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Transcript of Objectives To Bleed or Not To Bleed 2018. 4. 2.¢  2/3/2015 1 To Bleed or Not To Bleed: A...

  • 2/3/2015

    1

    To Bleed or Not To Bleed: A New Look at Anticoagulation

    Mid-Year Meeting

    MPhA, MDASCP, MPhS

    February 15, 2015

    David H. Jones, RPh, FASCP

    dhjRxConsulting

    Anticoagulation Update 2015

    Objectives

    To explain coagulation factors and risks.

    To better understand efficacy, safety and

    appropriate use of the newer oral

    anticoagulation agents

    – Dabigatran

    – Rivaroxaban

    – Apixaban

    To reinforce appropriate use and monitoring of

    warfarin.

    2

    Abbreviations List DVT: Deep Vein Thrombosis

    PE: Pulmonary Embolism

    VTE: Venous Thrombotic Event

    THR: Total Hip Replacement

    TKR: Total Knee Replacement

    ACS: Acute Coronary Syndrome

    CBC: Complete Blood Count

    FFP: Fresh Frozen Plasma

    PRBC: Packed Red Blood Cells

    CrCl: Creatinine Clearance

    NOACs: Novel Oral Anticoagulants

    Anticoagulation 2013 3 Anticoagulation Update 2015

    Coagulation

    Virchow’s Triad

    – Stasis

    – Vascular Injury

    – Hypercoagulability

    Rudolf Ludwig Karl Virchow (1859)

    developed the concepts of

    – Thrombosis

    – Embolism

    Coagulation Cascade American Society of Hematology

    4

    Anticoagulation Update 2015 5

    Risk Factors

    Age

    Gender

    Race / ethnicity

    Immobility

    Surgery

    Trauma

    Previous VTE

    Cancer

    Obesity

    Venous stasis

    Thrombophilic

    disorder

    Anticoagulation Update 2015 6

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    2

    Anticoagulation Update 2015

    Hypercoagulability: Higher Risk

    Protein C deficiency

    Protein S deficiency

    Factor V Leiden

    Antithrombin III deficiency

    Increased Factor XI

    Increased factor VII

    Hyperhomocysteinemia ?

    Idiopathic Reference: Chest 2014

    7 Anticoagulation Update 2015

    Indications for Anticoagulation

    Treatment of DVT

    Treatment of PE

    Prophylaxis for DVT / PE

    Atrial fibrillation

    Acute coronary ischemic syndrome

    Prosthetic heart valves

    Post-surgical prophylaxis

    Prophylaxis post stent placement

    8

    Anticoagulation Update 2015

    Goals of Anticoagulation

    Prevent formation of a deep vein thrombus

    Prevent progression or propagation of

    existing thrombus

    Prevent a thrombus from becoming

    dislodged and forming an embolus

    Reduce risk of stroke secondary to

    thrombus

    9

    Getting Away from Warfarin

    NOACs and You!

    “Every Form of Refuge Has It’s Price”

    “Lyin’ Eyes”, Eagles

    Anticoagulation Update 2015 10

    What Do You Want

    in a New Anticoagulant? Safe

    – Especially bleed risk

    – Limited drug-drug interaction risks

    Effective

    – Rapid onset

    – Proven anticoagulant profile

    Convenient

    – Oral route

    – Limited or no monitoring

    Anticoagulation Update 2015 11

    Some Universal Concerns

    Avoid use in patients with mechanical

    heart valves

    Sudden discontinuation of any agent may

    increase the risk for stroke

    Provide alternative anticoagulation

    All have bleeding risk

    – Always monitor

    All will require some monitoring

    Concerns about antidotes

    Anticoagulation Update 2015 12

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    3

    Great First Concept;

    Really Bad Reality Ximelagatran (Exanta®, Astra Zeneca)

    Promising alternative to warfarin

    Direct thrombin inhibitor

    Reliable anticoagulation with BID dosing

    – Post orthopedic prophylaxis

    – Atrial fibrillation

    High risk for severe liver damage

    FDA pulled application 2006.

    Anticoagulation Update 2015 13

    Pradaxa®

    Dabigatran etexilate

    Boehringer-Ingelheim

    This is a general overview and may discuss

    some off-label and non-approved information.

    Dabigatran Initial FDA Approval: October 2010

    Indicated for Reduction of risk of stroke and systemic embolism in

    patients with non-valvular atrial fibrillation

    Treatment of DVT or PE in patients previously treated

    with a parenteral anticoagulant

    Reduction of risk for recurrence of DVT or PE in

    patients previously treated

    Non-US approval for – VTE prophylaxis following total hip and knee

    replacement

    Anticoagulation Update 2015 15 Anticoagulation Update 2015

    Dabigatran

    Prodrug without anticoagulant activity that

    is converted in vivo to active dabigatran

    Competitive, reversible, direct Factor IIa

    inhibitor

    Inhibits thrombin, free and fibrin-bound,

    and thrombin-induced platelet aggregation – Acts to prevent effects, including cleavage of

    fibrinogen to fibrin monomers, activation of factors V,

    VIII, XI and XIII, and inhibition of thrombin-induced

    platelet aggregation.

