Oral anticoagulants

Anticoagulants are used for treating and preventing embolic events. The most common oral anticoagulatory agents are vitamin K antagonists such as warfarin and phenprocoumon. Non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran and rivaroxaban have also gained popularity in recent years. Vitamin K antagonists inhibit the enzyme vitamin K epoxide reductase, thereby blocking hepatic synthesis of the active, reduced form of vitamin K (needed for carboxylation of coagulation factors II, VII, IX, and X, protein C, protein S). This effect can last for several days, which complicates exact dosing and makes regular monitoring necessary. Vitamin K antagonists are also metabolized by C-P450 (CYP) enzymes and therefore interact with a broad range of foods and drugs. NOACs act selectively via inhibition of thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban). Because of their comparatively short half-life and fewer interactions, NOACs are easier to control and administer than warfarin and do not require regular monitoring to ensure their efficacy and safety. For all substances, it is important to consider the dose-dependent risk of bleeding, especially when combining different substances that affect hemostasis (e.g., aspirin, clopidogrel, ticagrelor).

See also “Periprocedural management of oral anticoagulant therapy” and “Anticoagulation reversal.”

Overview of commonly used oral anticoagulants

General notes regarding oral anticoagulation

• Indications for all oral anticoagulants
  • Prophylaxis of thromboembolism following:
    • DVT and/or pulmonary embolism
    • Prolonged immobilization after surgery (e.g., especially in knee or hip surgery)
    • Nonvalvular atrial fibrillation
  • For specific indications, see “Indications” below.
• Expected laboratory changes
  • Warfarin: increased PT/INR, no change to PTT or TT (routinely monitored)
  • Direct thrombin inhibitors; : prolonged thrombin time (TT), no change to PTT or PT (not routinely monitored)
  • Direct factor Xa inhibitors; : prolonged PT and PTT, unchanged thrombin time (not routinely monitored)

The most important side effect of all oral anticoagulants is a dose-dependent increase in bleeding risk.

DRAW: Dabigatran, Rivaroxaban, Apixaban, and Warfarin are the most important oral anticoagulants.

RivaroXaban, apiXaban, and edoXaban are factor Xa inhibitors.

WARsaw is an EXTRaordinary Place To check out: WARfarin affects the EXTRinsic pathway; therefore, PT should be regularly checked.

WEPT: Warfarin Extrinsic pathway PT

Comparison of heparin and warfarin

Coumarins

• Dose-dependent increased risk of bleeding
  • Small wounds cease to bleed spontaneously and no additional measures are required
  • Severe cases of hemorrhage are usually retroperitoneal, intracranial, or gastrointestinal.
  • Countermeasures for extensive or life-threatening bleeding include
    • Stop coumarins
    • Administer FFP or prothrombin complex concentrate (PCC) for rapid reversal of warfarin effect
    • Vitamin K: takes longer to take effect than FFP or PCC
• Warfarin-induced skin necrosis
  • Seen within the first few days of treatment with high doses of warfarin
  • Warfarin inhibits all vitamin K-dependent coagulation factors: anticoagulants protein C and protein S have a relatively short half-life and are depleted more quickly than procoagulants factors II, IX, and X; → increased factor V and VIII activity; → initial hypercoagulable state; → formation of microthrombi → vascular occlusion, tissue infarction, and blood extravasation
  • Increased risk in patients with underlying hereditary protein C deficiency
  • Presentation: painful purpura, hemorrhagic blisters, and large areas of necrosis; mostly affects subcutaneous adipose tissue
  • Immediate management: discontinue warfarin, administer IV vitamin K, unfractionated heparin, and source of protein C (protein C concentrate, FFP); surgical debridement and grafting in therapy-refractory cases
  • Prevention: temporary bridging anticoagulation with heparin until warfarin has started to act and the initial hypercoagulable state has been bridged

Individuals with protein C deficiency are at a higher risk of developing warfarin necrosis.

