3 - Anticoagulation: Focus on Oral Therapy

What are the main indications for antithrombotic drugs?

Treat/prevent venous thromboembolism (VTE) → DVT, PE, thrombophilias.

Prevent arterial thrombosis and stroke → atrial fibrillation/flutter, mechanical heart valves, and other conditions

What is venous thromboembolism (VTE)?

Decreased self-regulation of the clotting cascade increases clot formation

Blood flow becomes impaired, which can lead to DVT or PE

What is Virchow’s Triad?

Changes in any of three factors increase the risk of thrombosis:

• Hypercoagulability → increased tendency to form abnormal blood clots

• Hemodynamic changes/stasis

• Endothelial injury

Persistent risk factors for VTE?

Active cancer

Thrombophilias

Long-term immobility

Minor risk factors for VTE within 2 months of diagnosis?

General anesthesia <30 min

Hospital admission <3 days with acute illness

Bed confinement >3 days with acute illness

Prolonged car or air travel

Estrogen therapy, pregnancy, or puerperium

Leg injury with reduced mobility ≥3 days

Major risk factors VTE risk factors present within 3 months of diagnosis?

Surgery with general anesthesia >30 min

Hospital bed confinement with only “bathroom privileges” >3 days with acute illness

Cesarean section

Major trauma

What are the preferred treatments for VTE?

DOACs are preferred!!!

Rivaroxaban or apixaban → used alone

Dabigatran or edoxaban → used after 5–10 days of parenteral therapy

How is warfarin used to treat VTE?

Goal INR → 2.0–3.0

Use with LMWH/heparin for >5 days

What is the duration of initial treatment of VTE?

At least 3-6 months

Provoked by major / minor transient risk factors

When is extended/indefinite VTE therapy recommended after 3–6 months?

Ongoing permanent risk factors

Unprovoked VTE with no reversible risk factors

Recurrent VTE episodes

Based on bleeding risk

What is the role of warfarin in treating thrombophilias?

Preferred over DOACs for → antiphospholipid antibody syndrome (APS)

May be an option for all thrombophilias

INR goal is indication-specific, usually 2.0–3.0

What is the role of DOACs in treating thrombophilias?

No official guideline recommendations for thrombophilias

May have a role in treating most thrombophilias

NOT recommended for APS!!!!

Why does atrial fibrillation (AF) increase stroke risk?

Irregular atrial contraction causes blood pooling

Blood pooling can cause clot formation, which can embolize and cause a stroke

Artial fibrilation?

Most common cardiac rhythm disorder

Risk increases with age, especially >60 years

About 10% prevalence in people >80 years

Uncommon if <50 years.

More common in men than women

How is stroke risk assessed in atrial fibrillation/flutter?

Afib/flutter increases risk for stroke

Oral anticoagulation is used for stroke prevention

DOACs preferred unless moderate to severe mitral stenosis or mechanical heart valve

If warfarin used → range 2-3

CHA2DS2-VASc?

CHA2DS2-VASc is used to assess stroke risk

Low <1%/year → no anticoag → 0

Intermediate 1-2%/year → anticoag is reasonable, reevaluate need/choice periodically → 1 men, 2 women

High >2%/year → Indefinite anticoag is recommended → >2 men, >3 women

What are the two types of prosthetic heart valves?

Mechanical

Bioprosthetic

How do mechanical and bioprosthetic valves differ?

Mechanical → more thrombogenic, durable, last 20–30 years, require lifelong warfarin

Bioprosthetic → lower thrombogenicity, limited lifespan; 10–30% fail within 10–15 years

Mechanical and bioprosthetic valves preferences?

Mechanical valves are → generally preferred in younger patients who can take lifelong warfarin

Bioprosthetic valves are → generally preferred in older patients or those unable to take lifelong anticoagulants

Anticoag for heart valve replacement?

Mechanical → require lifelong warfarin

Bioprosthetic → 3-6 months aspirin 75-100mg/d OR warfarin (INR 2.5)

Never DOACs

Which heart valve position has a higher risk of thrombosis?

Mitral valves have a higher risk of thrombosis than aortic valves

Mechanical

Aortic mechanical valve with no other risk factors?

Duration of Warfarin → Indefinite

INR Range → 2-3

Aortic mechanical valve with risk factors?

Duration of Warfarin → Indefinite

INR Range → 2.5 - 3.5

Mitral mechanical valve?

Duration of Warfarin → Indefinite

INR Range → 2.5 - 3.5

On-X aortic mechanical valve?

Duration of Warfarin → Indefinite

3 months → 2-3 and ASA 81 mg

Ongoing → 1.5 - 2 and ASA 81 mg if no other risk factors

When should aspirin be added to warfarin for a mechanical mitral valve?

