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Anticoagulation UpdateA case study approach

Anita Ralstin, MS FNP-BC

Disclosures�None

Objectives� RX: Identify the frequent diagnoses

requiring anticoagulation decisions : outpatient and inpatient

� RX: Discuss the benefits/risks of warfarin vs novel agents.

� RX: State understanding of when to use reversal agents.

� Rx: Review the screening required when considering anticoagulation.

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Case 1� 71 y.o. female with diabetes, atrial flutter,

HTN and cardiomyopathy� Medications

� alendronate 70 mg weekly, Eliquis 5 mg BID, levothyroxine 88 mcg, Lisinopril 10 mg daily, metoprolol succinate 50 mg daily, ranitidine 150 mg daily, spironolactone 25 mg daily

Lab white blood cell count

7.9 normal

red blood cell count

4.25 normal

hemoglobin 13.6 normal

hematocrit 39.8 normal

MCV 93.7 normal

MCH 32.1 normal

MCHC 34.3 normal

RDW 14.5 normal

platelet count 212 normal

MPV 9.1 normal

Lab

glucose 150 high

(BUN) 29 high

creatinine 1.66 higheGFR non-afr.american

29 low

eGFR africanamerican

34 low

sodium 134 low

potassium 4.8 normalchloride 101 normal

alk phos 77 normal

AST 20 normal

ALT 10 normal

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ECG

Clinical Decisions� Diagnoses?

� Atrial fibrillation� Chronic Kidney Disease Stage 4� DM� HTN

� Anticoagulation?� If yes, is she on the right drug?

CHADS-VascRISK FACTORS SCORE

Congestive heart failure

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Hypertension 1Age ≥ 75 2Age 65-74 1Diabetes mellitus 1Stroke/TIA/thrombo-embolism 2

Vascular disease 1Sex Female 1

Score

Adjusted stroke rate (%/year) based on CHA2DS2-

VASc Score1 02 1.33 2.24 3.25 4.06 6.77 9.88 9.69 6.7

10 15.2

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HASBLED ScoreCLINICAL CHARACTERISTIC

POINTS

Hypertension 1Abnormal liver function 1

Abnormal renal function

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Stroke 1Bleeding 1Labile INRs 1Elderly (Age >65) 1DrugsAntiplatelet agents or NSAIDs

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Alcohol 1

Anticoagulation and Renal Function for Stroke Indication

Renal Function Warfarin Dabigatran Rivaroxaban Apixaban

Normal/Mild Impairment

Dose adjusted for INR 2.0–3.0

150 mg BID(CrCl >30 mL/min)

20 mg QD with the evening

meal(CrCl >50 mL/min)

5.0 or 2.5 mg BID

Moderate Impairment

Dose adjusted for INR 2.0–3.0

150 mg BID or 75 mg BID§

(CrCl >30 mL/min)

15 mg QD with the evening

meal(CrCl 30–50

mL/min)

5.0 or 2.5 mg BID

Severe Impairment

Dose adjusted for INR 2.0–3.0

75 mg BID(CrCl 15–30

mL/min)

15 mg QD with the evening

meal(CrCl 15–30

mL/min)

No adjustment

Lab Evaluation with Initiation of Anticoagulation� DOACs

� Creatinine at baseline� Warfarin

� Pregnancy at baseline, Hct, PT/INR� Reasonable to assess CBC at initiation of

any anticoagulant as well as renal and liver function.

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Anticoagulation Options� Warfarin – long considered the Gold

Standard� Onset of action = slow� Dosing = variable� Food effect = yes� Medication interaction = many� Therapeutic monitoring required = yes� Offset = long

Anticoagulation Decision� Warfarin

� FDA approved indications� Atrial fibrillation� Venous thromboembolism

� Valve replacement� Myocardial infarction

Anticoagulation Decision� Warfarin

� Safety� Higher risk of intracranial hemorrhage than

direct oral anticoagulants (DOACs)� Initial parenteral therapy needed = yes

� Time to peak effect = 4-5 days

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Anticoagulation Decision� Apixaban (Eliquis)

� Basic characteristics shared by all DOACs� Onset = rapid� Dosing = fixed� Food effect = none known except

rivaroxaban to be taken with largest meal� Medication interaction = few� Therapeutic monitoring = no� Offset = Shorter

Anticoagulation Decision� Apixaban (Eliquis)

� FDA Indications� Non valvular atrial fibrillation� VTE

� Treatment� Secondary prevention� prophylaxis

Anticoagulation Decision� Apixaban (Eliquis)

� Safety� Lower risk of major bleeding than warfarin� Reduced all-cause mortality compared to

warfarin� Initial parenteral therapy = no

� Time to peak effect = 1-2 hours

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Anticoagulation Decision� Apixaban (Eliquis)

� What about her renal disease?� DOACs are cleared via renal by varying

degrees.� Apixaban 25% renal clearance.

