Therapeutics of Venous Thromboembolism

Unfractionated Heparin (UFH) Dosing for VTE Treatment

IV: 80 units/kg IV Bolus, then 18 units/kg/hr continuous infusion

UFH Dosing for VTE Prophylaxis (preventative care)

5000 units SQ Q8H

AKA “Low-dose” UFH (LDUH)

Consider Q12H in certain patients (e.g., <50 kg, dialysis)

No dose adjustment required for renal/hepatic dysfunction

UFH: Monitoring

Efficacy - Continuous infusion (treatment dose) must be monitored and titrated for efficacy

Assess activated partial thromboplastin time (aPTT) or anti-factor Xa (anti-Xa) activity and adjust using weight-based protocol

Aim to achieve targeted therapeutic range in first 24 hours

Safety - Routine complete blood counts (CBC): platelets, hemoglobin (Hgb), and hematocrit (Hct)

UFH: Adverse Effects (AEs)

Bleeding - LDUH: minimal risk, Therapeutic UFH: ≤2%, GI, gingival, epistaxis, bruising

Osteopenia/osteoporosis (long-term use)

Thrombocytopenia - Platelet count <150 x 10³/mm³ , Heparin-associated thrombocytopenia vs. heparin-induced thrombocytopenia (HIT, more serious, requires immediate intervention)

UFH: Contraindications

History of HIT

Hypersensitivity to UFH or pork products

Active bleeding

Reversal of excessive anticoagulation

Discontinue UFH and administer protamine sulfate

Dose: 1 mg per 100 units of UFH received in past 2-3 hours (max: 50 mg)

Given as slow IV infusion over 10-15 min

LMWH: VTE Treatment Dosing (Enoxaparin)

Lovenox

1 mg/kg subcutaneously (SQ) Q12H

CrCl <30 mL/min: 1 mg/kg Q24H

Dose based on actual body weight

LMWH: Dosing (Enoxaparin) for VTE Prophylaxis

40 mg SQ Q24H or 30 mg SQ Q12H

CrCl <30 mL/min: 30 mg Q24H

Avoid in severe renal impairment (CrCl <15 ml/min, dialysis)

No hepatic dose adjustments

LMWH: Monitoring

Efficacy - Routine monitoring not required, Consider checking anti-Xa activity in certain populations (Weight <50 kg or >155 kg, pregnancy, renal insufficiency)

Drawn 4 hours after SQ LMWH dose

Goal depends on indication (treatment vs. prophylaxis)

Safety: Platelets, Hgb, Hct (rarely necessary), Serum creatinine (SCr)

LMWH: ADEs

Bleeding (incidence is ≤ UFH)

Epidural or spinal hematoma

Incidence of HIT and osteoporosis/osteopenia <<< UFH

LMWH Contraindications

History of HIT

Hypersensitivity to LMWH, UFH, or pork products

Active bleeding

LMWH: Reversal

Discontinue LMWH, Administer protamine sulfat

Dose: 1 mg IV per 100 anti-factor Xa units of LMWH dose within the past 8 hours

1 mg enoxaparin = 100 units of anti-factor Xa activity

Therefore, dose is 1 mg protamine per 1 mg enoxaparin

Max single dose of protamine remains 50 mg

Neutralizes only 60-75% LMWH anticoagulant activity

Fondaparinux Dosing for VTE Treatment

Arixtra

Indirect inhibitor of factor Xa

<50 kg → 5 mg SQ Q24H

50-100 kg → 7.5 mg SQ Q24H

>100 kg → 10 mg SQ Q24H

Fondaparinux Dosing for VTE Prophylaxis

2.5 mg SQ Q24H

Fondaparinux Dosing pearls

All indications: contraindicated in CrCl <30 mL/min

VTE prophylaxis: contraindicated in patients <50 kg

No hepatic dose adjustments; use with caution in severe liver impairment

Fondaparinux ADEs

Anemia, thrombocytopenia (mild; not HIT)

Bleeding (similar incidence to heparins)

No FDA-approved reversal agent available; discontinue fondaparinux (half-life 17-21 hours) and consider PCC

Fondaparinux CIs

Hypersensitivity to fondaparinux

Fondaparinux-induced thrombocytopenia

Active bleeding

Patient Education (LMWH/Fondaparinux)

Store prefilled syringes at room temperature

Given as a subcutaneous injection - Do NOT expel air bubble from syringe before injection

Choose and injection site on your abdomen - Clean area with alcohol, Position uncapped syringe at 90º angle and pinch skin, Insert needle and gently but firmly depress plunger, Once entire dose of medication has been injected, remove the needle and dispose of in an appropriate container

Rotate injection sites from side to side; avoid the area around your navel

Warfarin Initial Dosing

Coumadin, Jantoven

Significant inter- and intra-patient variability

5 mg PO daily for first 1-2 days - Then, adjust based on INR

Consider lower starting dose (2-3 mg) in - Elderly (>60), low body weight, heart failure, liver disease malnourishment/low albumin, drug interactions, etc.

