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Management of Anticoagulation
 Review of disease states and treatment guidelines most commonly encountered in outpatient AC management
 Review of LMWH and warfarin in the treatment of VTE and AF
 Discuss when bridging of anticoagulation is recommended
 Review DOACs and their differences
VTE
Venous Thromboembolism (VTE)
 Includes deep vein thrombosis (DVT) and pulmonary embolism (PE) DVT PE
 Virchow’s Triad: hypercoagulability, vessel wall injury, and circulatory
stasis
o These factors contribute to causation of thrombosis
o Many risk factors fall into this triad, including:

Hypercoagulability: malignancy, pregnancy/post-partum,

drug (hormone) therapy, antiphospholipid
antibody syndrome, Factor V Leiden thrombophilia,
protein C or S deficiency

Vessel wall injury: joint replacement surgery, trauma/fractures,

venous catheters

Circulatory stasis: CHF, major surgery (within 12 weeks),

paralysis, obesity, varicose veins

 Other risks include age and previous history of DVT

DVT PE

Signs and Symptoms

swelling/edema pain/tenderness dyspnea/tachypnea chest pain
erythema palpable cord hypoxia hemoptysis
Treatment Duration
First Episode of VTE VTE with malignancy
 Provoked: 3 months  First occurrence: 3 to 6 months, indefinitely with
 Unprovoked: 3 months to indefinitely active cancer*
 Recurrent VTE: indefinitely  Recurrent VTE: indefinitely
*
cancer diagnosed and/or treated within six months, or hematologic
cancer not in remission

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Atrial Fibrillation (AF)

 Stasis or turbulence of blood flow within the left atrium leads to thrombus formation
- Some evidence of hypercoagulability in AF, though mechanism is unknown (possibly
inflammatory process)
- Conversion to normal sinus rhythm (NSR) can lead to dislodging of existing thrombus in the left
atrium
- Left atrial appendage may contribute to stasis.
 Most frequent thromboembolic complication is stroke, though systemic embolization can occur
(<10%)
- Anticoagulation has been shown to lower thromboembolism risk in both paroxysmal and
chronic AF over antiplatelet therapy
- The most widely used risk prediction model is the CHA 2DS2-VASc as it better stratifies low-risk patients

CHADS2-VASc Score Anticoagulation therapy

0 – male - No therapy necessary
- OR -
1 – female
1 -male - No anticoagulation may be considered
(moderate risk of CVA) - Second line: ASA 75-325mg PLUS clopidogrel
2+ (high risk of CVA) - Oral anticoagulation*
*
In patients unsuitable for anticoagulation, ASA PLUS clopidogrel is always preferred over ASA alone

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Antithrombotic Agents

Signs and Symptoms of bleeding

headache
stiff neck
confusion
stroke symptoms
lightheadedness
SOB
low BP
blood in urine/stool
abdominal cramps
Suggested lifestyle modifications:
VKAs Factor Xa inhibitors get active
warfarin apixaban, rivaroxaban, edoxaban control cholesterol
improve diet
-manage BP
LMWH -lose weight
Direct thrombin inhibitors -reduce blood sugars
enoxaparin dabigitran -smoking cessation

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Low molecular weight heparin (LMWH): Enoxaparin

 Indirectly inhibits Factors Xa and IIa by binding to and increasing the potency of antithrombin III
 Provides a more predictable anticoagulation response compared to unfractionated heparin (UFH)

Administration Subcutaneous injection

Dosing Prophylaxis
- 30mg BID OR 40mg daily
- Renal dosing (CrCl < 30ml/min): 30mg daily
Treatment
- 1mg/kg BID OR 1.5mg/kg daily (ABW)
- Renal dosing (CrCl < 30ml/min): 1mg/kg daily
Monitoring - CBC, SCr
- Anti-Xa activity (pregnancy, obesity, weight <50kg, renal insufficiency, high TE risk surgery)
Use in therapy - Initial DVT/PE treatment prior to initiation of oral anticoagulation
- Preferred anticoagulant during pregnancy
- Bridging therapy
Contraindications - Active major bleeding
- H/o HIT, 100% cross reactivity to heparin antibodies

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Vitamin K Antagonist (VKA): Warfarin

