Anticoagulant Reviewneahec.org/Uploads/files/brown_Anticoagulation- Fall Pharmacy Foru… ·...

Anticoagulant Review

Brandy Brown, PharmDPGY1 Pharmacy ResidentSt. Claire Regional Medical [email protected]

Fall Pharmacy ForumSeptember 21st, 2019

Disclosure I have no actual or potential conflict of interest associated with this

presentation.

Objectives

Explain the mechanism of action of oral anticoagulants

Identify and design an appropriate therapeutic plan for patients requiring anticoagulation

Demonstrate use of point of care testing and provide an appropriate warfarin regimen

Background Anticoagulants reduce coagulability of the blood to prevent

clots

Indications

Deep vein thrombosis (DVT)

Pulmonary embolism (PE)

Atrial fibrillation (AF)

Stroke

Anticoagulants have been shown to be among the most frequently implicated drug classes in adverse drug events that contribute to emergency department visits and hospital admissions

Arch Intern Med. 2007;167(13):1414-9.

Virchows Triad

Lancet. 2009 Jan 10;373(9658):155-66.

Risk versus BenefitCHA2DS2VASC

Congestive heart failure 1

Hypertension 1

Age >75 2

Diabetes mellitius 1

Stroke/TIA/TE 2

Vascular disease 1

Age 65 – 74 1

Female 1

HAS-Bled ScoreHypertension 1

Abnormal renal/liver function 1

Stroke 1

Bleeding history 1

Labile INR 1

Elderly 1

Drug interactions/alcohol 1

• Determines need for anticoagulation• Score ≥2 usually warrants anticoagulation

• Risk factors for bleeding event• Score ≥3 usually indicates clinical review

Circulation. 2012;126:860-865.

Application Question #1JM is a 78 YOM with a PMH of hypertension, heart failure, atrial fibrillationand a recent stroke. JM used to drink 3+ alcoholic drinks daily but stoppedaround 5 year ago. The medical team asks you to decide if you think thispatient needs to be started on long term anticoagulation.

Relevant vitals/labs

140/96

EF 35%

A1C 8.5

Scr 0.7 (baseline 0.6-0.9)

INR 0.9

Normal LFTs

CHA2DS2VASC = 7

HAS-Bled Score = 2

Yes, he needs anticoagulation

Oral Anticoagulants Direct Thrombin Inhibitors

Dabigatran (Pradaxa®)

Factor Xa Inhibitors

Apixaban (Eliquis®)

Rivaroxaban (Xarelto®)

Edoxaban (Savaysa®)

Vitamin K Antagonist

Warfarin (Coumadin®)

Indian J Anaesth. 2014 Sep-Oct; 58(5): 515–523.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260295/

Direct Oral Anticoagulants (DOACs)

Apixaban (Eliquis®)

Dabigatran (Pradaxa®)Edoxaban (Savaysa®)Rivaroxaban (Xarelto®)

Direct Oral Anticoagulants (DOACs)

Indications Non-valvular atrial fibrillation

Treatment of DVT/PE

Prophylaxis for recurrent DVT/PE

Prophylaxis for DVT/PE following hip/knee replacement

DOAC Monitoring

No need for routine monitoring of therapeutic levels

No objective coagulation assays to dictate dose adjustments

Assess annually

Renal function

Changes in condition

Signs and symptoms of bleeding

Risk factors for increased bleeding

DOAC Cautions Side Effects

Bleeding risk

Hemorrhage

Nose bleeds

Gastritis-like symptoms

Dizziness/insomnia

Black Box Warnings

Neuraxial anesthesia/spinal puncture

Edoxaban

CrCL >95 mL/min

Contraindications

Active bleeding

Precautions

Caution with prosthetic valves

Moderate to severe hepatic impairment

European Heart Journal - Cardiovascular Pharmacotherapy, Volume 1, Issue 2, April 2015, Pages 134–145

Dabigatran (Pradaxa®) Approved in 2010 Prodrug Oral direct thrombin inhibitor Onset: 1 hour Half life:12-16 hours Drug drug interactions