10-20% dose reductions may be required in patients with impaired kidney function (eGFR <60), but still safe to use

For treatment of acute VTE, warfarin should be “bridged” with a parenteral anticoagulant

The Warfarin “Bridge”

Administer warfarin, Administer parenteral “bridging” agent (usually LMWH or UFH, at VTE treatment dosing)

Obtain therapeutic maintenance dose of warfarin: Overlap both therapies for ≥5 days, Until INR is therapeutic for ≥24 hours (2 readings)

Discontinue “bridging agent”

Continue warfarin

Warfarin: Therapeutic Monitoring

INR is the preferred monitoring parameter

Assessed at baseline and frequently upon initiation

Inpatient: Check INR on day 3, then every 1-2 days, Target an increase of 0.2-0.3 daily

Outpatient: at least every 3 to 5 days upon initiation

Recheck INR within 7-14 days of any dose adjustment

Once INR stable, can decrease checks to every 4-6 weeks

Warfarin: Goal INR

Low intensity (most indications) - INR 2.5 (range 2.0 – 3.0): Therapeutic range for VTE treatment/prophylaxis, atrial fibrillation, aortic mechanical valve replacement

High intensity - INR 3.0 (range 2.5 – 3.5): Therapeutic range for mitral mechanical valve replacement

Warfarin: Adverse Effects

Minor bleeding: >15% per year

Major bleeding 1-10% per year

Common site: GI

Life-threatening: Intracranial hemorrhage (ICH)

Non-hemorrhagic complications: Rare; present early in therapy, Purple toe syndrome, Warfarin-induced skin necrosis

Warfarin: Contraindications

Hypersensitivity to warfarin

Active bleeding

Pregnancy (teratogenic) - OK during breastfeeding

Unsupervised patients with a high potential for noncompliance

Relative: history of purple toe syndrome or warfarin-induced skin necrosis

Decreased INR

Vitamin K rich foods - Green, leafy vegetables, Green and black non-brewed teas, Enteral/parenteral nutrition

Cigarette smoking (CYP1A2)

Chewing tobacco

Alcohol use (chronic)

Increased INR

Grapefruit juice - High consumption (>24 oz)

Alcohol use (acute)

Warfarin: Drug-Drug Interactions

Increased bleeding risk (no effect on INR): NSAIDs, aspirin, SSRIs, thrombolytics, antiplatelets, “G”-supplements: garlic, ginger, gingko, ginseng, green tea

Displacement of warfarin from albumin - Phenytoin, valproic acid, ethacrynic acid (inc. INR)

Inhibition of absorption - Cholestyramine (dec. INR)

Theoretically, any antibiotic - Decreases vitamin K producing bacteria in GI tract (inc. INR)

Inhibition (“FAB-5” / “BAM-IF”) in Warfarin

Increase in INR

Amiodarone, fluconazole, fluoroquinolones, macrolides, metronidazole, omeprazole, simvastatin, trimethoprim/sulfamethoxazole

Acute alcohol use

Induction

Decrease in INR

Azathioprine, carbamazepine, rifampin, St. John’s Wort, Cigarette smoking, chronic alcohol use

Warfarin: Reversal

Vitamin K: warfarin antagonist

Oral - Preferred route (in absence of major bleeding), Reassess INR in 24-48 hours

Intravenous - Preferred route if urgent reversal needed, active bleeding, Risks: anaphylaxis (administer <1 mg/min), Reassess INR in 6-12 hours

Subcutaneous not recommended (erratic absorption)

High doses (≥10 mg) → prolonged resistance may occur

Warfarin: Patient Education

Written education, Purpose, target, duration, Importance of adherence, Importance of monitoring, Signs/symptoms of bleeding, Signs/symptoms of VTE, Dose and administration, Consistency of manufacturer, Drug-drug interactions - Report ALL new drugs, Drug-disease interactions, Vitamin K foods/sources - Consistency!, Teratogenicity, Medical ID, Warfarin interruption

