Anticoagulation Pharmacology

Kimberly Chapin, Pharm.D.

Course Outline

• Review hemostatic mechanisms

• Review mechanisms of action of each class of anticoagulant

• Compare and contrast pharmacology of agents in each anticoagulant class

• Identify unique places in therapy for each anticoagulant

Hemostasis • Normal physiological

response that prevents significant blood loss after vascular injury

• Clot formation involves multiple system responses: – Vasoconstriction – Platelet plug formation – Coagulation

• Once the vessel heals, primary fibrinolysis is triggered and clot formation processes are inhibited

Image source: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/hypercoagulable-states/

Hemostasis: A Balancing Act

Prohemorrhagic

Natural Anticoagulants (Protein C, Protein S, AT)

Fibrinolytic proteins

•Illness (i.e. Infection, Malignancy, CV Disease)

•Medications •Inherited and acquired bleeding disorders

•Immune Reactions •Trauma •Patient factors (i.e. Obesity, immobility, pregnancy)

•Toxins

Platelets Coagulation Factors

Fibrinolytic Inhibitors

Prothrombotic

Medications That Affect Hemostasis

• Antithrombotics prevent or interfere with the formation and growth of blood clots.

•Anticoagulants—interfere with clotting factors »Examples: heparin, low molecular weight heparins (LMWH),

warfarin, factor Xa inhibitors, direct thrombin inhibitors •Antiplatelet agents—decrease platelet activation and

aggregation »Examples: Aspirin, thienopyridines, glycoprotein IIb/IIIa

Inhibitors, P2Y12 platelet receptor inhibitors, Protease-Activated Receptor-1 (PAR-1) Antagonist

• Antifibrinolytics inhibit clot dissolution »Example: Aminocaproic Acid, tranexamic acid • Thrombolytics dissolve existing clots »Example: Alteplase (tPA)

Clotting Cascade • Anticoagulants inhibit clotting

factors

• The clotting cascade is a complex set of reactions involving approximately 30 different proteins.

• Tissue and Blood Vessel damage stimulate the Intrinsic and Extrinsic pathways, which converge at factor Xa activation.

• These reactions convert fibrinogen to insoluble strands of fibrin, which, together with platelets, forms a stable clot.

Anticoagulation Therapy: General Principles

• Weigh benefits of treatment against risk of bleeding • Monitor for signs and symptoms of bleeding

– Labs – Physical assessment – Patient reporting

• Check dose adjustments for renal impairment, hepatic dysfunction, age, body weight, interactions, and special patient populations

• Check recommended hold times around invasive procedures, particularly those involving neuraxial injection or catheters

• Follow recommended guidelines for use of agents in specific indications

Antithrombin (AT) Enhancers: Heparin, LMWH, Fondaparinux

• Most commonly used anticoagulants in the hospital setting

• Extensive clinical data to support use in multiple indications

• Years of experience using these agents

Anticoagulant Approval

Unfractionated Heparin (UFH)

1939

Low Molecular Weight Heparins (LMWHs)

Dalteparin (Fragmin®) Enoxaparin (Lovenox®) Nadroparin (Fraxiparine®)* Tinzaparin (Inohep®)*

1980s

Indirect Factor Xa Inhibitors Fondaparinux (Arixtra®)

2000s

*Not Available in the United States

AT Enhancers: Mechanism of Action Unfractionated Heparin (UFH) •Inhibits Thrombin (IIa), IXa, Xa, XIa and XIIa •Therapeutic action: Xa, thrombin

Low Molecular Weight Heparin (LMWH) •Predominantly inhibit factor Xa

Fondaparinux •Purely inhibits factor Xa

All Agents: –Require AT cofactor to exert

anticoagulant effect –Do not affect thrombin bound to fibrin

or Xa bound to platelets (only fluid form)

Antithrombin (AT) Enhancers: Heparin, LMWH, Fondaparinux

• Antithrombin (AT) inhibits factor Xa and thrombin (natural anticoagulant)

• UFH, LMWH, and Fondaparinux bind to AT, causing a conformational change.

• Activated complex increases Factor Xa inactivation by several fold over endogenous AT

• Longer chain polysaccharides:AT complexes irreversibly binds to an inhibits the active site of thrombin

–UFH>>>LMH –Fondaparinux does not bind

thrombin Image Source: Am J Health-Syst Pharm. 2002. American Society of Health System Pharmacists.

