has
emerged as a major cause of preventable death and morbidity, par-
ticularly in the developing world where stroke is the predominant
subtype of vascular disease. Demographic and vascular risk factor
trends suggest that there will be an even greater burden of disease
Figure 1. The Global Stroke-Belt. Relative mortality rate from stroke compared with ischemic heart disease, 2004 (based on WHO Global
Burden of Disease data).15

5. Stroke Types and Incidence
Ischemic stroke 85-88%
Hemorrhagic stroke 12-15%
Other
5%
Cryptogenic
30%
Cardiogenic
embolism
20%
Small vessel
disease
“lacunes”
25%
Atherosclerotic
cerebrovascular
disease
20%
5

6. Men and women without AF
at 40 years of age were
determined to have a 26%
and 23% likelihood of
developing incident AF by
80 years of age.
The estimated US prevalence
of atrial fibrillation (AF) in the
year 2050 ranges from 5.6
million to as high as 15.9 mil-
lion individuals.

7. Zone of Infarction
Embolism
“Hemorrhagic Conversion”
Reperfusion
Embolism breaks up, entering
into one branch

8. 70%
The Copenhagen stroke study, a prospective community-based study. n=1,197
**In hospital mortality: 72 deaths, n=217 with AF vs. 171 deaths n=968 without AF
†Discharge to own home: n=104 with AF vs. 662 deaths n=968 without AF
‡Length of hospital stay: 50.4 days with AF vs. 39.8 days without AF
Among patients who had a stroke, those with AF experienced a:
increase in in-hospital mortality**
40%
decrease in the relative
chance of discharge to own
home†
20%
increase in the length of
hospital stay‡
…compared to those without AF
AF-Related Strokes Are More Severe
than Strokes not Caused by AF
8

9. CARDIOEMBOLIC STROKES:
CLINICAL FEATURES
• Abrupt onset (vs. stuttering)
• LOC
• Aphasia without motor deficit
• Concurrent embolism to other organs
• Hemanopia without hemiparesis

11. irregular
!
Investigations:
EKG - AF
Prior Echo - EF 55%, LAE
INR 1.6
!
Medications:
Ramipril 5 mg/d
Coumadin 6 mg/d
Metoprolol 25 mg BID
7
!
There is a history of AF for which he is anticoagulated and hypertension

12. Preadmission medications in patients with known atrial fibrillation who were admitted
with acute ischemic stroke (high-risk cohort, n=597).

13. Warfarin Has a Narrow Therapeutic Window
Relationship between clinical events and INR intensity!
1. Hylek EM et al. Ann Intern Med. 1994;120:897-902.!
2. Hylek EM et al. N Engl J Med. 1996;335:540-546.!

14. 25%
66%
9%
38%
44%
18%
0%
10%
20%
30%
40%
50%
60%
70%
< 2.0 2.0 - 3.0 > 3.0
Clinical trial
Clinical practice
%ofeligiblepatientsreceivingwarfarin!
International Normalised Ratio (INR)!
1
2
INR Control:
Clinical Trial vs Clinical Practice (TTR)
1. Kalra L, et al. BMJ 2000;320:1236-1239 ."
2. Matchar DB, et al. Am J Med 2002; 113:42-51"

15. • 1 point for Congestive Heart Failure
• 1 point for Hypertension (treated or not)
• 1 point for Age ≥ 75 years
• 1 point for Diabetes Mellitus
• 2 points for Prior Stroke or Transient Ischemic Attack (TIA)
CHADS2 Score
(Simple Prediction Tool for Assessing Stroke Risk)
CHADS Stroke rate Stroke risk
0 1.9 (1.2 -3.0) Low
1 2.8 (2.0-3.8) Moderate
2 4.0 (3.1-5.1)
High
3 5.9 (4.6-7.3)
4 8.5 (6.3 -11.1)
5 12.5 (8.2-17.5)
6 18.2 (10.5-17.4)
15

16. HAS-BLED Bleeding Score
(Simple Tool for Assessing Bleeding Risk)
Letter Clinical Characteristic*
Points Awarded:
Score
H Hypertension 1
A Abnormal renal or liver function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INRs 1
E Elderly 1
D Drugs or alcohol (1 point each) 1 or 2
*Hypertension - uncontrolled, >160 mm Hg systolic; Abnormal renal/liver function (one point for presence of renal or liver impairment, maximum two points); Stroke (previous history, particularly
lacunar); Bleeding history or predisposition (anemia); Labile international normalized ratio (INR) (i.e. therapeutic time in range < 60%); Elderly ( >65 years); Drugs/alcohol concomitantly
(antiplatelet agents, nonsteroidal anti-inflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points).
16
HAS-BLED is based on data from warfarin and applying a risk
screening tool based on warfarin to the NOACs must be interpreted
with caution.

18. •Bleeding risk should be assessed in all patients prior to
prescribing anticoagulant therapy
•Bleeding risk assessment tools, such as HAS-BLED* are available
and are highly specific for patients with AF receiving warfarin
therapy
Bleeding Risk Assessment
*In HAS-BLED, major bleeding was defined as fatal or clinically overt bleeding associated with either transfusion of ≥
2 U of blood or ≥ 20 g/l decrease in hemoglobin or bleeding involving a critical anatomic site other than the brain
parenchyma
18
• A high score indicates a higher risk of bleeding but should not preclude the use
of an anticoagulant in patients at risk for stroke
• The absolute risk of ischemic stroke exceeds that of bleeding when CHADS2 and
HAS-BLED scores are equal
• A high score often indicates risk factors for bleeding that can be modified, such
as discontinuation of NSAIDs and control of hypertension

19. Bleeding Risk Management
Address reversible risk factors:
– Falling → provide mobility aid
– Hypertension → treat blood pressure to target
– Alcohol → encourage abstinence
– Labile INR → use NOACs
– Drugs → replace NSAIDs with other analgesics,
avoid ASA unless clearly indicated for secondary
prevention
– GI bleeding → use proton pump inhibitors (PPI)
Do not withhold anticoagulation
unless bleeding risk extreme
HIT Global Consulting Services Inc.
19

20. CCS 2012 Update to AF Guidelines
20
• Dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy to
warfarin for stroke prevention !
• Dabigatran and rivaroxaban are not more likely to cause major bleeding than warfarin
and apixaban is associated with a lower bleeding risk!
• All three NOACs have lower intracranial hemorrhage (ICH) rates than warfarin and are
much simpler to use!
• All the other guidelines (ESC, AHA, ACCF) agree with the CCS guidelines
When oral anticoagulant therapy is indicated, most
patients should receive dabigatran, rivaroxaban or
apixaban rather than warfarin