If there is another indication for aspirin AND bleeding risk is low

Consider adding aspirin 75–100 mg/day to warfarin

What are the key treatment principles for DVT/PE?

DOACs are preferred

If using warfarin → INR 2.0–3.0

Treatment lasts at least 3 months

Extended therapy may be needed depending on whether the VTE was unprovoked or caused by persistent/transient risk factors

When is anticoagulation recommended for AFib/flutter?

Recommended if CHA2DS2-VASc → >2 in men or >3 in women

DOACs are preferred unless mechanical heart valve or mitral stenosis

If using warfarin → INR 2.0–3.0 and maintain TTR >70%

What is the anticoagulation treatment for mechanical heart valves?

Warfarin ONLY

INR depends on valve position and risk factors

Aortic valve without risk factors → 2.0–3.0

Mitral valve or aortic valve with risk factors → 2.5–3.5

Duration → indefinitely

How does warfarin work?

Interferes with conversion of vitamin K.

Decreases production of vitamin K-dependent clotting factors II, VII, IX, and X.

Also decreases protein C and S

Indications of warfarin?

Effective for numerous anticoagulation indications

Universal anticoagulant for ALL indications and ages even if not labeled for use

Challenging to manage because it requires monitoring and dose adjustments

Brand names of warfarin?

Jantoven

Used to be called coumadin

Pharmacologic properties of warfarin?

Racemic mixture of 2 enantiomers: (S)- and (R)-warfarin.

(S)-warfarin is → 3x more potent than (R)-warfarin

Nearly 100% oral bioavailability

99% protein bound

How is warfarin metabolized?

Metabolized by CYP450 enzymes.

(S)-warfarin → CYP2C9 and CYP3A4

(R)-warfarin → CYP1A2 and CYP3A4

Extensive drug interactions can occur

Eliminated primarily through urinary excretion

How does dabigatran work?

Directly inhibits thrombin (Factor IIa)

Inhibits both clot-bound and circulating thrombin

Prodrug → dabigatran etexilate is converted to dabigatran by plasma esterases

What are the indications for dabigatran?

Stroke and systemic embolism prevention in non-valvular AF

Treatment and prevention of recurrent DVT/PE in adults and pediatric patients 8–17 years

VTE prevention after total hip replacement surgery

How does apixaban work?

Oral, direct selective Factor Xa inhibitor

What are the indications for apixaban?

Stroke and systemic embolism prevention in non-valvular AF

Treatment of DVT and PE

Reduces recurrence of DVT and PE after >6 months of therapy

VTE prevention after total hip or knee replacement surgery

How does rivaroxaban work?

Oral, direct, selective Factor Xa inhibitor

First approved oral Factor Xa inhibitor

What are the indications for rivaroxaban?

Stroke/systemic embolism prevention in non-valvular AF

Treatment of DVT/PE and reduction of recurrence after 6 months → of DVT and PE in adults and PEDs

VTE prevention after total hip or knee replacement

Reduces major cardiovascular events in chronic CAD or PAD when used with aspirin

VTE prophylaxis in acutely ill medical patients at moderate-to-high VTE risk

VTE prophylaxis in PEDs patients after the Fontan procedure

What is the adult VTE treatment regimen for apixaban?

10 mg BID for 7 days.

Then 5 mg BID through 6 months.

Then 2.5 mg BID after 6 months → optional reduced dose

20 - 10 - 5

What is the adult VTE treatment regimen for rivaroxaban?

15 mg BID for 21 days.

Then 20 mg daily through 6 months

Then 10 mg daily after 6 months → optional reduced dose

30 - 20 - 10

What is the adult VTE treatment regimen for dabigatran?

Use a parenteral anticoagulant for 5–10 days first

Then dabigatran 150 mg BID

What are the additional dosing considerations for dabigatran in adult VTE?

Recurrence reduction → 150 mg BID after previous treatment

Other → 75 mg BID with a P-gp inhibitor + CrCl 30–50 mL/min

Renal dosing of dabigatran?

Avoid P-gp inhibitor

Avoid CrCl <30ml/min

What are the additional dosing considerations for apixaban in adult VTE?

Recurrence reduction → 2.5mg BID after >6 months

Other → 2.5 BID if → strong dual P-gp/CYP3A4 inhibitors

Renal dosing of Apixaban?

No dose adjustment !

What are the additional dosing considerations for Rivaroxaban in adult VTE?

Recurrence reduction → 10mg daily with or without food, after 6 months

Renal dosing of Rivaroxaban?

CrCl <15 → AVOID!!

What is dabigatran dosing for AFib?

Normal → 150 mg BID

CrCl 15–30 → 75 mg BID

CrCl <15 or dialysis: Avoid!!

Renal elimination → 80%!!!

What is apixaban dosing for AFib?