Inducers: St. Johns Wort Inhibitors: Amiodarone, verapamil,

clarithromycin CI: Quindine

Administration Take with a full glass of water Store in original container

Reversal Idarizcizumab (Praxbind®)


Dabigatran (Pradaxa®) dosing

Indication Recommended Dose

Treatment of VTE and reduction of recurrent VTE

150 mg PO twice dailyBegin after 5 - 10 days of parenteral anticoagulation

Non-valvular atrial fibrillation150 mg PO twice daily

CrCl~ 15-30 mL/min: 75 mgCrCl~ <15 mL/min: contraindicated

Prophylaxis of VTE following hip replacement surgery 110 mg PO on day 1, then 220 mg PO once daily


Apixaban (Eliquis®) Approved in 2012 Oral factor Xa inhibitor Onset: 3-4 hours Half Life: 12 hours Excretion: Urine (~27%); feces Drug drug interactions (DDI)

Inducers: St. Johns Wort, rifampin Inhibitors: Amiodarone, verapamil,

clarithromycin Administration

Without regard to meals Crushable Suspend in water, D5W or apple

juice or mix with applesauceEuropean Heart Journal - Cardiovascular Pharmacotherapy, Volume 1, Issue 2, April 2015, Pages 134–145

Apixaban (Eliquis®) dosingIndication Recommended DoseDVT/PE 10 mg PO twice daily x 7 days, then 5 mg PO twice

daily

Non-valvular atrial fibrillation 5 mg PO twice daily2.5mg BID if two of the following are present:

• Wt ≤ 60 kg• Age ≥ 80 yrs• SCr ≥ 1.5 mg/dL

Prophylaxis of DVT following hip/knee replacement surgery

2.5 mg PO twice daily beginning 24 hours after surgery

Reducing the risk of recurrent DVT/PE 2.5 mg PO twice daily after 6 months of treatment dose


Edoxaban (Savaysa®) Approved in 2015

Oral factor Xa inhibitor

Onset: 30 min-1 hour

Half life: 10-14 hours

Excretion: urine; renal ~50%

Drug drug interactions

Inducers: St. Johns Wort, rifampin

Inhibitors: Amiodarone, verapamil, clarithromycin

CI: Quindine

Administration

Without regard to food

Can crush tablets, suspend in water, or mix with applesauce


Edoxaban (Savaysa®) dosing

Indication Recommended DoseTreatment of DVT/PE 60 mg PO daily

Begin after 5 - 10 days of parenteral anticoagulation

Non-valvular atrial fibrillation 60 mg PO dailyCrCL < 15mL/min: contraindicatedCrCL~ 50-95 mL/min: 60 mg dailyCrCl ~ 15-50mL/min: 30 mg daily CrCL~ >95mL/min: contraindicated


10 mg PO daily, with first dose 6 - 10 hours after surgery

Reducing the risk of recurrent VTE 20 mg PO daily


Rivaroxaban (Xarelto®) Approved in 2011

Oral factor Xa inhibitor

Onset: 1-2 hours

Half life: 5-9 hours; 11-13 hours (elderly)

Excretion: Urine (~66%), feces (28%)

Drug-drug interactions

Amiodarone, dronedarone, quinidine, diltiazem, propranolol, carvedilol, verapamil.

Administration

Doses ≥15mg with “largest” meal of the day

Can be crushed or mixed with applesauce


Rivaroxaban (Xarelto®) dosingIndication Recommended DoseTreatment of DVT/PE and prophylaxis against recurrent DVT/PE

15 mg PO twice daily with food x21 days, then 20 mg PO daily with food

Non-valvular atrial fibrillation 20 mg PO daily with evening mealCrCl~ 15-50 mL/min: 15 mgCrCl~ <15 mL/min: Contraindicated


10 mg PO daily with first dose 6-10 hours after surgery

Reducing the risk of recurrent VTE 20 mg PO daily


DOAC Summary


DOAC Frequency Renal Adjustment Crushable? Transitioning from

Warfarin With Food?

