Anticoagulation Problems, Pitfalls & Possibilities

George A. Davis, PharmD, BCPSUniversity of Kentucky HealthCare

April 16, 2014georgedavis@uky.edu

Disclosures

• I have no financial conflict of interest related to this presentation.

Objectives

• Describe dosing protocols for initiation of therapy and management dosing of anticoagulants.

• Illustrate the indications for use of the new oral anticoagulants.

• Evaluate the management of the in's and out's of the INR.

Outline

• Basics of Anticoagulant Drug Pharmacology• Review of Warfarin (VKA) and Target-Specific

or Novel Oral Anticoagulants (TSOAC or NOAC)• Dosing recommendations and monitoring of

oral anticoagulation

Hemostatic System

• Preserves integrity of circulatory system• A highly complex system– Vessel wall (endothelial cells)– Soluble plasma proteins (clotting factors)– Cellular components (platelets)– Microparticles (tissue factor)

• Activated by tissue injury or changes in the endothelial surface

Hemostasis Overview

• Hemostasis is the arrest of bleeding following blood vessel damage

• Rapid formation of impermeable platelet and fibrin plug at site of injury

• Localized to site of injury• Fibrin within clot triggers its own dissolution

(fibrinolysis)• Pathologic thrombus = normal regulatory

controls overwhelmedFurie B, Furie BC. N Engl J Med 2008;359:938-949.

Response to Vascular Injury

• Endothelial disruption (may not involve actual damage)

• Two pathways of platelet activation– Exposed collagen triggers

accumulation of activated platelets

– Exposed tissue factor initiates generation of thrombin• Generates fibrin• Activates platelets

Furie B, Furie BC. N Engl J Med 2008;359:938-949.

Cellular Model of Coagulation Process

Thromb Haemost 2013; 110: 859–867; Acta Anaesthesiol Scand 2014

Oral Anticoagulants in Coagulation Cascade

Clin Pharmacokinet (2013) 52:69–82

Warfarin

Anticoagulants Protein C, S

RivaroxabanApixiban

Dabigatran

Warfarin

• Developed in 1930s at the University of Wisconsin– Hemorrhagic death in cattle after eating spoiled sweet

clover• First used clinically in 1941• Most widely used OAC– Good bioavailability (>90%)

• Absorbed in upper GI tract• Peak absorption 60-120 min

– Predictable onset– Predictable duration of action

Warfarin: Racemic Mixture of Two Enantiomers

R-Warfarin S-Warfarin

Elimination half-life 45 hrs (20-70 hrs) 25 hrs (18-52 hrs)

Metabolism 40% Reduction60% Oxidation

10% Reduction90% Oxidation

Oxidative Metabolism

1A2 > 3A4 > 2C19 2C9 > 3A4

Potency 1.0 (reference) 2.7 – 3.8 X R-warfarin

Warfarin Pharmacology

• By suppressing the production of clotting factors, warfarin prevents the initial formation and propagation of thrombus– NOTE: Has no direct effect on

previously circulating clotting factors or previously formed thrombus

• Antithrombotic effect delayed until circulating vitamin K-dependent factors (II, VII, IX, X) are cleared from the blood

Vitamin K Dependent Proteins and Monitoring of Warfarin Effect (INR)

Factor Function Half-Life

Protein C Anticoagulant 8-10 hours

Protein S Anticoagulant 40-60 hours

Factor VII Procoagulant 6-8 hours

Factor IX Procoagulant 20-30 hours

Factor X Procoagulant 24-40 hours

Factor II (Prothrombin)

Procoagulant 60-100 hours

• Time to reach therapeutic INR is determined by the half-lives of the clotting factors

• Initial increase in INR due to decline in factor VII

• Full antithrombotic effect of warfarin due primarily to inhibition of factor II– Anticoagulant vs. Antithrombotic effect

• Full antithrombotic effect may take 1 week or more– Possible thrombogenic state in the intial

1-2 days of therapy• Early INR > 2.0 may not indicate

adequate antithrombotic protection

Vitamin K Dependent Proteins and Monitoring of Warfarin Effect (INR)

Ann Pharmacother 2004;38:2115-21.