 Prevents initial formation and propagation of thrombus by suppressing the production of vitamin K dependent clotting factors
 Has no direct effect on previously formed thrombi
 Time required to achieve pharmacologic effect depends on the half-life of existing, circulating clotting factors
 Dosing requirements vary between individuals due to genetic variations in
hepatic metabolism of warfarin, though many factors play a role in determining Clotting Factors Half-Life (hr)
an individual’s warfarin sensitivity: II 42-72
- Elevated baseline INR - Hyper-/hypothyroidism VII 4-6
- Hepatic disease - Malnutrition/diet IX 21-30
- Heart failure/fluid status - Alcohol use (acute vs. chronic) X 27-48
- Illness/fever/diarrhea - Drug interactions Protein C 9
Protein S 60

Administration Oral tablet (1mg, 2mg, 2.5mg, 3mg, 4mg, 5mg, 6mg, 7.5mg, 10mg)

Dosing Initiation
- For acute VTE, start on day 1 or 2 of LMWH/UFH therapy to allow time for therapeutic
response
- 5 to 10 mg daily
- CHEST guidelines suggest initiation with 10mg daily for 2 days in patients deemed
sufficiently healthy to be treated outpatient
- Lower starting doses may be considered for patients expected to be more sensitive to
warfarin (age >75y, malnutrition, hepatic disease, CHF, ESRD, hyperthyroid, acute illness,
existing drug interactions)
- INR should be monitored every 2 to 3 days during initiation, and less frequently as stable
response to a dose is achieved

Maintenance
- After initial 2 days of therapy dosing should be based on INR response
- INR should be monitored weekly to monthly, depending on stability (up to 12 weeks for
very stable patients)
- Dosing algorithms help standardize practice, provide guidance to new practitioners, and
can increase time in therapeutic range (%TTR)
- Helpful to dose in terms of total weekly dose (TWD)
Monitoring - INR as often as needed to guide dosing
- Target range 2-3 for most indications
- Target range 2.5-3.5 in mechanical heart valves
- CBC
Use in therapy - “Gold standard” of oral anticoagulants
- Valvular AF (AF plus mitral valve stenosis or mechanical valves) and antiphospholipid
syndrome
- Can be used in patients with renal insufficiency who cannot use other agents
Contraindications - Active major bleeding
- Malignant hypertension
- Pregnancy
- Unsupervised/non-compliant patients

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Warfarin dosing algorithm (follow your own hospital’s protocol):

Goal of INR 2.0-3.0

INR Action Follow-Up
≤1.5 Increase weekly dose by 10-15% Repeat INR in 7-10 days
1.51-1.79 If falling or low on two or more occasions, increase Repeat INR in 10-14 days
weekly dose by 5-10%
1.80-1.99 Consider not changing the dose unless a consistent Repeat INR in 14-21 days
pattern has been observed
2.00-3.00 Follow-up within 28 days
(in range) No change in dose If INR in-range 3x consecutively,
follow-up within 42 days
3.01-3.20 Consider not changing the dose unless a consistent Repeat INR in 14-21 days
pattern has been observed
3.21-3.69 Do not hold warfarin; if rising or high on two or more Repeat INR in 10-14 days
occasions, decrease weekly dose by 5-10%
3.70-4.99 Hold for 1 day and decrease weekly dose by 5-10% Repeat INR in 7-14 days
5.00-9.99 Hold warfarin; when INR is therapeutic, restart at lower Check INR in 2-7 days. Check INR at
dose (decrease weekly dose by 10-15%) least weekly until stable
≥10.0 Hold warfarin and give oral vitamin K (2.5mg) Check INR at least weekly until
(without bleeding) stable
Serious bleeding Hold warfarin and refer patient to emergency
(regardless of INR) department immediately

Note: Consider no dose adjustment for patients previously stable who present with a single out of range INR ≤0.5

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Drug interactions with warfarin:

Anticoagulation is enhanced Anticoagulation is inhibited

(Increase INR) (Decrease INR)
Metabolic interactions (CYP) amiodarone carbamazepine
propafenone rifampin
simvastatin phenobarbital
disulfiram primidone
capecitabine
tamoxifen
cimetidine
proton pump inhibitors

azole antifungals
metronidazole
sulfamethoxazole/trimethoprim
macrolide antibiotics
fluoroquinolones
doxycycline
Protein binding gemfibrozil
fenofibrate
corticosteroids

