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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

Practical application of anticoagulation therapy af and vte april 12

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Page 1: Practical application of  anticoagulation therapy af and vte april 12

Practical Applications of Anticoagulation Therapy

Atrial Fibrillation and Venous Thromboembolism

An AccreditedContinuing 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

Page 2: Practical application of  anticoagulation therapy af and vte april 12

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

Page 3: Practical application of  anticoagulation therapy af and vte april 12

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

Page 4: Practical application of  anticoagulation therapy af and vte april 12

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

Page 5: Practical application of  anticoagulation therapy af and vte april 12

Accreditation

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

Page 6: Practical application of  anticoagulation therapy af and vte april 12

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

Page 7: Practical application of  anticoagulation therapy af and vte april 12

Atrial Fibrillation

Page 8: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 9: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 10: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 11: Practical application of  anticoagulation therapy af and vte april 12

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

Page 12: Practical application of  anticoagulation therapy af and vte april 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

Page 13: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 14: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 15: Practical application of  anticoagulation therapy af and vte april 12

Case study: James (contd.)

2. Should James receive anticoagulation for reducing his risk of stroke?

a) Yes

b) No

Page 16: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 17: Practical application of  anticoagulation therapy af and vte april 12

Skanes AC et al. Can J Cardiol 2012;28(2):125-136.

Click icon to add picture

CCS recommendations

Note: Newer agents, i.e., dabigatran, rivaroxaban and apixaban, are preferred over warfarin for stroke prevention in AF

Page 18: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 19: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 20: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 21: Practical application of  anticoagulation therapy af and vte april 12

Warfarin: Food and drug interactionsIncrease anticoagulation Decrease anticoagulation

Foods St. John’s WortGinsengGarlic

Gingko bilobaAvocadoSpinachBrocolli

Drugs Acetaminophen AmiodaroneAndrogens AllopurinolAspirin (high dose) CimetidineClofibrate ChloramphenicolDisulfiram DipyridamoleErythromycin FluconazoleFluoxetine HClGlucagon

Indomethacin Liquid paraffinMetronidazole PhenylbutazonePhenytoin ProbenecidPhenformin QuinidineSulfinpyrazone TamoxifenTolbutamide Thyroid hormoneTrimethoprim-sulfamethoxazole

Antithyroid drugsBarbituratesCarbamazepineCholestyramineGluthimideGriseofulvinOral contraceptiveRifampicinSucralfate

Gogna A, Arun S. Oral Anticoagulation in Clinical Practice. JIACM 2005;6(1):53-66

Page 22: Practical application of  anticoagulation therapy af and vte april 12

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%

Page 23: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 24: Practical application of  anticoagulation therapy af and vte april 12

Once-Daily Dosing Is Associated With Higher Adherence Rates Than Twice-Daily Dosing

Total Population ≥ 65 years old60

65

70

75

80 OD BID

Adherence to Chronic Medications in Non-valvular AF patients

Laliberté F et al. Adv Ther (2012) 29(8):675-690.

Page 25: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 26: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 27: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 28: Practical application of  anticoagulation therapy af and vte april 12

Novel Oral Anticoagulants – Pharmacological PropertiesCharacteristic 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 inhibitorsof both CYP3A4 and P-

gp

P-gp inhibitors Potent inhibitorsof both CYP3A4 and

P-gp

* When the 15mg and 20mg dose is taken with food

Page 29: Practical application of  anticoagulation therapy af and vte april 12

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 and150 mg BID

20 mg OD

Adjusted Dose Studied

2.5 mg BIDFor 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 ODFor 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.

Page 30: Practical application of  anticoagulation therapy af and vte april 12

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

Page 31: Practical application of  anticoagulation therapy af and vte april 12

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

Page 32: Practical application of  anticoagulation therapy af and vte april 12

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

Page 33: Practical application of  anticoagulation therapy af and vte april 12

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

Page 34: Practical application of  anticoagulation therapy af and vte april 12

Case study: Linda (contd)

2. What is Linda’s CHA2DS2-VASc score?

a) 0

b) 2

c) 4

d) 6

e) 8

f) 10

Page 35: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 36: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 37: Practical application of  anticoagulation therapy af and vte april 12

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

Page 38: Practical application of  anticoagulation therapy af and vte april 12

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

Page 39: Practical application of  anticoagulation therapy af and vte april 12

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 AgeCheck 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

Page 40: Practical application of  anticoagulation therapy af and vte april 12

Patient has risk factor for stroke

Estimate CrCl

<30 mL/min

30-49 mL/min

>50 mL/min

Elderly and/or

risk factors

forbleeding

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.

Page 41: Practical application of  anticoagulation therapy af and vte april 12

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

Page 42: Practical application of  anticoagulation therapy af and vte april 12

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

Page 43: Practical application of  anticoagulation therapy af and vte april 12

Venous Thromboembolism

Page 44: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 45: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 46: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 47: Practical application of  anticoagulation therapy af and vte april 12

Leg veins

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

Page 48: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 49: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 50: Practical application of  anticoagulation therapy af and vte april 12

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

Page 51: Practical application of  anticoagulation therapy af and vte april 12

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

Page 52: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 53: Practical application of  anticoagulation therapy af and vte april 12

Risk factors for VTE• Surgery

• Trauma (major or lower extremity)

• Immobility, paresis

• Malignancy

• Cancer therapy (hormonal, chemotherapy, radiotherapy)

• 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.

Page 54: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 55: Practical application of  anticoagulation therapy af and vte april 12

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.

Page 56: Practical application of  anticoagulation therapy af and vte april 12

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.

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Choice of therapyInjectable • 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

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Clinical trials with apixabanStudy 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

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Clinical trials with dabigatranStudy 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

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Clinical trials with rivaroxabanStudy 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.

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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

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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

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Practical Usage

New Anticoagulants in AF and VTE

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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

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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

dabigatranINR 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

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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

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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

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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.

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Interruption of dabigatran or rivaroxaban before surgery or invasive procedures

Schulman S, Crowther MA. Blood 2012;119(13):3016-3023.

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Renal impairmentRenal 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.

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Choice of anticoagulant

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

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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

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Managing bleeding with new anticoagulants

Siegal DM, Crowther MA. Eur Heart J 2012.

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Useful resources

• CCS guidelines for AF: 2012 update

• ACCP 2012 guidelines: Antithrombotic Therapy for VTE