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+ Faculty/Presenter Disclosure
Faculty: Sudeep Shivakumar
Relationships with commercial interests:
Grants/Research Support: N/A
Speakers Bureau/Honoraria: Boehringer Ingelheim, Bayer
Inc, Leo Pharma
Consulting Fees: N/A
Other: N/A
+ Disclosure of Commercial Support
No commercial support
+ Mitigating Potential Bias
No input into slides or content of talk by anyone but
the speaker
+
Anticoagulants: When and what to use
Family Medicine Assembly, NSCFP
September 27th, 2013
Dr. Sudeep Shivakumar, Hematology
Dalhousie University
+ Objectives
To review indications for anticoagulation
To discuss the new oral anticoagulants
To discuss the management of bleeding
+ Overview
Anticoagulants are widely used
Vitamin K antagonists used to be the only oral option
Times are changing…
+
+
+ Overview
Big advantage:
No lab monitoring
Big disadvantage:
No lab monitoring
Unpredictability of coagulation tests
But very predictable action
No reversal agents
But ?less bleeding
Variety of different agents with different characteristics
+ Indications for anticoagulation
Atrial fibrillation
DVT/PE
Mechanical heart valves
No evidence for new anticoagulants as of yet
+ Atrial fibrillation
Most common cardiac rhythm disorder
Affects >10% in those > 80 years old
Krahn et al, Am J Med, 1995
Incidence of atrial fibrillation in 4000 male air crew recruits
+ Atrial fibrillation
Lifetime risk for a 40 year old is ~25% (Framingham1)
Independent risk factor for ischemic stroke
Rate of stroke in those not on antithrombotic therapy is ~4.5%/year
Increases the risk of stroke 5x across all age groups
Incidence of stroke increases with age2
1.3% per year for those aged 50-59
5.1% per year for those aged 80-89
2Frost, Am J Med, 2000
1Wolf, Stroke, 1991
+ Pathogenesis of stroke
Multifactorial
Blood stasis
Especially in the left atrial appendage
Can lead to thrombus formation
?possibly due to LA shape and presence of trabeculations
Increased erythrocyte aggregation
Fibrillating atrium leads to altered LAA flow and uncoordinated LA
systole
Thought to lead to low shear rate and increased RBC aggregation
Hypercoagulable state
Mechanism not entirely understood
+ Prevention of thromboembolism
Warfarin and aspirin both extensively studied
Both significantly reduce the incidence of stroke in non-valvular
atrial fibrillation
Both approved as antithrombotic therapy for atrial fibrillation
+ Compared to placebo…
Aspirin
Meta-analysis of 6 RCT’s comparing ASA to placebo in atrial fibrillation
ASA reduced the incidence of stroke or TIA by 22 %
Warfarin
Various studies have compared warfarin to placebo in atrial fibrillation
Warfarin reduced the incidence of stroke by 68 %
3x as effective as ASA
For those 65-75 years old with no other risk factors
Risk of stroke 4.3% per year with no therapy
Risk of stroke 1.4% per year with aspirin
Risk of stroke 1.1% per year with warfarin
Hart, Ann Int Med, 1999
+ Warfarin compared to ASA
Consistent benefit for warfarin seen
Pooled analysis of 5 RCT’s comparing warfarin to ASA in non-
valvular AF (over 4000 patients):
Adjusted-dose warfarin significantly reduced stroke risk in patients
compared to placebo or ASA
However, risk of bleeding higher with warfarin:
Absolute rate increase of major bleeding was 0.9 events per 100
patient years
2.2 events per 100 patient years in warfarin arm vs. 1.3 events per
100 patients years in ASA arm
Atrial Fibrillation Investigators, Arch Int Med, 1994
+ Who is at risk for stroke?