21. the reduction of stroke/SSE (ischemic and hemorrhagic, and
driven by hemorrhagic).6
Interestingly, all 3 NOACs were
associated with less intracranial bleeding compared with
warfarin irrespective of time spent in the therapeutic range
(TTR) in the warfarin arm. However, more gastrointestinal
(GI) bleeding was observed with dabigatran and rivaroxaban.
Importance of Renal Function and NOAC
Clearance
The extent of renal excretion is an important distinguish-
ing feature of NOACs. Up to 80% of circulating dabigatran is
eliminated renally, whereas only 33% and 25% of unchanged
rivaroxaban and apixaban is cleared by the kidney.7-9
After
150 mg administration, total dabigatran area under the
concentration curve (AUC) was increased by 1.5-, 3.1-, and
6.3-fold in individuals with mild, moderate, and severe renal
carboxylesterases in the enterocytes, portal circulation, and
hepatocytes.7,13,15
Very recently, a genome-wide subanalysis
of the RE-LY trial demonstrated that a single-nucleotide
polymorphism (SNP) in the carboxyesterase 1 gene (CES1;
rs2244613) attenuated dabigatran formation leading to lower
trough concentrations and the ABCB1 SNP rs4148738 and
CES1 SNP rs8192935 were associated with higher and lower
peak dabigatran concentrations, respectively.16
Rivaroxaban’s
bioavailability is dose-dependent; the absolute bioavailability
of 10 mg rivaroxaban ranged from 80% to 100%, and
bioavailability of 20 mg in fasting conditions was 66%.17
Coadministration of 15 or 20 mg rivaroxaban with food
increased the AUC by 39%.18
The low bioavailability in
fasting conditions might result in risk of inadequate anti-
coagulation and thus, rivaroxaban should be administered
with food. Apixaban’s absolute bioavailability is 50% and not
9
Figure 1. Summary of absorption, metabolism, and excretion of dabigatran, rivaroxaban, and apixaban. BCRP, breast cancer resistance protein;
CYP, cytochrome P450; P-gp, P-glycoprotein.
, 150 mg
ower rates
ar rate of
ith similar
warfarin.3
oral direct
ban Once
ared With
Vitamin K Antagonist for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin-
ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin
and 20 mg rivaroxaban once daily (OD) resulted in similar
rates of stroke/SSE and major bleeding.5
In the Apixaban for
Reduction in Stroke and Other ThromboemboLic Events
in Atrial Fibrillation (ARISTOTLE) trial (double-blinded;
n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in
farin, dabigatran, rivaroxaban and apixaban
Dabigatran Rivaroxaban Apixaban
Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Fast Fast Fast
Short Short Short
Rapid, acid-dependent Rapid Rapid
6.5 80* 50
1.0-3.0 2.5-4.0 1.0-3.0
60-70 50-55 21
18,133), 150 mg
ed with lower rates
t a similar rate of
ociated with similar
ared with warfarin.3
d second oral direct
Rivaroxaban Once
n Compared With
Vitamin K Antagonist for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin-
ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin
and 20 mg rivaroxaban once daily (OD) resulted in similar
rates of stroke/SSE and major bleeding.5
In the Apixaban for
Reduction in Stroke and Other ThromboemboLic Events
in Atrial Fibrillation (ARISTOTLE) trial (double-blinded;
n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in
es of warfarin, dabigatran, rivaroxaban and apixaban
Dabigatran Rivaroxaban Apixaban
Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
on
nthesis
Fast Fast Fast
Short Short Short
Rapid, acid-dependent Rapid Rapid
6.5 80* 50
1.0-3.0 2.5-4.0 1.0-3.0
60-70 50-55 21
35 95 87
12-17 9-13 8-15
80 33 25
20 28 50-70
metabolisme (CYP3A4) et le transport (glycoproteine P) du
medicament, nous pouvons être capables de mieux predire le risque
de reponse au traitement anticoagulant sous-therapeutique et supra-
therapeutique, et d’individualiser la selection et le dosage de l’ACO.
Therapy (RE-LY) trial (open-label; n ¼ 18,133), 150 mg
dabigatran twice daily (BID) was associated with lower rates
of stroke/SSE, achieving superiority, but a similar rate of
major bleeding and 110 mg BID was associated with similar
rates of stroke/SSE but fewer bleeds compared with warfarin.3
Rivaroxaban and apixaban are the first and second oral direct
FXa inhibitors approved for AF.4
In the Rivaroxaban Once
Daily Oral Direct Factor Xa Inhibition Compared With
Vitamin K Antagonist for Prevention
Trial in Atrial Fibrillation (ROCKE
ded, n ¼ 14,264), rivaroxaban wa
and 20 mg rivaroxaban once daily
rates of stroke/SSE and major bleed
Reduction in Stroke and Other T
in Atrial Fibrillation (ARISTOTLE
n ¼ 18, 201), 5 mg BID apixaban w
Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Parameter Warfarin Dabigatran Rivaroxaban
Mechanism of action Inhibition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Onset of action Slow, indirect inhibition
of clotting factor synthesis
Fast Fast
Offset of action Long Short Short
Absorption Rapid Rapid, acid-dependent Rapid
Bioavailability (%) 100 6.5 80*
tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0
Vd (L) 10 60-70 50-55
Protein binding (%) 99 35 95
t1/2b (h) 40 12-17 9-13
Renal excretion None 80 33
Fecal excretion None 20 28
CL/F (L/h) 0.35 70-140 10
l’âge, le fonctionnement renal, l’interva
metabolisme (CYP3A4) et le transp
medicament, nous pouvons être capable
de reponse au traitement anticoagulant
therapeutique, et d’individualiser la selec
n-label; n ¼ 18,133), 150 mg
) was associated with lower rates
periority, but a similar rate of
BID was associated with similar
bleeds compared with warfarin.3
re the first and second oral direct
AF.4
In the Rivaroxaban Once
Xa Inhibition Compared With
Vitamin K Antagonist for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin-
ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin
and 20 mg rivaroxaban once daily (OD) resulted in similar
rates of stroke/SSE and major bleeding.5
In the Apixaban for
Reduction in Stroke and Other ThromboemboLic Events
in Atrial Fibrillation (ARISTOTLE) trial (double-blinded;
n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in
cokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Warfarin Dabigatran Rivaroxaban Apixaban
ition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
indirect inhibition
clotting factor synthesis
Fast Fast Fast
Short Short Short
d Rapid, acid-dependent Rapid Rapid
6.5 80* 50
.0 1.0-3.0 2.5-4.0 1.0-3.0
60-70 50-55 21
35 95 87
12-17 9-13 8-15
80 33 25
20 28 50-70
70-140 10 5
l’âge, le fonctionnement renal, l’intervalle posologique ainsi que le
metabolisme (CYP3A4) et le transport (glycoproteine P) du
medicament, nous pouvons être capables de mieux predire le risque
de reponse au traitement anticoagulant sous-therapeutique et supra-
therapeutique, et d’individualiser la selection et le dosage de l’ACO.
of stroke/SSE, achieving superiority, but a similar rate of
major bleeding and 110 mg BID was associated with similar
rates of stroke/SSE but fewer bleeds compared with warfarin.3
Rivaroxaban and apixaban are the first and second oral direct
FXa inhibitors approved for AF.4
In the Rivaroxaban Once
Daily Oral Direct Factor Xa Inhibition Compared With
ded, n ¼ 14,264), ri
and 20 mg rivaroxaba
rates of stroke/SSE an
Reduction in Stroke
in Atrial Fibrillation
n ¼ 18, 201), 5 mg B
Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Parameter Warfarin Dabigatran Rivarox
Mechanism of action Inhibition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibi
(free or bound
Onset of action Slow, indirect inhibition
of clotting factor synthesis
Fast Fast
Offset of action Long Short Short
Absorption Rapid Rapid, acid-dependent Rapid
Bioavailability (%) 100 6.5 80*
tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0
Vd (L) 10 60-70 50-55
Protein binding (%) 99 35 95
t1/2b (h) 40 12-17 9-13
Renal excretion None 80 33
Fecal excretion None 20 28
CL/F (L/h) 0.35 70-140 10
Accumulation in plasma Dependent on CYP2C9
metabolic efficiency
None None
Food effect No effect on absorption;
dietary vitamin K
influence on PD
Delayed absorption with
food with no influence
on bioavailability
Delayed absorpt
with increased
ial (open-label; n ¼ 18,133), 150 mg
y (BID) was associated with lower rates
eving superiority, but a similar rate of
110 mg BID was associated with similar
ut fewer bleeds compared with warfarin.3
xaban are the first and second oral direct
oved for AF.4
In the Rivaroxaban Once
Factor Xa Inhibition Compared With
Vitamin K Antagonist for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin-
ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin
and 20 mg rivaroxaban once daily (OD) resulted in similar
rates of stroke/SSE and major bleeding.5
In the Apixaban for
Reduction in Stroke and Other ThromboemboLic Events
in Atrial Fibrillation (ARISTOTLE) trial (double-blinded;
n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in
f pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Warfarin Dabigatran Rivaroxaban Apixaban
Inhibition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Slow, indirect inhibition
of clotting factor synthesis
Fast Fast Fast
Long Short Short Short
Rapid Rapid, acid-dependent Rapid Rapid
100 6.5 80* 50
2.0-4.0 1.0-3.0 2.5-4.0 1.0-3.0
10 60-70 50-55 21
99 35 95 87
40 12-17 9-13 8-15
None 80 33 25
None 20 28 50-70
0.35 70-140 10 5
Dependent on CYP2C9
metabolic efficiency
None None 1.3-1.9
No effect on absorption;
dietary vitamin K
influence on PD
Delayed absorption with
food with no influence
on bioavailability
Delayed absorption with food
with increased bioavailability
None
Yes, lower CL/F as age
increases
Yes, lower CL/F as age
increases
None Yes, lower CL/F as age
increases
Yes, higher dose for
increased weight
None None Yes, higher exposure with low
body weight ( 60 kg)
Yes, lower CL/F in women Yes, lower CL/F in women None Yes, higher exposure in women
Lower dose in Asian
patients; higher dose in
African-American patients
None Lower dose in Japanese
patients
None
None P-gp P-gp, BCRP P-gp, BCRP
Dabigatran Rivaroxaban Apixaban
Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
ion
ynthesis
Fast Fast Fast
Short Short Short
Rapid, acid-dependent Rapid Rapid
6.5 80* 50
1.0-3.0 2.5-4.0 1.0-3.0
60-70 50-55 21
35 95 87
12-17 9-13 8-15
80 33 25
20 28 50-70
70-140 10 5
C9
y
None None 1.3-1.9
ion; Delayed absorption with
food with no influence
on bioavailability
Delayed absorption with food
with increased bioavailability
None
ge Yes, lower CL/F as age
increases
None Yes, lower CL/F as age
increases
None None Yes, higher exposure with low
body weight ( 60 kg)
women Yes, lower CL/F in women None Yes, higher exposure in women
ose in
patients
None Lower dose in Japanese
patients
None
P-gp P-gp, BCRP P-gp, BCRP
A2
None CYP3A4/5, CYP2J2 (equal) CYP3A4/5, CYP2J2 (minor),
CYP1A2 (minor)
bolism Potent P-gp inhibitors;
affecting absorption
Potent CYP3A4 and P-gp
inhibitors; affecting
absorption, metabolism,
and excretion
Potent CYP3A4 and P-gp
inhibitors; affecting
absorption, metabolism,
and excretion
OD) 150, 110 mg BID 20, 15 mg OD 5, 2.5 mg BID
TT Hemoclot ECT anti-FXa PT anti-FXa
Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Parameter Warfarin Dabigatran Rivaroxaban
Mechanism of action Inhibition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Fac
(
Onset of action Slow, indirect inhibition
of clotting factor synthesis
Fast Fast Fas
Offset of action Long Short Short Sho
Absorption Rapid Rapid, acid-dependent Rapid Rap
Bioavailability (%) 100 6.5 80* 50
tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0 1.0
Vd (L) 10 60-70 50-55 21
Protein binding (%) 99 35 95 87
t1/2b (h) 40 12-17 9-13 8-1
Renal excretion None 80 33 25
Fecal excretion None 20 28 50-
CL/F (L/h) 0.35 70-140 10 5
Accumulation in plasma Dependent on CYP2C9
metabolic efficiency
None None 1.3
Food effect No effect on absorption;
dietary vitamin K
influence on PD
Delayed absorption with
food with no influence
on bioavailability
Delayed absorption with food
with increased bioavailability
No
Age Yes, lower CL/F as age
increases
Yes, lower CL/F as age
increases
None Yes
i
Body weight Yes, higher dose for
increased weight
None None Yes
b
Sex Yes, lower CL/F in women Yes, lower CL/F in women None Yes