� Approved for use in renal patients with mild to severe disease.

� Warfarin is not cleared via renal, it is metabolized in the liver.

Case 2� 71 y.o. female with diabetes, atrial

fibrillation, HTN and cardiomyopathy� Medications

� alendronate 70 mg weekly, Eliquis 5 mg BID, levothyroxine 88 mcg, Lisinopril 10 mg daily, metoprolol succinate 50 mg daily, ranitidine 150 mg daily, spironolactone 25 mg daily

� Admitted to ER post MVA with bleeding; multiple fractures requiring surgery.

Lab glucose 500 Highurea nitrogen (BUN) 29 highcreatinine 1.77 higheGFR non-afr.american

25 low

eGFR african american 34 low

sodium 134 lowpotassium 4.9 normalchloride 101 normalalkaline phosphatase 77 normal

AST 20 normalALT 10 normal

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Lab white blood cell count 11.0 normal

red blood cell count 4.25 normal

hemoglobin 9.2 low

hematocrit 32.0 low

MCV 93.7 normal

MCH 32.1 normal

MCHC 34.3 normal

RDW 14.5 normal

platelet count 212 normal

MPV 9.1 normal

Bleeding Management� apixaban, rivaroxaban or edoxaban

� Minor bleeding� Hold dose until bleeding controlled� Local measures

� Major bleeding� Activated charcoal of dose < 2 hours ago� ANDEXXA (for apixaban or rivaroxaban)

Bleeding Management� Half life of DOACs

� Dabigatran = 14-17 hours� Rivaroxaban = 7-11 hours� Edoxaban = 9-11 hours� Apixaban = 10-14 hours

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ANDEXXA (coagulation factor Xa(recombinant), inactivated-zhzo) � Coagulation factor Xa (recombinant),

inactivated-zhzo exerts its procoagulanteffect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban.

� Onset of action:� Rapid with bolus

� Approved May 2018 � FDA accelerated approval� Quantities are limited, not readily available

coagulation factor Xa(recombinant), inactivated-zhzo� Thromboembolic and ischemic risk

� 18% (median time of first event = 6 days)� DVT, PE, shock, stroke

� 14% deaths by day 30� Intracranial bleed� GI bleed� Other bleeding

coagulation factor Xa(recombinant), inactivated-zhzo

Dose Initial IV Bolus Follow-On IV Infusion

Low Dose 400 mg at a target rate of 30 mg/min

4 mg/min for up to 120 minutes

High 800 mg at a target rate of 30 mg/min

Dose 8 mg/min for up to 120 minutes

Prescribing information: Portola Pharmaceuticals, Inc. 2017

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Dose Based on Rivaroxaban or Apixaban

FXa Inhibitor ≥ 8 Hours

FXa Inhibitor Last Dose

< 8 Hours or Unknown

≥ 8 Hours

Apixaban ≤ 5 mg Low DoseLow Dose

Apixaban > 5 mg / Unknown High Dose

Rivaroxaban ≤ 10 mg Low Dose

Rivaroxaban > 10 mg / Unknown High Dose

Prescribing information: Portola Pharmaceuticals, Inc. 2017

Restarting anticoagulation� Restart appropriate anticoagulation as

soon as bleeding risk allows� Which medication will you choose?

Questions� How does this reversal agent vary from

treating bleeding while on warfarin?� Why was the mortality high in the study?� How do you weigh the risk of urgent

treatment vs the risk of bleeding?� …..

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Case 3� 65 y.o. male admitted for left total hip

replacement� Discharged home on rivaroxaban 10 mg

daily� Returns to the ER 48 hours post discharge

with chest pain and shortness of breath.

ECG

LAB/Radiology� CBC = mild reduction in Hgb/HCT� CMP = normal renal function, electrolytes

and liver function� D dimer = elevated� CTA chest = PE left upper lobe� Venous ultrasound = VTE left femoral vein

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Treatment Decisions� PE is the cause of over 100,00 deaths

annually� Anticoagulation – which agent?

� Continue rivaroxaban? � Did he fail?

� What about risk of bleeding?� Is bridging needed?� PE dose 15 mg BID for 21 days then 20 mg

daily for 6 months

Treatment Decisions� Anticoagulation – which agent?

� Unfractionated heparin vs. low molecular weight heparin?

� Warfarin� What initial dose?� Bridging� Patient education� Outpatient management

Treatment Decisions� Duration of anticoagulation?

� Previous PE/DVT?� Minimum of 6 months…

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Case 4� 83 year old male with new onset atrial

fibrillation� Previous failure with warfarin for history of

DVT

� Lab work shows mild iron deficient anemia� Liver function – WNL� Renal Function CrCl 1.7

What else do you need to know?� Weight – 150 lbs� No fall history� No bleeding history� Recent colonoscopy – negative� Reluctant to start anticoagulation� Valvular heart disease?