Normal → 5 mg BID

2.5 mg BID if ≥2 of the following

• Age >80 years

• Body Weight <60 kg

• SCr >1.5 mg/dL

When administration specifics of Warfarin?

With or without food

Crushing allowed

Generally in evening → for adjusting for INR

When administration specifics of Dabigatran?

With or without food

Swallow WHOLE

MUST be in OG bottle/blister pack

Not in MED BOXES

When administration specifics of Apixaban?

With or without food

When administration specifics of Rivaroxaban?

Afib → evening meal

VTE → with heaviest meal

Crushing allowed

What factors should be considered when choosing an anticoagulant?

Indication

SCr/BUN and CBC

Age

Weight/BMI

Other medications

Dietary intake

Adherence/pill box use

Once vs twice daily dosing

INR control if on warfarin

Cost/insurance

When should anticoagulation be initiated?

Initiate immediately after diagnosis of the indication

What factors should be considered when initiating warfarin?

Previous stable warfarin dose

Age, weight, diet, alcohol

Interacting medications

Baseline INR (usual 0.9–1.1)

Ethnic background

Pharmacogenetic-based dosing

Why is warfarin dosing challenging?

Narrow therapeutic window

Large variability in dose response

No standardized dosing

Multiple factors affect therapy

How quickly does warfarin take effect?

Initial INR effects → 2–7 days

When is a <5 mg warfarin starting dose used?

Consider in patients with increased sensitivity/risk →

Age >60

Debilitated or malnourished

Heart failure or liver disease

Recent major surgery

Interacting medications, such as amiodarone

When is a 5 mg warfarin starting dose used?

Standard starting dose for most patients

When can 10 mg x 2 days be used for warfarin?

May be used in healthy outpatients

10 mg/loading doses are generally not preferred

Rapid decreases in Protein C and S can cause a temporary procoagulant effect

Heparin/LMWH may be discontinued prematurely

How is INR monitored when starting warfarin?

Check INR 2–5 days after starting

Monitor about 2x/week for 1–2 weeks

INR may increase 0.1–0.2/day during the first week

Steady state → about 10–14 days

How often should INR be monitored once warfarin is stable?

Monitor periodically

4 weeks → Stable patients → monitoring can be extended up to 12 weeks if consistently stable for >3–6 months.

<2 weeks → Unstable patients → monitor more frequently after dose changes, abnormal INRs, or other factors

What is the most common adverse effect of warfarin?

Bleeding

Common bleeding sites: nose/pharynx, soft tissue, GI tract, urinary tract, intracranial, and thoracic

Warfarin is the 2nd most common drug implicated in ER visits

What should be assessed when monitoring warfarin therapy?

Current warfarin dose

Missed or extra doses

Changes in vitamin K intake

Alcohol use

Drug interactions

Changes in health: fever, diarrhea, nausea, vomiting

Signs/symptoms of bleeding or thromboembolism

Fall risk

Whether changes are consistent or temporary and when they occurred

What is important about dietary vitamin K when taking warfarin?

Vitamin K diet consistency is key

High vitamin K foods → green leafy vegetables, green tea, canola/soybean oils.

High-vitamin K supplements → SlimFast, Boost, Ensure, enteral nutrition

Also found in multivitamins and Viactiv calcium chews

Consider seasonal changes in produce availability

What can increase INR?

Alcohol binge

Medication changes

Decreased dietary K

Acute illness, persistent fever, and/or diarrhea

Signs of bleeding

Significant weight loss

What can decrease INR?

Missed doses

Medication changes

Increased dietary K

New vitamins, slimfast, boost, ensure, viactiv calcium

Weight gain, increased activity

How is a high INR managed if the patient is NOT bleeding?

Decrease dose 5–15% and/or hold doses

>1 point above range → hold 1 dose

>2 points above range → hold 2 doses

INR >4.5 or bleeding: follow warfarin reversal protocol

Recheck INR in <2 weeks

How is a low INR managed?

Missed dose → give a boost and/or resume normal dose.

Consistent change/unknown cause → increase dose 5–15% and/or give an extra ½ to 1 dose

INR <1.8 → may increase thrombus risk; bridging is generally not advised

Recheck INR in <2 weeks

How is excessive warfarin anticoagulation managed when there is NO bleeding?

INR <4.5 → Omit or lower dose; no change if minimally above range.

INR 4.5–10 → Omit 1–2 doses, then resume at a lower dose when INR is therapeutic. Avoid routine vitamin K

INR >10 → Hold warfarin and give oral vitamin K

Monitor INR more frequently

How is major bleeding managed in a patient taking warfarin?

Hold warfarin

Rapid reversal with 4-factor PCC instead of FFP

Give vitamin K 5–10 mg IV

Evaluate/admit for reversal as necessary

What are the types of warfarin drug interactions?