Ethnicity Lower dose in Asian
patients; higher dose in
African-American patients
None Lower dose in Japanese
patients
No
Drug transporter None P-gp P-gp, BCRP P-g
CYP-mediated metabolism CYP2C9, CYP3A4,
CYP2C19, CYP1A2
None CYP3A4/5, CYP2J2 (equal) CY
C
Drug-drug interactions Many; affecting metabolism Potent P-gp inhibitors;
affecting absorption
Potent CYP3A4 and P-gp
inhibitors; affecting
absorption, metabolism,
and excretion
Pot
i
a
a
Dosing for AF Variable (0.5-16 mg OD) 150, 110 mg BID 20, 15 mg OD 5,
Coagulation measurement INR TT Hemoclot ECT
aPTT
anti-FXa PT ant
harmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban
Warfarin Dabigatran Rivaroxaban Apixaban
Inhibition of VKOR Direct thrombin inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Factor Xa inhibitor
(free or bound), reversible
Slow, indirect inhibition
of clotting factor synthesis
Fast Fast Fast
Long Short Short Short
Rapid Rapid, acid-dependent Rapid Rapid
100 6.5 80* 50
2.0-4.0 1.0-3.0 2.5-4.0 1.0-3.0
10 60-70 50-55 21
99 35 95 87
40 12-17 9-13 8-15
None 80 33 25
None 20 28 50-70
0.35 70-140 10 5
Dependent on CYP2C9
metabolic efficiency
None None 1.3-1.9
No effect on absorption;
dietary vitamin K
influence on PD
Delayed absorption with
food with no influence
on bioavailability
Delayed absorption with food
with increased bioavailability
None
Yes, lower CL/F as age
increases
Yes, lower CL/F as age
increases
None Yes, lower CL/F as age
increases
Yes, higher dose for
increased weight
None None Yes, higher exposure with low
body weight ( 60 kg)
Yes, lower CL/F in women Yes, lower CL/F in women None Yes, higher exposure in women
Lower dose in Asian
patients; higher dose in
African-American patients
None Lower dose in Japanese
patients
None
None P-gp P-gp, BCRP P-gp, BCRP
CYP2C9, CYP3A4,
CYP2C19, CYP1A2
None CYP3A4/5, CYP2J2 (equal) CYP3A4/5, CYP2J2 (minor),
CYP1A2 (minor)
Many; affecting metabolism Potent P-gp inhibitors;
affecting absorption
Potent CYP3A4 and P-gp
inhibitors; affecting
absorption, metabolism,
and excretion
Potent CYP3A4 and P-gp
inhibitors; affecting
absorption, metabolism,
and excretion
Variable (0.5-16 mg OD) 150, 110 mg BID 20, 15 mg OD 5, 2.5 mg BID
INR TT Hemoclot ECT
aPTT
anti-FXa PT anti-FXa
Review
Importance of Pharmacokinetic Profile and Variability as
Determinants of Dose and Response to Dabigatran,
Rivaroxaban, and Apixaban
Inna Y. Gong, BMSc,a,b
and Richard B. Kim, MDa,b
a
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
b
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
ABSTRACT
Warfarin has been the mainstay oral anticoagulant (OAC) medication
prescribed for stroke prevention in atrial fibrillation (AF) patients.
However, warfarin therapy is challenging because of marked interin-
dividual variability in dose and response, requiring frequent monitoring
and dose titration. These limitations have prompted the clinical
development of new OACs (NOACs) that directly target the coagulation
cascade with rapid onset/offset of action, lower risk for drug-drug
interactions, and more predictable response. Recently, NOACs dabi-
gatran (direct thrombin inhibitor), and rivaroxaban and apixaban
(factor Xa [FXa] inhibitors) have gained regulatory approval as alter-
native therapies to warfarin. Though the anticoagulation efficacy of
these NOACs has been characterized, differences in their pharmaco-
kinetic and pharmacodynamic profiles have become a significant
consideration in terms of drug selection and dosing. In this review, we
outline key pharmacokinetic and pharmacodynamic features of each
compound and provide guidance on selection and dosing of the 3
NOACs relative to warfarin when considering OAC therapy for AF
patients. Importantly, we show that by better understanding the effect
RESUME
La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour
la prevention de l’accident vasculaire cerebral chez les patients ayant
une fibrillation auriculaire (FA). Cependant, le traitement par la war-
farine est difficile en raison de la variabilite interindividuelle marquee
de la dose et de la reponse, ce qui rend necessaire une surveillance
frequente et un reglage posologique. Ces limites ont suscite le
developpement clinique de nouveaux ACO (NACO) qui ciblent directe-
ment la cascade de coagulation par un delai d’action rapide et une
duree d’action, un plus faible risque d’interactions medicamenteuses
et une reponse plus previsible. Recemment, les NACO dont le dabi-
gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban
(inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution
de rechange au traitement par la warfarine. Tandis que l’efficacite de
l’anticoagulation de ces NACO a ete etablie, les differences dans leurs
profils pharmacocinetiques et pharmacodynamiques sont devenues
une preoccupation importante en ce qui a trait à la selection du
medicament et du dosage. Dans cette revue, nous exposons les
grandes lignes des principales caracteristiques pharmacocinetiques et
Atrial fibrillation (AF) is associated with a 5-fold increase
in risk of disabling stroke.1
Therefore, antithrombotic therapy
is required for stroke and systemic embolism (SSE) prophy-
laxis. Until recently, the vitamin K antagonist warfarin was
the primary choice for long-term oral anticoagulant (OAC)
treatment because stroke risk is reduced by 60% in non-
valvular AF patients.1
However, warfarin has a number of
limitations including delayed onset of action, large interindi-
vidual variability in response, unpredictable pharmacokinetic
characteristics (PK), drug-drug interactions, and polymor-
phisms in genes affecting metabolism and pharmacodynamic
(PD) characteristics. Intensive monitoring using international
normalized ratio (INR) and frequent dose adjustments are
necessary to provide adequate anticoagulation within warfa-
rin’s narrow therapeutic window.
Significant effort has been made to develop new OACs
(NOACs) with direct mechanisms of action with a sufficiently
wide therapeutic window to allow for fixed-dose administra-
tion without the need for routine response monitoring.
NOACs directly inhibit the coagulation pathway, either FXa
or thrombin, for rapid onset of antithrombotic effects. The
PK and pharmacology of these NOACs are distinct from that
of warfarin (Table 1, Fig. 1). In the present review, we will
highlight the PK and PD features of the 3 NOACs that have
recently been approved for stroke prevention in AF patients
and provide NOAC selection and dosing recommendations
based on their PK-PD profiles.
Clinical Outcomes Data Comparing NOACs With
Warfarin
Dabigatran etexilate is the first oral direct thrombin
inhibitor to be approved for its clinical use in AF patients.2
In
the Randomized Evaluation of Long-term Anticoagulation
Received for publication February 3, 2013. Accepted April 4, 2013.
Corresponding author: Dr Richard B. Kim, University Hospital,
339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada.
Tel.: þ1-519-663-3553; fax: þ1-519-663-3232.
E-mail: Richard.Kim@lhsc.on.ca
See page S32 for disclosure information.
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cjca.2013.04.002
Canadian Journal of Cardiology 29 (2013) S24eS33
Review
Importance of Pharmacokinetic Profile and Variability as
Determinants of Dose and Response to Dabigatran,
Rivaroxaban, and Apixaban
Inna Y. Gong, BMSc,a,b
and Richard B. Kim, MDa,b
a
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
b
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
ABSTRACT
Warfarin has been the mainstay oral anticoagulant (OAC) medication
prescribed for stroke prevention in atrial fibrillation (AF) patients.
However, warfarin therapy is challenging because of marked interin-
dividual variability in dose and response, requiring frequent monitoring
and dose titration. These limitations have prompted the clinical
development of new OACs (NOACs) that directly target the coagulation
cascade with rapid onset/offset of action, lower risk for drug-drug
interactions, and more predictable response. Recently, NOACs dabi-
gatran (direct thrombin inhibitor), and rivaroxaban and apixaban
(factor Xa [FXa] inhibitors) have gained regulatory approval as alter-
native therapies to warfarin. Though the anticoagulation efficacy of
these NOACs has been characterized, differences in their pharmaco-
kinetic and pharmacodynamic profiles have become a significant
consideration in terms of drug selection and dosing. In this review, we
outline key pharmacokinetic and pharmacodynamic features of each
compound and provide guidance on selection and dosing of the 3
NOACs relative to warfarin when considering OAC therapy for AF
patients. Importantly, we show that by better understanding the effect
RESUME
La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour
la prevention de l’accident vasculaire cerebral chez les patients ayant
une fibrillation auriculaire (FA). Cependant, le traitement par la war-
farine est difficile en raison de la variabilite interindividuelle marquee
de la dose et de la reponse, ce qui rend necessaire une surveillance
frequente et un reglage posologique. Ces limites ont suscite le
developpement clinique de nouveaux ACO (NACO) qui ciblent directe-
ment la cascade de coagulation par un delai d’action rapide et une
duree d’action, un plus faible risque d’interactions medicamenteuses
et une reponse plus previsible. Recemment, les NACO dont le dabi-
gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban
(inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution
de rechange au traitement par la warfarine. Tandis que l’efficacite de
l’anticoagulation de ces NACO a ete etablie, les differences dans leurs
profils pharmacocinetiques et pharmacodynamiques sont devenues
une preoccupation importante en ce qui a trait à la selection du
medicament et du dosage. Dans cette revue, nous exposons les
grandes lignes des principales caracteristiques pharmacocinetiques et
Atrial fibrillation (AF) is associated with a 5-fold increase
in risk of disabling stroke.1
Therefore, antithrombotic therapy
is required for stroke and systemic embolism (SSE) prophy-
laxis. Until recently, the vitamin K antagonist warfarin was
the primary choice for long-term oral anticoagulant (OAC)
treatment because stroke risk is reduced by 60% in non-
valvular AF patients.1
However, warfarin has a number of
limitations including delayed onset of action, large interindi-
vidual variability in response, unpredictable pharmacokinetic
characteristics (PK), drug-drug interactions, and polymor-
phisms in genes affecting metabolism and pharmacodynamic
(PD) characteristics. Intensive monitoring using international
normalized ratio (INR) and frequent dose adjustments are
necessary to provide adequate anticoagulation within warfa-
rin’s narrow therapeutic window.
Significant effort has been made to develop new OACs
(NOACs) with direct mechanisms of action with a sufficiently
wide therapeutic window to allow for fixed-dose administra-
tion without the need for routine response monitoring.
NOACs directly inhibit the coagulation pathway, either FXa
or thrombin, for rapid onset of antithrombotic effects. The
PK and pharmacology of these NOACs are distinct from that
of warfarin (Table 1, Fig. 1). In the present review, we will
highlight the PK and PD features of the 3 NOACs that have
recently been approved for stroke prevention in AF patients
and provide NOAC selection and dosing recommendations
based on their PK-PD profiles.
Clinical Outcomes Data Comparing NOACs With
Warfarin
Dabigatran etexilate is the first oral direct thrombin
inhibitor to be approved for its clinical use in AF patients.2
In
the Randomized Evaluation of Long-term Anticoagulation
Received for publication February 3, 2013. Accepted April 4, 2013.
Corresponding author: Dr Richard B. Kim, University Hospital,
339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada.
Tel.: þ1-519-663-3553; fax: þ1-519-663-3232.
E-mail: Richard.Kim@lhsc.on.ca
See page S32 for disclosure information.
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Canadian Journal of Cardiology 29 (2013) S24eS33

