Coagulation 2014 PA State Lecture - Presentations/Novel...Coagulation and New Anticoagulants! Maureen E. Mays, ... may be taken with food/antacids, ... introduction of new oral anticoagulants that

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  • 10/21/14

    1

    Coagulation and New Anticoagulants

    Maureen E. Mays, MD, MS, FACC Director ~ Portland Preventive Cardiology

    Diplomate, American Board of Clinical Lipidology

    www.portlandpreventivecardiology.com

    October 2014

    Overview

    Blood and blood clotting

    Anti-platelet medications

    Anticoagulants

    Heparins

    Warfarin

    New Drugs

    direct thrombin inhibitor(s)

    Factor Xa inhibitors

    Blood Composition

    connective tissue with cells suspended in plasma

    Plasma (55%)

    Cellular Elements (45%)

    water

    Ions /electrolytes (K+ Cl- Ca++)

    plasma proteins (Fibrinogen)

    transported substances

    erythrocytes (red blood cells)

    leukocytes (white blood cells)

    platelets

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    How blood clots

    Damage to endothelium

    Platelet plug

    Coagulation Factors from

    plasma, platelets & damaged cells

    Leading to:

    Activated Fibrin

    fibers woven into a patch

    The Coagulation Cascade

    Fibrin Clot

    XII

    VII

    VIII

    IX

    XI

    Fibrinogen

    II

    V

    X

    TF

    Intrinsic

    Extrinsic

    The Balance

    Bleeding Clotting

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    Anti-Platelet Therapy

    Prodrug: metabolized to salicylate

    Absorption: affected by food, antacid

    buffer, enteric coating, chewing

    Irreversible COX-1, COX-2 inhibition

    Effect within minutes, peak in 1-2 hours

    Aspirin Pharmacology

    Beneficial in PTCA (cath)

    77% reduction in ischemic complications

    Maintenance dose 81-162 mg

    Low dose has similar efficacy but decreased

    bleeding than with higher doses

    Aspirin

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    Aspirin blunts but does not eliminate circadian variation of AMI

    Ridker PM et al. Circulation. 1990;82:897-902.

    Physicians Health Study; N = 22,071 men

    30

    20

    10

    00 12 24 0 12 24

    30

    20

    10

    0

    Placebo Aspirin

    Hour of day Hour of day

    Absorption: Not affected by food or antacids, however,

    inactivated by some PPIs

    Prodrug converted by liver to active metabolites

    Elimination half life = 8 hours

    Irreversible binding: biologic effects = platelet life

    Clopidogrel:

    CURE: Patients continue to have recurrent CV events despite dual antiplatelet therapyN = 12,562 with NSTE-ACS; all patients received ASA; Primary outcome = CV death, MI, stroke

    CURE Trial Investigators. N Engl J Med.2001;345:494-502.

    CURE = Clopidogrel in Unstable Angina to Prevent Recurrent Events

    Cumulative hazard rate for primary

    outcome

    0.14

    0.12

    0.10

    0.08

    0.06

    0.04

    0.02

    0.000 3 6 9 12

    P < 0.001

    Clopidogrel

    Placebo

    Follow-up (months)

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    Absorption: may be taken with food/antacids, although absorption decreased after fatty meal

    Prodrug: intestinal/liver conversion to active

    Elimination half-life = 7hours

    Irreversible binding to P2Y12 receptor: biologic

    effects = platelet life (5-10days)

    Prasugrel

    Absorption: not affected by food or antacids

    Non-Prodrug: Onset of action within 1-2 hours

    Elimination half-life = 8 hours

    Reversible binding: biologic t1/2 = 6 hours

    clinical effect 3-5 days

    Ticagrelor

    Therapy in ACS is Complex

    Anticoagulants: UFH LMWH

    Antiplatelets: ASA Clopidogrel Prasugrel Ticagrelor

    IV anitplatelets: None Abciximab Eptifibatide/Tirofiban

    Cath strategy:

    Early

    Delayed

    Never

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    Long Term Antiplatelet Rx.Acute & Stable Coronary

    Syndrome

    Medical

    Theraphy

    Without stent or

    PTCA alone

    Drug-eluting

    Stent group

    Bare-metal

    Stent group

    ASA 162-325 mg/d indefinitely

    +

    Clodpidogrel 75mg/d

    or ? Prasugrel

    or ?Ticagrelor

    for at least 1 mo (class 1A) & up to 12 months

    ASA 162-325mg/d for

    at least 3 mo for SES,

    6mo for PES, then

    75-100mg/d indefinitely

    +

    Clodpidogrel 75mg/d or

    Prasugrel 10mg/d or Ticagrelor 90mg BID

    for at 6-12 months

    Shorter duration if bleeding risk >benefit

    ASA 162-325 mg/d

    for 1mo then

    75-100mg/d indefinitely

    +

    Clodpidogrel 75mg/d or Prasugrel 10mg/d or Ticagrelor 90mg BID

    for at 6-12 months

    Shorter duration if bleeding risk >benefit

    Anticoagulation

    Thromboembolism in the U.S.