Apixaban(Eliquis®) Twice daily Y Y < 2.0 N

Dabigatran(Pradaxa®) Twice daily Y N < 2.0 N

Edoxaban(Savaysa®) Once daily Y Y ≤2.5 N

Rivaroxaban(Xarelto®) Once daily Y Y <3.0 Y

Application Question #2JMs PCP calls the pharmacy about another patient he istreating who has difficult swallowing pills. He wants to knowwhich of the following DOACs can be crushed?

A. apixabanB. dabigatranC. edoxabanD. rivaroxabanE. warfarinF. heparinG.none of the above

Vitamin K AntagonistsWarfarin (Coumadin®)

Mechanism of Action Inhibits reduction of Vitamin K epoxide, thereby limiting

activation of Vitamin K dependent clotting factors II, VII, IX, X and proteins C and S

Racemic mixture of two isomers (R and S)

Advanced Emergency Nursing Journal. Vol. 38, No. 4, pp. 279–294

Warfarin (Coumadin®) Most widely used and effective, if

taken and dosed the correct way Dosing

Varies per patient based on international normalized ratio (INR)

Administration Take at the same time each day Can take +/- with food Store at room temperature Missed doses Pill box or calendar maybe helpful

Circulation. 2012;126:860–865.

Warfarin Pharmacokinetics Absorption: Rapidly and completely

absorbed

Distribution: primarily intravascular, highly protein bound

Approx. 99% protein bound

Substrate of the following CYP enzymes

CYP1A2 (minor)

CYP2C19 (minor)

CYP2C9 (major)

CYP3A4 (minor)

Half life: 36-42 hours, approx. 10 days

Half life clotting factors

Factor II= 60 hours

Factor VII= 6 hours

Factor IX= 24 hours

Factor X= 40 hours

Half life Endogenous factors

Protein C= 8-10 hours

Protein S= 40-60 hours

Excretion: Urine 92%

Not affected by dialysis

Advanced Emergency Nursing Journal. Vol. 38, No. 4, pp. 279–294

International Normalized Ratio

Warfarin therapy is monitored using the prothrombin time

Determines the time to clot formation

INR represents the PT according the international reference thromboplastin

𝐼𝐼𝐼𝐼𝐼𝐼 = [[𝑃𝑃𝑇𝑇𝑝𝑝𝑝𝑝][𝑃𝑃𝑇𝑇𝑟𝑟𝑟𝑟𝑟𝑟]

]𝐼𝐼𝐼𝐼𝐼𝐼

𝑃𝑃𝑇𝑇𝑝𝑝𝑝𝑝: prothrombin time of patient

𝑃𝑃𝑇𝑇𝑟𝑟𝑟𝑟𝑟𝑟: prothrombin time of normal pooled sample

ISI: International Sensitivity Index

Thrombosis Journal; volume 10, Article number: 5 (2012)

Goal INR

Indication Goal INR Range

DVT and PE 2-3

Non-valvular atrial fibrillation

2-3

Mechanical heart valve 2.5-3.5

Other heart valves 2-3

Ann Pharmacother 2003;37:905-8.

Warfarin Sensitivity

•INR baseline <2•Age <50 YO and no other risk factors•Begin with 7.5 mg to 10 mg

Low Sensitivity

•INR baseline 1.2-1.5•Age 50-65 YO•Concurrent CYP450 hepatic enzyme inhibitors•Begin with 5 mg to 7.5 mg

Moderate Sensitivity

•INR baseline >1.5•Age > 65 YO•hepatic disease, decompensated congestive heart failure, malabsorption syndrome, cancer, hypoalbuminemia, thyrotoxicosis, genetic polymorphism of CYP2C9 enzyme

•Begin with 2.5 mg to 5 mg

High Sensitivity

Circulation. 2012;126:860–865.

Warfarin Monitoring Start with sensitivity in warfarin naive

patients

How often should we check the INR?

Established vs new patient

Inpatient

Out of range daily

In range with little change weekly

Outpatient

Out of range weekly

In range with little change monthly

Think about patient specific factors

Measured INR Dosage Adjustment<1.5 • Consider an extra dose

• Increase weekly dose by 1-20%

1.5-1.9 • Increase weekly dose by 5-10%

2.0-3.0 • No changes

3.1-3.5 • Decrease weekly dose by 5-10%

3.6-4.0 • Decrease weekly dose by 10-20%

4.1-4.9 • Hold 0–2 days• Decrease weekly dose by 20%

Circulation. 2012;126:860–865.

