1. Practical Applications
of Anticoagulation Therapy
Atrial Fibrillation and Venous
Thromboembolism
An Accredited
Continuing Medical Education Program
Developed by:
George Dresser, MD, PhD, FRCPC
Lorne Gula, MD, FRCPC
Peter L. Gross, MD, FRCPC
David Dixon, MD, MCISc(FM), CCFP, FCFP
Murray Awde, MD, CCFP, FCFP
Sol Stern, BSc, MSc, MD, MCFP

2. Faculty/Presenter Disclosure
• Faculty: Dr. John Ward: MD, CCFP(EM), FRCPC (Med),
Clinical Associate Professor, Dept of Emergency
Medicine, UBC
• Relationships with commercial interests:
• Grants/Research Support: n/a
• Speakers Bureau/Honoraria: Astra Zenica, Bayer, Pfizer
• Consulting Fees: n/a
• Other: n/a
CFPC CoI Templates: Slide 1

3. Disclosure of Commercial Support
• This program has received financial support from Bayer
HealthCare in the form of an unrestricted educational grant.
• Potential for conflict(s) of interest:
• Dr. John Ward has received honorarium from Bayer HealthCare.
CFPC CoI Templates: Slide 2

4. Mitigating Potential Bias
• The speaker had provided a full disclosure in advance of
the program. The scientific content of the program is
evidence based and all content related to pharmacotherapy
is within product label. The program has been peer
reviewed and is nationally accredited by the College of
Family Physicians of Canada.
CFPC CoI Templates: Slide 3

5. Accreditation
This program has been accredited by the College of Family
Physicians of Canada for up to 1 Mainpro-M1 credit.

6. Learning objectives
Upon completion of the program, participants will be able to:
• Describe the role of anticoagulation for stroke prevention
in atrial fibrillation (AF), and for the treatment of venous
thromboembolism (VTE)
• Evaluate stroke risk in patients with AF
• Discuss the indications for anticoagulation therapy in
patients with AF
• Discuss new oral anticoagulant treatment options for
patients with AF and VTE
• Determine how to most effectively implement the new
oral anticoagulants for the prevention of stroke in
patients with AF and the treatment of VTE into clinical
practice

7. Atrial Fibrillation

8. Atrial fibrillation
• Irregular, ineffective atrial contraction
• Worsens over time, leads to atrial remodeling1
• Slow but steady progression to chronic AF after
initial paroxysmal AF2
1. Allessie M et al. Cardiovascular Research 2002;54(2):230-246. 2. Kerr CR et al. Am Heart J 2005;149(3):489-496.

9. Atrial fibrillation: Epidemiology
• Affects about 1% of population - about 350,000
Canadians1,2
• Most common cardiac arrhythmia requiring medical
care1
• Lifetime risk 1 in 4 for age ≥ 40 years3
• Prevalence increases with age; hence increasing
due to increasingly elderly population2
1. Go As. et al. JAMA 2001;285(18):2370-2375. 2. Brembilla-Perrot B et al.. Pacing and Clinical Electrophysiology 2004;27(3):287-292.
3. Lloyd-Jones DM et al. Circulation 2004;110(9):1042-1046.

10. Stroke risk in AF
• 4-5 fold increase in stroke risk in AF; 1 in 6 strokes
occurs in AF patients1,2
• Stroke risk in AF increases from 1.5% at age 50-59
to 23.5% at age 80-891
• About 40% of AF patients in primary care may be at
high risk of stroke3
1. Kannel WB et al. Am J Cardiol 1998;82(7):2N-9N. 2. Mattle HP. Cerebrovascular Diseases 2003;16(Suppl. 1):3-8. 3. Carroll K,
Majeed A. Br J Gen Pract 2001;51(472):884-6, 889-91.

11. Case study: James
• James, 72-year male, newly
diagnosed with AF
• H/o hypertension and diabetes,
no H/o TIA or stroke
• Had MI 2 years ago; since then
has had intermittent CHF with
exacerbation 1 month ago
• He is now assessed for stroke
risk, and considered for
antithrombotic therapy

12. Case study: James (contd.)
1. What is this patient’s CHADS2 score?
1) 0
2) 1
3) 2
4) 3
5) 4
6) 5
7) 6

13. CHADS2 score and stroke risk
Risk factor Points
C - Congestive heart failure 1
H - Hypertension 1
A - Age >75 years 1
D - Diabetes 1
S - Prior Stroke or TIA 2
CHADS2 score
Stroke rate per
100 patient-
years
0 1.9
1 2.8
2 4.0
3 5.9
4 8.5
5 12.5
6 18.2
Gage BF et al. JAMA 2001;285(22):2864-2870.

14. CHA2DS2-VASc score
Risk Factor Score
C - Congestive heart failure 1
H - Hypertension 1
A - Age ≥ 75 yrs 2
D - Diabetes mellitus 1
S2 - Prior stroke or TIA 2
V - Vascular disease 1
A - Age 65-74 years old 1
Sc - Sex category (female) 1
Lip GYH, Halperin JL. Am J Med 2010;123(6):484-488.

15. Case study: James (contd.)
2. Should James receive anticoagulation for reducing
his risk of stroke?
a) Yes
b) No

16. Antithrombotic therapy in AF
• Aims at preventing thromboembolism
• ACTIVE-W: Oral anticoagulant therapy was
superior to clopidogrel plus ASA for preventing
vascular events in AF patients at high risk of stroke1
• ACTIVE-A: Clopidogrel plus ASA, compared with
ASA alone, reduced major vascular events in AF
patients at increased risk for stroke but for whom
VKA was unsuitable2
1. Lancet 2006;367(9526):1903-1912. 2. N Engl J Med 2009;360(20):2066-2078.

17. Skanes AC et al. Can J Cardiol 2012;28(2):125-136.
CCS recommendations
Note: Newer agents, i.e., dabigatran, rivaroxaban and
apixaban, are preferred over warfarin for stroke
prevention in AF

18. HAS-BLED score
Condition Points
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 (> 65 years) 1
D - Drugs or alcohol (1 point each) 1 or 2
HAS-BLED
score
Bleeds per
100 patient-
years
0 1.13
1 1.02
2 1.88
3 3.74
4 8.70
5 12.5
Pisters R et al. Chest 2010;138(5):1093-1100.
Note: HAS-BLED has been validated for warfarin, but not for the new anticoagulants.

19. Warfarin
• Traditional choice for anticoagulation in AF
• Superior to antiplatelet therapy1
• Reduction in stroke risk1
• Warfarin 64%
• Antiplatelet agents 22%
• However, use is suboptimal2
1. Hart RG et al. Ann Intern Med 2007;146(12):857-867. 2. Verhovsek M et al. BMC Geriatrics 2008;8(1):13.

20. Limitations of warfarin
• Unpredictable INR prolongation; monthly
(sometimes weekly) measurements needed to
maintain INR 2.0-3.01
• Food/drug interactions cause INR fluctuations
necessitating dosage adjustments
• Difficulty achieving therapeutic INR range >65% of
time1
• Major bleeding 3.0%/year approx1
• Patient and HCP reluctance to employ warfarin2
1. Skanes AC et al. Can J Cardiol 2012;28(2):125-136. 2. Kuzniatsova N, Lip GYH. Eur Cardiol 2011;7(1):37-43. 3. Horton JD,
Bushwick BM. Am Fam Physician 1999;59(3):635-46.

21. Warfarin: Food and drug interactions
Increase anticoagulation Decrease anticoagulation
Foods St. John’s Wort
Ginseng
Garlic
Gingko biloba
Avocado
Spinach
Brocolli
Drugs Acetaminophen
Amiodarone
Androgens
Allopurinol
Aspirin (high dose)
Cimetidine
Clofibrate
Chloramphenicol
Disulfiram
Dipyridamole
Erythromycin
Fluconazole
Fluoxetine HCl
Glucagon
Indomethacin
Liquid paraffin
Metronidazole
Phenylbutazone
Phenytoin
Probenecid
Phenformin
Quinidine
Sulfinpyrazone
Tamoxifen
Tolbutamide
Thyroid hormone
Trimethoprim-
sulfamethoxazole
Antithyroid drugs
Barbiturates
Carbamazepine
Cholestyramine
Gluthimide
Griseofulvin
Oral contraceptive
Rifampicin
Sucralfate
Gogna A, Arun S. Oral Anticoagulation in Clinical Practice. JIACM 2005;6(1):53-66

22. Underutilization of anticoagulation in
high risk AF patients
Gladstone DJ, et al. Stroke. 2009;40:235-40.
Warfarin
subtherapeutic
Warfarin
therapeutic
Single
antiplatelet
agent
No
antithrombotics
Dual antiplatelet
therapy
In addition, only 18% of AF patients who had a previous
stroke had a therapeutic INR of warfarin at the time of stroke
Preadmission treatment in patients with known AF admitted with acute ischemic stroke and
classified as high risk for systemic emboli according to published guidelines (n=597)
29%
29%
30%
10%
2%