22. CCS 2012 Update to AF Guidelines:
Renal Function
GFR Warfarin Dabigatran Rivoraxaban Apixaban
GFR 50 mL/min
Dose adjusted for INR
2.0-3.0
150 mg BID or
110 mg BID
20 mg daily 5 mg BID
GFR 30-49 mL/min
Dose adjusted for INR
2.0-3.0
150 mg BID or
110 mg BID
15 mg daily
5 mg BID (for GFR 25 ml/min
only)
Consider 2.5 mg BID
GFR 30 mL/min No RCT data Contraindicated No RCT data No RCT data
†Consider Apixaban 2.5 mg po bid if GFR ≤ 25 mL/min, especially if age 80 or body weight 60 kg
‡Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting
¶No published studies support a dose for this level of renal function; product monographs suggest the drug is not recommended for this level
of renal function
22
The patient’s eGFR should be regularly reassessed in order to ensure
that changes in the NOAC drug or dose correspond to changes in the
eGFR.

23. NOACs: Possible Drug Interactions
DABIGATRAN RIVAROXABAN APIXABAN
P-gp inhibitors
(e.g., ketoconazole, verapamil,
quinidine, amiodarone)
Potent CYP3A4 and
P-gp inhibitors
(e.g., ketoconazole, itraconazole,
voriconazole, posaconazole, ritonavir)
Potent CYP3A4 and
P-gp inhibitors
(e.g., ketoconazole, itraconazole,
voriconazole, posaconazole, ritonavir)
P-gp inducers
(e.g., carbamazepine,
St. John’s Wort)
Potent CYP3A4 and
P-gp inducers
(e.g., rifampicin, and the anticonvulsants
phenytoin, carbamazapine, phenobarbitone)
Potent CYP3A4 and
P-gp inducers
(e.g., rifampicin, and the anticonvulsants
phenytoin, carbamazapine, phenobarbitone)
*P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban
†P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban
‡Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban
‡‡Combined potent CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban
23

24. between apixaban plasma concentrations and anti-FXa activity
was confirmed in elective hip/knee replacement patients.12
It is important to keep in mind that the sensitivity
and precision of different reagents and instruments used for
these coagulation assays is yet to be established. Further
validation of these coagulation assays in measuring NOAC
anticoagulation response is required in the real-world clinical
setting. Moreover, is it evident that variability in NOAC
plasma exposure will have a significant effect on anti-
coagulation efficacy considering the direct PK-PD relationship
and its association with clinical outcomes; thus, quantifying
NOAC plasma concentration is likely the most reliable
assessment of response and bleeding risk.
Selecting the Right OAC
Although the NOACs have shown efficacy similar or
greater than warfarin, it is unlikely that they will fully replace
warfarin. The interindividual variability in exposure/response
of NOACs and bleeding risk associated with anticoagulation
therapy remains a pertinent issue. Indeed, even in a clinical
trial setting with stringent enrollment criteria, the 1-dose-fits-
all dosing regimen strategy did not appear successful for
NOACs, likely due to the various clinical covariates that
significantly affected extent of drug exposure and response
(Fig. 2).41,44-47
Moreover, dabigatran and rivaroxaban use
outside of the clinical trial setting has recently been noted to
exhibit large interindividual variability in concentration and
response.47,48
The same trend is likely to be observed with
apixaban as its clinical use increases.
Nevertheless, the emergence of multiple NOACs has
meant greater therapeutic options for treating physicians.
However, we are now starting to face the question of how to
select the most appropriate NOAC for individual patients.
Factors to be assessed for deciding the right anticoagulant
include patient bleeding risk (Hypertension, Abnormal Renal/
Liver Function, Stroke, Bleeding History or Predisposition,
Labile INR, Elderly [ 65 Years], Drugs/Alcohol Concomi-
tantly [HAS-BLED]) and benefit (Congestive Heart Failure,
Figure 2. Plasma concentration profiles of dabigatran, rivaroxaban,
and apixaban in atrial fibrillation patients. (A) Mean steady-state
dabigatran plasma concentrations after 150 mg twice-daily adminis-
With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial
in Atrial Fibrillation (ROCKET-AF) trial and the dashed line represents
the average Ctrough. (C) Predicted mean steady-state apixaban plasma
concentrations after 5 mg twice-daily administration is represented by
the dashed black line (digitized from Leil et al.).46
Coloured solid lines
represent the predicted effect of various clinical variables on apixaban
S28 Canadian Journal of Cardiology
Volume 29 2013 e
r
a
m
H
s
F
i
L
L
t
Figure 2. Plasma concentration profiles of dabigatran, rivaroxaban,
and apixaban in atrial fibrillation patients. (A) Mean steady-state
dabigatran plasma concentrations after 150 mg twice-daily adminis-
tration is represented by the dashed black line (digitized from Dan-
sirikul et al.).43
Coloured solid lines represent the predicted effect of
various clinical variables and a genetic variation in the carboxylester-
ase 1 (CES1) gene on dabigatran concentration based on known area
under the concentration curve (AUC) change.44
The shaded area
represents Ctrough dabigatran concentrations associated with
increased antithrombotic efficacy and decreased major bleeding risk
according to population pharmacokinetics modelling of the Random-
ized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial data.
(B) Mean steady-state rivaroxaban plasma concentrations following 20
mg once daily administration is represented by the dashed black line
(digitized from Mueck et al.).45
Coloured solid lines represent the
predicted effect of various clinical variables on rivaroxaban concen-
tration based on known AUC change.45
Although the optimal plasma
Ctrough of rivaroxaban has not been well defined as of yet, the shaded
area represents the 5%-95% confidence interval of Ctrough observed in
W
i
t
c
t
r
c
r
c
e
s
e
c
C
p
C
c
m
D
c
h
c
Review
Importance of Pharmacokinetic Profile and Variability as
Determinants of Dose and Response to Dabigatran,
Rivaroxaban, and Apixaban
Inna Y. Gong, BMSc,a,b
and Richard B. Kim, MDa,b
a
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
b
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
ABSTRACT
Warfarin has been the mainstay oral anticoagulant (OAC) medication
prescribed for stroke prevention in atrial fibrillation (AF) patients.
However, warfarin therapy is challenging because of marked interin-
dividual variability in dose and response, requiring frequent monitoring
and dose titration. These limitations have prompted the clinical
development of new OACs (NOACs) that directly target the coagulation
cascade with rapid onset/offset of action, lower risk for drug-drug
interactions, and more predictable response. Recently, NOACs dabi-
gatran (direct thrombin inhibitor), and rivaroxaban and apixaban
(factor Xa [FXa] inhibitors) have gained regulatory approval as alter-
native therapies to warfarin. Though the anticoagulation efficacy of
these NOACs has been characterized, differences in their pharmaco-
kinetic and pharmacodynamic profiles have become a significant
consideration in terms of drug selection and dosing. In this review, we
outline key pharmacokinetic and pharmacodynamic features of each
compound and provide guidance on selection and dosing of the 3
NOACs relative to warfarin when considering OAC therapy for AF
patients. Importantly, we show that by better understanding the effect
RESUME
La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour
la prevention de l’accident vasculaire cerebral chez les patients ayant
une fibrillation auriculaire (FA). Cependant, le traitement par la war-
farine est difficile en raison de la variabilite interindividuelle marquee
de la dose et de la reponse, ce qui rend necessaire une surveillance
frequente et un reglage posologique. Ces limites ont suscite le
developpement clinique de nouveaux ACO (NACO) qui ciblent directe-
ment la cascade de coagulation par un delai d’action rapide et une
duree d’action, un plus faible risque d’interactions medicamenteuses
et une reponse plus previsible. Recemment, les NACO dont le dabi-
gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban
(inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution
de rechange au traitement par la warfarine. Tandis que l’efficacite de
l’anticoagulation de ces NACO a ete etablie, les differences dans leurs
profils pharmacocinetiques et pharmacodynamiques sont devenues
une preoccupation importante en ce qui a trait à la selection du
medicament et du dosage. Dans cette revue, nous exposons les
grandes lignes des principales caracteristiques pharmacocinetiques et
Atrial fibrillation (AF) is associated with a 5-fold increase
in risk of disabling stroke.1
Therefore, antithrombotic therapy
is required for stroke and systemic embolism (SSE) prophy-
laxis. Until recently, the vitamin K antagonist warfarin was
the primary choice for long-term oral anticoagulant (OAC)
treatment because stroke risk is reduced by 60% in non-
valvular AF patients.1
However, warfarin has a number of
limitations including delayed onset of action, large interindi-
vidual variability in response, unpredictable pharmacokinetic
characteristics (PK), drug-drug interactions, and polymor-
phisms in genes affecting metabolism and pharmacodynamic
(PD) characteristics. Intensive monitoring using international
normalized ratio (INR) and frequent dose adjustments are
necessary to provide adequate anticoagulation within warfa-
rin’s narrow therapeutic window.
Significant effort has been made to develop new OACs
(NOACs) with direct mechanisms of action with a sufficiently
wide therapeutic window to allow for fixed-dose administra-
tion without the need for routine response monitoring.
NOACs directly inhibit the coagulation pathway, either FXa
or thrombin, for rapid onset of antithrombotic effects. The
PK and pharmacology of these NOACs are distinct from that
of warfarin (Table 1, Fig. 1). In the present review, we will
highlight the PK and PD features of the 3 NOACs that have
recently been approved for stroke prevention in AF patients
and provide NOAC selection and dosing recommendations
based on their PK-PD profiles.
Clinical Outcomes Data Comparing NOACs With
Warfarin
Dabigatran etexilate is the first oral direct thrombin
inhibitor to be approved for its clinical use in AF patients.2
In
the Randomized Evaluation of Long-term Anticoagulation
Received for publication February 3, 2013. Accepted April 4, 2013.
Corresponding author: Dr Richard B. Kim, University Hospital,
339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada.
Tel.: þ1-519-663-3553; fax: þ1-519-663-3232.
E-mail: Richard.Kim@lhsc.on.ca
See page S32 for disclosure information.
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cjca.2013.04.002
Canadian Journal of Cardiology 29 (2013) S24eS33
Review
Importance of Pharmacokinetic Profile and Variability as
Determinants of Dose and Response to Dabigatran,
Rivaroxaban, and Apixaban
Inna Y. Gong, BMSc,a,b
and Richard B. Kim, MDa,b
a
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
b
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
ABSTRACT
Warfarin has been the mainstay oral anticoagulant (OAC) medication
prescribed for stroke prevention in atrial fibrillation (AF) patients.
However, warfarin therapy is challenging because of marked interin-
dividual variability in dose and response, requiring frequent monitoring
and dose titration. These limitations have prompted the clinical
development of new OACs (NOACs) that directly target the coagulation
cascade with rapid onset/offset of action, lower risk for drug-drug
interactions, and more predictable response. Recently, NOACs dabi-
gatran (direct thrombin inhibitor), and rivaroxaban and apixaban
(factor Xa [FXa] inhibitors) have gained regulatory approval as alter-
native therapies to warfarin. Though the anticoagulation efficacy of
these NOACs has been characterized, differences in their pharmaco-
kinetic and pharmacodynamic profiles have become a significant
consideration in terms of drug selection and dosing. In this review, we
outline key pharmacokinetic and pharmacodynamic features of each
compound and provide guidance on selection and dosing of the 3
NOACs relative to warfarin when considering OAC therapy for AF
patients. Importantly, we show that by better understanding the effect
RESUME
La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour
la prevention de l’accident vasculaire cerebral chez les patients ayant
une fibrillation auriculaire (FA). Cependant, le traitement par la war-
farine est difficile en raison de la variabilite interindividuelle marquee
de la dose et de la reponse, ce qui rend necessaire une surveillance
frequente et un reglage posologique. Ces limites ont suscite le
developpement clinique de nouveaux ACO (NACO) qui ciblent directe-
ment la cascade de coagulation par un delai d’action rapide et une
duree d’action, un plus faible risque d’interactions medicamenteuses
et une reponse plus previsible. Recemment, les NACO dont le dabi-
gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban
(inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution
de rechange au traitement par la warfarine. Tandis que l’efficacite de
l’anticoagulation de ces NACO a ete etablie, les differences dans leurs
profils pharmacocinetiques et pharmacodynamiques sont devenues
une preoccupation importante en ce qui a trait à la selection du
medicament et du dosage. Dans cette revue, nous exposons les
grandes lignes des principales caracteristiques pharmacocinetiques et
Atrial fibrillation (AF) is associated with a 5-fold increase
in risk of disabling stroke.1
Therefore, antithrombotic therapy
is required for stroke and systemic embolism (SSE) prophy-
laxis. Until recently, the vitamin K antagonist warfarin was
the primary choice for long-term oral anticoagulant (OAC)
treatment because stroke risk is reduced by 60% in non-
valvular AF patients.1
However, warfarin has a number of
limitations including delayed onset of action, large interindi-
vidual variability in response, unpredictable pharmacokinetic
characteristics (PK), drug-drug interactions, and polymor-
phisms in genes affecting metabolism and pharmacodynamic
(PD) characteristics. Intensive monitoring using international
normalized ratio (INR) and frequent dose adjustments are
necessary to provide adequate anticoagulation within warfa-
rin’s narrow therapeutic window.
Significant effort has been made to develop new OACs
(NOACs) with direct mechanisms of action with a sufficiently
wide therapeutic window to allow for fixed-dose administra-
tion without the need for routine response monitoring.
NOACs directly inhibit the coagulation pathway, either FXa
or thrombin, for rapid onset of antithrombotic effects. The
PK and pharmacology of these NOACs are distinct from that
of warfarin (Table 1, Fig. 1). In the present review, we will
highlight the PK and PD features of the 3 NOACs that have
recently been approved for stroke prevention in AF patients
and provide NOAC selection and dosing recommendations
based on their PK-PD profiles.
Clinical Outcomes Data Comparing NOACs With
Warfarin
Dabigatran etexilate is the first oral direct thrombin
inhibitor to be approved for its clinical use in AF patients.2
In
the Randomized Evaluation of Long-term Anticoagulation
Received for publication February 3, 2013. Accepted April 4, 2013.
Corresponding author: Dr Richard B. Kim, University Hospital,
339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada.
Tel.: þ1-519-663-3553; fax: þ1-519-663-3232.
E-mail: Richard.Kim@lhsc.on.ca
See page S32 for disclosure information.
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Canadian Journal of Cardiology 29 (2013) S24eS33