Warfarin Tablets

“Please Let Granny Brown Bring Peaches To Your Wedding”

Vitamin K Containing Foods Vegetables

Broccoli

Kale/Spinach

Brussel sprouts

Lettuce

Greens

Cabbage

Green onions

Asparagus

Cauliflower

Peas

Fruit

Kiwi

Blueberries

Oils/Spices

Mayonnaise

Parsley

Margarine

Canola Oil

Soybean Oil

Meats

Beef liver/Pork Liver

Boost/Ensure/V8 Juice

Cashews

Alcohol

Vitamin K drink

Consistency is key!West J Emerg Med. 2015 Jan; 16(1): 11–17.


Warfarin DDIIncreased Warfarin Effect Decreased Warfarin Effect

AcetaminophenAlcohol

AllopurinolAmiodarone

AspirinCimetidine

CiprofloxacinClarithromycinDexamethasone

DisulfiramFluconazoleItraconazole

IsoniazidLevothyroxineMetronidazoleOmeprazolePhenytoin

SulfonylureaSulfamethoxazole/trimethoprim

BarbituratesCarbamazepineCholestyramine

DicloxacillinGriseofulvin

NafcillinPhenytoinSucralfate

Dietary Supplements/Herbals Increased bleeding risk

The 5 G’s

Gingko bilboa

Ginseng

Garlic

Ginger

Glucosamine

Cranberry

Vitamin E

Decreased Bleeding Risk

Multivitamin

Coenzyme Q10

St. Johns wart

Proc (Bayl Univ Med Cent). 2001 Jul; 14(3): 305–306.


Application Question #3After returning home JMs wife calls you because JM couldn’t remember his goal INR range. What would you tell JMs wife?

A. 2.0 – 3.0

B. 3.0 – 4.0

C. 2.5 - 3.5

D.1.0 – 2.0

Application Question #4JM and his wife come to the pharmacy for his follow up INR check (1 week later), they tell you that JM took 5 mg once daily as instructed.

JMs wife then pulls the bottle out of her purse and says “see” here they are

1. What tablet is this?

4mg

2. What color tablet should JM have?

Peach

Warfarin Side Effects Bleeding (1-3% per person-year)

Mild: epistaxis, hematuria

Severe: retroperitoneal or GI bleed

Life threatening: intracranial bleeding

Boxed warning

Easy bruising

Skin necrosis

Purple toe syndrome

Osteoporosis

Less commonly

Agranulocytosis, leukopenia, N/D

Major contraindications Pregnancy

Hemorrhagic tendencies

Blood dyscrasias

Uncontrolled hypertension

Recent or potential surgery or eyes or CNS

Major regional lumbar block anesthesia or traumatic surgery

Pericarditis or pericardial effusion

Bacterial endocarditis

Eclampsia



Warfarin Induced Bleeding Patient characteristics

Advanced age(>65 yrs)

History of bleeding

Hypertension

Cerebrovascular disease

Severe heart disease

Malignancy

Liver disease

Renal insufficiency

Thrombocytopenia

Recent surgery

Frequent falls

Labile INRs

Intensity of anticoagulant therapy

Use of drugs that interfere with homeostasis

Antiplatelets, NSAIDS

CHEST 2012; 141(2)(Suppl):e44S–e88S

Warfarin and Procedures No consensus on optimal management of warfarin prior to invasive

procedures

Management strategy is individualized based on estimation of patients risk of thromboembolism and bleeding, patient preference, provider preference and cost

Common to hold for 5 days prior or until goal INR is reached as determined by physician usually providing the procedure

Those at high risk maybe bridged with low molecular weight heparin (LMWH) or unfractionated heparin

If using LMWH stop 12 - 24 hours prior to surgery

If using unfratctionated heparin stop 4 - 6 hours prior to surgery

Arch Intern Med 2003:163:901-08; CHEST 2008;133:160S-198S

Time in Therapeutic Range Quality measure for

anticoagulation therapy with warfarin

Time when INR falls within goal to provide the most benefit for preventing stroke, major hemorrhage, and death