23. Need for medication adherence
• Risk of subtherapeutic INR with warfarin: Relative risk of stroke
with INR 1.5 is 3.3 times higher than with INR 2.01
• Findings in stroke patients2:
• High risk patients: Only 40% of were taking warfarin for
primary prevention before first stroke
• Highest risk patients (with history of stroke/TIA): 43% were
not taking warfarin
• Adherence is related to complexity of regimen
• 26% higher adherence with once daily regimen than with
twice daily regimen3
1. Horton JD, Bushwick BM. Am Fam Physician 1999;59(3):635-46. Gladstone DJ et al. Stroke 2009;40(1):235-240. 3. Laliberté
Fo, et al. Adv Ther 2012;29(8):675-690.

24. Once-Daily Dosing Is Associated With Higher
Adherence Rates Than Twice-Daily Dosing
60
65
70
75
80
Total Population ≥ 65 years old
OD BID
Adherence to Chronic Medications in Non-valvular AF patients
Laliberté F et al. Adv Ther (2012) 29(8):675-690.

25. Case study: James (contd.)
3. Which one of the following statements about
the choice of anticoagulant therapy most
correctly reflects the CCS recommendations?
a) Warfarin is the first line choice for stroke risk
reduction in AF; newer anticoagulants should
only be considered if warfarin is contraindicated.
b) The efficacy of new anticoagulants for stroke risk
reduction in AF is dabigatran > rivaroxaban >
apixaban.
c) When oral anticoagulant therapy is indicated, AF
patients should receive dabigatran, rivaroxaban
or apixaban in preference to a VKA.
James is being considered for anticoagulant therapy.

26. Case study: James (contd.)
4. In the ROCKET-AF trial:
a) Dabigatran was inferior to warfarin in
preventing stroke or systemic embolism.
b) Rivaroxaban was noninferior to warfarin
for the prevention of stroke or systemic
embolism in AF patients.
c) Apixaban was inferior to warfarin in
preventing stroke or systemic embolism.

27. Newer anticoagulants
(apixaban, dabigatran, rivaroxaban)
• Quickly achieve maximal blood levels and
anticoagulant effects following oral administration
• Absorption and elimination largely unaffected by
food or other medications.
• Administered in fixed daily doses
• Anticoagulation monitoring not required
• Relatively short serum and receptor inhibition half-
lives; anticoagulant effects diminish quickly after
discontinuation
Skanes AC et al. Can J Cardiol 2012;28(2):125-136.

28. Novel Oral Anticoagulants –
Pharmacological Properties
Characteristic Apixaban Dabigatran Rivaroxaban
Target Factor Xa Factor IIa Factor Xa
Prodrug No Yes No
Dosing BID BID OD
Bioavailability, % 50% 6.5% 80-100%*
Half-life 8-15 h 12-14 h 5-13h
Renal clearance
(unchanged drug)
27% 85% ~33%
Cmax 3-4 h 1-2 h 2-4 h
Drug interactions Potent inhibitors
of both CYP3A4 and P-
gp
P-gp inhibitors Potent inhibitors
of both CYP3A4 and
P-gp
* When the 15mg and 20mg dose is taken with food

29. Trials Comparing New Anticoagulants
vs. Warfarin
ARISTOTLE1,2 RE-LY3 ROCKET AF4
No. of patients 18,201 18,113 14,264
CHADS2 score 2.1 2.1 3.5
Statistical
objective
Non-inferiority Non-inferiority Non-inferiority
Study drugs Double-blind apixaban Two doses of double-
blind dabigatran
Double-blind rivaroxaban
Control Double-blind warfarin
(INR 2–3)
Open-label warfarin
(INR 2–3)
Double-blind warfarin
(INR 2–3)
Primary Dose(s)
Studied
5 mg BID 110 mg BID and
150 mg BID
20 mg OD
Adjusted Dose
Studied
2.5 mg BID
For patient with any two of
the following:
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5
mg/dl (133 µmol/l)
(27% renal excretion)
None
(~85% renal excretion)
15 mg OD
For patients with CrCl =
30-49 mL/min
(~33% renal excretion)
1. Lopes RD et al, 2010; 2.Granger CB et al, 2011; 3. Connolly SJ et al, 2009; 4. Patel MR et al, 2011.