Antithrombin (AT) Enhancers: Heparin, LMWH, Fondaparinux Heparin LMWH (enoxaparin) Fondaparinux

Source Endogenous Polysaccharide (bovine and porcine lung/intestine)

Derived from UFH Synthetic (small molecule)

Chain Length ~45 saccharide units ~15 saccharide units 5 saccharide units

Route IV, Subcutaneous Subcutaneous, IV Subcutaneous, IV

Time to Cmax SC: 20-30 min (erratic absorption)

SC: 3-4.5 hours (predictable absorption)

SC: 2-3 hours (predictable absorption)

Half Life 0.5 to 2 hours

~4 to 7 hours (Daily to BID dosing)

15-17 hours (Daily SC dosing)

Dosing in Renal Impairment

No adjustment needed; Preferred agent for ESRD/dialysis patients

Adjust doses; Not recommended for dialysis patients

Adjust doses; Contraindicated when CrCl<30 mL/min

Laboratory monitoring

aPTT, ACT, anti-factor Xa Platelet monitoring

Not routinely recommended; optional anti-factor Xa assay Platelet monitoring

Not routinely recommended; optional anti-factor Xa assay

Antithrombin (AT) Enhancers: Heparin, LMWH, Fondaparinux Heparin LMWH (enoxaparin) Fondaparinux

Additional Binding

Proteins, macrophages, platelets, osteoblasts

Less protein, osteoblast, platelet binding than UFH

No additional binding

Bleeding Incidence

Higher than LMWHs (rates vary based on indication and patient)

0-13% Any bleeding 0-4% Major bleeding

2-3 % Minor bleeding 1-3% Major bleeding

Incidence of thrombocytopenia

1-5% HIT 30% Non-HIT

<1%HIT 3-5% Non-HIT

0% HIT 3% Non-HIT

Pregnancy

Preferred anticoagulant Preferred anticoagulant Category B (not routinely used)

Body Weight Caution with obese Initial doses often capped, and/or adjusted body weights are used

Caution in extremes of weight (<45kg and >~180kg) Actual body weight used for weight-based doses

Treatment dose tiered according to body weight. Contraindicated for body weight <50kg

Reversal

Protamine (100%) Protamine (~60 to 75%) No specific reversal agent available

Generic Available

Yes Yes (Biosimilar) Yes

Unfractionated Heparin (UFH): Pros and Cons

• Pros: – Rapid onset and clearance, titratable, monitoring readily

available, rapidly reversed with protamine – Preferred for anticoagulation during procedures

• Cons: – Narrow window of adequate anticoagulation without bleeding – Highly variable dose-response – Hematologic side effects (including HIT) – Not easily used in outpatient setting/no oral formulation – Reduced ability to inactivate thrombin bound to fibrin or factor

Xa bound to activated platelets within a thrombus Potential extension of thrombus

Low Molecular Weight Heparins (LMWHs): Pros and Cons

• Pros: – Does not require routine monitoring – Subcutaneous administration and predictable dose response

allows for easier dosing and outpatient use – Lower risk of HIT and osteoporosis than UFH – Preferred agent for pregnancy, malignancy

• Cons: – Prolonged half-life in patients with renal failure, challenging

dosing at extremes of body weight – Generic availability challenging because of biologic status – If monitoring is required, anti-factor Xa activity testing with a

rapid turnaround time may be less widely available – No oral LMWH

Fondaparinux (Arixtra®): Pros and Cons

• Pros: – Synthetic small molecule – Little to no risk of HIT (some use in history of HIT) – Long duration of action Daily administration – No routine monitoring, easy dosing – No effect on thrombin or platelets

• Cons – No reversal agent – Limited to parenteral administration – Significantly longer half-life in renal insufficiency – Contraindicated with low body weight

Vitamin K Antagonists • Warfarin (Coumadin®) –Oral

– IV formulation no longer available on the US market

• Medical use started in the 1955 – Originally found in sweet clover that was responsible for

hemorrhagic death in cattle in the 1930s – Similar compound marketed as rat poison

• Only oral anticoagulant on the market for over 50 years – Extensive clinical trial data and provider experience for

multiple indications

Warfarin: Mechanism of Action

– Antagonist of Vitamin K

– Interferes with hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as natural anticoagulants protein C and protein S

Warfarin Pharmacology • Onset of action:

– Dependent on clearance of existing factors

– Earliest changes in INR seen 24-36 hours after first dose

– Full antithromboitc effect not seen until 4-5 days (when prothrombin is depleted)

– Overlap with another anticoagulant is required for immediate anticoagulation. Must be continued for 5 days AND until INR is at desired range.