Direct factor Xa inhibitors and direct thrombin inhibitors

• Dose-dependent increased risk of bleeding
  • Interventional steps to stop the bleeding
  • If life-threatening bleeding occurs, administer PCC
  • General management and specific medication antidotes
    • Antifibrinolytic agents (e.g., tranexamic acid)
    • Oral activated charcoal; reduces absorption if anticoagulants were ingested in the past couple of hours.
    • Apixaban and rivaroxaban: andexanet alfa (recombinant modified factor Xa protein)
    • Dabigatran: idarucizumab (monoclonal antibody)

RivaroXaban and apiXaban can be reversed with andeXanet alfa.

References:^[5][6][7][8]

We list the most important adverse effects. The selection is not exhaustive.

• General contraindications
  • Coagulopathies; hepatic dysfunction with impaired hepatic production of coagulation factors
  • Acute bleeding
  • Suspected vascular lesions, increased risk of severe bleeding
    • Severe arterial hypertension, aneurysm
    • Endocarditis
    • Recent cardiovascular events (e.g., cerebral ischemia)
    • Gastrointestinal bleeding
    • Surgery or interventional procedures (e.g., biopsy)
    • Tendency to fall
  • Severe renal insufficiency
  • Concurrent administration of several anticoagulants
  • Pregnancy and breastfeeding
    • Warfarin crosses the placenta, causing teratogenicity and fetal bleeding
    • Side effects of NOACs during pregnancy and breastfeeding are unknown. Therefore, they are currently not recommended.
• Specific contraindications
  • Dabigatran: concurrent administration of ketoconazole, itraconazole, ciclosporin, tacrolimus, or dronedarone

Warfarin crosses the placenta and is teratogenic, in contrast to heparin, which does not cross the placenta.

References:^[10][11]

We list the most important contraindications. The selection is not exhaustive.

Warfarin interactions

Warfarin is metabolized by cytochrome P450 (CYP) enzymes. Its effects can be significantly impacted by a variety of interactions; for this reason, warfarin serum levels should be monitored regularly.

• Decrease of anticoagulant effect
  • Rifampicin, carbamazepine, St. John's wort, ginger, licorice: induce metabolic breakdown of warfarin via induction of cytochrome P450
  • Foods rich in vitamin K (e.g., kale, spinach): counter effect of warfarin
  • Gastric acid inhibition (PPI use), cholestyramine treatment: impaired uptake of warfarin
• Increase of anticoagulant effect
  • Several antidepressants and antibiotics, PPIs, amiodarone, grapefruit: impair metabolic breakdown via inhibition of cytochrome P450
  • Acetaminophen: metabolite of acetaminophen interrupts vitamin K cycle via inhibition of vitamin K-dependent carboxylase
  • Sulfonamides, sulfonylureas: competitively block or displace warfarin at plasma protein binding sites
  • Damage to gut flora (e.g., antibiotic therapy): impaired bacterial vitamin K synthesis

“Chronic alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs): Chronic alcohol use, St. John's wort, Phenytoin, Phenobarbital, Nevirapine, Rifampin, Griseofulvin, and Carbamazepine are P450 inducers (↓ warfarin levels).

“sickfaces.com group”: Sulfonamides, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (binge drinking), Ciprofloxacin, Erythromycin, Sodium valproate, Chloramphenicol, Omeprazole, Metronidazole, and Grapefruit juice are P450 inhibitors.
References:^[12]

• Bridging anticoagulation: the administration of heparin for the duration of the transient hypercoagulable state caused by warfarin therapy. Heparin prevents coagulation by activating antithrombin.
  • Reduces risk of venous thromboembolism and skin necrosis
  • May also be used during interruptions of warfarin therapy (e.g., surgery)
• Periprocedural bridging anticoagulation (see “Periprocedural management of VKAs” for details)
  1. Interrupt VKAs as needed (e.g., patients with high periprocedural bleeding risk) a few days before the procedure.
  2. Initiate bridging anticoagulation once the INR is in the subtherapeutic range,
  3. Administer the last dose of LMWH 24 hours before the procedure (4–6 hours before the procedure for UFH).
  4. Resume VKA after surgery; ; consider postprocedural bridging anticoagulation as needed (e.g., patients with high periprocedural thrombotic risk.

References:^[13]