    Annually, more individuals may die from DVT complications than from the combination of AIDS, breast cancer, and motor vehicle accidents combined

    900,000 to 2,000,000 VTE cases per year in U.S.

    Estimates of death rates per year vary from 50,000 to

    300,000

    700,000 Strokes per year

    15% of strokes are in people with Atrial Fibrillation

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    New Data on Prevention of Stroke in Nonvalvular AF

    A-Fib in the USA

    Approx 5 million people

    Increase with age

    Increasing incidence & prevalence in the US

    Life time Risk: 25%

    Independent predictor of mortality

    Risk of stroke 3-7%/year

    Increase with age

    Almost half of all embolic strokes

    About 100,000 strokes/year

    A growing Epidemic

    Approx 15M by 2050

    Stroke Risk Stratification

    CHADS2 Risk Score

    CHF 1

    Hypertension 1

    Age >75 1

    DM 1

    CVA or TIA 2

    Total 6

    CHADS2-VASc Score

    CHF 1

    Hypertension 1

    Age>75 2

    DM 1

    CVA/TIA 2

    Vascular Ds 1

    (MI, PAD)

    Aged 65-74 1

    Female 1

    Total 9

    Score CVA

    (%/Yr)

    0 1.9%

    1 2.8 %

    2 4.0%

    3 5.9%

    4 8.5%

    5 12.5%

    6 18.2%

    Score CVA

    (%/Yr)

    0 0%

    1 1.3%

    2 2.2%

    3 3.2%

    4 4.0%

    5 6.7%

    6 9.8%

    7 9.6%

    8 6.7%

    9 15.2%

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    Anticoagulants

    CURRENT DRUGS

    Unfractionated Heparin______________

    Low Molecular Weight Heparin________

    Lepirudin (DTI)____________________

    Bivalirudin (DTI) ___________________

    Argatroban(DTI)____________________

    Danaparoid_______________________

    Drotrecogin Alfa____________________

    Vitamin K antagonists (Warfarin)_______

    NEW/ in DEVELOPMENT DRUGS

    Fondaparinux_____________________

    Idraparinux_______________________

    SSR 126517______________________

    Rivaroxaban______________________

    Apixaban_________________________

    LY517717________________________

    YM150__________________________

    DU-176b_________________________

    Betrixaban________________________

    Ximelagatran*_____________________

    Dabigatran etexilate________________

    *taken off the market

    Italics are Oral Drugs

    TARGETED FACTOR

    Antithrombin (indirectly Xa and IIa)

    Antithrombin (indirectly Xa and IIa)

    Thrombin (IIa)

    Thrombin (IIa)

    Thrombin (IIa)

    Antithrombin

    Va, VIIIa

    Prothrombin (II), VII, IX, X

    Xa

    Xa

    Xa

    Xa

    Xa

    Xa

    Xa

    Xa

    Xa

    Thrombin (IIa)

    Thrombin (IIa)

    Heparin

    and other current

    Parenteral Anticoagulants

    Basics of Heparin

    Derived from mucosal tissues of slaughtered meat animals.

    Increases Antithrombin activity. (Indirect inhibition of IIa

    & Xa)

    Usually intravenous adminstration

    Low molecular weight heparin: different composition; more

    predictable; subcutaneous injection twice daily; use preferred over unfractionated heparin

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    More about Heparin

    Fast action intravenously or sub-Q

    peak after injection 2 - 4 hr

    half life 1 - 5 hr

    Few drug-drug interactions

    Toxicities: Bleeding & Heparin-Induced Thrombocytopenia

    Other Parenteral Anticoagulants

    Lepirudin (DTI) derived from hirudin from leech salivary glands

    Bivalirudin (DTI) approved for use during heparin-induced thrombocytopenia (HIT) & percutaneous coronary interventions

    Argatroban (DTI) can be used in patients with risk of (HIT)

    Danaparoid no longer available in the U.S.

    Drotrecogin Alfa used in patients with sepsis; recombinant

    form of activated protein C that inhibits f Va and f VIIIa

    DTI = direct thrombin inhibitor; HIT = heparin induced thrombocytopenia

    Oral Anticoagulants

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    Site of Action for Oral Anticoagulants

    Fibrin Clot

    Intrinsic

    Extrinsic

    XII

    VII

    VIII

    IX

    XI

    Fibrinogen

    II

    V

    Tissue Factor

    X

    Direct Xa Inhibitors

    -xaban

    AT

    Direct Thrombin Inhibitors

    -gatran

    warfarin

    Vitamin K antagonists:

    Warfarin Sodium

    Dicoumarol

    Phenprocoumon

    Acenocoumarol

    Anisindione

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