25. 56 PT®
bleeding or invasive surgery should be minimized when pos-
sible.14
Dabigatran should be withheld for 1 to 2 days before
an invasive procedure in patients with normal renal function
and for 3 to 5 days in patients if the CrCl is 50 mL/minute or
below.14
TCT and aPTT can be used to determine the residual
anticoagulation activity of dabigatran before the procedure.17,27
There is no known reversal agent for dabigatran. Symptomatic
management is the primary approach for bleeding because
of dabigatran’s relatively short half-life. Recombinant factor
VIIa (rFVIIa), prothrombin complex concentrates (PCCs), or
95% CI, 1.19–1.89; P 0.05). Outcomes in the RE-LY trial are
summarized in Table 4.32–35
The percentage of time in the therapeutic INR range (TTR)
of 2 to 3 in patients receiving warfarin was approximately
64%, which is similar to the 66.4% TTR reported in a meta-
regression analysis of warfarin trials published in 2006 and
2010.36,37
Available INR home-monitoring systems may produce
higher rates of TTR than conventional INR monitoring in ambu-
latory settings.35
An indirect comparison of home monitoring of
vitamin K antagonist (VKA) treatment with dabigatran found no
(
Study design Randomized, open-label Randomized, double-blind Randomized, double-blind
Follow-up period, median 2 years 1.9 years 1.8 years
Age, mean 71.5 years 73 years* 70 years
Male sex 63.6% 61.3% 64.5%
CHADS2 score, mean ± SD32–35
2.1 ± 1.1 3.48 ± 0.94 2.1 ± 1.1
Prior stroke (%) 20.3 54.9 19.2
Prior vitamin K antagonist
therapy (%)
50.2 62.3 57.1
Mean TTR (%) 64 55 62
*Median.
TTR = time in therapeutic range (for warfarin therapy).
Data from Connelly et al.,31–33
Granger et al.,34
and Patel et al.35
PT_1401_Shafeeq_7fin.indd 56 12/27/13 4:23 PT®
RACT
fibrillation (AF) is the most common cardiac arrhyth-
he U.S. Anticoagulation is recommended for stroke
on in AF patients with intermediate-to-high stroke risk
ients with a CHADS2 score of 1 or greater). Warfarin
viously the only option for oral anticoagulation in these
but three new oral anticoagulants have become avail-
alternatives for warfarin in patients with nonvalvular
advantages of the newer agents include a rapid onset,
ble pharmacokinetics, and no need for routine anti-
ion monitoring.
atran (Pradaxa) and apixaban (Eliquis) have dem-
ed improved efficacy compared with warfarin.
aban (Xarelto) was non-inferior to warfarin for stroke
on in AF. Apixaban demonstrated a reduced incidence
bleeding compared with warfarin and a reduction in
mortality.
ations to the use of the new oral anticoagulants include
of a reversal agent; an inability to use the therapies in
patient populations (such as those with severe renal or
mpairment); limited experience with drug–drug and
sease interactions; and a lack of available coagulation
quantify their effects. Although the newer agents have
cquisition costs, the benefits of cost savings may be
from the potential for decreasing the incidence of
hagic stroke and intracranial bleeding and reducing the
anticoagulation monitoring. Benefits and risks should
ully weighed before these agents are prescribed for
presenting with new-onset AF.
fibrillation (AF) is the most common cardiac arrhyth-
.S.1
The incidence and prevalence of AF increase with
he number of people affected by AF is projected to
12 million by 2050.3
The lifetime risk of AF in patients
of age and older is estimated at 25%.3,4
Stroke is a major
ation associated with AF, which contributes to the mor-
d mortality associated with the disease. Patients with
a four-fold to five-fold increased risk of stroke. This
es among patient populations, according to age, sex,
presence of comorbid disease states (e.g., diabetes,
nsion, congestive heart failure, and vascular disease).3,5,6
oagulation is recommended for stroke prevention
mediate-risk and high-risk patients (i.e., those with a
CHADS2 score of 1 or higher (Congestive Heart failure, Age
over 75, Diabetes, and Stroke).5,7–11
The presence of additional
risk factors (female sex, age 65–74 years, and vascular dis-
ease) should be considered when health care professionals are
determining whether patients in the intermediate-risk category
should receive anticoagulation.7–11
Previously, warfarin was the
only option for oral anticoagulation in these patients.
Currently, three oral anticoagulants are approved by the
FDA as alternatives to warfarin in patients with AF. Dabigatran
(Pradaxa, Boehringer Ingelheim) was the first new oral anti-
coagulant approved for stroke prevention in AF, followed by the
oral anti–factor Xa inhibitors rivaroxaban (Xarelto, Janssen) and
apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). Rivaroxaban is
also approved for the treatment of deep vein thrombosis (DVT)
and pulmonary embolism (PE), along with prevention of DVT/
PE in patients undergoing knee or hip replacement surgeries.12
Apixaban, the newest anti-Xa inhibitor, was approved for stroke
prevention in December 2012.13
None of the new agents are approved for use in patients
with AF secondary to valvular heart disease or mechanical
heart valves. The labeling for anti-Xa inhibitors does not in-
clude any specific wording regarding their use in patients with
bioprosthetic heart valves; however, dabigatran is specifically
contraindicated in patients with mechanical bioprosthetic heart
valves.14
Results were published for a phase 2 dose–validation
study comparing dabigatran with warfarin in 252 patients with
mechanical heart values. The study was prematurely termi-
nated because of an increased incidence of thromboembolic
and bleeding events with dabigatran.15
A summary of FDA-approved indications and doses of these
oral agents is provided in Table 1.12–14
An ideal oral anticoagulant has a rapid onset and predictable
pharmacokinetics with easily quantifiable and reversible thera-
peutic effects. Above all, the medication should be efficacious.
When compared with warfarin, the new oral anticoagulants
have a faster onset and predicable pharmacokinetics (Table
2).12–14
In addition, routine anticoagulation monitoring is not
required, and these agents are at least as efficacious as warfarin.
Warfarin exerts its anticoagulation effect by inhibiting the
synthesis of vitamin K–dependent coagulation factors II, VII, IX,
and X. The primary pharmacological effect of warfarin results
from the inhibition of factor II or thrombin.16
More frequent
monitoring of the International Normalized Ratio (INR) may
be required at the initiation of therapy in order to determine
the patient’s individual steady-state dose.
Inhibition of multiple vitamin K–dependent coagulation
Hira Shafeeq, PharmD, BCPS; and Tran H. Tran, PharmD, BCPS
eq is Assistant Clinical Professor in the College of Pharmacy
th Sciences at St. John’s University in Queens, New York,
ical Specialist in the Neurosurgical Intensive Care Unit at
ore University Hospital in Manhasset, New York. Dr. Tran is
Clinical Professor at the university and Clinical Pharmacy
at New York–Presbyterian Hospital/Columbia University
Center in New York, New York.
Disclosure: The authors report that they have no financial or com-
mercial relationships in regard to this article.
in.indd 54 12/27/13 4:23 PM
54 PT®
the patient’s individual steady-state dose.
Inhibition of multiple vitamin K–dependent coagulation
and Clinical Specialist in the Neurosurgical Intensive Care Unit at
North Shore University Hospital in Manhasset, New York. Dr. Tran is
Assistant Clinical Professor at the university and Clinical Pharmacy
Manager at New York–Presbyterian Hospital/Columbia University
Medical Center in New York, New York.
Disclosure: The authors report that they have no financial or com-
mercial relationships in regard to this article.
PT_1401_Shafeeq_7fin.indd 54 12/27/13 4:23 PM

26. PT® 57
A retrospective Canadian study also reported a beneficial
ICER of dabigatran as $10,440/QALY versus warfarin and
$3,962/QALY versus “real-world” prescribing. This analysis
incorporated a lower time in the therapeutic range (59%) and
more warfarin-eligible patients taking aspirin (11%) or no treat-
ment at all (6%).42,43
A U.S. analysis of the RE-LY data found an ICER of $25,000/
QALY, based on a dabigatran cost of $6.75 per day ($210/
month).14,44
In this analysis, the ICER continued to show
and apixaban work by binding to the active site of factor Xa to
inhibit clot formation independent of cofactor anti-thrombin III.
This mechanism differs from that of parenteral factor Xa inhibi-
tors, such as fondaparinux (e.g., Arixtra, GlaxoSmithKline).25
Rivaroxaban (Xarelto) was the first oral reversible factor Xa
inhibitor approved by the FDA for stroke prevention in nonval-
vular AF in November 2011. It is also approved for treatment
Stroke/systemic embolism 1.71% warfarin
1.54% dabigatran 110 mg
1.11% dabigatran 150 mga,b
2.4% warfarin
2.1% rivaroxaban
1.6% warfarin
1.27% apixabana,b
Safety
Major bleeding 3.57% warfarin
2.87% dabigatran 110 mga
3.32% dabigatran 150 mg
3.4% warfarin
3.6% rivaroxaban
3.09% warfarin
2.13% apixabana
Intracranial hemorrhage (%/year) 0.74% warfarin
0.23% dabigatran 110 mga
0.3% dabigatran 150 mga
0.7% warfarin
0.5% rivaroxabana
0.8% warfarin
0.33% apixaban
Myocardial Infarction 0.64% warfarin
0.82% dabigatran 110 mg
0.81% dabigatran 150 mg
1.1% warfarin
0.9% rivaroxaban
0.61% warfarin
0.53% apixaban
a
P 0.05.
b
Superiority.
Data from Connelly et al., Granger et al., and Patel et al.32–35
PT_1401_Shafeeq_7fin.indd 57 12/27/13 4:23 PM
T®
RACT
fibrillation (AF) is the most common cardiac arrhyth-
he U.S. Anticoagulation is recommended for stroke
on in AF patients with intermediate-to-high stroke risk
ients with a CHADS2 score of 1 or greater). Warfarin
viously the only option for oral anticoagulation in these
but three new oral anticoagulants have become avail-
alternatives for warfarin in patients with nonvalvular
advantages of the newer agents include a rapid onset,
ble pharmacokinetics, and no need for routine anti-
ion monitoring.
atran (Pradaxa) and apixaban (Eliquis) have dem-
ed improved efficacy compared with warfarin.
aban (Xarelto) was non-inferior to warfarin for stroke
on in AF. Apixaban demonstrated a reduced incidence
bleeding compared with warfarin and a reduction in
mortality.
ations to the use of the new oral anticoagulants include
of a reversal agent; an inability to use the therapies in
patient populations (such as those with severe renal or
mpairment); limited experience with drug–drug and
sease interactions; and a lack of available coagulation
quantify their effects. Although the newer agents have
cquisition costs, the benefits of cost savings may be
from the potential for decreasing the incidence of
hagic stroke and intracranial bleeding and reducing the
anticoagulation monitoring. Benefits and risks should
ully weighed before these agents are prescribed for
presenting with new-onset AF.
fibrillation (AF) is the most common cardiac arrhyth-
.S.1
The incidence and prevalence of AF increase with
he number of people affected by AF is projected to
12 million by 2050.3
The lifetime risk of AF in patients
of age and older is estimated at 25%.3,4
Stroke is a major
ation associated with AF, which contributes to the mor-
d mortality associated with the disease. Patients with
a four-fold to five-fold increased risk of stroke. This
es among patient populations, according to age, sex,
presence of comorbid disease states (e.g., diabetes,
nsion, congestive heart failure, and vascular disease).3,5,6
oagulation is recommended for stroke prevention
mediate-risk and high-risk patients (i.e., those with a
CHADS2 score of 1 or higher (Congestive Heart failure, Age
over 75, Diabetes, and Stroke).5,7–11
The presence of additional
risk factors (female sex, age 65–74 years, and vascular dis-
ease) should be considered when health care professionals are
determining whether patients in the intermediate-risk category
should receive anticoagulation.7–11
Previously, warfarin was the
only option for oral anticoagulation in these patients.
Currently, three oral anticoagulants are approved by the
FDA as alternatives to warfarin in patients with AF. Dabigatran
(Pradaxa, Boehringer Ingelheim) was the first new oral anti-
coagulant approved for stroke prevention in AF, followed by the
oral anti–factor Xa inhibitors rivaroxaban (Xarelto, Janssen) and
apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). Rivaroxaban is
also approved for the treatment of deep vein thrombosis (DVT)
and pulmonary embolism (PE), along with prevention of DVT/
PE in patients undergoing knee or hip replacement surgeries.12
Apixaban, the newest anti-Xa inhibitor, was approved for stroke
prevention in December 2012.13
None of the new agents are approved for use in patients
with AF secondary to valvular heart disease or mechanical
heart valves. The labeling for anti-Xa inhibitors does not in-
clude any specific wording regarding their use in patients with
bioprosthetic heart valves; however, dabigatran is specifically
contraindicated in patients with mechanical bioprosthetic heart
valves.14
Results were published for a phase 2 dose–validation
study comparing dabigatran with warfarin in 252 patients with
mechanical heart values. The study was prematurely termi-
nated because of an increased incidence of thromboembolic
and bleeding events with dabigatran.15
A summary of FDA-approved indications and doses of these
oral agents is provided in Table 1.12–14
An ideal oral anticoagulant has a rapid onset and predictable
pharmacokinetics with easily quantifiable and reversible thera-
peutic effects. Above all, the medication should be efficacious.
When compared with warfarin, the new oral anticoagulants
have a faster onset and predicable pharmacokinetics (Table
2).12–14
In addition, routine anticoagulation monitoring is not
required, and these agents are at least as efficacious as warfarin.
Warfarin exerts its anticoagulation effect by inhibiting the
synthesis of vitamin K–dependent coagulation factors II, VII, IX,
and X. The primary pharmacological effect of warfarin results
from the inhibition of factor II or thrombin.16
More frequent
monitoring of the International Normalized Ratio (INR) may
be required at the initiation of therapy in order to determine
the patient’s individual steady-state dose.
Inhibition of multiple vitamin K–dependent coagulation
Hira Shafeeq, PharmD, BCPS; and Tran H. Tran, PharmD, BCPS
eq is Assistant Clinical Professor in the College of Pharmacy
th Sciences at St. John’s University in Queens, New York,
ical Specialist in the Neurosurgical Intensive Care Unit at
ore University Hospital in Manhasset, New York. Dr. Tran is
Clinical Professor at the university and Clinical Pharmacy
at New York–Presbyterian Hospital/Columbia University
Center in New York, New York.
Disclosure: The authors report that they have no financial or com-
mercial relationships in regard to this article.
in.indd 54 12/27/13 4:23 PM
54 PT®
the patient’s individual steady-state dose.
Inhibition of multiple vitamin K–dependent coagulation
and Clinical Specialist in the Neurosurgical Intensive Care Unit at
North Shore University Hospital in Manhasset, New York. Dr. Tran is
Assistant Clinical Professor at the university and Clinical Pharmacy
Manager at New York–Presbyterian Hospital/Columbia University
Medical Center in New York, New York.
Disclosure: The authors report that they have no financial or com-
mercial relationships in regard to this article.
PT_1401_Shafeeq_7fin.indd 54 12/27/13 4:23 PM

27. Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarin
in Preventing Stroke and Other Cardiovascular Events in Patients with
Atrial Fibrillation
Doug Coyle, PhD1,2
, Kathryn Coyle, BScPharm, MSc2
, Chris Cameron, MSc1,3
, Karen Lee, MSc4
, Shannon Kelly, BA(Hons)1,3
,
Sabine Steiner, MD, MSc5
, George A. Wells, PhD1,3,Ã
1
Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada; 2
Applied Health Economic Research Unit,
Ottawa, Canada; 3
University of Ottawa Heart Institute, Ottawa, Canada; 4
Canadian Agency for Drugs and Technologies in Health Ottawa, Canada;
5
Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Vienna, Austria
A B S T R A C T
Objectives: The primary objective was to assess the cost-
effectiveness of new oral anticoagulants compared with warfarin
in patients with nonvalvular atrial fibrillation. Secondary objectives
related to assessing the cost-effectiveness of new oral anticoagu-
lants stratified by center-specific time in therapeutic range, age, and
CHADS2 score. Methods: Cost-effectiveness was assessed by the
incremental cost per quality-adjusted life-year (QALY) gained. Anal-
ysis used a Markov cohort model that followed patients from
initiation of pharmacotherapy to death. Transition probabilities
were obtained from a concurrent network meta-analysis. Utility
values and costs were obtained from published data. Numerous
deterministic sensitivity analyses and probabilistic analysis were
conducted. Results: The incremental cost per QALY gained for
dabigatran 150 mg versus warfarin was $20,797. Apixaban produced
equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban
were dominated by dabigatran 150 mg and apixaban. Results were
sensitive to the drug costs of apixaban, the time horizon adopted,
and the consequences from major and minor bleeds with dabiga-
tran. Results varied by a center’s average time in therapeutic range, a
patient’s CHADS2 score, and patient age, with either dabigatran 150
mg or apixaban being optimal. Conclusions: Results were highly
sensitive to patient characteristics. Rivaroxaban and dabigatran 110
mg were unlikely to be cost-effective. For different characteristics,
apixaban or dabigatran 150 mg were optimal. Thus, the choice
between these two options may come down to the price of apixaban
and further evidence on the impact of major and minor bleeds with
dabigatran.
Keywords: anticoagulants, atrial fibrillation, cardiovascular, cost-
effectiveness, warfarin.
Copyright 2013, International Society for Pharmacoeconomics and
Outcomes Research (ISPOR). Published by Elsevier Inc.
Introduction
Approximately 250,000 Canadians are affected by atrial fibrilla-
tion (AF) [1]. Patients with AF have a substantially increased risk
of death and have higher annual rates of mortality [1,2]. AF and
stroke are more common among the elderly [3,4].
Preventing events such as stroke is an important part of
managing patients with AF. Antithrombotic strategies for
patients with AF include anticoagulant drugs, vitamin K antag-
onists , such as warfarin, and antiplatelet agents, such as aspirin.
Vitamin K antagonists reduce the risk of stroke in patients with
AF but are associated with some drawbacks, including a need for
laboratory monitoring, an increased risk of bleeding complica-
tions, and several food and drug interactions [5,6]. Recently, a
number of new oral anticoagulants (NOACs) have been approved,
including dabigatran, a direct thrombin inhibitor, and the direct
factor Xa inhibitors, rivaroxaban and apixaban.
While dabigatran, apixaban, and rivaroxaban have been dem-
onstrated to be effective in preventing stroke/systemic embolism
in patients with AF, the comparative cost-effectiveness of these
NOACs is not clear. Currently, treatment with warfarin including
regular international normalized ratio monitoring costs less than
$300 per annum. The new anticoagulants examined in this study
cost more than $1100 per annum. Thus, the cost-effectiveness of
these agents will depend on the balance between the increased
benefits in terms of stroke prevention, the effect on bleeding
rates, and the increased drug costs [7–11]. This analysis is the first
systematic, independent analysis of the cost-effectiveness of all
three NOACs in comparison to warfarin in patients with
nonvalvular AF.
This study involved incorporating data from a concurrent
systematic review into an economic model of NOAC use in
Canada [12]. The primary objective was to assess the cost-
effectiveness of NOACs compared with warfarin—with additional
1098-3015/$36.00 – see front matter Copyright 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.jval.2013.01.009
E-mail: gawells@ottawaheart.ca.
* Address correspondence to: George A. Wells, Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin
Street, Ottawa, ON, Canada K1Y 4W7.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/
Cost-Effectiveness of New Oral Anticoagulants Comp
in Preventing Stroke and Other Cardiovascular Event
Atrial Fibrillation
Doug Coyle, PhD1,2
, Kathryn Coyle, BScPharm, MSc2
, Chris Cameron, MSc1,3
, Karen Lee
Sabine Steiner, MD, MSc5
, George A. Wells, PhD1,3,Ã
1
Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, C
Ottawa, Canada; 3
University of Ottawa Heart Institute, Ottawa, Canada; 4
Canadian Agency for Drugs and T
5
Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Vienna, Austria
A B S T R A C T
Objectives: The primary objective was to assess the cost-
effectiveness of new oral anticoagulants compared with warfarin
in patients with nonvalvular atrial fibrillation. Secondary objectives
related to assessing the cost-effectiveness of new oral anticoagu-
lants stratified by center-specific time in therapeutic range, age, and
CHADS2 score. Methods: Cost-effectiveness was assessed by the
incremental cost per quality-adjusted life-year (QALY) gained. Anal-
ysis used a Markov cohort model that followed patients from
initiation of pharmacotherapy to death. Transition probabilities
were obtained from a concurrent network meta-analysis. Utility
values and costs were obtained from published data. Numerous
sensitive to the drug cos
and the consequences fr
tran. Results varied by a c
patient’s CHADS2 score, a
mg or apixaban being o
sensitive to patient chara
mg were unlikely to be c
apixaban or dabigatran
between these two option
and further evidence on t
dabigatran.
VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6
warfarin event rates from other major RCTs to assess the impact
on results. No differences in event fatality rates between treat-
ments were assumed. For incorporation into the economic
model, transition probabilities for the duration of cycle length
were obtained by using standard methodology.
The estimate for the transition probability for each event for
dabigatran, apixaban, and rivaroxaban was derived by using the
odds ratio for each treatment obtained from a network meta-
analysis. A detailed description of the methods and results of the
network meta-analysis are available elsewhere [12]. Based on the
available results, the following events were modeled to vary by
anticoagulant: stroke, MI, major bleeds, and ICH. In addition, the
model incorporated the same risks of minor bleeds, PE, and TIA
for all anticoagulants. Sensitivity analyses were conducted incor-
porating the relative risks of minor bleeds and nonvascular
deaths.
Utility Values
Utility values were based on whether the patients experienced an
event (MI, stroke, PE, TIA, ICH, and extracranial hemorrhage) in
the current cycle and their event history (previous MI or stroke).
Utility values were sourced from published data (Table 1)
[7,24–26,33]. Analysis assumed no difference in utility values on
treatment. Sensitivity analysis assumed reduced utility on war-
farin and other anticoagulants as per previous studies [7,24,25].
Costs
Costs for all resources were adjusted to 2011 Canadian dollars by
using the Bank of Canada Inflation Calculator [34]. Drug costs
were obtained from the Ontario Drug Benefit formulary or from
the drug manufacturer [27]. Because no drug costs were available
for apixaban at the time of the analysis, the costs were assumed
to equal the drug costs for dabigatran. For each drug therapy,
annual drug treatment costs include a $7 prescription fee (every 3
months) and an 8% pharmacist’s markup. For warfarin, an addi-
tional cost of international normalized ratio monitoring was
added [28]. The costs of events and any associated long-term
the range and results of these analyses.
Threshold Analysis
Threshold analysis was conducted to assess the value of a
parameter required to lead to change in the interpretation of
the base result. This was based on assuming a willingness-to-pay
value of $50,000 for a QALY. Analysis was conducted for param-
eters for which there was limited information: that is, the price of
apixaban and the consequences of minor and major bleeds with
dabigatran.
Probabilistic Sensitivity Analysis
Probabilistic sensitivity analysis was conducted by using a Monte
Carlo simulation [29]. For the Monte Carlo simulation, probability
distributions related to natural history parameters, relative risks
and odds ratios, costs, and utilities were incorporated into the
analysis. Analysis adopted standard methods for defining uncer-
tainty around parameters (Table 1). Estimates of incremental
costs and QALYs were obtained by re-running the model employ-
ing values from the related probability distributions. In this study,
5000 replications were conducted; that is, a set of 5000 outcome
estimates was obtained. Cost-effectiveness acceptability curves
that present the probability that each treatment is optimal given
different values of willingness to pay for an additional QALY were
derived [36].
Analysis of Variability
Stratified analyses were conducted to assess the sensitivity of the
results to changes in the underlying patient population. Stratified
analyses incorporated, where possible, different warfarin-related
event rates based on the patient profile and available data. In
addition, where possible, different estimates of the relative
treatment effect of the newer oral anticoagulants compared with
warfarin were included. Analyses were conducted to stratify
patient by three criteria: CHADS2 score, age, and center’s TTR.
Table 2 – Base results.
Cost ($) QALYs Incremental cost per QALY gained (ICER) ($)
vs. warfarin Sequential ICER
Warfarin 18,620 6.480
Dabigatran 150 mg 21,486 6.617 20,797 20,797
Dominated therapies
Apixaban 21,966 6.617 24,312 Dominated by dabigatran 150 mg
Rivaroxaban 22,016 6.541 55,757 Dominated by dabigatran 150 mg and apixaban
Dabigatran 110 mg 22,804 6.543 66,354 Dominated by dabigatran 150 mg and apixaban
Note. Dominated ¼ more costly and equal or fewer QALYs; Extended dominance ¼ the combination of two other alternatives dominates the
treatment.
ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
were included, rivaroxaban would be optimal as the ICUR for
rivaroxaban versus that for warfarin was $8278.
If treatment discontinuations not related to vascular events
were included in the analysis, apixaban produced more QALYs
in which the TTR was 6
Discussion
In the base-case analysi
optimal treatment choic
willing to pay at least $20
are uncertain given tha
QALYs at only a slightly
bilistic analysis illustrate
dabigatran was optimal
insensitive to many of
model except for the
consequences from min
The results need to b
this area. Five separate
dabigatran versus warfa
been published [7–11,37
clinical data from the R
models of similar forma
rivaroxaban or apixaban
Similar to our study, a U
Council found that dab
centers in which patie
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
$0 $20,000 $40,000 $60,000 $80,000 $100,000
ProbabilityTreatmentisOpƟmal
Threshold Value for a QALY
Warfarin Dabigatran 150mg Rivaroxaban Apixaban Dabigatran 110mg
Fig. 2 – Cost-effectiveness Acceptability Curve.