Initiation of Warfarin with Parenteral Anticoagulant

• Required due to warfarin’s delayed onset of action

• Recommended to overlap parenteral anticoagulant and warfarin for at LEAST 5 days– INR should be in range and stable before

discontinuation of parenteral anticoagulant– Warfarin does NOT affect existing clotting factors

• Consider UFH/LMWH when clinical appropriate– TSOACs are not recommended to bridge warfarin but

there are ongoing studiesChest. 2012 Feb;141(2 Suppl):e44S-88S.

Warfarin-Induced Skin Necrosis

• Ischemia-related skin necrosis– 1 in 10,000 patients– Secondary to rapid decline in

Protein C when warfarin is initiated

• Risk factors– High warfarin dose– Obesity– Female gender

• Manifestation– Plaques, hemorrhagic blisters,

or scars

Ann Dermatol 26(1) 96-98, 2014; J Gen Intern Med 29(1):248–9, 2013

Warfarin-Induced Skin Necrosis

• Avoidance– Avoid warfarin loading doses– Adequate parenteral anticoagulation

• Treatment– Reversal of warfarin effect with vitamin K– Administration of heparin– Re-challenge? MUST be very careful!

Warfarin: Dose / Response Relationships

CYP2C9 Genotype VKORC1 Haplotype

Warfarin: Major Drug-Drug Interactions

Effect on INR Level of causation= Level I (highly probable)

Potentiation↑ INR and increase bleeding risk

Alcohol (if concomitant liver disease)Anabolic steroidsAmiodaroneCimetidineCiprofloxacin CitalopramCotrimoxazoleDiltiazemEntacaponeErythromycinFenofibrate

Fish oilFluconazoleIsoniazid (≥ 600 mg daily)Mango (1–6 daily)MetronidazoleMiconazole oral gelMiconazole vaginal suppositoriesOmeprazolePiroxicamPropranololQuilinggaoSertralineVoriconazole

Inhibition↓ INR and increase thromboembolic risk

Avocado (large amounts ≥ 100 g daily)Barbiturates (e.g. phenobarbitone)CarbamazepineCholestyramineGriseofulvin

High vitamin K containing foods/enteral feedsMercaptopurineMesalazineRibavirinRifampicin

Arch Intern Med. 2005;165:1095-1106c

Warfarin Dose: Genetic Influence

• Genetic polymorphisms account for up to 50% of individual variation in dose responsiveness

Warfarin product labeling. Rev. October 2011.

Warfarin: Genetics vs. Dosing Algorithm

N Engl J Med 2013;369:2283-93; N Engl J Med 2013; 369:2294-2303

• Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

Warfarin Dosing/Monitoring Considerations

• Must consider long half-life– Every dose for last 5-7 days should be considered

in making dosing considerations• Dose from last 2-3 days will most effect on current INR

– Should allow dose changes sufficient time for INR changes to occur• Changes should not be made more than ever 3 days• Small dose changes may not become evident for 5-7

days

Warfarin Dosing/Monitoring Considerations

• Usual maintenance dose is 2.5 – 7.5 mg/day but can range from 0.5 – 30 mg/day

• Zero order kinetics – small dose changes can result in large changes in INR

• Alterations of 5-20% of WEEKLY dose are recommended

• Simplified dosing regimens should be implemented to promote adherence

Target-Specific Oral Anticoagulants (TSOACs)

• Approved in the US– Dabigatran (Pradaxa)– Rivaroxaban (Xarelto)– Apixaban (Eliquis)

J Thromb Thrombolysis (2013) 36:133–140

Pharmacology of TSOACsDabigatran(Pradaxa)

Rivaroxaban(Xarelto)

Apixaban(Eliquis)

Drug Class Direct Factor Xa Inhibitor Direct Factor Xa Inhibitor Direct Factor IIa Inhibitor

