*2.2.3. Sulodexide*

outcome of gastrointestinal hemorrhage and reported higher risk of rivaroxaban compared with warfarin (HR, 1.24; 95% CI, 1.08–1.41). Authors reported a significant heterogeneity for

Compared with warfarin, apixaban is associated with lower risk for intracranial hemorrhage in several real-world studies that included 66.482 patients (HR, 0.45; 95% CI, 0.31–0.63); lower risk for gastrointestinal hemorrhage in 2 studies that included 33.323 patients (HR, 0.63; 95% CI, 0.42–0.95); and lower risk for major hemorrhage in 4 studies that included 89.036 patients (HR, 0.55; 95% CI, 0.48–0.63) [36]. Authors identified only one study of 41.785 patients which assessed death; it reported lower risk with apixaban compared with warfarin (HR, 0.65; 95% CI, 0.56–0.75). Also, they identified only one study of 15.390 patients which assessed the outcome of any stroke or systemic embolism; it reported lower risk of apixaban compared with warfarin (HR, 0.67; 95% CI, 0.46–0.98). There is neither a statistical difference between apixaban and warfarin for the outcomes of ischemic stroke (HR, 0.95; 95% CI, 0.75–1.19) nor for ischemic stroke or systemic embolism (HR, 1.07; 95% CI, 0.87–1.31). Authors reported a significant degree of heterogeneity in the analysis of the outcomes of gastrointestinal hemor-

Betrixaban is an oral factor Xa inhibitor whose extended duration treatment reduced a composite of asymptomatic DVT, symptomatic DVT, nonfatal PE, and venous thromboembolism (VTE)–related death compared to enoxaparin, without an increase in major bleeding [37]. It acts by competitively binding to the active site of Xa, preventing its ability to convert prothrombin to thrombin. Betrixaban is rapidly absorbed with mean peak concentrations occurring within 3–4 hours after oral administration. Excretion is mostly unchanged through the bile with renal excretion accounting for 5–7% of the orally administered dose. Betrixaban is not a substrate for major cytochrome P450 enzymes, but it is a substrate for P-gp. Potent inhibitors of P-gp (i.e., ketoconazole, amiodarone, and diltiazem) increase betrixaban concentrations around twofold [38]. A recent network meta-analysis aimed to comprehensively analyze the thromboprophylactic drugs that are used to prevent thrombosis and reduce bleeding risk. Results showed that sudoxicam, FXI-ASO (factor XI antisense oligonucleotide), and betrixaban were likely to be associated with the lowest risk of all-cause bleeding after major joint surgery. Furthermore, betrixaban, dalteparin, and warfarin were associated with the lowest risk of major bleeding/nonmajor clinically

The FDA (Food and Drug Administration) approved betrixaban on June 2017 for the prophylaxis of VTE in adult patients hospitalized for an acute medical illness, who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. The recommended dose of betrixaban is an initial single dose of 160 mg starting on day 1, followed by 80 mg once daily taken for 35–42 days at the same time each day with food. Dose should be reduced in case of severe renal and hepatic impairment or

the outcomes of intracranial hemorrhage and death.

rhage but not for the other outcomes.

relevant bleeding events [39].

*2.2.1.6.3. Apixaban*

90 Anticoagulant Drugs

*2.2.2. Betrixaban*

Sulodexide belongs to a class of substances known as glycosaminoglycans (GAGs), composed of a fast-moving heparin fraction (80%) with affinity for antithrombin III and a dermatan sulfate fraction (20%) with affinity for heparin cofactor II.
