Overview of Direct Oral Anticoagulants (DOACs)
January 11, 2021
Virchow’s Triad—risk factors for venous thrombosis.
| STASIS OF BLOOD FLOW | ENDOTHELIAL INJURY | HYPERCOAGUABILITY |
| Atrial fibrillation | Smoking | Obesity |
| Varicose veins | Cholesterol plaques | Pregnancy |
| Prolonged immobilization | Chronic high BP | Cancer/Chemotherapy |
| Genetic factors (Factor-V) | ||
| Oral contraceptives |
DOAC-NOAC- TSOAC?
Direct oral anticoagulants (DOACs) are oral medications that specifically inhibit factors IIa or Xa. They are also known as new (or novel) oral anticoagulants (NOACs) or target-specific oral anticoagulants (TSOACs). DOACs are the preferred name according to the International Society of Thrombosis and Haemostasias
Where DOAC’s work:
Prothrombin—- ((Xa))—— Thrombin (Rivaroxaban works here)
Fibrinogen—-((Thrombin))—–Fibrin (Dabigatran works here)
Fibrin does the cross linking to stabilize the clot that is formed
DABIGATRAN (PRADAXA®) (released- November 2010)
Mechanism: Direct Thrombin Inhibitor. Dabigatran was the first ORAL anticoagulant to be introduced in over 50 years!! Referred to as a “univalent direct thrombin inhibitor” that binds directly to the active site on factor IIa (thrombin). Thrombin is a naturally occurring enzyme in our circulatory system that converts fibrinogen into fibrin, which is an important step in clot formation. By tying up thrombin, clots are not so readily formed.
Dosage: 150mg BID 75mg BID if CrCl is 15-30mL/min
Advantages compared to warfarin:
- Prevents more strokes, including hemorrhagic (5/1000 a/fib patients/year)
- Extensive monitoring not necessary
- Fewer food and drug interactions
- Less intracranial bleeding
Disadvantages compared to warfarin:
- COST: $15/day costs more than warfarin + monitoring
- TWICE DAILY DOSING must have excellent patient compliance
- GI upset- give with food. Increase GI bleed
Prescribing info: Make sure INR is below 2 before starting therapy.
- Some drug interactions with P-glycoprotein inhibitors (Ketoconazole, Clarithromycin, others)
- Rifampin speeds metabolism.
- Due to costs, this drug is ideal for patients with uncontrolled INR on warfarin therapy.
FACTOR Xa INHIBITORS
Role of Factor Xa: Factor Xa is responsible for the conversion of prothrombin to thrombin. Blocking Xa blocks that conversion to thrombin and clot formation is impeded.
Rivaroxaban (Xarelto®) available August-2011 (490.00/month)
The first oral, selective inhibitor of Factor Xa approved by the FDA
Nonvalvular Atrial Fibrillation:
- For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal
- For patients with CrCl 15 – 50 mL/min: 15 mg orally, once daily with the evening meal
Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE:
- 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE. Reduce to 10mg after 1 year.
- Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally, once daily with or without food
Indications:
- to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation
- for treatment of deep vein thrombosis (DVT)
- for treatment of pulmonary embolism (PE)
- for reduction in the risk of recurrence of DVT or PE
- for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (10mg daily)
- for prophylaxis of venous thromboembolism (VTE) in acutely ill
- to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease
ADVANTAGES:
- Convenient once-daily, oral dosing
- No routine monitoring of INR or other coagulation parameters is required. Fast onset.
- AVOID use in severe renal impairment (creatinine clearance <30 mL/min).
- AVOID in patients with hepatic impairment.
- AVOID drugs that Inhibit Cytochrome P450 CYP3A4 Enzymes and Drug Transport Systems such as P-gp and strong CYP3A4 inhibitors, which cause significant increases in rivaroxaban exposure. May double dose if giving concurrently with P4503A4 inducer.
(October 2018) Rivaroxaban XARELTO® is indicated, in combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
- Dose is 2.5mg BID + 81mg aspirin/day
Apixaban (Eliquis®) (approved Dec 28, 2012) ($485.00/month)
Indications
ELIQUIS® is a factor Xa inhibitor anticoagulant indicated:
- to reduce the risk of stroke and systemic embolism in patients with nonvalvular
atrial fibrillation. - for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary
embolism (PE), in patients who have undergone hip or knee replacement surgery. - for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT
and PE following initial therapy. VTE prevention after initial treatment. Reduces risk of symptomatic recurrent VTE or death
Apixaban Indications and Dosages: - Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF): The recommended dose is 5 mg orally twice daily.
In patients with at least 2 of the following characteristics reduce dose to 2.5mg twice daily:
- Age: over age 80,
- body weight less than 60kg (132lbs),
- serum creatinine ≥1.5 mg/dL
Indications and dosage:
- Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily
- Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
- Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2.5 mg taken orally twice daily.
A fib: for every 1000 patients treated per year, apixaban prevents three more strokes, avoids ten major bleeds, and prevents four deaths compared to warfarin
Edoxaban (Savaysa®) (2015) ($400/month)
Treatment of NVAF: Assess CrCL before initiating therapy. The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.
- Do not use SAVAYSA in patients with CrCL over 95 mL/min (sorry, your kidneys are “too” good for this drug!)
- Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min
Treatment of DVT and PE: The recommended dose is 60 mg once daily. The recommended dose is 30 mg once daily for patients with CrCL 15 to 50 mL/min or bodyweight less than or equal to 60 kg or who use certain P-gp inhibitors.
In the next session, we will discuss when to stop these drugs before elective surgical procedures.
With nearly 50% of our warfarin patients having uncontrolled INR’s, DOACs have been a Godsend. They do not require extensive monitoring, do not hang around very long in the body, and have excellent efficacy.
One of the biggest challenges we see, however, is the cost of these medications. Adherence becomes a challenge when patients struggle to pay even a percentage of the costs of these medications.
Rudolf Virchow (1821-1902) was a German physician who is credited for elucidating the origins of thromboembolism. In fact, he coined the term “thrombosis” which is the process by which a clot forms in a blood vessel as well as the term “embolism”, which is a clot that has moved and blocks off a vessel. Virchow also had a brilliant career in which he clarified how cells divide, as well being a strong social medicine advocate. Considered by many to be the most brilliant physician of the 1800’s and the ‘father of cell pathology’, he even has a lymph node named after him!
In the next session, we will discuss when to stop these drugs before elective surgical procedures.
Have a Great Day on the Bench!!