Initial US Approval Year 2010 2011 2012

Approved Indication Reduce risk of stroke in NONVALVULAR atrial fibrillation

(April 2014) DVT/PE treatment after parenteral anticoagulant for 5-10 days

Reduce risk of stroke in NONVALVULAR atrial fibrillation

DVT/PE treatment

Reduce risk of stroke in NONVALVULAR atrial fibrillation

Onset of anticoagulation 1-2 hours 2-4 hours 3-4 hours

Dosage form Capsule Tablet Tablet

Dosing Frequency Twice Daily Twice Daily/Daily Twice Daily

Antidote No No No

Black Box Warnings *Discontinuation increases risk of thrombotic events*Spinal/epidural hematoma

*Discontinuation increases risk of thrombotic events*Spinal/epidural hematoma

*Discontinuation increases risk of thrombotic events*Spinal/epidural hematoma

TSOACs: Clinical Trials in AFib

P&T. 2014 Jan;39(1):54-64

TSOACs: Clinical Trials in VTE

Best Practice & Research Clinical Haematology 26 (2013) 151–161

Pharmacology of TSOACs

Adapted from J Thromb Thrombolysis (2013) 36:133–140

TSOACs: Clinical Implications of Onset of Anticoagulation Effect for VTE

Warfarin

Dabigatran

RivaroxabanApixaban

WarfarinBridgingLMWH, UFH

Dabigatran 150mg BIDSwitchingLMWH

Rivaroxaban 15mg BID X 3 weeks, then 20mg QD

Apixiban 10mg BID X 1 week, then 5mg BID

Day 1 Day 6-11 At least 3 months

Day 1 Single Drug Approach At least 3 months

TSOACs: Potential for Drug InteractionsCYP 3A4*

Inducer InhibitorCarbamazepine Amiodarone Itraconazole

Efavirenz Aprepitant Ketoconazole

Glucocorticoids Cimetidine Nefazodone

Nevirapine Clarithromycin Protease inhibitors

Phenobarbital Cyclosporine Verapamil

Phenytoin Diltiazem Voriconazole

Primidone Erythromycin Fluconazole

Rifampin Fluoxetine Fluvoxamine

Rifapentine

St. John’s Wort

P-glycoprotein*Inducer Inhibitor

Midazolam AmiodaroneDronaderone

NifedipineNicardipine

Phenobarbital Ceftriaxone Propranolol

Phenytoin Clarithromycin Quinidine

Rifampin Diltiazem Verapamil

St. John’s Wort Dipyridamole

Erythromycin

Hydrocortosone

Itraconazole

Ketoconazole

Adapted from J Thromb Thrombolysis (2013) 36:133–140

*Does not include every potential drug-drug interaction

TSOACs: Different Mindset for Evaluating Drug Interactions

Warfarin• Interacting drugs are NOT

contraindicated• Drug interactions can be

managed through increased INR monitoring and dose adjustment

TSOACs

• Drug interactions are contraindications or precautions

• No ability to monitor and adjust dose based on response

• Less drug-food interactions versus warfarin

TSOACs: Formulation Issues, Food Effects

Dabigatran Rivaroxaban Apixaban

Formulation • Capsules cannot be crushed (no feeding tube), broken or chewed

• Expires in 4 months after bottle opened

• May be crushed and mixed with applesauce in a feeding tube (G-tube)

• No information

Food Effects • May be taken with or without food

• 10mg tablet – May be taken with or without food

• 15mg and 20mg tablets – Should be taken with largest meal of the day

• Bioavailability not affected by food

TSOACs: Dosing RegimensNonvalvular Atrial Fibrillation

VTE Prevention for HIP or Knee Replacement Surgery

VTE Treatment or Reduction in Risk of Recurrence

Dabigatran (Pradaxa)

Clcr ≥ 30 ml/min: 150mg BID;Clcr 15-30 ml/min or 30-50 ml/min and strong P-gp inhibitor: 75mg BID Clcr <50 mL/min withconcomitant use of P-gpinhibitors: Avoid co-administrationClcr < 15: Avoid use

