Comparative Pharmacology of NOACs (DOACs)

Comparative Pharmacology of NOACs (DOACs)

Non–vitamin K oral anticoagulants (NOACs), also called direct oral anticoagulants (DOACs), include:

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

They differ in mechanism, pharmacokinetics, renal dependence, drug interactions, and reversal strategies.

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1. Mechanism of Action

Drug Target Site in Coagulation Cascade

Dabigatran Direct Thrombin (Factor IIa) inhibitor Final step – prevents fibrin formation

Rivaroxaban Direct Factor Xa inhibitor Blocks conversion of prothrombin → thrombin

Apixaban Direct Factor Xa inhibitor Same

Edoxaban Direct Factor Xa inhibitor Same

Key distinction:

Dabigatran → Thrombin inhibitor

Others → Factor Xa inhibitors

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2. Pharmacokinetics Comparison

Parameter Dabigatran Rivaroxaban Apixaban Edoxaban

Bioavailability 6–7% 80–100% (10 mg) ~50% ~62%

Tmax 1–3 h 2–4 h 3–4 h 1–2 h

Half-life 12–17 h 5–13 h 8–15 h 10–14 h

Dosing BID OD (or BID ACS) BID OD

Food effect No major Required for 15/20 mg No No

Clinical pearl:

Rivaroxaban 15–20 mg must be taken with food to optimize absorption.

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3. Renal Elimination

Drug % Renal Clearance Renal Dependence

Dabigatran ~80% Highest

Edoxaban ~50% Moderate

Rivaroxaban ~33% Moderate

Apixaban ~27% Lowest

Practical implication:

Apixaban preferred in CKD.

Dabigatran avoided in severe renal failure.

Edoxaban less effective if CrCl >95 mL/min (NVAF).

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4. Hepatic Metabolism

Rivaroxaban, Apixaban → CYP3A4 metabolism

Edoxaban → Minimal CYP involvement

Dabigatran → No CYP metabolism (P-gp substrate)

Drug interaction risk highest with:

Strong CYP3A4 inhibitors/inducers (azoles, rifampin, protease inhibitors)

P-gp inhibitors (verapamil, amiodarone)

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5. Protein Binding

Drug Protein Binding

Dabigatran ~35%

Rivaroxaban ~95%

Apixaban ~87%

Edoxaban ~55%

Clinical relevance:

Highly protein-bound drugs are not dialyzable.

Dabigatran (low binding) can be dialyzed.

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6. Monitoring Effects on Coagulation Tests

Drug PT aPTT Anti-Xa

Dabigatran Variable Prolonged No

Rivaroxaban Prolonged Mild Yes

Apixaban Minimal PT effect Minimal Yes

Edoxaban Mild PT Mild Yes

No routine monitoring required.

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7. Reversal Agents

Drug Reversal

Dabigatran Idarucizumab

Rivaroxaban 

Apixaban → Andexanet alfa

Edoxaban 

If unavailable → 4-factor PCC.

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8. Bleeding Profile Differences

All reduce ICH compared to warfarin.

Relative GI bleeding risk:

Higher: Dabigatran (150 mg), Rivaroxaban

Lower: Apixaban (best GI safety profile)

Apixaban consistently shows lowest major bleeding in real-world data.

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9. Dosing Convenience

Once daily: Rivaroxaban, Edoxaban

Twice daily: Dabigatran, Apixaban

BID dosing may provide steadier anticoagulation levels.

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10. Special Clinical Considerations

Mechanical valves

Contraindicated (dabigatran trial showed harm).

Obesity

Standard dosing up to BMI 40; beyond that limited data.

Cancer-associated thrombosis

Factor Xa inhibitors preferred (apixaban often favored).

Elderly

Apixaban preferred due to bleeding profile.

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Summary Table

Feature Dabigatran Rivaroxaban Apixaban Edoxaban

Class IIa inhibitor Xa inhibitor Xa inhibitor Xa inhibitor

Renal dependence Highest Moderate Lowest Moderate

Dialyzable Yes No No No

GI bleeding Higher Higher Lower Moderate

Dosing BID OD BID OD

Best in CKD No Caution Yes Caution

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High-Yield Exam Pearls

Dabigatran → Only direct thrombin inhibitor

Apixaban → Safest bleeding profile

Rivaroxaban → Must take with food (15–20 mg)

Dabigatran → Dialyzable

Edoxaban → Avoid if CrCl >95 in AF