*2.2.1.4. Interactions*

All DOACs are substrate of P-glycoprotein (P-gp), and apixaban and rivaroxaban are substrates for CYP3A4 metabolism. Thus, concomitant medications that are inducers or inhibitors of these pathways should be evaluated for potential interactions [34]. In particular, concomitant use of rifampin (P-gp inducer), carbamazepine, phenytoin (both P-gp and CYP3A4 inducers) and cyclosporine, ketoconazole, verapamil, and HIV protease inhibitors (both P-gp and CYP3A4 inhibitors) should be avoided or needs an adjustment of DOACs treatment [34, 35].

#### *2.2.1.5. Therapy management*

The main advantage of DOACs is a more rapid onset and offset of action that eliminates the necessity of routine INR monitoring. In case of acute care or perioperative settings, when there is uncertainty about the timing of last ingestion, renal function, and gastrointestinal absorption, there are several values that can be checked to assess DOACs effect, such as activated partial thromboplastin time (aPPT), prothrombin time (PT), and antifactor Xa activity. During rivaroxaban treatment renal function (CrCl), complete blood count (CBC) tests and hepatic function monitoring are required periodically, at least annually.

**Dabigatran** treatment of nonvalvular AF provides:


**Rivaroxaban** is administered with the evening meal on the basis of CrCl values:

• 20 mg daily if CrCl<50 mL/min;

*2.2.1.3. Pharmacokinetics*

88 Anticoagulant Drugs

(66%) and feces (28%).

*2.2.1.4. Interactions*

*2.2.1.5. Therapy management*

(27%) and intestinal and biliary tract.

drug is recovered in urine and 86% is excreted in feces.

**Dabigatran** etexilate has a bioavailability of 3–7%, and it is bound to plasma proteins for a total amount of 35%. Its plasma half-life ranges between 12 and 17 hours but increases to 18–28 hours in case of mild to severe renal impairment. Dabigatran is converted into active dabigatran through hepatic and plasma hydrolysis and hepatic glucuronidation. Excretion occurs through the kidney after i.v. administration, while after oral administration, 7% of

**Rivaroxaban** reaches the peak of plasma concentration in 2–4 hours, and its bioavailability ranges between 66% (20 mg) and 80–100% (10 mg); 92–95% of the drug administered is bound to plasma proteins for a total volume of distribution of 50 L. Hepatic oxidation by CYP3A4/5, CYP2J2, and hydrolysis converts rivaroxaban to inactive metabolites excreted through kidney

**Apixaban** has a bioavailability of 50% and reaches plasma peak concentration in 3–4 hours. It is bound for 87% to plasmatic proteins, and it is metabolized by CYP3A4/5, 1A2, 2C9, 2C19, 2 J2, O-demethylation, and hydroxylation in the liver. Excretion occurs through the kidney

**Edoxaban** reaches the peak of plasma concentration in 1–2 hours, has a bioavailability of 62%, and it is bound for 55% to plasma protein. Its plasma half-life ranges from 10 to 14 hours. Edoxaban is converted through CYP3A4, hydrolysis, conjugation, and oxidation. Metabolites

All DOACs are substrate of P-glycoprotein (P-gp), and apixaban and rivaroxaban are substrates for CYP3A4 metabolism. Thus, concomitant medications that are inducers or inhibitors of these pathways should be evaluated for potential interactions [34]. In particular, concomitant use of rifampin (P-gp inducer), carbamazepine, phenytoin (both P-gp and CYP3A4 inducers) and cyclosporine, ketoconazole, verapamil, and HIV protease inhibitors (both P-gp and CYP3A4 inhibitors) should be avoided or needs an adjustment of DOACs treatment [34, 35].

The main advantage of DOACs is a more rapid onset and offset of action that eliminates the necessity of routine INR monitoring. In case of acute care or perioperative settings, when there is uncertainty about the timing of last ingestion, renal function, and gastrointestinal absorption, there are several values that can be checked to assess DOACs effect, such as activated partial thromboplastin time (aPPT), prothrombin time (PT), and antifactor Xa activity. During rivaroxaban treatment renal function (CrCl), complete blood count (CBC) tests and

• 75 mg twice daily if CrCl is between 30 and 50 mL/min with concomitant P-gp inhibitors.

are excreted through kidneys (50%) and biliary/intestinal excretion [33].

hepatic function monitoring are required periodically, at least annually.

**Dabigatran** treatment of nonvalvular AF provides:

• 75 mg twice daily if CrCl is between 15 and 30 mL/min;

• 150 mg twice daily if CrCl>30 mL/min;

• 15 mg daily if CrCl is between 15 and 50 mL/min.

**Apixaban** is given at the dose of 5 mg twice daily in patients with nonvalvular AF and reduced to 2.5 mg twice daily if there are at least two of the following conditions: body weight ≤ 60 kg, creatinine ≥ 1.5 mg/dL, age ≥ 80 years. Apixaban is not recommended in case of severe hepatic impairment.

**Edoxaban** is administered on the basis of CrCl:


#### *2.2.1.6. Real-world safety aspects*