• Duration of action: – 2 to 5 days

Factors Half-Life

II 42-72 hours

VII 4-6 hours

IX 21-30 hours

X 27-48 hours

Protein C 8 hours

Protein S 60 hours

Warfarin Pharmacology • Varied Dose Response

– Monitoring: PT/INR measures the intensity of anticoagulation • Therapeutic target usually INR of 2-3 • Higher targets for certain types of heart valves and recurrent thrombosis

events

• Metabolism: Liver (Hepatic P450 enzymes, CYP2C19, CYP1A2, CYP3A4) • Protein bound: 99% (albumin)—Only unbound drug is active • Interactions:

– Medications • Hepatic CYP interactions, interference with Vitamin K stores, protein

displacers – Lifestyle factors affecting Vitamin K Stores

• Activity Level, Diet, Alcohol, Illness (diarrhea, fever) • Adverse events

– Bleeding (variable rates) – Skin necrosis (rare)

Warfarin Reversal 1. Vitamin K

– Oral preferred if bleeding is absent or not life-threatening – IV preferred for life-threatening bleeds or non-PO

• Sub-Q has erratic absorption, delay in onset Not recommended • IM can lead to hematoma formation

– Administer in addition to FFP or PCC to prevent rebound INR rise

For Life-threatening bleeds, ADD: 2a. 4-Factor Prothrombin Complex Concentrate (PCC) KCentra

– FDA approved for warfarin reversal – Preferred in guidelines for serious/life-threatening bleeds.

• Due to risk of thrombosis, not recommended in the absence of severe bleeding – Less volume and faster to prepare than FFP

OR 2b. Fresh Frozen Plasma

Warfarin: Pros and Cons • Pros:

– Years of experience, especially in special populations (i.e. hypercoagulability, heart valves, ESRD)

– Measurable anticoagulation – Cheap cost of medication

• Cons: – Slow onset of action – Varied response to dosing

• Caution advised for: elderly (>70 years), low body weight (<50kg), malnourished (low albumin), liver impairment, decompensated CHF, active malignancy, high risk of bleeding, drug interactions, clinical hyperthyroidism, ESRD

– Patient must be knowledgeable about interactions – Lots of interactions – Monitoring requirements

Direct Thrombin Inhibitors (DTIs)

• Hirudin first anticoagulant

• Places in therapy: – Parenteral

formulations largely limited to patients with HIT/hx of HIT and PCI

– Dabigatran was first of the new oral anticoagulants

Anticoagulant Route Approval

Hirudin IV 1909 (1920s) (not available)

Lepirudin (Refludan®)

IV Late 1990s (discontinued in 2012)

Argatroban IV 2000

Bivalirudin (Angiomax®)

IV 2000

Desirudin (Iprivask®)

Sub-Q/IV 2003

Dabigatran Etexilate (Pradaxa®)

Oral

2010 (2008 in Canada and Europe)

Direct Thrombin Inhibitors (DTIs) DTIs exert their

antithrombotic effect by direct, selective, and reversible binding to the active site of thrombin (factor IIa)

– Argatroban and Dabigatran only bind the active site of the thrombin enzyme

– Bivalirudin and Desirudin also bind to Exosite I on thrombin

• DTIs bind free and clot bound thrombin

Direct Thrombin Inhibitors (Parenteral)

Argatroban Bivalirudin (Angiomax®)

Source Derivative of amino acid L-arginine

Synthetic analog of recombinant hirudin (protein from leech saliva)

Route IV bolus and infusion IV bolus and infusion

Half Life 39-51 min 25 min

Metabolism/ Clearance

Hepatic* *Requires adjustment for impaired hepatic function

Metabolism: Blood proteases Excretion*: Urine (20%) *Adjust for severe impaired renal function (CrCl<30 mL/min)

