Transcript transfusionSS - Transfusion Medicine

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Impact of New Anticoagulants on the Blood Bank
January 24th, 2012
Transfusion Medicine Resident Teaching Session
Dr. Sudeep Shivakumar, Hematology
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Objectives
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To briefly review the concepts of hemostasis and thrombosis
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To provide an overview of anticoagulants currently in use
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To discuss the new anticoagulant agents and their mechanism
of action
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To review the evidence for the new anticoagulants in DVT/PE
and atrial fibrillation
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To discuss implications of these medications for the blood bank
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Overview
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Anticoagulants are widely used
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Vitamin K antagonists used to be the only oral option
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Times are changing…
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Overview
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Big advantage:
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No lab monitoring
Big disadvantage:
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No lab monitoring
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Unpredictability of coagulation tests
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No reversal agents
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Variety of different agents with different characteristics
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Background
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What are anticoagulants?
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Substances that prevent blood from clotting
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“Blood thinners”
How do they do this?
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Interfering with coagulation mechanisms
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Hemostasis
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Complex process which causes bleeding to stop:
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Formation of blood clot formation at the site of vessel injury
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Carefully regulated system
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Involves platelets and coagulation factors
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Lack of coagulation factors  bleeding
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Overactive coagulation cascade  thrombosis
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Thrombosis
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The formation of a blood clot within a blood vessel
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Can occur in the arterial or venous systems
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Leads to obstruction of a blood vessel in the circulatory system
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Can lead to ischemia and infarction, and even death
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Can also lead to embolism
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Clot within a vessel breaks free and travels through body
(“embolizes”)
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Thromboembolism is combination of a thrombosis and embolus
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Atrial fibrillation
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Most common cardiac rhythm disorder
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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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Atrial fibrillation
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Lifetime risk for a 40 year old is ~25% (Framingham1)
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Independent risk factor for ischemic stroke
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Rate of stroke in those not on antithrombotic therapy is ~4.5%/year
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Increases the risk of stroke 5x across all age groups
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Incidence of stroke increases with age2
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1.3% per year for those aged 50-59
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5.1% per year for those aged 80-89
1Wolf,
2Frost,
Stroke, 1991
Am J Med, 2000
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Anticoagulants in atrial fibrillation
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Goal is to prevent stroke
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Reduces risk to ~1% per year
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Warfarin shown to be more effective than aspirin
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Warfarin in atrial fibrillation
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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Anticoagulants in atrial fibrillation
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Most recent Canadian Cardiovascular Society guidelines
(2010):
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Patients with CHADS2 score of 1 or higher should be on oral
anticoagulants
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Venous thromboembolism
Deep venous thrombosis
Pulmonary embolism
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Venous thromboembolism
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Incidence estimated at 1-2 in 1000
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Known predisposing conditions – Virchow’s triad:
Venous stasis
Hypercoagulability
Vessel wall injury
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Venous thromboembolism
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Not uncommon
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Major cause of morbidity and mortality
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Longitudinal investigation of thromboembolism etiology (LITE)
study1
>21 000 participants
Cohort study
Incidence of 1st time VTE = 1.92 per 1000 person years
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,
2Dismuke,
Am J Med, 2004
JAMA, 1986
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Pulmonary embolism
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Untreated PE
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Mortality rate of ~30%1
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Most die within hours of diagnosis
Treated PE
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Prospective NEJM study looked at 399 patients with newly
diagnosed PE
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94% received anticoagulant treatment
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Only 2.5% (10 patients) died of PE
Treatment of PE is life-saving!