Time in therapeutic range (TTR) in trials

RE-LY (dabigatran) ~ 64%

ROCKET-AF (rivaroxaban) ~55%

ARISTOLE (apixaban) ~62.2%

Higher than in community practice

The 2014 National Institute for Health and Care Excellence guideline for the prevention of stroke in people with AF advises the use of DOACs in favor of warfarin when the TTR is less than 65%

Chest. 2006 May;129(5):1155-66Can Fam Physician. 2017 Oct; 63(10): e425–e431

https://www.ncbi.nlm.nih.gov/pubmed/16685005


Monitoring INR Things to consider

Missed doses Diet changes Changes in medications

New medications OTC Herbal supplements

Goal INR targets Watch for signs/symptoms of bleeding Use talkback methods Follow up



DOACs versus WarfarinWhat is best for my patient?

Anticoagulant Comparison

Warfarin

Narrow therapeutic index

Long half life, slow onset, long duration

Multiple drug drug interactions

Multiple drug food interactions

More predictable

Monitoring required

DOACs

More consistent

Fewer drug interactions

No monitoring to measure efficacy/safety

Relatively quick onset of action

Costly

Anticoagulant Indications

Comparison of Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. May 2016

Anticoagulant Atrial Fibrillation VTE Post Op

Prophylaxis Other

Apixaban(Eliquis®)

Dabigatran(Pradaxa®)

Edoxaban(Savaysa®)

• Cancer

Rivaroxaban(Xarelto®)

Warfarin(Coumadin®)

• Heart valves• Myocardial infraction (MI)

Clinical Trials Summary

European Heart Journal - Cardiovascular Pharmacotherapy, Volume 1, Issue 2, April 2015, Pages 134–145.

Switching between anticoagulants

• Once the INR is lower than 2.0

VKA to DOAC

• Concomitant treatment until INR 2-3

DOAC to VKA

• When the next dose of DOAC is planned

Between DOACs

European Heart Journal. Cardiovascular Pharmacotherapy, Volume 1, Issue 2, April 2015, Pages 134–145

Patient Case- RKRK is a 75 year old female who has new onset atrialfibrillation, this is her first visit to the warfarin clinic andshe was referred to you. She had a PMH of HTN and T2DM.

Current home meds:

Lisinopril 10mg once daily

Metformin 500mg BID

What do you want to know? Verify indication

Baseline INR

Current medications, including OTC/herbals

Patient specific factors Diet

Lifestyle

CHA2DS2VASC, HAS-Bled Score

What things do you want to counsel RK about? Indication and “basic” mechanism of action

Dosing/administration

Dose and schedule

Handling of missed or extra doses

INR goals and monitoring

Drug drug interactions

Drug food interactions

Dietary instructions

Talking to all medical doctors about being on warfarin

Signs/Symptoms associated with side effects

Bleeding

Check RK’s INR As groups, please check RKs INR and determine what

regimen of warfarin you would start RK on

Put pencils/pens down when complete

Follow Up RK is interested in the new DOACs her cousin told her

about. Is RK a candidate for DOAC therapy? What would you

suggest? Think about!

Medication

Dose

Follow up plan

Baseline labs needed

When you have a recommendation that you’re willing to share please raise your hand!

Summary Anticoagulants are approved for many indications

DOACs now the first choice in many patients with VTE or atrial fibrillation Important to weigh the risk vs benefits

Most common adverse effect is bleeding Less with the DOACs

Consider costs and patient comfort

Provide detailed counseling to ensure patient understanding Use physical handouts/aids when possible

Talkback method

Pharmacists can be patient advocates

Anticoagulant Review

Brandy Brown, PharmDPGY1 Pharmacy ResidentSt. Claire Regional Medical [email protected]

Fall Pharmacy ForumSeptember 21st, 2019

Anticoagulant Reviewneahec.org/Uploads/files/brown_Anticoagulation- Fall Pharmacy Foru… ·...

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