Laboratory monitoring aPTT , ACT (prolongs PT/INR)

ACT, aPTT

Major non-bleeding adverse events

Hypotension, Chest pain, GI upset, arrhythmias, SOB, hypersensitivity

Hypotension, Headache, back pain, GI upset

Bleeding rates 5.3% (major) 3.7% (major)

Reversal Supportive measures Supportive measures

Direct Thrombin Inhibitors (DTIs) • Pros:

– Agents of choice for treatment of HIT or history of HIT – Does not affect platelets – Argatroban may be used in renal impairment (even ESRD)

• Cons – Argatroban has a narrow therapeutic index and is

unpredictable in hepatic impairment, ICU patients – Cardiovascular adverse events – Requires continuous infusion and monitoring – Agents unpredictably prolongs PT/INR, making transition

to warfarin difficult – Expensive

Direct Factor Xa Inhibitors

• First oral agent approved in 2012, most recent agent 2015 – No generic products available until

at least 2020

• FDA approvals for reduction of stroke in non-valvular atrial fibrillation, VTE prophylaxis, VTE treatment, prevention of recurrent VTE

Direct Factor Xa Inhibitors (Oral)

FDA Approval (initial)

Apixaban (Eliquis®) 2012

Betrixaban Not yet FDA-approved

Edoxaban (Savaysa®)

2015

Rivaroxaban (Xarelto®) 2011

Direct Factor Xa Inhibitors

• Highly selective for Factor Xa • Inhibits free, prothrombinase-

associated and clot-associated Factor Xa

• No cofactors required (no AT) • Indirect effect on platelet

aggregation

New Oral Anticoagulants Dabigatran Apixaban Edoxaban Rivaroxaban

Bioavailability 3-7% (Prodrug) *Take with food

50% 62% 10mg: 80-100% 20 mg*: 66% *Take with food

Time to Cmax 1 hour 3-4 hours 1-2 hours 2-4 hours

Half-Life 12-17 hours ~12 hours 10-14 hours 5-9 hrs 11-13 hrs (elderly)

Drug Interaction concerns

P-gp Hepatic CYP and P-gp

P-gp Dual CYP 3A4 and P-gp

Adjustment for renal function

Yes AVOID if CrCl <15 mg/mL

Yes Adjust when SCr >1.5 (including ESRD w/HD) IF ≥ 80 yrs OR ≤60 kg

Yes AVOID for NVAF if CrCl >95 mg/mL; AVOID if CrCl <15 mg/mL

Yes VTE: AVOID if CrCl <30 mg/mL; NVAF: AVOID if CrCl <15 mg/mL

Other Adjustments

Extreme caution if >80 years old

AVOID in severe hepatic dysfunction

AVOID in moderate to severe hepatic dysfunction

AVOID in moderate to severe hepatic dysfunction

New Oral Anticoagulants Dabigatran Apixaban Edoxaban Rivaroxaban

Bleed rates Any: 16.6% Major: 3.3%

Any: 1-12% Major: <2%

Any: 22% Major: <2%

Any: 5-28% Major: <6%

Major or Common side effects

GI distress (35%) Well tolerated Abnormal hepatic function tests, skin rash

Well tolerated

Effect on common Coagulation labs

Prolongs PT, INR, and PTT ECT and TT reliable, but not available

Prolongs PT, INR, and PTT

Prolongs PT, INR, and PTT

PT, INR, and PTT

Dosing frequency (NVAF)

BID BID Daily Daily

Unique points

Not recommended if previous MI; 5-10 days of parenteral tx recommended for new VTE.

