Page 2444 - Hematology_ Basic Principles and Practice ( PDFDrive )

2182 Part XII Hemostasis and Thrombosis

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in both hemorrhagic and ischemic stroke. Rates of major bleeding Dabigatran crosses the placenta and should not be used in preg-
were similar with dabigatran and warfarin, whereas rates of intra- nant women. The safety of dabigatran in women who are breastfeed-
cranial and life-threatening bleeding were lower with dabigatran. At ing and in children has not been established.
the 110-mg twice-daily dose, dabigatran was noninferior to warfarin
for stroke prevention but was associated with significantly less intra-
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cranial and major bleeding. In those over the age of 75 years, there Rivaroxaban
was more gastrointestinal bleeding with dabigatran than with warfarin
with the 150-mg dose but not with the 110-mg dose. 22 An oral factor Xa inhibitor, rivaroxaban is an active drug that targets
For treatment of acute venous thromboembolism, dabigatran was the active site of factor Xa even when the enzyme is incorporated into
compared with warfarin after a 5- to 7-day course of heparin or the prothrombinase complex.
LMWH. Dabigatran was noninferior to warfarin for prevention of
recurrent venous thromboembolism, but it produced less major plus
clinically relevant nonmajor bleeding. 23 Mechanism of Action
When dabigatran was compared with warfarin in patients with
mechanical heart valves, there was a trend for more ischemic strokes Rivaroxaban has an oral bioavailability of 80%, and plasma levels
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and more bleeding with dabigatran. Consequently, dabigatran and peak 2 to 3 hours after drug administration. Absorption of rivaroxa-
the other NOACs are contraindicated in patients with mechanical ban is enhanced by food; consequently, when given in doses of 15 or
heart valves; warfarin remains the anticoagulant of choice for such 20 mg once daily, rivaroxaban should be taken with a meal. The
patients. half-life of rivaroxaban is 5 to 9 hours in healthy young subjects and
11 to 13 hours in elderly subjects (Table 149.8). About one-third of
the drug is cleared unchanged by the kidneys. The remainder is
Dosing metabolized in the liver, and half of the inactive metabolites is cleared
by the kidneys; the rest is excreted in the feces. The pharmacokinetic
For thromboprophylaxis after hip or knee arthroplasty, dabigatran is and pharmacodynamic profile is dose dependent and is not influenced
given once daily at a dose of 220 mg; a half-dose is given on the day by age, gender, or body weight.
of surgery. For stroke prevention in atrial fibrillation, dabigatran is
given at a dose of 150 mg twice daily. A dose of 75 mg twice daily
is used in the United States for patients with a creatinine clearance Indications
of 15 to 30 mL/min, whereas the 150-mg twice-daily dose is recom-
mended for those with a creatinine clearance over 30 mL/min. In Rivaroxaban is licensed for thromboprophylaxis after elective hip or
other countries, a dose of 110 mg twice daily is used for patients over knee arthroplasty, for treatment of venous thromboembolism, and
the age of 80 years or in those 75 years of age or older who have risk for stroke prevention in patients with nonvalvular atrial fibrillation.
factors for bleeding. For treatment of venous thromboembolism, When compared with enoxaparin for thromboprophylaxis after hip
dabigatran is given at a dose of 150 mg twice daily. or knee arthroplasty, rivaroxaban significantly reduced the risk of
venous thromboembolism with similar or slightly higher rates of
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major bleeding. In patients with atrial fibrillation, rivaroxaban was
Monitoring noninferior to warfarin for prevention of stroke and systemic embo-
lism, but it was associated with less intracranial bleeding and hemor-
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Routine coagulation monitoring is unnecessary. However, determina- rhagic stroke and a similar rate of major bleeding. In patients with
tion of the anticoagulant activity of dabigatran can be helpful to acute venous thromboembolism, an all-oral rivaroxaban regimen was
assess adherence, detect accumulation or overdose, determine its as effective as conventional anticoagulant therapy consisting of
contribution to bleeding, and optimize the timing of surgery or heparin followed by a vitamin K antagonist, but it was associated
intervention. The aPTT and thrombin time can be used for qualita- with less major bleeding. 28,29 When compared with placebo as an
tive assessment of the anticoagulant activity of dabigatran, whereas adjunct to dual antiplatelet therapy in patients with acute coronary
the diluted thrombin time or ecarin clotting time can be used to syndrome, rivaroxaban (at a dose of 2.5 mg twice daily) reduced the
quantify dabigatran levels if the tests are performed with dabigatran primary efficacy endpoint—the composite of cardiovascular death,
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calibrators. myocardial infarction and stroke—from 10.7% to 9.1%. Rivaroxa-
ban increased the risk of bleeding, including intracranial bleeding,
compared with placebo, but there was no increase in fatal bleeding.
Drug Interactions
Dabigatran is a substrate of the efflux P-GP transporter. Conse- Dosing
quently, coadministration with potent P-GP inhibitors such as
quinidine, ketoconazole, amiodarone, and verapamil can increase For thromboprophylaxis after hip or knee replacement surgery, riva-
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plasma concentrations of dabigatran by decreasing its reabsorption roxaban is given once daily at a dose of 10 mg. When used for stroke
into the gastrointestinal tract. In contrast, potent P-GP inducers such prevention in patients with atrial fibrillation, the dose is 20 mg once
as rifampicin can reduce plasma dabigatran concentrations by increas- daily. The dose is reduced to 15 mg once daily for those with a creati-
ing its reabsorption. nine clearance of 15 to 49 mL/min. For treatment of venous throm-
boembolism, rivaroxaban is started at a dose of 15 mg twice daily for
3 weeks, followed by 20 mg once daily thereafter. When used as an
Side Effects adjunct to antiplatelet therapy in stabilized patients with acute coro-
nary syndrome, rivaroxaban is given at a dose of 2.5 mg twice daily.
Dabigatran can be associated with dyspepsia. Taking the drug with
food often helps to alleviate this problem. Bleeding is the major side
effect of dabigatran. Dabigatran can rapidly be reversed with idaru- Monitoring
cizumab, a humanized monoclonal antibody fragment that binds
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dabigatran with high affinity. Idarucizumab is given as an intrave- Rivaroxaban prolongs the prothrombin time more than the aPTT,
nous bolus of 5 g and is licensed for dabigatran reversal in patients but its effect on these tests is reagent dependent. Plasma concentra-
with serious bleeding or in those requiring urgent surgery or tions of rivaroxaban can be quantified using a chromogenic anti–factor
intervention. Xa assay with drug-specific calibrators.