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January 24 th , 2012
Transfusion Medicine Resident Teaching Session
Dr. Sudeep Shivakumar, Hematology

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 To briefly review the concepts of hemostasis and thrombosis
 To provide an overview of anticoagulants currently in use
 To discuss the new anticoagulant agents and their mechanism of action
 To review the evidence for the new anticoagulants in DVT/PE and atrial fibrillation
 To discuss implications of these medications for the blood bank

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 Anticoagulants are widely used
 Vitamin K antagonists used to be the only oral option
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Times are changing…

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 Big advantage:
 No lab monitoring
 Big disadvantage:
 No lab monitoring
 Unpredictability of coagulation tests
 No reversal agents
 Variety of different agents with different characteristics

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 What are anticoagulants?
 Substances that prevent blood from clotting
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“Blood thinners”
 How do they do this?
 Interfering with coagulation mechanisms

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 Complex process which causes bleeding to stop:
 Formation of blood clot formation at the site of vessel injury
 Carefully regulated system
 Involves platelets and coagulation factors
 Lack of coagulation factors  bleeding
 Overactive coagulation cascade  thrombosis

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 The formation of a blood clot within a blood vessel
 Can occur in the arterial or venous systems
 Leads to obstruction of a blood vessel in the circulatory system
 Can lead to ischemia and infarction, and even death
 Can also lead to embolism
 Clot within a vessel breaks free and travels through body
(“embolizes”)
 Thromboembolism is combination of a thrombosis and embolus

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 Most common cardiac rhythm disorder
 Affects >10% in those > 80 years old
Incidence of atrial fibrillation in 4000 male air crew recruits
Krahn et al, Am J Med, 1995

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 Lifetime risk for a 40 year old is ~25% (Framingham 1 )
 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 age 2
 1.3% per year for those aged 50-59
 5.1% per year for those aged 80-89
1 Wolf, Stroke, 1991
2 Frost, Am J Med, 2000

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 Goal is to prevent stroke
 Reduces risk to ~1% per year
 Warfarin shown to be more effective than aspirin

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Warfarin
Better
Control
Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
100% 50% 0 -50% -100%
Hart R, et al. Ann Intern Med 1999;131:492

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 Most recent Canadian Cardiovascular Society guidelines
(2010):
 Patients with CHADS2 score of 1 or higher should be on oral anticoagulants

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Deep venous thrombosis Pulmonary embolism

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 Incidence estimated at 1-2 in 1000
 Known predisposing conditions – Virchow’s triad:
Venous stasis
Hypercoagulability Vessel wall injury

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 Not uncommon
 Longitudinal investigation of thromboembolism etiology (LITE) study 1
 >21 000 participants
 Cohort study
 Incidence of 1 st time VTE = 1.92 per 1000 person years
 Major cause of morbidity and mortality
 JAMA study 2 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
1 Cushman, Am J Med, 2004
2 Dismuke, JAMA, 1986

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 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!
1 Dalen, Prog Cardiovasc Dis, 1975
2 Carson,NEJM, 1992

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 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

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 Unfractionated heparin
 Low molecular weight heparin
 Vitamin K antagonists
 Ie. warfarin

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 Can be reversed:
 Vitamin K
 Fresh frozen plasma
 Activated prothrombin complex concentrates

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 Dosage varies because of:
 Vitamin K status
 Dietary factors
 Nausea/vomiting
 Absorption
 Activity level
 Other medications
 Genetics
 Monitoring by INR necessary!

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 Requires monitoring
 Numerous drug and diet interactions
 Narrow therapeutic range
 Difficult to control – takes time to get in or out of the system
Role for new anticoagulants?

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 Many new targets being explored
 Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIII
 New agents developed
 Direct thrombin inhibitors
 Factor Xa inhibitors
 Novel anticoagulants
 Oral agents increasingly in studies
 Venous thromboembolism often studied first because of shorter follow up
 Increasing data on dabigatran and rivaroxaban

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 Ideal anticoagulant:
 Equally efficacious
 Equally safe
 No monitoring
 Fewer interactions
 Oral
 Reversible

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 Direct thrombin inhibitors
 Dabigatran
 Factor Xa inhibitors
 Rivaroxaban

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Leung, The Hematologist, 2011

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 Ximelagatran studies showed possible use for oral direct thrombin inhibitors in atrial fibrillation
 Dabigatran
 Oral prodrug of dabigatran etixalate
 Inhibitor of thrombin
 Predictable anticoagulant response
 No need for monitoring
 Excreted by kidneys
 Less than 1% see a transaminase elevation

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 An ideal anticoagulant:
 No monitoring
 Fewer interactions
 Oral
 Reversible
 Equally efficacious
 Equally safe

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 An ideal anticoagulant:
 No monitoring
 Fewer interactions
 Oral
 Reversible
 Equally efficacious
 Equally safe
✓
✓
✓
✗
?
?