Concomitant chronic NSAIDs allowed in some studies

5 -10 days of parenteral tx recommended for new VTE

Concomitant clopidogrel allowed in some studies

New Oral Anticoagulants • Pros:

– Very close to “ideal” for an anticoagulant • Rapid onset • Predictable dose response, no routine monitoring • Oral dosing • Most have minimal/tolerable non-bleeding side effects

• Cons: – Expensive – Increased risk of bleeding with advancing age and decreased renal

function – No reliable monitoring for adjustments or assessment of coagulation

status – No data in special populations (i.e. Valvular disease, prosthetic heart

valves, hypercoagulable states, oncology, pediatrics, pregnancy) – Reversal options are available, but limited (for now)

Reversal of New Oral Anticoagulants

• No specific antidote available for any of the new OACs

• Limited studies with factor replacements – Laboratory corrections not always indicative of

positive clinical outcomes (i.e. correction of bleeding, thrombotic events)

– Dosing not established for all agents

• Minimize use to life-threatening bleeds

Recommended Dosing of Concentrated Clotting Factor Products for Oral Anticoagulants

Repletion Agent

Clotting Factors

Replaced1,2 Dose(s) for

Repletion of Specific OACs†

Dose(s) for Repletion of Specific OACs†

Warfarin1 Dabigatran1 Rivaroxaban1/Apixaban2¶

PCC3 II, IX, X (inactivated)

25-50 units/kg — 50 units/kg

PCC4

KCentra®

II, VII, IX, X (inactivated)

25-50 units/kg 25-50 units/kg 25-50 units/kg

aPCC II, IX, X (inactivated)

VII (activated,

FEIBA)

500 units for INR <5; 1000 units for INR ≥5

Up to 25 units/kg initially; subsequent doses based on response1

FEIBA: 50 IE/kg, up to 200 IE/kg/d3

Up to 25 units/kg initially; no data available in patients with active

bleeding; 80 units/kg1

FEIBA: 50 IE /kg up to 200 IE/kg/day3

rFVIIa VII (activated)

17.7-53.4 μg/kg 20-120 μg/kg 20-120 μg/kg

†Experience with doses listed in this table is limited; consult current references and product label for most current information. ¶Limited data are available for apixaban reversal; however, it may be rational to apply information from rivaroxaban because of their similar mechanisms of action.

1. Nutescu EA et al. Am J Health Syst Pharm. 2013;70:1914-1929. ©2013, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. 2. Babilonia K et al. Thromb J. 2014;12:8. 3. Heidbuchel H et al. Europace. 2013;15:625-651.

Reversal Agents: The Future (?)

• Two new reversal agents in clinical trials – Idarucizumab

• Reversal of dabigatran (Pradaxa) • Analysis of Phase II trials underway • Likely the first to market (currently under priority

review by the FDA)

– Andexanet alfa • Currently under Phase III trials • Positive results reversing Direct AND Indirect Factor Xa

inhibitors 1. Idarucizumab. Boehringer Ingelheim. http://us.boehringer-

ingelheim.com/content/dam/internet/opu/us_EN/documents/Media_Press_Releases/2015/Idarucizumab-Media-Fact-Sheet.pdf 2. Andexanet alfa: FXa Inhibitor Antidote. Portola Pharmaceuticals. https://www.portola.com/clinical-development/andexanet-alfa-prt4445-

fxa-inhibitor-antidote/.

Potential Future Anticoagulants

• Tissue factor pathway inhibitors • Factor VIII inhibitor • Thrombomodulin • Factor IXa inhibitor • Factor XI inhibitor • Factor XIIa inhibitor • Polyphosphate inhibitors

Summary

• Several clotting factors may be targeted to achieve therapeutic anticoagulation – Most approved agents focus on factor Xa and/or

thrombin

• Different agents all have a place in therapy • Clinical data, pharmacology, bleed risk, and

patient specific factors must all be considered for safe use of anticoagulation

Additional References • American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th

Edition). February 2012. • Angiomax® prescribing information. The Medicines Company. May 2013 • Apixiban® prescribing information. Bristol-Meyers Squibb Company. August 2014. • Argatroban prescribing information. Teva. February, 2015. • Arixtra® prescribing information. Glaxo SmithKline. August 2011. • Dobesh PP, et al. New Oral Anticoagulants for the treatemtn of Venous Thromboembolism:

Understanding Differences and Similarities. Drugs (2014) 74:2015–2032. • Facts and Comparisons Database. Accessed 9/2015 • Lovenox® prescribing information. Sanofi-Aventis US, LLC. April 2013. • Lexi-Comp Online Database. Accessed 9/2015 • Pradaxa® prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. January

2015. • Savasya® prescribing information. Daiichi Sankyo Co., LTD. September 2015. • Xarelto® prescribing information. Janssen Pharmaceuticals. December 2014.