Newer oral Anticoagulants MOA SIDE EFFECTS USE AND DOSE
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direct oral anticoagulants
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FDA prescribing information Eliquis Xarelto Pradaxa Savaysa adult dosing nonvalvular atrial fibrillation VTE treatment
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https://packageinserts.bms.com/pi/pi_eliquis.pdf
Newer oral anticoagulants
Also called direct oral anticoagulants (DOACs) or NOACs. They have rapid onset, predictable effect, and usually do not need routine INR monitoring.
Drugs and mechanism of action
| Drug | Class | Mechanism |
|---|---|---|
| Dabigatran | Direct thrombin inhibitor | Directly inhibits factor IIa (thrombin), preventing conversion of fibrinogen to fibrin |
| Rivaroxaban | Direct factor Xa inhibitor | Inhibits factor Xa, reducing thrombin generation |
| Apixaban | Direct factor Xa inhibitor | Inhibits factor Xa |
| Edoxaban | Direct factor Xa inhibitor | Inhibits factor Xa |
Key point: Dabigatran inhibits thrombin. The other common DOACs inhibit factor Xa. They have a faster onset and wider therapeutic window than warfarin.
The Washington Manual of Medical Therapeutics, “Anticoagulants, oral.”
The Washington Manual of Medical Therapeutics, “Anticoagulants, oral.”
Uses
- Prevention of ischemic stroke and systemic embolism in non-valvular atrial fibrillation (NVAF)
- Treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE)
- Prevention of recurrent DVT/PE
- Postoperative DVT prophylaxis, especially after hip or knee replacement
- Rivaroxaban: selected patients with coronary artery disease or peripheral artery disease, in combination with aspirin, under specialist direction.
Important situations where DOACs are generally avoided
- Mechanical prosthetic heart valves
- Moderate-to-severe rheumatic mitral stenosis
- Pregnancy and breastfeeding
- Active major bleeding
- Severe renal failure or significant liver disease, depending on the agent
- Antiphospholipid syndrome, particularly triple-positive disease
DOACs cross the placenta and should not be used in pregnancy or nursing mothers.
Braunwald’s Heart Disease, “Direct Oral Anticoagulants.”
Braunwald’s Heart Disease, “Direct Oral Anticoagulants.”
Usual adult doses
Doses must be selected using the indication, age, body weight, renal function, liver function, and interacting drugs. This is a study summary, not an individualized prescription.
| Drug | NVAF | Acute DVT/PE treatment | Extended prevention of recurrent DVT/PE |
|---|---|---|---|
| Dabigatran | 150 mg twice daily in patients with adequate renal function | 150 mg twice daily after 5-10 days of parenteral anticoagulation | 150 mg twice daily |
| Rivaroxaban | 20 mg once daily with evening meal. Reduced dose may be required in renal impairment. | 15 mg twice daily with food for 21 days, then 20 mg once daily with food | 10 mg once daily after at least 6 months of initial treatment |
| Apixaban | 5 mg twice daily. Use 2.5 mg twice daily if at least 2 of 3: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL | 10 mg twice daily for 7 days, then 5 mg twice daily | 2.5 mg twice daily after at least 6 months |
| Edoxaban | 60 mg once daily. Reduce to 30 mg daily in specified renal impairment or body weight ≤60 kg | 60 mg once daily after 5-10 days of parenteral anticoagulation. Reduce to 30 mg daily when indicated. | Same regimen if continued |
For DVT/PE, apixaban and rivaroxaban can be started orally immediately. Dabigatran and edoxaban require initial treatment with heparin or LMWH for 5-10 days.
Harrison’s Principles of Internal Medicine, 22e, “Non-Warfarin Anticoagulation.”
Harrison’s Principles of Internal Medicine, 22e, “Non-Warfarin Anticoagulation.”
The current apixaban prescribing information confirms the 10 mg twice-daily for 7 days, then 5 mg twice-daily DVT/PE regimen. The rivaroxaban FDA label lists 15 mg twice daily for 21 days followed by 20 mg once daily for DVT/PE.
Adverse effects
Common to all DOACs
- Bleeding: bruising, epistaxis, gum bleeding, hematuria, gastrointestinal bleeding
- Major hemorrhage, including intracranial hemorrhage
- Anemia due to occult blood loss
- Nausea or dyspepsia
- Higher bleeding risk with NSAIDs, aspirin, clopidogrel, thrombolytics, alcohol excess, and other anticoagulants
Drug-specific effects
| Drug | Important adverse effect / point |
|---|---|
| Dabigatran | Dyspepsia, gastritis-like symptoms, GI bleeding; more dependent on renal clearance |
| Rivaroxaban | GI bleeding; take 15 mg and 20 mg doses with food |
| Apixaban | Bleeding; often associated with a relatively favorable GI bleeding profile among DOACs |
| Edoxaban | Bleeding; efficacy concern in NVAF if creatinine clearance is >95 mL/min in US labeling |
Important interactions and monitoring
- Avoid or use specialist advice with strong P-glycoprotein and CYP3A4 inhibitors/inducers.
- Examples: azole antifungals, ritonavir, rifampicin, carbamazepine, phenytoin.
- Check renal function before starting and periodically thereafter.
- Routine INR monitoring is not required, unlike warfarin.
- Do not stop abruptly unless advised, because thrombosis or stroke risk can rise.
Reversal in serious bleeding
- Dabigatran: idarucizumab
- Factor Xa inhibitors: andexanet alfa where available, or a 4-factor prothrombin-complex concentrate in appropriate situations.
Dabigatran can be removed by hemodialysis in severe bleeding with renal failure, unlike the factor Xa inhibitors because they are more protein-bound.
Goodman & Gilman’s The Pharmacological Basis of Therapeutics, “Reversal Agents for Direct Oral Anticoagulants.”
Goodman & Gilman’s The Pharmacological Basis of Therapeutics, “Reversal Agents for Direct Oral Anticoagulants.”
Memory aid:
“Dabi = thrombin; RAE = Xa”
“Dabi = thrombin; RAE = Xa”
- Dabigatran: factor IIa
- Rivaroxaban, Apixaban, Edoxaban: factor Xa
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