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 Pharmacokinetics
 Half life 12-17 hours
 Time to peak, plasma 1 hour
 Hepatic metabolism
 Not recommended for CrCl <30

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 Many studies for VTE prophylaxis:
 REMODEL – thromboprophylaxis after knee surgery
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REMOBILIZE – thromboprohylaxis after knee surgery
RENOVATE I and II – thromboprophylaxis after hip surgery
 Studies for VTE treatment:
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RECOVER – acute VTE treatment
REMEDY – secondary VTE prevention
 Studies for atrial fibrillation:
 PETRO study – phase II
 RELY study – phase III

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 RELY trial
 Looked at stroke prevention in patients with atrial fibrillation
 Compared warfarin to dabigatran
 >18 000 patients
 Results:
 110 mg BID dose of dabigatran as effective and less bleeding
 150 mg BID dose more effective, similar bleeding
 Published in NEJM in September 2009 (Connolly et al)

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 RELY trial
 Note trend towards increased MI rates with dabigatran 150 mg BID
 Also increased dyspepsia
 Consider higher dose if <80 and low risk of bleeding

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 RECOVER trial
 Dabigatran exilate vs warfarin in the treatment of acute thromboembolism
 Randomized double blind trial
 2539 patients with acute VTE
 All treated initially with 5 to 11 days of LMWH or UFH
 Randomized to dabigatran 150 mg BID vs warfarin
 Primary outcome: objective recurrent VTE, or VTE-related death up to 6 months of treatment

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 RECOVER trial
 Results:
 Recurrent VTE:
 34 patients (2.7%) in dabigatran group
 32 patients (2.5%) in warfarin group (not significant)
 Major bleeding:
 20 patients (1.6%) in dabigatran group
 24 patients (1.9%) in warfarin group (significant)
 Deaths similar between groups
 Conclusions:
 Dabigatran as safe and efficacious as warfarin
 Published in NEJM in December 2009 (Schulman et al)

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 Approved by Health Canada for atrial fibrillation
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Not covered by MSI… yet
 Not approved for VTE treatment
 Costs $2.30 per day

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 aPTT affected at peak concentrations
 aPTT >90 sec suggests over-dosing or accumulation
 PT not affected
 Fibrinogen testing underestimated results in 2 of 4 reagents
 Antithrombin levels varied greatly
 Overall, unpredictable results, but elevated aPTT suggested accumulation

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•Lack of direct thrombin inhibition = less bleeding?

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 Oral, direct factor Xa inhibitor
 Potent (greater selectivity for factor Xa than other drugs)
 Fixed, once-daily dosing
 Predictable pharmacokinetics
 Half life 7-11 hours
 Peak concentration 4hrs after administration
 Excreted via biliary and renal routes
 Does have interactions CYP3A4 inhibitors
 Ie. ketoconazole, macrolides

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 EINSTEIN study
 NEJM study (Dec 2010)
 Complicated – 2 studies in one
 One study compared rivaroxaban to warfarin for DVT/PE
 1700 patients
 Similar outcomes in both arms for bleeding/thrombosis
 No LMWH briding in rivaroxaban arm
 Conclusion: rivaroxaban as safe and effective as warfarin
 Not currently approved or covered for DVT/PE

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 Studied in ROCKET-AF trial
 Rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation
 Phase III, non-inferiority, double-blind study of rivaroxaban 20 mg OD vs. warfarin in patients with non-valvular atrial fibrillation and 2 other stroke risk factors
 Recently approved by Health Canada for stroke prevention in atrial fibrillation

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 aPTT affected at therapeutic doses, but varied greatly
 Depended on reagents used
 Unpredictable
 PT completely unpredictable
 Antithrombin levels depended on reagent used
 Fibrinogen not affected
 Xa (sensitive to rivaroxaban) only affected slightly
 Overall, varied, unpredictable results

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 ~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

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 Warfarin
 Give vitamin K 5-10 mg
 Fresh frozen plasma
 Octaplex
 Prothrombin complex concentrate
 Works within 1 hour
 More effective than plasma at reversing INR
 Small volume
 40 ml usually enough for most patients
 $$$$$

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 Warfarin had several predictable options for reversal:
 Vitamin K
 Fresh frozen plasma
 Activated prothrombin complex concentrates
 No reversal agents for new anticoagulants

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Circulation, 2011

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 Randomized, double-blind, placebo controlled study
 12 healthy male volunteers received rivaroxaban 20mg BID or dabigatran 150 mg BID for 2.5 days
 Followed by bolus of 50IU/kg PCC (Cofact) or saline
 Procedure then repeated with the other anticoagulant treatment

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 Rivaroxaban:
 Prolonged the PT
 Immediately reversed by PCC completely
 Endogenous thrombin potential inhibited
 Also completely normalized with PC
 Dabigatran:
 Affected PTT, ecarin clotting time, and thrombin time
 Not reversed by PCC

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 Dabigatran, rivaroxaban and other new agents
 No known antidotes
 Half-lives roughly 11-14 hours
 Blood product support
 Fresh frozen plasma
 Consider activated factor VIIa if ongoing bleed
 Watch for thrombosis

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 Suggested approach:
 Transfuse as necessary
 Packed red blood cells
 Platelets if less than 50
 Consider use of other blood products
 Fresh frozen plasma
 Activated factor VII
 No good evidence!

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 New anticoagulants are coming that may replace warfarin
 Dabigatran has been approved for atrial fibrillation, and will likely be approved for DVT/PE
 Rivaroxaban has been approved for atrial fibrillation, and will likely be approved for DVT/PE
 No antidotes for new agents
 Coagulation tests not standardized
 Research needed!

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 shivakumars@cdha.nshealth.ca