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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
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
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
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
Accreditation
This program has been accredited by the College of Family Physicians of Canada for up to 1 Mainpro-M1 credit.
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
Atrial Fibrillation
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.
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.
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.
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
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
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.
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.
Case study: James (contd.)
2. Should James receive anticoagulation for reducing his risk of stroke?
a) Yes
b) No
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.
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
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.
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.
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.
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
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%
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.
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.
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.
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.
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.
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
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.
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
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
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
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
Case study: Linda (contd)
2. What is Linda’s CHA2DS2-VASc score?
a) 0
b) 2
c) 4
d) 6
e) 8
f) 10
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.
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.
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
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
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
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.
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
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
Venous Thromboembolism
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.
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.
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.
Leg veins
Scarvelis D, Wells PS. CMAJ 2006;175(9):1087-92.
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.
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.
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
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
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.
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.
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.
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.
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.
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
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
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
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.
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
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
Practical Usage
New Anticoagulants in AF and VTE
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
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
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
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
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.
Interruption of dabigatran or rivaroxaban before surgery or invasive procedures
Schulman S, Crowther MA. Blood 2012;119(13):3016-3023.
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.
Choice of anticoagulant
Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540.
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
Managing bleeding with new anticoagulants
Siegal DM, Crowther MA. Eur Heart J 2012.
Useful resources
• CCS guidelines for AF: 2012 update
• ACCP 2012 guidelines: Antithrombotic Therapy for VTE