Post on 23-Dec-2015
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