Page 2445 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 149 Antithrombotic Drugs 2183

Drug Interactions thromboembolism, but it was associated with less bleeding. Apixaban
was superior to aspirin for stroke prevention in atrial fibrillation
Coadministration of rivaroxaban with dual inhibitors of CYP3A4 and patients unwilling or unable to take warfarin and did not significantly
36
P-GP, such as ketoconazole, itraconazole, ritonavir, and clarithromy- increase the risk of bleeding. When compared with warfarin in
cin, increases drug exposure and the risk of bleeding, whereas coadmin- patients with atrial fibrillation, apixaban significantly reduced the
istration with dual inducers of CYP3A4 and P-GP, such as rifampin, risk of stroke and systemic embolism, and it was associated with less
carbamazepine, phenytoin, and St. John’s wort, decreases exposure and major bleeding and lower all-cause mortality. 37
increases the risk of stroke and other thromboembolic events.
Dosing
Side Effects
For thromboprophylaxis, apixaban is given twice daily at a dose of
The major side effect is bleeding. Although prothrombin complex 2.5 mg. For stroke prevention in patients with atrial fibrillation, the
concentrate partly reverses the anticoagulant effects of rivaroxaban in dose is 5 mg twice daily, and the dose is reduced to 2.5 mg twice
volunteers, its utility for treatment of bleeding is uncertain. Nonethe- daily in patients with at least two of the following criteria; age of 80
less, prothrombin complex concentrate (30 to 50 U/kg) should be years or older, body weight of 60 kg or less, and serum creatinine of
considered for patients with life-threatening bleeds. If the bleeding 1.5 mg/dL or higher. In patients with venous thromboembolism,
continues, activated prothrombin complex concentrate or recombi- apixaban is started at a dose of 10 mg twice daily for 7 days followed
nant factor VIIa can be used. by 5 mg twice daily thereafter. After 6 months, the dose can be
Specific reversal agents for rivaroxaban are in development. Most reduced to 2.5 mg twice daily.
advanced is andexanet alfa. A recombinant variant of factor Xa that
has its active site serine residue replaced with an alanine residue to
eliminate catalytic activity and its membrane-binding domain Monitoring
removed to circumvent incorporation into the prothrombinase
complex, andexanet competes with factor Xa for binding rivaroxaban Routine monitoring is unnecessary. Apixaban has little effect on the
and sequesters it until it can be cleared. 25,31 Andexanet also reverses prothrombin time or aPTT. Plasma drug levels can be quantified
heparin, LMWH, and fondaparinux by competing with factor Xa using an anti–factor Xa assay with apixaban calibrators.
and thrombin for the antithrombin–heparin complex.
Ciraparantag is a second reversal agent that is at an earlier stage
of development than andexanet. A synthetic, cationic small molecule, Drug Interactions
ciraparantag binds rivaroxaban and neutralizes its anticoagulant activ-
32
ity. Ciraparantag also binds dabigatran, apixaban, edoxaban, Coadministration of apixaban with dual inhibitors of CYP3A4 and
heparin, LMWH, and fondaparinux. P-GP, such as ketoconazole, itraconazole, ritonavir, and clarithromy-
Rivaroxaban crosses the placenta and should not be used in cin, increases drug exposure and may increase the risk of bleeding.
pregnant women. The safety of rivaroxaban in women who are In contrast, coadministration with dual inducers of CYP3A4 and
breastfeeding and in children has not been established. P-GP, such as rifampin, carbamazepine, phenytoin, and St. John’s
wort, decreases exposure and may increase the risk of stroke and other
thromboembolic events.
Apixaban

An oral factor Xa inhibitor, apixaban inhibits free factor Xa and factor Side Effects
Xa incorporated into the prothrombinase complex. It is licensed in
many countries, for thromboprophylaxis after hip or knee replace- The major side effect is bleeding. Management of bleeding with
ment surgery, for treatment and secondary prevention of venous apixaban is identical to that with rivaroxaban. Apixaban crosses the
thromboembolism, and for stroke prevention in atrial fibrillation. placenta and should not be used in pregnant women. The safety of
apixaban in women who are breastfeeding and in children has not
been established.
Mechanism of Action

Apixaban binds reversibly to the active site of free factor Xa or factor Edoxaban
Xa incorporated into the prothrombinase complex. The drug has 50%
oral bioavailability, and plasma levels peak 3 to 4 hours after drug Another oral factor Xa inhibitor, edoxaban inhibits free factor Xa and
administration. The half-life of apixaban is about 12 hours (Table factor Xa incorporated into the prothrombinase complex.
149.8). Apixaban is metabolized in the liver via CYP3A4/5-dependent
and independent pathways. About 27% of the drug is cleared
unchanged by the kidneys, and the remainder is excreted in the feces. Mechanism of Action

Edoxaban binds reversibly to the active site of free factor Xa or factor
Indications Xa incorporated into the prothrombinase complex. The oral bioavail-
ability is 62%, and plasma levels of edoxaban peak 1 to 2 hours after
Apixaban is licensed for thromboprophylaxis after elective hip or drug administration. The half-life of edoxaban is 10 to 14 hours. Of
knee arthroplasty, for stroke prevention in patients with nonvalvular the administered edoxaban dose, about 50% is excreted via the
atrial fibrillation, and for treatment of venous thromboembolism. kidneys as unchanged drug, and the remainder is excreted in the feces
When compared with enoxaparin for thromboprophylaxis after hip (Table 149.8).
or knee arthroplasty, apixaban was at least as effective and safe. 33–35
For treatment of venous thromboembolism, an all-oral regimen of
apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily Indications
thereafter) was compared with conventional anticoagulant therapy
consisting of enoxaparin followed by warfarin. Apixaban was non- Edoxaban is licensed for stroke prevention in patients with nonval-
inferior to conventional therapy for prevention of recurrent venous vular atrial fibrillation and for treatment of venous thromboembolism.