30. Comparison of new anticoagulants
• No head-to-head comparative studies comparing
new anticoagulants with each other
• Different study designs and patient populations;
hence indirect comparisons are difficult

31. Indirect comparison/meta-analysis of
new anticoagulants
1. Lip GYH et al. J Am Coll Cardiol 2012;60(8):738-746. 2. Adam SS et al. Ann Intern Med 2012. 3. Miller CS et al. Am
J Cardiol 2012;110(3):453-460.
Lip1 • No significant differences between new anticoagulants for
preventing stroke and systemic embolism
• Less major bleeding with apixaban than dabigatran 150 mg BID
and rivaroxaban, but not significantly different from dabigatran
110 mg BID
Adam2 Higher MI risk with direct thrombin inhibitors than with factor Xa
inhibitors
Miller3 • New anticoagulants decreased risk for stroke, systemic
embolism, all-cause mortality, and vascular mortality
• Also lower risk for intracranial bleeding
• Inconclusive data on risks for major bleeding and GI bleeding

32. Case study: Linda
• Linda, a 73-year old female with AF and moderate
renal impairment
• No H/o hypertension, diabetes, heart failure or
TIA/stroke
• Prescribed warfarin to reduce stroke risk;
however, she has a busy lifestyle and her INRs are
regularly out of range

33. Case study: Linda
1. What is this patient’s CHADS2 score?
a) 0
b) 1
c) 2
d) 3
e) 4
f) 5
g) 6

34. Case study: Linda (contd)
2. What is Linda’s CHA2DS2-VASc score?
a) 0
b) 2
c) 4
d) 6
e) 8
f) 10

35. Case study: Linda (contd)
3. As per CCS guidelines, should Linda receive
anticoagulation?
a) Linda`s CHADS2 = 0, and hence she should not
receive anticoagulation.
b) Although Linda has CHADS2 = 0, she should
receive anticoagulation because she has
additional risk factors, i.e., age ≥ 65 years and
female sex.

36. Case study: Linda (contd)
Linda is being considered for a switch from warfarin to
a newer anticoagulant for stroke risk reduction.
4. Which of the following statements is correct?
a) Warfarin therapy is associated with INR
fluctuations, and measurements of INR are
required at least monthly to maintain a safe and
effective INR.
b) Compared to warfarin, the newer anticoagulants
dabigatran, rivaroxaban and apixaban are less
effective for stroke risk reduction.

37. New anticoagulants in AF
CHADS2
score
HAS-
BLED
score
CHADS2
≥2
CHADS2
≥1
Consider
anticoagulation
for all patients
New AF
patient
Balance stroke risk against
bleeding risk. HAS-BLED score of
≥ 3 indicates increased risk of
major bleeding
Consider
anticoagulation
for most patients

38. Starting a new oral anticoagulant in a
new patient
Apixaban Dabigatran Rivaroxaban
Usual dosage 5 mg BID 150 mg BID 20 mg OD
Take with
food?
- - Yes
Renal
impairment
CrCl ≥ 30 mL/min:
No dose adjustment
CrCl 15-30 ml/min:
Use with caution
CrCl <15 ml/min: not
recommended
CrCl 30-50 ml/min: No dose
adjustment (consider 110
mg dosage); use with
caution; assess renal
function at least twice a
year and with changes in
clinical status
CrCl <30 ml/min:
contraindicated
CrCl 30-49
mL/min: 15 mg
OD
CrCl <30 ml/min:
not recommended
Other Age ≥75 with other risk
factor(s) for bleeding: 110
mg BID; also assess renal
function

39. Patient has
risk factor
for stroke
Estimate
CrCl
≥25
mL/min
5 mg BID2.5 mg BID
<15
mL/min
Not
recommended
Recommended dose
Apixaban
Check Age
Check
Weight
Check Serum
Creatinine
≥ 80 years ≤ 60 kg
≥ 133
micromol/L
If ≥ 2
features
If ≤ 1
features
Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Eliquis® PM November 27, 2012.
Canadian Dosing Recommendations for
Stroke Prevention in AF
≥15 - 24
mL/min
No dosing
recommendation
can be made

40. Patient has
risk factor
for stroke
Estimate
CrCl
<30
mL/min
30-49
mL/min
>50
mL/min
Elderly
and/or
risk
factors
for
bleeding
Age <75
years
Age 75-
80 years
Age >80
years
110mg BID 150mg BID 150mg BID 110mg BID 110mg BID150mg BID
Contra-
indicated
One
other risk
factor for
bleeding
Recommended dose
Dose can be considered
Dabigatran
Canadian Dosing Recommendations
for Stroke Prevention in AF
Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Pradaxa ® PM November 12, 2012.