Many risk factors for embolization in atrial fibrillation have been
evaluated
Multivariate risk models have been devised
Pooled analysis from the Atrial Fibrillation Investigators (AFI)
Stroke Prevention in Atrial Fibrillation (SPAF)
ACC/AHA/ESA guidelines
ACCP guidelines
Framingham study community risk model
CHADS2 score
+ CHADS2 score
Generated from independent clinical predictors from the AFI
and SPAF
Tested and validated in other cohorts
Best validated in various patient populations
More effective than other models in comparison studies
Simple to remember
Simple to use
Gage et al, JAMA, 2001
+ CHADS2 score
Score
CHF or LV dysfunction 1
Hypertension 1
Age > 75 1
Diabetes 1
Stroke/TIA 2
•Score of 0 to 1
•1.5 to 2.5% risk per year of stroke
•Score of 2 or greater
•4.0 to 18.2% risk per year of stroke
+
+ Venous thromboembolism
Deep venous thrombosis Pulmonary embolism
+
Venous thromboembolism
Known predisposing conditions – Virchow’s triad:
Venous stasis
Hypercoagulability Vessel wall injury
+ Venous thromboembolism
Not uncommon
Longitudinal investigation of thromboembolism etiology (LITE) study1
>21 000 participants
Cohort study
Incidence of 1st time VTE = 1.92 per 1000 person years
Major cause of morbidity and mortality
JAMA study2 looking at post-mortems of 3 412 hospitalized patients between 1966 and 1980
6% of deceased patients had evidence of massive pulmonary embolism
Most common preventable cause of in-hospital death
1Cushman, Am J Med, 2004
2Dismuke, JAMA, 1986
+ Pulmonary embolism
Untreated PE
Mortality rate of ~30%1
Most die within hours of diagnosis
Treated PE
Prospective NEJM study looked at 399 patients with newly
diagnosed PE
94% received anticoagulant treatment
Only 2.5% (10 patients) died of PE
Treatment of PE is life-saving!
1Dalen, Prog Cardiovasc Dis, 1975
2Carson,NEJM, 1992
+ Anticoagulants in DVT/PE
Goals of treatment:
Short term:
Prevent the extension of thrombus and embolization for DVT
Reduce mortality for PE by reducing recurrent events
Relief of symptoms
Long term:
Prevent recurrent events
+ Anticoagulants
Substance that prevents clotting
Usually by inhibiting steps in the coagulation cascade
Heparins
LMWHs
Vitamin K antagonists
Direct thrombin inhibitors
Factor Xa inhibitors
Other targets
+ Warfarin
Oral vitamin K antagonist
Been in use since the 1950’s
Effect measured by the INR
Reduces stroke risk in atrial fibrillation by 68%
Also used for treatment of DVT/PE and prevention of
thrombosis with mechanical valves
Frost, Am J Med, 2000
+ New anticoagulants
Many new targets being explored
Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIII
Increasing data on:
Dabigatran – oral direct thrombin inhibitor
Rivaroxaban – oral factor Xa inhibitor
Apixaban – oral factor Xa inhibitor
+ New anticoagulants
Leung, The Hematologist, 2011
+ Dabigatran
Pharmacokinetics
Half life 12-17 hours
Time to peak, plasma 1 hour
Not recommended for CrCl <30
+
+
+
+ Dabigatran
Approved by Health Canada for atrial fibrillation
Covered by MSI if not able to tolerate warfarin
Not approved for VTE treatment
Costs $3.20 per day
+ Factor Xa inhibitors
•Lack of direct thrombin inhibition = less bleeding?
+ Rivaroxaban
Oral, direct factor Xa inhibitor
Fixed, once-daily dosing
Predictable pharmacokinetics
Half life 7-11 hours
+
+
+
+
+ Rivaroxaban
Approved for atrial fibrillation
Approved for DVT and PE
No bridging with LMWH needed
15 mg po BID x 3 weeks, then 20 mg po OD
~$2.84 per day
+ Apixaban
Oral, direct factor Xa inhibitor
Primary difference from rivaroxaban is mode of excretion
More hepatobiliary excretion than renal
+
+ Apixaban
Primary outcome = stroke or systemic thromboembolism
1.6% with warfarin
1.27% with apixaban
Major bleeding
3.09% with warfarin
2.13% with apixaban
Decreased intracranial and GI bleeding
Now approved for atrial fibrillation in Canada
+ Bleeding
~2% of patients/year on long term anticoagulants will end up
with a major bleed requiring medical attention
Holding anticoagulants is the first step, but often other steps
are needed
Depends on anticoagulant
+ Warfarin
Clear options for reversal:
Vitamin K
Fresh frozen plasma
Prothrombin complex concentrates
+
+ Vitamin K for those with high INRs
but no bleeding
For patients taking VKAs with INRs between 4.5 and 10 and
with no evidence of bleeding, we suggest against the routine
use of vitamin K (Grade 2B)
For patients taking VKAs with INRs > 10.0 and with no
evidence of bleeding, we suggest that oral vitamin K be
administered (Grade 2C)
CHEST guidelines, 2012
+ Bleeding with warfarin
Vitamin K
5-10 mg if acute bleed
Takes ~1 day to reverse effect
Fresh frozen plasma
Large volume
Incomplete reversal
Prothrombin complex concentrate
Works within 1 hour
More effective than plasma at reversing INR
Small volume
+
http://www.gov.ns.ca/health/nspbcp/
+
http://www.gov.ns.ca/health/nspbcp/
+ Reversal of new anticoagulants
Warfarin had several predictable options for reversal:
Vitamin K
Fresh frozen plasma
Activated prothrombin complex concentrates
No reversal agents for new anticoagulants
However, lower risk of bleeding
+ Bleeding
Dabigatran, rivaroxaban and other new agents
No known antidotes
Half-lives roughly 7-17 hours
Supportive care
Blood product support
Fresh frozen plasma
Can consider dialysis with dabigatran
+ Reversal of new anticoagulants
Suggested approach:
Transfuse as necessary
Packed red blood cells
Platelets as needed
Fresh frozen plasma as needed
Consider use of other blood products
?Prothrombin complex concentrates
?Activated factor VIIa – should it even be offered?
Cochrane review showed increased rate of arterial thrombosis
No good evidence!
+
+
+ Perioperative management of
warfarin
Warfarin confers increased risk of bleeding
Needs to be stopped for many procedures or surgeries
Given long half life, warfarin needs to be stopped 5 days before
surgery
+ Perioperative management of new
oral anticoagulants
No data
However, stopping dabigatran or rivaroxaban 48 hours before
surgery seems reasonable
Based on half life less than 17 hours
As long as CrCl >50 ml/min
Monographs do suggest minimum of 24 hours
Not evidence based as of yet
In practice, appears to be safe
Ongoing studies based on creatinine clearance
+
Renal function
(CrCl)
Estimated
half-life (hrs)
Stop dabigatran before surgery
higher-risk for bleeding
low-risk for bleeding
≥50 mL/min (mild dysfunction or normal)
14-17 2-3 days 1 day
30 to <50 mL/min (moderate dysfunction)
18-24 4 days 2-3 days
<30 mL/min (severe dysfunction)
>24 >5 days 2-5 days
Van Rijn J, et al. Thromb Haemost 2010;103:1116 Douketis JD. Curr Pharm Des 2010;16:3436
Pre-operative Management of Dabigatran
+ Post-operative management
Standard bleeding risk and good hemostasis
Dabigatran may be resumed the same evening after a minimum of 6
hours post-op
75 mg for the first post-op dose and then the usual maintenance
dose
High bleeding risk (e.g. vascular surgery, neurosurgery, etc)
Resume dabigatran on POD 2 or 3
Incomplete hemostasis
Delay dabigatran until no drainage or other evidence of bleeding
Do not use dabigatran if bowel paralysis (consider LMWH or UFH)
+ Summary
New anticoagulants are increasingly being used
Dabigatran, rivaroxaban and apixaban are approved for stroke
prevention in atrial fibrillation
No reversal agents as of yet, so supportive care only for
bleeding complications
However, trend towards less bleeding with all new agents
Stopping novel agents 48 hours before surgery is reasonable,
as long as renal function is adequate