Pharmacokinetic:

• Absorption: bile acid sequestrants

• Protein binding: valproic acid, phenytoin

• Metabolism: CYP450 induction or inhibition

Pharmacodynamic:

• Changes in clotting factor synthesis/degradation

• Platelet inhibition

Other: antibiotics, herbal/natural products

How does CYP450 induction affect warfarin?

Decreases INR

Induces CYP2C9, which metabolizes (S)-warfarin

Increases warfarin metabolism → decreases INR

After stopping the inducer → INR increases

Onset → gradual, few days to 1–2 weeks

Dissipation → 1–2 weeks

Inducers of CYP2C9 with warfarin?

Rifampin

Nafcillin

Dicloxacillin
Carbamazepine

Phenytoin

Barbiturates

How does CYP450 inhibition affect warfarin?

Increases INR

Inhibits warfarin metabolism → increases INR

CYP2C9 inhibition has the strongest effect

Onset → immediate once sufficient drug levels are reached.

Dissipation depends on the inhibitor's half-life.

More common than induction interactions

Inhibitors of CYP2C9 with warfarin?

TMP-SMX

Metronidazole

Azole antifungals

Amiodarone.

All require an empiric warfarin dose decrease!!!

How do certain drugs affect warfarin by changing clotting factor synthesis or catabolism?

Levothyroxine → Increases catabolism of clotting factors → increases INR

Salicylates (Pepto-Bismol, aspirin >2 g/day) and quinidine → Decrease production of clotting factors → increases INR

Propylthiouracil/methimazole → Decrease thyroid hormone → decrease catabolism of clotting factors → decreases INR

How do drugs that inhibit platelet function affect warfarin therapy?

Increase bleeding risk, especially GI bleeding

Examples → NSAIDs, aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel

Salsalate → Minimal platelet effects and less likely to cause gastric erosions.

Acetaminophen → Preferred analgesic; >2 g/day may affect INR!!

These drugs have no direct effect on INR

How do antibiotics affect warfarin and INR?

Safe → Most penicillins and cephalosporins.

Increase INR → Ciprofloxacin, metronidazole, sulfamethoxazole/trimethoprim

Decrease INR → Dicloxacillin, nafcillin, rifampin

All interfere in some way

How do herbal and natural products affect warfarin therapy?

Increase INR → CBD

Decrease INR → Coenzyme Q-10, St. John’s Wort, green tea

Increase bleeding → Garlic, ginkgo, ginseng

Patients may not report these products, so always ask and investigate

How should warfarin drug interactions be managed?

Educate patients to call when starting or stopping high-risk medications

Take a thorough medication history: prescription, OTC, and herbal products

Avoid interacting drugs when possible

Anticipate INR changes and adjust warfarin dose appropriately

Monitor INR frequently

Check drug interaction sources when unsure

What should patients know about anticoagulant therapy?

Dose, INR, and adherence

Drug interactions

Diet → consistent vitamin K with warfarin; rivaroxaban with food

Limit alcohol

Lab monitoring

Pregnancy risks with warfarin

Report bleeding, thrombosis, illness, or weight changes

Tell all healthcare providers

What are key points about warfarin therapy?

Used for many thrombosis indications

INR range and duration depend on indication

Narrow therapeutic window requires close monitoring

Many factors affect INR and dose

Can be life-saving but dangerous if not monitored

Patient education is key

Which DOACs can be used for VTE in obesity?

Apixaban and rivaroxaban → Safe/effective

Avoid → Dabigatran, edoxaban, betrixaban

After bariatric surgery → Avoid initially; consider after 4 weeks

Which anticoagulant can be used for AF in severe obesity?

BMI >40 → DOACs are reasonable over warfarin

After bariatric surgery → Warfarin may be reasonable due to absorption concerns

Q: What drugs interact with dabigatran?

P-gp inhibitors: decrease dose or avoid

• Dronedarone, oral ketoconazole

P-gp inducers: Avoid

• Rifampin

• Carbamazepine, phenytoin, St. John’s wort

What drugs interact with apixaban and rivaroxaban?

P-gp/CYP3A4 inhibitors: Avoid

• Itraconazole, ketoconazole, ritonavir

P-gp/CYP3A4 inducers: Avoid

• Carbamazepine, phenytoin, rifampin, St. John’s wort

When switching from warfarin to a DOAC, when should the DOAC be started?

Rivaroxaban → Start when INR <3.0

Edoxaban → Start when INR <2.5

Apixaban → Start when INR <2.0

Dabigatran → Start when INR <2.0

What is included in ongoing DOAC management?

Education → Adherence, bleeding, diet (rivaroxaban), stroke/VTE, procedures, reversibility, cost

Follow-up → 2–4 weeks, 3 months, then every 3–6 months (high-risk) or 6–12 months (low-risk)

Monitoring → Renal function, CBC, and LFTs at baseline and periodically/annually