41. Patient has
risk factor
for stroke
Estimate
CrCl
30-49
mL/min
>50
mL/min
20 mg OD15 mg OD
<30
mL/min
Not
recommended
Rivaroxaban
Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Xarelto® PM, July 18, 2012.
Recommended dose
Canadian Dosing Recommendations for
Stroke Prevention in AF

42. Key learning points
• AF is associated with 4-5-fold increase in stroke risk, and with
increased morbidity and mortality
• Oral anticoagulant therapy should be considered for patients at
high risk of stroke (CHADS2 ≥2) and for most patients at
intermediate risk (CHADS2 1). CHA2DS2-VASc score can
identify patients with stroke risk factors not identified by
CHADS2
• Warfarin has been in use for several years, but has many
limitations.
• Apixaban, dabigatran and rivaroxaban overcome many of
warfarin’s limitations. Their absorption and elimination is
largely unaffected by food or other medications, they can be
administered in fixed daily doses, and anticoagulation
monitoring is not required

43. Venous Thromboembolism

44. Venous thromboembolism (VTE)
• Third most common cardiovascular disease after
coronary artery disease and stroke1
• Diagnosed VTE: 1-2 events/1000 population/year2,3
• Uncommon before age 20, but incidence about
doubles with each decade after age 402
1. Douketis JD. Can Fam Physician 2005;51(2):217-23. 2. Kearon CSemin Vasc Med 2001;1(1):7-26. 3. Silverstein MD et al. Arch
Intern Med 1998;158(6):585-593.

45. Types of VTE
• VTE may be:
• Provoked
• Transient/reversible factors, e.g., surgery, hospitalization
• Continuing/irreversible factors, e.g., cancer
• Unprovoked: No identifiable cause
• VTE includes:
• Deep vein thrombosis (DVT)
• Incidence 48 cases/100,000 population/year1
• Estimated to affect 45,000 individuals/year in Canada2
• Pulmonary embolism (PE)
• Incidence: 69 cases/100,000 population/year1
• Can be fatal; accounts for 10% of hospital deaths3
1. Silverstein MD et al. Arch Intern Med 1998;158(6):585-593. 2. Douketis JD. Can Fam Physician 2005;51(2):217-23.
3. Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S.

46. Deep vein thrombosis (DVT)
• Usually starts in calf veins, extends to proximal
veins, embolizes to pulmonary arteries (PE)
• Calf DVT often resolves spontaneously in 72 hours;
only 1/6 involve proximal vein
• DVT resolves with anticoagulant treatment, but can
recur after discontinuation of therapy.
• Highest risk in first 6-12 months
• Cumulative recurrence: 25% at 5 years, 30% at 10 years
• 33-50% of DVT patients develop post-thrombotic
syndrome; higher with recurrent DVT
1. Kearon C. Semin Vasc Med 2001;1(1):7-26. 2. Kearon C. Circulation 2003;107(23 suppl 1):I-22-I-30.

47. Leg veins
Scarvelis D, Wells PS. CMAJ 2006;175(9):1087-92.

48. Pulmonary Embolism (PE)
• Estimated annual incidence: 69 cases per 100,000
population 1
• Acute PE can be fatal. Approximately 10% of
hospital deaths are attributed to PE 2
• In about 5% of patients, poor resolution of PE or
recurrent PE leads to development of pulmonary
hypertension 3,4,5
1. Silverstein MD et al. Arch Intern Med 1998;158(6):585-593. 2. Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S. 3.
Kearon C. Circulation 2003;107(23 suppl 1):I-22-I-30. 4. de Perrot M et al. CMAJ 2006;174(12):1706. 5. Hoeper MM et al.
Circulation 2006;113(16):2011-2020.

49. Recurrence
• Rates of recurrent VTE 1
• At 1 month: 4%
• At 1 year 11%
1. Spencer F et al. Arch Intern Med 2008;168:425-43.

50. Case study: Jack
• Jack, 55-year old
male, develops pain, swelling
and redness in his left leg
• On investigation, diagnosed as
having DVT involving
superficial femoral vein

51. Case study: Jack (contd.)
1. As per American College of Chest Physicians
(ACCP) 2012 recommendations, any of the following
anticoagulants can be employed for the initial (0 to
~7 days) management of VTE, except for
a) Unfractionated heparin (UFH)
b) Low molecular weight heparin (LWMH)
c) Rivaroxaban
d) Warfarin

52. Case study: Jack (contd.)
2. Which of the following statements regarding
anticoagulation for the treatment of VTE is correct?
a) INR monitoring is not needed if warfarin is used
for anticoagulation.
b) Patients receiving rivaroxaban report improved
treatment satisfaction compared with those
using traditional anticoagulants such as
enoxaparin/VKA.
c) Dabigatran is the drug of choice for acute
treatment of VTE.