Considerations� Nonvalvular atrial fibrillation definition

� Mitral stenosis or artificial heart valves� Review of the ORBIT-AF registry

� 5210 patients at 155 sites� 59% of the measured INRs were between

2.0-3.0; time in therapeutic range (TTR)

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DOAC Medications� Dabigatran (Pradaxa) 75 mg, 110, mg,

150 mg� Indications: stroke prophylaxis, DVT/PE

(recurrent, prophy, treatment)� Renal dosing

� Rivaroxaban (Xarelto) 2.5 mg, 10 mg, 15 mg, 20 mg

� Indications: Indications: stroke prophylaxis, DVT/PE (recurrent, prophy, treatment), CV risk reduction

� Renal and hepatic dosing

DOAC Medications� Apixaban (Eliquis) 2.5 mg, 5 mg.

� Indications: stroke prophylaxis, DVT/PE (recurrent, prophy, treatment)

� Renal Dose: can be used with dialysis� Hepatic Dose: Avoid with Child-Pugh Class

C (Class B: not defined)

DOAC Medications� Betrixaban (Bevyxxa) 40 mg; 80 mg

� Indications: VTE prophylaxis� Adjust dose for CrCl 10-30

� Edoxaban (Savaysa) 15 mg; 30 mg; 60 mg� Indications: VTE prophylaxis and DVT/PE

treatment� Renal dosing and hepatic dosing guidelines

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Considerations� Apixaban has no reduction in dose for

renal disease� Reduce dose to 2.5 mg BID if 2 of the

following� Older than 80 years, less than 60 kg or

serum creatinine equal to or greater than than 1.5 mg/dl

Alternative to Anticoagulation in Atrial Fibrillation� Left atrial appendage exclusion

� Recommended for AC prior and post procedure until occlusion of the appendage is verified.

� Antiplatelet medication is used post AC for several weeks.

DOAC vs Vitamin K Antagonist (VKA)Advantages Disadvantages

No routine monitoring No reliable, readily available measurement assay

Improved safety profile Dose reduction or avoidance in renal impairment and avoidance in moderate or severe hepatic impairment

Rapid onset

Short half-life (advantageous for invasive procedures or in the setting of active bleed)

Short half-life (mandates strict adherence)

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Advantages Disadvantages

Fixed dosing Less flexibility in dosing

Greater convenience, patient satisfaction and quality of life

Contraindicated in mechanical valve replacement. Increasing number of studies/use.

Potentially more cost-effective from health system perspective

Potentially higher drug acquisition costs for patients

Fewer drug, disease and diet interactions

DOAC drug interactions do exist that may preclude use

DOAC vs Vitamin K Antagonist (VKA)

Considerations� Rivaroxaban: avoid using in patients with

Cr/Cl < 30mL/min� No DOAC is indicated during pregnancy,

lactation or in under 18 years old.

Considerations� Small studies of the use of apixaban or

rivaroxaban show these are attractive options for the treatment of heparin induced thrombocytopenia (HIT).

� Antiphospholipid syndrome (APS)� DOAC’s are to be avoided; warfarin is

recommended.

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ConsiderationsSWITCHING TO DOAC

FROM WARFARIN Stop warfarin and start DOAC when INR is <3.0

FROM UNFRACTIONATED HEPARIN Stop the infusion and start rivaroxaban at the

same time

FROM LOW MOLECULAR WEIGHT HEPARIN/FONDAPARINUX

Start DOAC 0 to 2 hours prior to the next

scheduled evening administration of the other anticoagulant

SWITCHING FROM DOACTO WARFARIN One approach is to stop DOAC and start

parenteral anticoagulant and warfarin at time of next scheduled rivaroxaban doseOr start warfarin and stop DOAC 3 days later.

TO PARENTERAL ANTICOAGULANT Stop DOAC and start first dose of parenteral anticoagulant when the next dose of DOAC would have been given

ONE DOAC TO ANOTHER DOAC Stop initial DOAC and begin the other agent at the time of the next scheduled dose.

Ongoing Evaluation� Anticoagulation routine lab evaluation

� CBC, Liver and Renal � When indicated by patient status or every

6-12 months� Medication adherence� Bleeding risk/fall risk� End of life considerations

References/Resources� Acute Management of Pulmonary Embolism. Oct 24,

2017 Vikas Aggarwal, MBBS, MPH , FACC; Charles D Nicolais, MD; Aaron Lee, MD; Dr. Riyaz Bashir, MBBS, FACC

� https://acforum-excellence.org/Resource-Center/Anticoagulation Forum and Anticoagulation Centers of Excellence

� Patient’s time in therapeutic range on warfarin among US patients with atrial fibrillation: Results fro ORBIT-AF registry. Sean D. Pokorney, MD MBA; et al. Americal Heart Journal, July 2015

� Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review Theodore E. Warkentin, Menaka Pai, and Lori-Ann Linkins. Blood August 2017

� Prescribing information from each of the drugs

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Questions?� Thank you!