28. AVERROES Study
28
Apixaban Event
rate
(%/year)
ASA Event rate
(%/year)
Apixaban vs
ASA
P Value
Stroke or
systemic
embolism
1.62 3.63 0.001
Ischemic stroke 1.37 3.11 0.001
Hemorrhagic
stroke
0.19 0.28 0.45
Major bleeding 1.41 0.92 0.07

29. Patients Unsuitable for NOAC
Agents
AF patients for whom the NOACs are not approved for
stroke prevention include:
!
• Patients with significant valvular heart disease,
particularly severe mitral stenosis
• Patients with prosthetic valves
• Patients with eGFR 30 mL/min
• Patients with active bleeding
• Patients with hepatic disease (rivaroxaban and
apixaban)
• Patients with concomitant systemic treatment with
strong inhibitors of CYP3A4 and P-gp
• Patients with concomitant systemic treatment with
strong inducers of CYP3A4 and P-gp
29

30. Non-Valvular AF
TTR ≥ 70% for 6 months
despite compliance/adherence
Yes
Continue on Warfarin
or switch to NOACs
based on patient’s
preference, benefits
risks and costs
Yes No
Male or female 65 yrs + lone AF
If NOACs are chosen
On Warfarin
Switch to NOACs
if good compliance/adherence
Yes
No
No antithrombotic therapy
CHA2DS2-VASc ≥ 1
No
Yes No
Age 75 yrs Age ≥ 75 yrs
Upper GI history
Prior MI/ACS
CrCl 30-60 mL/min
HAS-BLED ≥ 3
either Apixaban
or Dabigatran
or Rivaroxaban
either Apixaban
or Rivaroxaban
Yes for 1 or more
Upper GI history
Prior MI/ACS
CrCl 30-60 mL/min
HAS-BLED ≥ 3
Yes for 1 or more
either Apixaban
or Rivaroxaban
Apixaban
Aspirin plus clopidogrel, or, less effectively, aspirin alone may be considered only when patients at
Warfarin therapy or NOACs
Decision based on patient’s preference and values
following evaluation of benefits, risks and cost
SAMe-TT2R2 score0-1 ≥ 2
Warfarin therapy considered NOACs use encouraged
No Yes for 1 or more No Yes for 1 or more
10 S. Rosanio et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Review
Pharmacology, benefits, unaddressed questions, and pragmatic issues of
the newer oral anticoagulants for stroke prophylaxis in non-valvular
atrial fibrillation and proposal of a management algorithm
Salvatore Rosanio a,
⁎, Abdul M. Keylani a
, Darrin C. D'Agostino a
, Craig M. DeLaughter a
, Antonio Vitarelli b
a
Department of Internal Medicine, Division of Cardiology, University of North Texas Health Science Center, Fort Worth, TX, United States
b
Cardio-Respiratory Department, La Sapienza University, Rome, Italy
a b s t r a c ta r t i c l e i n f o
Article history:
Received 17 December 2013
Received in revised form 6 March 2014
Accepted 17 April 2014
Available online xxxx
Keywords:
Atrial fibrillation
Stroke
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct
thrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to
warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common
clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians'
reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly;
3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary
stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects
presented in current guidelines are covered and we also propose an evidence-based anticoagulation management
algorithm.
© 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Non-valvular atrial fibrillation (AF) in the absence of rheumatic
mitral stenosis or a prosthetic heart valve is the most common sustained
cardiac rhythm disorder worldwide, occurring in 1 to 2% of the general
population [1,2]. AF affects over 2 million people in the US and over
6 million across the European Union and occurs more frequently in
the elderly [1,2]. As such, the prevalence of AF is projected to double
in the next 50 years as much of the population ages [3].
Approximately one in three patients with AF will develop an ische-
mic stroke in their lifetime, with almost two-thirds being cardioembolic
and one-third being atherothrombotic [4].
Atrial fibrillation-related strokes are more likely to be massive, are
often fatal or associated with long-term disability and exhibit high
recurrence rates compared to strokes of other etiologies [5]. Due to
the nature of these events, strokes represent a major public health prob-
lem with a huge economic burden. In the US, the estimated direct and
indirect costs of stroke were $34.3 billion in 2008 [6].
The long-term risk of stroke in AF depends on the clinical predictors
collectively assessed in the CHADS2 scoring scheme in which Congestive
heart failure, Hypertension, Age ≥ 75 years and Diabetes mellitus are
each assigned one point or two points for a history of Stroke/transient
ischemic attack [TIA] or CHA2DS2-VASc, which considers additional risk
factors, such as vascular disease (myocardial infarction [MI], complex
aortic plaque, peripheral artery disease) and sex category (female sex),
each of which is awarded one point, including age of 65 to 74 years,
and 2 points if age ≥ 75 years [7–9].
The American College of Chest Physicians and European Society
of Cardiology guidelines recommend that all patients with AF and a
CHADS2 or CHA2DS2-VASc score ≥ 1 should be on long-term oral
anticoagulation [1,10].
Warfarin, the most prescribed oral anticoagulant acts by lowering
the serum levels of vitamin K-dependent pro-coagulant proteins and
is highly effective for the prevention of AF-related stroke, resulting in
a 64% risk reduction compared to placebo and a 37% risk reduction com-
pared with antiplatelet therapy [11]. However, warfarin has several
drawbacks (slow onset and offset of action; narrow therapeutic range
[international normalized ratio, INR of 2.0–3.0] that requires regular
monitoring; several interactions with food, alcohol, and drugs; potential
ethnic, genetic, and age-related variations in dose response; and high
bleeding risk [0.3–0.5%/yr]), which have resulted in its suboptimal use
in clinical practice and promoted the search for more convenient and
safer oral anticoagulants [12–18].
⁎ Corresponding author at: Department of Internal Medicine, Division of Cardiology,
855 Montgomery Street, PCC Room 315, Fort Worth, TX 76107, United States. Tel.: +1 817
735 7624x2072 (office); fax: +1 817 735 2748.
E-mail address: Salvatore.Rosanio@unthsc.edu (S. Rosanio).
http://dx.doi.org/10.1016/j.ijcard.2014.04.179
0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
journal homepage: www.elsevier.com/locate/ijcard
Please cite this article as: Rosanio S, et al, Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants
for stroke prophylaxis in non..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.179
ddressed questions, and pragmatic issues of
ts for stroke prophylaxis in non-valvular
al of a management algorithm
ani a
, Darrin C. D'Agostino a
, Craig M. DeLaughter a
, Antonio Vitarelli b
ersity of North Texas Health Science Center, Fort Worth, TX, United States
e, Italy
b s t r a c t
is systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct
rombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to
arfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common
nical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians'
luctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly;
patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary
enting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects
esented in current guidelines are covered and we also propose an evidence-based anticoagulation management
gorithm.
© 2014 Elsevier Ireland Ltd. All rights reserved.
International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
ernational Journal of Cardiology
al homepage: www.elsevier.com/locate/ijcard

31. RATIONAL PHARMACY
Dagbigitran 150 mg BID
Rivaroxaban/Apixiban/
Dagbigitran 110 mg BID
80 yrs and normal renal function
Previous and significant
bleeding
Superior to warfarin in reducing
ischemic strokes
80 yrs, eGFR 30-50
Very low body weight
Dyspepsia, active CAD
*from Dr. Ken Butcher, University of Alberta

32. Summary
Three key lessons:
1) Atrial fibrillation is an increasingly important and preventable
cause of ischemic stroke.
2) NOACs are associated with reduced ICH, ischemic strokes and
systemic embolism compared with warfarin.
3) NOACs are not “prescribe and forget” drugs. Knowledge of the
pharmacokinetics, monitoring (including patient compliance, renal
function (dabigitran), take with food (rivaroxaban)), and drug-
drug interactions will improve real-world safety.

33. Coumadin Dabigatran 150 Rivaroxaban Apixaban
STROKE
ICH
GIB NNH 100/2yrs NNH 100/2yrs
REVERSAL
MI
D/C Dyspepsia
RENAL CrCl30 CrCl30 CrCl15
COST
MONITORING