53. Risk factors for VTE
• Surgery
• Trauma (major or lower extremity)
• Immobility, paresis
• Malignancy
• Cancer therapy
(hormonal, chemotherapy, radioth
erapy)
• Previous VTE
• Increasing age
• Pregnancy, postpartum period
• Estrogen-containing oral
contraception, hormone
replacement therapy
• Selective estrogen receptor
modulators
• Acute medical illness
• Heart or respiratory failure
• Inflammatory bowel disease
• Nephrotic syndrome
• Myeloproliferative disorders
• Paroxysmal nocturnal
hemoglobinuria
• Obesity
• Smoking
• Varicose veins
• Central venous catheterization
• Inherited or acquired thrombophilia
Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S.

54. Wells Prediction Rule for DVT
Clinical variable Score
Active cancer (treatment ongoing or within previous 6 months, or palliative) 1
Paralysis, paresis, or immobilization of lower extremity 1
Bedridden for > 3 days or major surgery within previous 12 weeks requiring general or
regional anesthesia
1
Localized tenderness along distribution of deep veins 1
Swelling of entire leg 1
Calf swelling at least 3 cm larger than asymptomatic leg (10 cm below tibial tuberosity) 1
Pitting edema confined to symptomatic leg 1
Collateral superficial veins (non-varicose) 1
Previously documented DVT 1
Alternative diagnosis as least as likely as DVT -2
Clinical risk (probability) Total
High >2
Moderate 1-2
Low <1
Wells PS et al. Lancet 1997;350(9094):1795-1798.

55. Wells Prediction Rule for PE
Clinical variable Score
Clinical signs and symptoms of DVT (minimum leg swelling and pain
with palpation of deep veins)
3
PE as or more likely than an alternative diagnosis 3
Heart rate > 100 beats/minute 1.5
Immobilization or surgery within previous 4 weeks 1.5
Previous DVT or PE 1.5
Hemoptysis 1
Malignancy (on treatment, treated in the last 6 months or palliative) 1
Clinical risk (probability) Total
High >6
Moderate 2-6
Low <2
Wells PS et al.Thromb Haemost 2000;83(3):416-20.

56. Antithrombotic Therapy for VTE
• Initial (0 to ~7 days): Parenteral anticoagulant or
oral rivaroxaban
• Thereafter
• Provoked VTE: Long term (i.e., 3 months) therapy –
VKA, LMWH, dabigatran (not approved) or rivaroxaban
• Unprovoked VTE: Extended therapy (i.e., > 3 months) –
VKA, LMWH, dabigatran (not approved), apixaban (not
approved) or rivaroxaban
Kearon C et al. Chest 2012;141(2 Suppl):e419S-94S.

57. Choice of therapy
Injectable • UFH: IV route; unpredictable dose response, narrow therapeutic
window; needs close monitoring
• LMWHs: More predictable pharmacokinetics , greater
bioavailability than UFH
• Fondaparinux (factor Xa inhibitor): SC route; similar efficacy to
UFH, but may be higher risk for bleeding
Oral - warfarin Several food and drug interactions, INR fluctuations needing dosage
adjustments and associated with bleeding risk
Oral - new
anticoagulants
• Quickly achieve maximal blood levels and anticoagulant effects
• Absorption, elimination largely unaffected by food or other
medications
• Fixed daily doses
• Anticoagulation monitoring not required
• Reduced doses (especially for dabigatran) considered in reduced
renal function, advanced age (> 75 years), or low BMI
• Relatively short half-lives, hence effects diminish quickly after
discontinuation
• Only rivaroxaban is approved for VTE treatment and prevention of
recurrent VTE in Canada

58. Clinical trials with apixaban
Study Main methods Main Results
BOTTICELLI
DVT1
• Phase 2 dose-ranging study to
assess efficacy and safety of three
different doses of apixaban vs.
treatment with LMWH or fondaparinux
and VKA
• Treatment of acute symptomatic DVT
Apixaban is suitable for
fixed-dose administration
AMPLIFY-
EXT2
• Apixaban treatment dose (5 mg) and
thromboprophylactic dose (2.5 mg)
• Extended anticoagulation for VTE
Apixaban reduced risk of
recurrent VTE compared to
placebo, without increasing
rate of major bleeding
1. Buller H et al. Journal of Thrombosis and Haemostasis 2008;6(8):1313-1318. 2. Agnelli G et al.. N Engl J Med 2012.
Note: Apixaban and dabigatran are not currently approved for VTE treatment