1Dalen,
Prog Cardiovasc Dis, 1975
2Carson,NEJM,
1992
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Anticoagulants in DVT/PE
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Goals of treatment:
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Short term:
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Prevent the extension of thrombus and embolization for DVT
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Reduce mortality for PE by reducing recurrent events
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Relief of symptoms
Long term:
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Prevent recurrent events
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Anticoagulants currently used
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Unfractionated heparin
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Low molecular weight heparin
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Vitamin K antagonists
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Ie. warfarin
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Warfarin
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Can be reversed:
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Vitamin K
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Fresh frozen plasma
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Activated prothrombin complex concentrates
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Warfarin
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Dosage varies because of:
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Vitamin K status
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Dietary factors
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Nausea/vomiting
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Absorption
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Activity level
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Other medications
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Genetics
Monitoring by INR necessary!
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Difficulties with warfarin use
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Requires monitoring
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Numerous drug and diet interactions
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Narrow therapeutic range
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Difficult to control – takes time to get in or out of the system
Role for new anticoagulants?
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New anticoagulants
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Many new targets being explored
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New agents developed
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Direct thrombin inhibitors
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Factor Xa inhibitors
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Novel anticoagulants
Oral agents increasingly in studies
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Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIII
Venous thromboembolism often studied first because of shorter
follow up
Increasing data on dabigatran and rivaroxaban
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New anticoagulants
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Ideal anticoagulant:
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Equally efficacious
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Equally safe
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No monitoring
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Fewer interactions
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Oral
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Reversible
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New anticoagulants
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Direct thrombin inhibitors
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Dabigatran
Factor Xa inhibitors
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Rivaroxaban
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New anticoagulants
Leung, The Hematologist, 2011
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Dabigatran
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Ximelagatran studies showed possible use for oral direct
thrombin inhibitors in atrial fibrillation
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Dabigatran
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Oral prodrug of dabigatran etixalate
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Inhibitor of thrombin
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Predictable anticoagulant response
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No need for monitoring
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Excreted by kidneys
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Less than 1% see a transaminase elevation
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Dabigatran
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An ideal anticoagulant:
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No monitoring
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Fewer interactions
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Oral
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Reversible
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Equally efficacious
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Equally safe
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Dabigatran
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An ideal anticoagulant:
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No monitoring
✓
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Fewer interactions
✓
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Oral
✓
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Reversible
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Equally efficacious
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Equally safe
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Dabigatran
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Pharmacokinetics
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Half life 12-17 hours
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Time to peak, plasma 1 hour
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Hepatic metabolism
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Not recommended for CrCl <30
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Dabigatran
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Many studies for VTE prophylaxis:
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REMODEL – thromboprophylaxis after knee surgery
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REMOBILIZE – thromboprohylaxis after knee surgery
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RENOVATE I and II – thromboprophylaxis after hip surgery
Studies for VTE treatment:
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RECOVER – acute VTE treatment
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REMEDY – secondary VTE prevention
Studies for atrial fibrillation:
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PETRO study – phase II
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RELY study – phase III
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Dabigatran for atrial fibrillation
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RELY trial
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Looked at stroke prevention in patients with atrial fibrillation
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Compared warfarin to dabigatran
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>18 000 patients
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Results:
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110 mg BID dose of dabigatran as effective and less bleeding
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150 mg BID dose more effective, similar bleeding
Published in NEJM in September 2009 (Connolly et al)
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Dabigatran for atrial fibrillation
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RELY trial
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Note trend towards increased MI rates with dabigatran 150 mg BID
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Also increased dyspepsia
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Consider higher dose if <80 and low risk of bleeding
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Dabigatran for VTE
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RECOVER trial
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Dabigatran exilate vs warfarin in the treatment of acute
thromboembolism
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Randomized double blind trial
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2539 patients with acute VTE
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All treated initially with 5 to 11 days of LMWH or UFH
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Randomized to dabigatran 150 mg BID vs warfarin
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Primary outcome: objective recurrent VTE, or VTE-related death up
to 6 months of treatment
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Dabigatran for VTE
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RECOVER trial
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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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Dabigatran
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Approved by Health Canada for atrial fibrillation
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Not covered by MSI… yet
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Not approved for VTE treatment
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Costs $2.30 per day
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Dabigatran and coagulation assays
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Dabigatran and coagulation assays
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aPTT affected at peak concentrations
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aPTT >90 sec suggests over-dosing or accumulation
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PT not affected
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Fibrinogen testing underestimated results in 2 of 4 reagents
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Antithrombin levels varied greatly
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Overall, unpredictable results, but elevated aPTT suggested
accumulation
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Factor Xa inhibitors
•Lack of direct thrombin inhibition = less bleeding?