NA

Clcr≥30 mL/min: 150 mg BID after 5-10 days of parenteral anticoagulationClcr <30 ml/min: No recommendationsClcr <50 mL/min withconcomitant use of P-gpinhibitors: Avoid co-administration

Rivaroxaban (Xarelto)

Clcr > 50 ml/min: 20mg daily;Clcr 15-50 ml/min: 15mg daily;Clcr < 15 ml/min: Avoid use

Clcr≥30 mL/min: 10mg dailyClcr <30 ml/min: Avoid use

Clcr≥30 mL/min: Clcr 15mg BID x 21 days then 20mg dailyClcr <30 ml/min: Avoid use

Apixaban (Eliquis)

5mg daily; Dose adjusted to 2.5mg daily if the patient is taking a strong dual inhibitor of CYP3A4 and P-gp, or has two or more of: ≥80 years age, body weight ≤60 kg, or Scr ≥ 1.5 mg/dL

NA NA

TSOACs: Timing of interruption of before surgery or invasive procedures

Calculated Clcr (ml/min)

Half-life (hours)

Timing of last dose Before SurgeryStandard Risk of

BleedingHigh Risk of

BleedingDabigatran

≥ 80 14 24 hours 2 days

50-79 17 24 hours 2 days

31-49 19 2 days 4 days

≥ 30 28 4 days 6 day

Apixaban/Rivaroxaban Apix Riva

≥ 80 15 8 24 hours 2 days

50-79 15 9 1-2 days 3-4 days

31-49 17 9 1-2 days 3-4 days

≥ 30 18 10 2 days 4 days

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

TSOACs: Monitoring versus Measuring

• Monitoring: Implies dose adjustment according to test result (e.g., warfarin/INR)

• Measuring (or quantifying) the drug or drug effect may be useful in:– Over dosage– Questionable compliance– Urgent surgery, interventions, thrombolysis– Extreme body weights– Renal insufficiency

Measuring the Effect of TSOACs

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

Reversal of Oral Anticoagulants

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

A The intervention may need to be modified based on changes in the patient’s clinical status (e.g., if status worsens, expedited or emergent treatment options should be considered). INR = International Normalized Ratio, PCC4 = four-factor prothrombin complex concentrate, PCC3 = three-factor prothrombin complex concentrate, rFVIIa = recombinant factor VIIa, aPCC = activated prothrombin complex concentrate, FFP = fresh frozen plasma.B Contraindicated in the setting of gastrointestinal bleeding.

Checklist during following up on TSOACsInterval Comments

1. Compliance Each visit • Instruct patient to bring remaining medication: note and calculate average adherence

• Re-educate on importance of strict intake schedule• Inform about compliance aids (special boxes; smartphone applications)

2. Thromboembolism Each visit • Systemic circulation (TIA, stroke, peripheral)• Pulmonary circulation

3. Bleeding Each visit • ‘Nuisance’ bleeding: preventive measures possible• Motivate patient to diligently continue anticoagulation• Bleeding with impact on quality-of-life or with risk: prevention

possible? Need for revision of anticoagulation indication or dose?4. Other side effects Each visit • Carefully assess relation with NOAC: decide for continuation (and

motivate), temporary cessation (with bridging), or change of anticoagulant drug.

5. Co-medications Each visit • Prescription drugs; over-the-counter drugs (see Section 4)

6. Blood sampling YearlyEvery 6 months

Every 3 monthsOn indication

• Hemoglobin, renal and liver function• Renal function if CrCl 30–60 ml/min, or if on dabigatran and .75 years

or fragile• If CrCl 15–30 ml/min• If intercurring condition that may impact renal or hepatic function

Europace (2013) 15, 625–651

Summary

• Warfarin is still mainstay of oral anticoagulation• New oral anticoagulants are emerging as an

alternative to warfarin in select patients– Less lab testing but still need to monitor response and

safety– Drug-drug interactions and renal function are important

• Understanding current guidelines will be important to inpatient or outpatient management

Questions?

George A. Davis, PharmD, BCPSUniversity of Kentucky HealthCare

georgedavis@uky.edu