59. Clinical trials with dabigatran
Study Main methods Main Results
RE-COVER 11 &
RE-COVER 2 2
• Dabigatran 150 mg BID vs
adjusted dose warfarin (INR 2-
3)
• Treatment of acute VTE
• Dabigatran 150 mg BID is as effective as
adjusted dose warfarin
• Safety profile similar to warfarin, and
without the need for laboratory monitoring
• RE-COVER 2 confirmed dabigatran is
non-inferior to warfarin, with lower risk for
bleeding
RE-MEDY3 • Dabigatran 150 mg twice daily
vs. warfarin (6-36 months)
• Patients who had received
anticoagulant therapy for
acute VTE
• Dabigatran is as effective as warfarin for
preventing recurrent VTE, with lower risk
for bleeding, but higher incidence of acute
coronary event
RE-SONATE4 • Dabigatran vs. Placebo
• Patients who had received
anticoagulant therapy for
acute VTE
92% relative risk reduction with dabigatran in
recurrent VTE compared to placebo, no
significant difference in the incidence of
major bleeding
1. Schulman S et al. N Engl J Med 2009;361(24):2342-2352. 2. Schulman S et al. ASH 2011 Annual Meeting. Abstract 205. 3. Schulman S
et al. XXIII Congress of ISTH, 2011. Abstract O-TH-033, 4. Schulman S et al. XXIII Congress of ISTH, 2011. Abstract O-MO-037.
Note: Apixaban and dabigatran are not currently approved for VTE treatment

60. Clinical trials with rivaroxaban
Study Main methods Main Results
EINSTEIN-
DVT1
• Rivaroxaban (15 mg BID x 3
weeks followed by 20 mg daily)
vs. enoxaparin followed by VKA
for 3, 6 or 12 months
• Patients with acute symptomatic
DVT
• Rivaroxaban is noninferior for prevention of
symptomatic recurrent DVT; similar rates of
bleeding compared to enoxaparin/VKA
• Improved patient satisfaction with rivaroxaban
compared with enoxaparin/VKA, particularly in
reducing anticoagulation burden
EINSTEIN-PE2 • Rivaroxaban (15 mg BID x 3
weeks followed by 20 mg daily)
vs. enoxaparin 40 mg BID
followed by VKA for 3, 6 or 12
months
• Patients with acute symptomatic
PE with/without symptomatic
DVT
Rivaroxaban is noninferior to standard therapy for
initial and long-term treatment of PE, with potentially
improved benefit-risk profile, and significantly
reduced the number of major bleeding events
EINSTEIN-
extension1
• VTE patients who had completed
their standard treatment course
• Rivaroxaban 20 mg once daily
for additional 6 or 12 months
compared with placebo
• Rivaroxaban significantly reduced the risk of
recurrent VTE
1. N Engl J Med 2010;363(26):2499-2510. 2. N Engl J Med;366(14):1287-1297.

61. Starting rivaroxaban in a new patient
Usual dosage 15 mg BID for 3 weeks (one 15 mg tablet in the
morning and one in the evening with food),
followed by 20 mg once daily.
Maximum daily dose 30 mg in the first 3 weeks;
20 mg thereafter
Renal
impairment
CrCL < 30 ml/min: not recommended

62. Key learning points
• VTE is the third most common cardiovascular disease after
coronary artery disease and stroke. Complications include PE
and post-thrombotic syndrome
• Risk factors for VTE include hip/lower limb fractures, marked
reduction in mobility after major surgery. Risk increases with
advanced age and/or cancer
• VKA, LMWH, UFH, fondaparinux and rivaroxaban are indicated in
VTE. However, traditional anticoagulants are associated with
concerns about bruising and bleeding, lifestyle limitations, and
need for regular monitoring
• Rivaroxaban – the only new anticoagulant currently approved
for VTE treatment and prevention of recurrent VTE – offers
greater convenience, and may provide better clinical outcomes
than with VKA or LMWH therapy

63. Practical Usage
New Anticoagulants in AF and VTE

64. Switching from warfarin to new
anticoagulant
1. Advisory Committee Briefing Document. 2. Wartak SA, Bartholomew JR. Cleveland Clin J Med 2011;78(10):657-664. 3.
XARELTO® Product Monograph. 4. Eliquis 2.5 mg film-coated tablets information.
To apixaban Discontinue warfarin and start
apixaban when INR is <2.0
To dabigatran Start dabigatran only after warfarin
has been discontinued and INR is
< 2.0
To rivaroxaban Stop warfarin and determine INR
• INR ≤2.5: Start rivaroxaban at
usual dose
• INR >2.5: Delay start rivaroxaban
until INR is ≤2.5