Warfarin: Tablet Colors

Pink - 1 mg

Lavender - 2 mg

Green - 2.5 mg

Brown - 3 mg

Bring - 4 mg

Pink - 5 mg

Teal - 6 mg

Yellow - 7.5 mg

Wedding - 10 mg

Please Let Georgia Brown Bring Peaches To Your Wedding

Dabigatran VTE Treatment Dose

Pradaxa, Oral direct thrombin inhibitor

150 mg PO BID

Started after 5-10 days of parenteral anticoagulation

Dabigatran Dosing VTE Prophylaxis

total hip arthroplasty only

110 mg PO, given 1-4 hours after surgery, then 220 mg daily

Dabigatran Pearls

Avoid use if CrCl <30 mL/min

Should be swallowed whole; do not crush or chew

Dispense and keep drug in original container

Dabigatran ADEs

Bleeding (especially GI)

Spinal hematoma

Dyspepsia (major)

Dabigatran DDIs

Increased levels with P-glycoprotein (P-gp) inhibitors (e.g., amiodarone)

Decreased levels with P-gp inducers (e.g., rifampin)

Increased bleeding with drugs impacting hemostasis

Dabigatran CI

Hypersensitivity

Active bleeding

Pregnancy (not studied; may cross placenta)

Dabigatran: Reversal

Excessive anticoagulation and/or bleeding - Discontinue dabigatran (t1/2 = 12-17 hours), Hemodialysis may be considered

Idarucizumab [Praxbind] - FDA-approved for the reversal of dabigatran only

Monoclonal antibody fragment; binds to dabigatran and metabolites with high affinity (↑ than affinity for thrombin)

Total dose = 5 g; 2.5 g IV given ≤15 minutes apart

Limited data support a second 5 g dose if bleeding persists

Rivaroxaban Treatment Dose

Xarelto

15 mg PO BID x 21 days, then 20 mg daily

Rivaroxaban Prophylactic dosing

10 mg PO daily

Rivaroxaban Pearls

Avoid if CrCl <30 mL/min

Hepatic: Avoid in moderate to severe liver impairment (Child-Pugh B, C)

Doses ≥15 mg must be taken with food (↑ absorption)

Apixaban Treatment Dose

Eliquis

10 mg PO BID x 7 days, then 5 mg BID

No dosage adjustment is recommended by the manufacturer for any degree of reduced kidney function

Hepatic: use is not recommended in patients with severe liver impairment (Child-Pugh C)

Apixaban Prophylactic dose

2.5 mg PO BID

Edoxaban Treatment dose

Savaysa

after 5-10 days parenteral anticoagulation

60 mg PO daily

30 mg PO daily if CrCl 15-50 mL/min or weight <60 kg

Prophylactic dosing: No approved indication

Renal: Avoid if CrCl <15 or >95 mL/min

Hepatic: Avoid in moderate to severe liver impairment (Child-Pugh B, C)

Factor Xa Inhibitors: ADEs

Bleeding (fewer ICH and fatal bleeding, more GI)

Spinal/epidural hematoma

Factor Xa Inhibitors CIs

Hypersensitivity

Active bleeding

Generally avoided in pregnancy (not well-studied; may cross placenta) and breastfeeding (present in breast milk;manufacturers do not recommend use)

Factor Xa Inhibitors: Drug Interactions

Extensive interactions through CYP3A4 and P-gp

Avoid use with strong 3A4/P-gp inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort)

Varied guidance with strong 3A4/P-gp inhibitors (itraconazole, ritonavir, cobicistat):

Rivaroxaban → avoid

Apixaban, Edoxaban → some data to support dosage reductions for specific indications

Increased bleeding with drugs impacting hemostasis

Factor Xa Inhibitors: Reversal (?)

PCC

Andexanet alfa [Andexxa] withdrawn from market due to safety concerns

DOAC Advantages

- No routine monitoring required

- Improved safety profile

- Rapid onset

- Short half-life (bleeding/reversal)

- Fixed dosing

- Greater patient satisfaction, quality of life

- Fewer drug interactions

- Reversal agents now available for most

DOAC Disadvantages

- No reliable, readily-available therapeutic assay

- Dose reduction or avoidance in renal/hepatic impairment

- Short half-lives (adherence)

- Less flexibility in dosing

- Fewer studies and approved indications

- Higher drug acquisition costs

- Drug interactions exist that may preclude use

Good candidates for DOACs

Patient preference and/or willingness to take

No contraindications

Relatively preserved/stable organ function

No significant drug-drug interactions

Highly likely to be adherent

Ability to afford DOAC on chronic basis (insurance?manufacturer’s coupons?)

Unable/unwilling to obtain routine INR monitoring

Good candidates for warfarin:

Preference for and willingness to take

Ability/willingness to obtain routine INR monitoring

History of poor medication adherence?

Severe renal and/or hepatic impairment

Cannot afford DOACs

Inability to avoid significant drug interactions with DOACs