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Rivaroxaban
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Oral, direct factor Xa inhibitor
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Potent (greater selectivity for factor Xa than other drugs)
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Fixed, once-daily dosing
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Predictable pharmacokinetics
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Half life 7-11 hours
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Peak concentration 4hrs after administration
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Excreted via biliary and renal routes
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Does have interactions CYP3A4 inhibitors
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Ie. ketoconazole, macrolides
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Rivaroxaban
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EINSTEIN study
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NEJM study (Dec 2010)
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Complicated – 2 studies in one
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One study compared rivaroxaban to warfarin for DVT/PE
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1700 patients
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Similar outcomes in both arms for bleeding/thrombosis
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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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Rivaroxaban
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Studied in ROCKET-AF trial
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Rivaroxaban once daily oral direct factor Xa inhibition compared
with vitamin K antagonism for prevention of stroke and embolism
trial in atrial fibrillation
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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
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Recently approved by Health Canada for stroke prevention in
atrial fibrillation
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Rivaroxaban and coagulation
assays
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Rivaroxaban and coagulation
assays
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aPTT affected at therapeutic doses, but varied greatly
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Depended on reagents used
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Unpredictable
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PT completely unpredictable
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Antithrombin levels depended on reagent used
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Fibrinogen not affected
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Xa (sensitive to rivaroxaban) only affected slightly
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Overall, varied, unpredictable results
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Bleeding
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~2% of patients/year on long term anticoagulants will end up
with a major bleed requiring medical attention
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Holding anticoagulants is the first step, but often other steps
are needed
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Depends on anticoagulant
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Bleeding
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Warfarin
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Give vitamin K 5-10 mg
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Fresh frozen plasma
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Octaplex
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Prothrombin complex concentrate
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Works within 1 hour
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More effective than plasma at reversing INR
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Small volume
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40 ml usually enough for most patients
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$$$$$
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Reversal of new anticoagulants
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Warfarin had several predictable options for reversal:
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Vitamin K
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Fresh frozen plasma
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Activated prothrombin complex concentrates
No reversal agents for new anticoagulants
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Circulation, 2011
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Reversal using PCC
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Randomized, double-blind, placebo controlled study
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12 healthy male volunteers received rivaroxaban 20mg BID or
dabigatran 150 mg BID for 2.5 days
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Followed by bolus of 50IU/kg PCC (Cofact) or saline
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Procedure then repeated with the other anticoagulant treatment
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Reversal using PCC
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Rivaroxaban:
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Prolonged the PT
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Immediately reversed by PCC completely
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Endogenous thrombin potential inhibited
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Also completely normalized with PC
Dabigatran:
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Affected PTT, ecarin clotting time, and thrombin time
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Not reversed by PCC
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Bleeding
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Dabigatran, rivaroxaban and other new agents
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No known antidotes
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Half-lives roughly 11-14 hours
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Blood product support
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Fresh frozen plasma
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Consider activated factor VIIa if ongoing bleed
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Watch for thrombosis
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Reversal of new anticoagulants
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Suggested approach:
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Transfuse as necessary
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Packed red blood cells
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Platelets if less than 50
Consider use of other blood products
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Fresh frozen plasma
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Activated factor VII
No good evidence!
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Summary
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New anticoagulants are coming that may replace warfarin
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Dabigatran has been approved for atrial fibrillation, and will
likely be approved for DVT/PE
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Rivaroxaban has been approved for atrial fibrillation, and will
likely be approved for DVT/PE
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No antidotes for new agents
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Coagulation tests not standardized
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Research needed!
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Thank you!
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[email protected]