Clearance/metabolism of levothyroxine
clotting factors
Absorption inhibitors cholestyramine
colestipol
sucralfate
Others acetaminophen (>1.5g/day) MVI containing VitK

Increased bleeding risk

(no effect on INR)
Platelet inhibitors ASA, NSAIDs, clopidogrel, ASA/dipyridamole (Aggrenox), bismuth, salicylates

Dietary and herbal interactions with warfarin

 Foods that can increase INR: grapefruit, cranberries, black licorice, energy drinks
 Foods high in vitamin K will decrease the INR

Vitmain K Foods (per 3.5oz serving)

content
Very high brussels sprouts, collard greens, kale, spinach,
liver, green tea
High broccoli, coleslaw, canola oil, soybean oil,
cucumber peel, basil
Medium cabbage, mayonnaise, summer squash,
asparagus
Low Avocado, beans, celery, iceberg lettuce

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Periprocedural management of warfarin therapy

 If a surgery or procedure requires that anticoagulation be held, clinical decision must be made whether or not to bridge
 For patients taking warfarin for the treatment VTE, the decision to bridge with LMWH depends on how recent or remote VTE
was, and risk factors that increase the risk of acute TE
- Bridging should be pursued for recent VTE within 3 months or isolated/recurrent VTE in the setting of thrombophilia
- Bridging could be considered in the settings of VTE within the last year
- Bridging should not be used when VTE >12 months ago and patient has no other risk factors for developing acute TE
 For most patients taking warfarin for AF, data increasingly supports NOT bridging with LMWH
- BRIDGE trial (2015) found that bridging warfarin therapy with LMWH in the setting of AF increased the risk of major
bleeding vs. no bridging.
- Found that perioperative interruption of warfarin therapy without bridging was non-inferior to bridging in preventing
acute TE
 Bridging therapy in AF should be reserved for patients considered HIGH risk of acute TE
- Presence of mechanical heart valve, recent cardioversion (within one month), recent CVA (3-6 months)

 If NOT bridging, warfarin should be stopped 5 days prior to the procedure date and may typically be resumed 24
hours post procedure (surgeon or provider may opt for longer based on inherent bleed risk or outcome of
procedure)

 Typically, appropriate to resume at patients previous stable dose, though may consider a loading dose for 2 days
to decrease the time needed to return INR to goal range

 When bridging, treatment dose enoxaparin should be initiated when INR is <2 or after omitting 2-3 doses of
warfarin, and continued until the day prior to surgery/procedure

 On the day before the procedure the dose of LMWH should be reduced by 50%
- For enoxaparin 1mg/kg Q12, administer the morning dose only
- For enoxaparin 1.5mg/kg daily, administer half the daily dose in the morning

 LMWH should be resumed 24-72 hours after procedure at surgeon/provider discretion, and discontinued once
warfarin has been resumed and INR is within goal range

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Outpatient Management of Anticoagulation

DOACs: Direct oral anticoagulants
 Approved indications for treatment and prevention of VTE, as well as non-valvular AF
 Demonstrated superiority or non-inferiority to warfarin in reducing risk of TE with no increase in bleeding risk
 Advantages over warfarin include less frequent monitoring and follow up, quicker onset and offset of therapeutic effects,
and fewer drug and dietary interactions

Two main categories include direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban).

General DOAC counseling:

 ADR of bleeding for all DOACs, counsel on s/sx, lifestyle management
 Stress importance of compliance, suggest/offer pill box (except dabigatran)
 Avoidance of oral NSAIDs, and notify clinic of medication changes
 Notify all providers of anticoagulation, notify clinic prior to any procedures
 Lab monitoring? What are we measuring?

