*2.2.1.3. Pharmacokinetics*

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

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

**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

Real-World Safety of Anticoagulants http://dx.doi.org/10.5772/intechopen.78023 89

A systematic review and meta-analysis was performed with the aim of summarizing all available evidence from high-quality real-world observational studies regarding efficacy and safety of non–vitamin-K oral anticoagulants compared with vitamin-K antagonists in patients with atrial fibrillation [36]. Compared with warfarin, dabigatran is associated with lower risk for intracranial hemorrhage in several studies that included 606.855 patients (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.37–0.49) and lower risk for death in 319.486 patients (HR, 0.63; 95% CI, 0.52–0.76). There is no statistical difference between dabigatran and warfarin for the outcomes of ischemic strokes (HR, 0.96; 95% CI, 0.80–1.16); ischemic stroke or systemic embolism (HR, 1.17; 95% CI, 0.92–1.50); any stroke or systemic embolism (HR, 0.93; 95% CI, 0.77–1.14); major hemorrhage (HR, 0.83; 95% CI, 0.65–1.05); and myocardial infarction (HR, 0.96; 95% CI, 0.77–1.21). Authors identified 10 studies that included 537.770 patients which assessed the outcome of gastrointestinal hemorrhage and reported higher risk of dabigatran compared with warfarin (HR, 1.20; 95% CI, 1.06–1.36). Authors also reported the presence of a significant heterogeneity in all analyses with the exception of the outcome of intracranial hemorrhage and any stroke or

As reported in the study authored by Ntaios and Colleagues [36], compared with warfarin, rivaroxaban is associated with lower risk for intracranial hemorrhage in several real-world studies that included 136,221 patients (HR, 0.64; 95% CI, 0.47–0.86). There is no statistical difference between rivaroxaban and warfarin for the outcomes of ischemic stroke (HR, 0.89; 95% CI, 0.76–1.04); ischemic stroke or systemic embolism (HR, 0.73; 95% CI, 0.52–1.04); any stroke or systemic embolism (HR, 0.87; 95% CI, 0.71–1.07); major hemorrhage (HR, 1.00; 95% CI, 0.92–1.08); myocardial infarction (HR, 1.02; 95% CI, 0.54–1.89); and death (HR, 0.67; 95% CI, 0.35–1.30). Authors identified four studies that included 71.368 patients which assessed the

• 20 mg daily if CrCl<50 mL/min;

*2.2.1.6. Real-world safety aspects*

*2.2.1.6.1. Dabigatran*

systemic embolism.

*2.2.1.6.2. Rivaroxaban*

impairment.

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

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

• 60 mg daily if CrCl is between 50 and 95 mL/min; • 30 mg daily if CrCl is between 15 and 50 mL/min.

**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 (66%) and feces (28%).

**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 (27%) and intestinal and biliary tract.

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