65. Switching from new anticoagulant to
warfarin
1. Advisory Committee Briefing Document. 2. Wartak SA, Bartholomew JR. Cleveland Clin J Med 2011;78(10):657-664. 3.
XARELTO® Product Monograph. 4. Eliquis 2.5 mg film-coated tablets information.
From apixaban • Start warfarin and continue apixaban for ≥2 days
• After 2 days, obtain INR prior to next apixaban dose
• Continue coadministration until INR is ≥ 2.0
From
dabigatran
Start warfarin according to CrCl:
• ≥50 ml/min: 3 days before discontinuing dabigatran
• 30- <50 ml/min: 2 days before discontinuing
dabigatran
INR not reliable to assess warfarin effect till ≥2 days
after discontinuation
From
rivaroxaban
• First 2 days: give warfarin at usual starting dose; no
INR testing
• Continue rivaroxaban till INR ≥2.0; then discontinue
• INR ≥24 hours after last dose of rivaroxaban for
warfarin effect

66. Switching from parenteral anticoagulant
to new anticoagulant
To apixaban Done at the next scheduled dose
To dabigatran Initiate dabigatran 0-2 hours before next dose
of other agent is due, or at time of
discontinuation in case of continuous
treatment
To rivaroxaban Start rivaroxaban when heparin is stopped, or
0-2 hours before next scheduled injection of
full-dose of LMWH or fondaparinux. If
receiving prophylactic anticoagulant, start
rivaroxaban ≥6 hours after the last dose

67. Switching from new anticoagulant to
parenteral anticoagulant
From apixaban Done at the next scheduled dose
From dabigatran For prevention of VTE after hip- or knee-
replacement surgery, wait 12 hours after
last dose of dabigatran before switching
From rivaroxaban Discontinue rivaroxaban; give first dose of
parenteral anticoagulant when next
rivaroxaban dose was scheduled

68. Bridging anticoagulation
• Bridging anticoagulation with LMWH is often used
empirically, before and after surgery
• Debate on need for bridging anticoagulation1-4
• Manufacturers’ recommendations for dabigatran and
rivaroxaban:
• Discontinue these drugs at least 1 day before the procedure
• Consider longer times if major surgery, spinal puncture, or
placement of a spinal or epidural catheter or port, where
complete hemostasis may be required, or if moderate renal
impairment
1. ACCP Guidelines 2012. 2. Douketis JD. Blood 2011;117(19):5044-5049. 3. Wysokinski WE, McBane RD. Circulation 2012;126(4):486-490.
4. BRIDGE Study Overview.

69. Interruption of dabigatran or rivaroxaban
before surgery or invasive procedures
Schulman S, Crowther MA. Blood 2012;119(13):3016-3023.

70. Renal impairment
Renal impairment - a risk factor for bleeding with anticoagulants
Apixaban Dabigatran Rivaroxaban
Renal clearance 25%1 80%1 33%1
Severe
impairment
Not recommended
for CrCl <15
ml/min 3-5
Contraindicated 2 Not recommended
for CrCl
<15 ml/min 3-5
Other Less affected than
dabigatran,
preferred in
moderate
impairment 3-5
Lower dose if age
≥75 with risk
factors for
bleeding 2
Less affected than
dabigatran,
preferred in
moderate
impairment 3-5
1. Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540. 2. PradaxTM Product Monograph. 3.
Eliquis 2.5 mg film-coated tablets information. 4. Harder S. J Clin Pharmacol 2012;52(7):964-975. 5. Eliquis Product Monograph.

71. Choice of anticoagulant
Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540.

72. Bleeding with new anticoagulants
• Up to ∼3% of patients may develop major bleeding
• Major bleeding rates comparable/lower than with
warfarin
• Factors for increased risk: ↑ age, renal impairment
• No effective antidotes known
• INR is unreliable for new anticoagulants
• No precise information with aPTT, PT; but may be
qualitative indicator of drug presence
1. Siegal DM, Crowther MA. Eur Heart J 2012. 2. Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540.
3. Crowther MA, Warkentin TE. J Thrombosis Haemostasis 2009;7:107-110. 4. Schulman S, Crowther MA. Blood 2012;119(13):3016-3023

73. Managing bleeding with new
anticoagulants
Siegal DM, Crowther MA. Eur Heart J 2012.

74. Useful resources
• CCS guidelines for AF: 2012 update
• ACCP 2012 guidelines: Antithrombotic Therapy for
VTE