Dabigatran
Dosing VTE treatment VTE secondary prevention
Must be preceded by 5-10 days of 150mg BID
parenteral AC, then 150mg BID CrCl <30m/min: Avoid
CrCl <30m/min: Avoid

Non-valvular AF
150mg BID
CrCl 15-30ml/min:75mg BID
CrCl <15ml/min: avoid
Monitoring CBC, SCr

PK/Metabolism Time to peak effect: 1-2 hours Clearance: 80% renal

ADRs  Dyspepsia, nausea
 Higher rate of GI bleeds, but lower rate of ICH compared to warfarin
 Statistically significant increase in bleed risk at age 80 and older
Drug Interactions  Strong P-gp inducers such as rifampin decrease dabigatran concentrations - AVOID
 P-gp inhibitors (amiodarone, dronedarone, ketoconazole, verapamil) increase dabigatran
concentration
- Consider decreased for dose to 75mg BID for AF if CrCl < 50ml/min
 Antiplatelets, NSAIDs, SSRI, SNRI - increase bleeding risk

Contraindications Active bleeding, mechanical heart valves, severe renal insufficiency or hepatic disease
(Child’s Pugh Class C)
Counseling  Can be taken with or without food, but taking with food can reduce dyspepsia
 Capsules MUST be stored in original container (no pill boxes) and used within 4
months of opening
 Skip a missed dose if it cannot be taken at least 6 hours before the next dose. Do NOT
take 2 doses together

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Outpatient Management of Anticoagulation

Rivaroxaban
Dosing VTE treatment VTE secondary prevention
15mg BID x21d, then 20mg daily with food 10mg daily with food
CrCl <30ml/min: avoid CrCl <30ml/min: avoid

Non-valvular AF
20mg daily with food
CrCl 15-50ml/min: 15mg daily with food
CrCl <15ml/min: avoid
Monitoring CBC, SCr

PK/Metabolism Time to peak effect: 2-3 hours Clearance: 50% renal, some hepatic, 33%
eliminated on-metabolized
ADRs  Nausea, peripheral edema, hypotension, dizziness
 Compared w/warfarin – similar major bleeds, less intracranial, fatal, & critical bleeds,
more GI bleed and transfusions d/t Hgb drop
Drug Interactions  P-gp PLUS strong CYP3A4 inducers decrease effectiveness, AVOID
 P-gp PLUS strong CYP3A4 inhibitors increase effectiveness, AVOID
 Antiplatelets, NSAIDs, SSRI, SNRI – increase bleeding risk
Contraindications Active bleeding, mechanical heart valves, severe hepatic impairment (Child’s Pugh Class
B/C)
Counseling  15mg and 20mg tablets must be taken with food, 10mg tablets can be taken without
 For BID dosing, take missed dose as soon as remembered. CAN take two doses together
to make up a missed dose
 For daily dosing, take missed dose as soon as remembered but DO NOT double up doses

Apixaban
Dosing VTE treatment VTE secondary prevention
10mg BID x7d, then 5mg PO BID 2.5mg BID
CrCl <25ml/min of SCr >2.5: Caution advised CrCl <25ml/min of SCr >2.5: Caution advised

Non-valvular AF
5mg BID
2.5mg BID if ≥ 2 of the following: age ≥80,
weight ≤60kg, SCr ≥1.5
CrCl <25ml/min of SCr >2.5: Caution advised
Monitoring CBC, SCr, LFTs at baseline

PK/Metabolism Time to peak effect: 3-4 hours Clearance: 73% hepatic, 27% renal
ADRs  Thrombocytopenia
Drug Interactions  P-gp PLUS strong CYP3A4 inducers decrease effectiveness, AVOID
 P-gp PLUS strong CYP3A4 inhibitors increase effectiveness, CAUTION and reduce 5mg BID
to 2.5mg BID
 Antiplatelets, NSAIDs, SSRI, SNRI – increase bleeding risk
Contraindications Active bleeding, mechanical heart valves, severe hepatic impairment (Child’s Pugh Class C)
Counseling  Avoid grapefruit juice

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 Take missed dose as soon as remembered, but do not double up doses

Outpatient Management of Anticoagulation

Edoxaban
Dosing VTE treatment VTE secondary prevention
Must be preceded by 5-10 days of Not approved
parenteral AC, then 60mg daily
CrCl 15-50ml/min: 30mg daily