    16

    Dabigatran

    Bioavailability: 3 to 7%

    Plasma concentration peaks within 1 to 2

    hours

    Half-life: 12 to 17 hours

    Metabolism:

    – Liver microsomal carboxylesterases

    Excretion:

    – Urine: 7%

    – Feces: 86%

    Anticoagulation Update 2015 17

    Precautions

    Hepatic

    Use cautiously in patients with moderate

    liver impairment

    Child-Pugh Class B or C

    Transaminases that are > 2 X upper

    normal limits

    Anticoagulation Update 2015 18

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    4

    Precautions Renal

    Cautious use for patients with creatinine

    clearance of 15 to 30 ml/ min

    Avoid use in patients with creatinine clearance ≤

    15 ml/ min

    – Lack of sufficient clinical evidence for safe and

    effective use

    Canadian labeling is more restrictive: avoid use

    if value is < 30

    – Best practice for most patients

    – 110 mg dose available in Canada

    Anticoagulation Update 2015 19

    Cautions

    Higher bleed risk

    – Patient age over 75

    Especially for those over 80

    – Patient weight less than 50 kg

    – Creatinine clearance < 50

    Beer’s List Drug – Limited RCT data for those 85 or older

    Acute coronary events – RE-LY Trial; Higher risk for MI/ ACS vs. warfarin

    Anticoagulation Update 2015 20

    Adverse Events

    Bleeding – Up to 6% in trial populations

    – Frequent FDA/ BI information updates

    GI symptoms – Up to 16%

    – Dyspepsia

    – Diarrhea

    Joint Pain

    Fatigue

    Dizziness

    Dyspnea

    Peripheral edema

    Anticoagulation Update 2015 21

    Drug-drug Interactions

    Other anticoagulants

    Antiplatelets

    P-glycoprotein inducers

    – Rifampin - AVOID combination with

    dabigatran

    – St. John’s Wort

    22Anticoagulation Update 2015

    Drug-Drug Interactions

    P-glycoprotein Inhibitors

    – Amiodarone/ dronedarone

    – Clarithromycin

    – Cyclosporine

    – Diltiazem

    – Indinavir/ ritonavir

    – Itraconazole/ ketoconazole

    – Sirolimus/ tacrolimus

    Anticoagulation Update 2015 23

    Drug-Food Interactions

    Food has no effect on bioavailability

    Delays time to peak serum concentrations

    by about 2 hours

    Risk of GI distress may indicate need to

    give with or after meals

    Anticoagulation Update 2015 24

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    5

    Monitoring Parameters

    Activated Partial Thromboplastin Time (aPTT)

    – Values > 2.5 X control; overly anticoagulated?

    – Sensitivity?

    Thrombin Time (TT)

    – Dilute TT may be more valuable

    Ecarin-based clotting time

    CBC with differential

    Always: creatinine clearance

    Serum dabigatran levels (Value?)

    PT/INR: PT can be affected 25Anticoagulation Update 2015

    Monitoring Concerns

    Potential risk for bleeding higher than that

    discovered in RCT submitted for approval

    Serum level dose adjustment could lower

    risk of bleed by 30 to 40%

    No defined optimal therapeutic range

    110 mg dose optimal to permit dose

    adjustment BMJ July 2014

    Anticoagulation Update 2015 26

    PT/ INR Monitoring

    Dabigatran can elevate PT and INR

    No direct clinical monitoring value

    Usually transient and more prevalent with

    initial dosing

    Switching from dabigatran to warfarin,

    check INR 2 days after dabigatran is

    stopped

    Anticoagulation Update 2015 27

    Recovery No gold standard antidote

    – Idarucizmab under development

    Discontinue the drug

    Maintain adequate hydration/ diuresis

    Dialysis: limited data, possible benefit

    Consider transfusion

    – Fresh frozen plasma (FFP)

    – Packed red blood cells (PRBC)

    – Platelet concentrates

    Anticoagulation Update 2015 28

    Dabigatran

    Dosing

    – 150 mg PO BID

    Renal Dosing

    – Creatinine clearance > 30 ml/ min: No change

    – Creatinine clearance 15 to 30 ml/ min

    75 mg PO BID with caution

    – Creatinine clearance < 15 ml/ min

    Avoid use

    Hepatic Dosing: