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Impact of New Anticoagulants on the Blood Bank

January 24th, 2012Transfusion Medicine Resident Teaching Session

Dr. Sudeep Shivakumar, Hematology

+Objectives

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

+Overview

Anticoagulants are widely used

Vitamin K antagonists used to be the only oral option

Times are changing…

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+Overview

Big advantage: No lab monitoring

Big disadvantage: No lab monitoring

Unpredictability of coagulation tests No reversal agents Variety of different agents with different characteristics

+Background

What are anticoagulants? Substances that prevent blood from clotting

“Blood thinners”

How do they do this? Interfering with coagulation mechanisms

+Hemostasis

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

+Thrombosis

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

+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

+Anticoagulants in atrial fibrillation

Goal is to prevent stroke

Reduces risk to ~1% per year

Warfarin shown to be more effective than aspirin

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Hart R, et al. Ann Intern Med 1999;131:492

WarfarinWarfarinBetterBetter

ControlControlBetterBetter

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

100%100% 50%50% 00 -50%-50% -100%-100%

Aggregate

Warfarin in atrial fibrillation

+Anticoagulants in atrial fibrillation

Most recent Canadian Cardiovascular Society guidelines (2010):

Patients with CHADS2 score of 1 or higher should be on oral anticoagulants

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+Venous thromboembolism

Deep venous thrombosis Pulmonary embolism

+Venous thromboembolism

Incidence estimated at 1-2 in 1000

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 death1Cushman, 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 currently used

Unfractionated heparin

Low molecular weight heparin

Vitamin K antagonists Ie. warfarin

+Warfarin

Can be reversed:

Vitamin K Fresh frozen plasma Activated prothrombin complex concentrates

+Warfarin

Dosage varies because of:

Vitamin K status Dietary factors Nausea/vomiting Absorption

Activity level Other medications Genetics

Monitoring by INR necessary!

+Difficulties with warfarin use

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?

+New anticoagulants

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

+New anticoagulants

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

+New anticoagulants

Direct thrombin inhibitors Dabigatran

Factor Xa inhibitors Rivaroxaban

+New anticoagulants

Leung, The Hematologist, 2011

+Dabigatran

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

+Dabigatran

An ideal anticoagulant:

No monitoring

Fewer interactions

Oral

Reversible

Equally efficacious

Equally safe

+Dabigatran

An ideal anticoagulant:

No monitoring

Fewer interactions

Oral

Reversible

Equally efficacious

Equally safe

✓

✓

✓

✗

?

?

+Dabigatran

Pharmacokinetics

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

+Dabigatran

Many studies for VTE prophylaxis: REMODEL – thromboprophylaxis after knee surgery REMOBILIZE – thromboprohylaxis after knee surgery RENOVATE I and II – thromboprophylaxis after hip surgery

Studies for VTE treatment: RECOVER – acute VTE treatment REMEDY – secondary VTE prevention

Studies for atrial fibrillation: PETRO study – phase II RELY study – phase III

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+Dabigatran for atrial fibrillation

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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+Dabigatran for atrial fibrillation

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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+Dabigatran for VTE

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

+Dabigatran for VTE

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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+Dabigatran

Approved by Health Canada for atrial fibrillation

Not covered by MSI… yet

Not approved for VTE treatment

Costs $2.30 per day

+Dabigatran and coagulation assays

+Dabigatran and coagulation assays

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

+Factor Xa inhibitors

•Lack of direct thrombin inhibition = less bleeding?

+Rivaroxaban

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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+Rivaroxaban

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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+Rivaroxaban

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

+Rivaroxaban and coagulation assays

+Rivaroxaban and coagulation assays

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

+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

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+Bleeding

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 $$$$$

+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

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Circulation, 2011

+Reversal using PCC

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

+Reversal using PCC

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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+Bleeding

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

+Reversal of new anticoagulants

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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+Summary

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!

+Thank you!

shivakumars@cdha.nshealth.ca