30mg daily if weight ≤60kg or with

P-gp inhibitors

Non-valvular AF
60mg daily
CrCl 15-50ml/min: 30mg daily

DO NOT USE if
Crcl >95ml/min
Monitoring CBC, SCr

PK/Metabolism Time to peak effect: 1-2 hours Clearance: 50% renal, 50% biliary/intestinal
ADRs  Rash, abnormal LFTs
 Compared w/warfarin – less major bleeding, higher risk of major GI bleeding)
Drug Interactions  Strong P-gp inducers such as rifampin will decrease edoxaban efficacy - AVOID
 P-gp inhibitors increase edoxaban efficacy
- Reduce dose to 30 mg daily for VTE
 Antiplatelets, NSAIDs, SSRI, SNRI – increase bleeding risk
Contraindications Active bleeding, mechanical heart valves, severe hepatic impairment (Child’s Pugh Class C)

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Outpatient Management of Anticoagulation

Periprocedural management of DOAC therapy
 Because of the fast onset and offset of DOACs therapeutic effect, bridging is not required
 Recommendations for when to hold doses are based on procedure bleed risk and expected time for drug to clear based on
the patient’s renal function

DOAC Renal function Doses to hold before the day of surgery: Doses to hold before the day of surgery:
Low bleed risk High bleed risk
Dabigatran CrCl > 80ml/min Hold 2 doses Hold 5-6 doses
BID dosing CrCl 50-79ml/min Hold 3-4 doses Hold 6-7 doses
CrCl 30-49ml/min Hold 4-5 doses Hold 7-8 doses
CrCl 15-29ml/min Hold 5-7 doses Hold 9-12 doses
Rivaroxaban CrCl >80ml/min Hold 1 dose Hold 2 doses
One daily dosing CrCl 30-79ml/min Hold 1 dose Hold 2 doses
CrCl 15-29ml/min Hold 1-2 doses Hold 2-3 doses
Apixaban CrCl >50ml/min Hold 2 doses Hold 4 doses
BID dosing CrCl 15-49ml/min Hold 3-4 doses Hold 6-7 doses
Edoxaban CrCl >50ml/min Hold 1 dose Hold 2 doses
Once daily dosing CrCl 30-49ml/min Hold 1 dose Hold 2 doses
CrCl 15-29ml/min Hold 2 doses Hold 3-4 doses

Transitioning between anticoagulants

Warfarin  DOAC
 Discontinue warfarin and initiate DOAC when
- INR <2 when starting dabigatran
- INR <3 when starting rivaroxaban
- INR < 2 when starting apixaban
- INR <2.5 when starting Edoxaban

DOAC  Warfarin
 Dabigatran  Warfarin
- CrCl > 50: start warfarin 3 days before stopping dabigatran
- CrCl 30-50: start warfarin 2 days before stopping dabigatran
- CrCl 15-30: start warfarin 1 day before stopping dabigatran
- Note: Dabigatran can slightly increase INR but INR should be accurate 2 days after stopping dabigatran

 Rivaroxaban or Apixaban  Warfarin

- Can elevate the INR, interpretation of INR during overlap may not be useful
- Start warfarin 2-3 days before stopping rivaroxaban
- May also stop rivaroxaban and start warfarin on the same day and employ LMWH bridging until INR is therapeutic

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Outpatient Management of Anticoagulation

 Edoxaban  Warfarin
- Reduce edoxaban 60mg to 30mg daily and begin warfarin
- Reduce edoxaban 30mg to 15mg daily and begin warfarin
- Discontinue edoxaban once stable INR ≥ 2.0 is achieved
- INR should be measured just prior to the daily dose of edoxaban to minimize DOAC effect on INR

DOAC  DOAC
 Start new DOAC when next dose of previous DOAC is due

LMWH  DOAC
 Start DOAC at the same time the next dose of LMWH would have been given

DOAC  LMWH
 Start LMWH at the same time the next dose of DOAC would have been given

Sources used:
Chen A, Stecker E, Warden BA. Direct Oral Anticoagulant Use: A Practical Guide of Common Clinical Challenges. JAHA 15 Jun 2020.
https://doi.org/10.1161/JAHA.120.017559

Chest Guidelines. CHEST 2012; 141(2)(Suppl):36695-e6905

Burnett AE, Mahan CE, Vasquz SR, etal. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis
(2016) 41:206-232. DOI 10.1007/s11239-015-1310-7

Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp Inc.: 2020 [cited 17 Sept 2020]. Available from: http://online.lexi.com. Subscription required to
view.
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