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398 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 399

Clinical studies have evaluated the use of fondaparinux in several seconds. As with other direct thrombin inhibitors, the main side effect is
conditions, and it is approved by the FDA for prevention of venous bleeding, and no specific agent is available to reverse its action. The anti-
thromboembolism (VTE) in patients undergoing major orthopedic coagulant effect may be prolonged in patients with hepatic impairment.
surgery or with hip fracture, prophylaxis after abdominal surgery, and If overdosage or excess bleeding occurs, the infusion should be discon-
treatment of deep venous thrombosis (DVT) or pulmonary embolism tinued and the aPTT and other coagulation parameters monitored.
(PE). For prophylaxis it is administered subcutaneously in a dose of 2.5 The transition from argatroban to warfarin in patients requiring
mg once daily, whereas a weight-adjusted dose is used for treatment long-term anticoagulation is complicated because argatroban has a sig-
of VTE. The principal adverse effect is bleeding, and its frequency and nificant effect on both the PT and the aPTT. In patients transitioning to
severity have been comparable to those observed with LMWH. Elevated warfarin an INR should be measured; if it is greater than 4.0, the arga-
levels may occur in patients with renal insufficiency, and caution should troban should be stopped for several hours and the INR remeasured.
be exercised in using fondaparinux in patients with renal compromise. If the INR is still greater than 2.0, the argatroban can be discontinued;
Fondaparinux is a good choice for an anticoagulant in patients with if it is less than 2.0, the argatroban should be reinstituted and the same
HIT as there is no cross-reactivity. 66 procedure followed on the next day.

BIVALIRUDIN LEPIRUDIN
Bivalirudin, a direct thrombin inhibitor, is a recombinant protein based Lepirudin is closely related to hirudin, a natural anticoagulant found in
on the structure of hirudin, is composed of a dodecapeptide analogue the salivary glands of the leech. The half-life is 1 to 3 hours in normal
of the carboxyterminal region of hirudin linked by a four-glycine res- volunteers with predominantly renal catabolism, but it may be as long as
idue to a structure directed to the active site of thrombin. Pharmacok- 2 days in dialysis-dependent patients. Lepirudin prolongs the aPTT in
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inetic studies show that plasma clearance is rapid (4.6 mL/min/kg) in a concentration-dependent manner. The manufacturer discontinued
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patients with normal renal function with a volume of distribution of marketing of this product and it is no longer available.
0.2 L/kg and elimination half-life of approximately 30 minutes. There
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is dose-dependent prolongation of the ACT and aPTT that correlates DABIGATRAN ETEXILATE
with plasma concentrations. the drug is eliminated by both renal and
hepatic clearance, and consequently, dose modification is recommended Dabigatran etexilate, one of the novel oral anticoagulants, is a direct
for patients with moderate-to-severe functional liver or kidney disease. thrombin inhibitor prodrug with a bioavailability of approximately
Bivalirudin is effective when used with aspirin in patients with 6 percent after oral administration. The absorbed drug is rapidly con-
unstable angina or postinfarction angina undergoing angioplasty, and verted by esterases to dabigatran. Peak levels occur 1 to 2 hours after an
it is approved for this use. It is also approved for patients with HIT oral dose; the half-life is approximately 12 hours. Dabigatran does not
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undergoing percutaneous coronary intervention. In some clinical tri- require a cofactor and reversibly inhibits the active site of thrombin.
als, bivalirudin also shows efficacy in preventing restenosis after cor- Dabigatran does not interfere with drugs that are metabolized by
onary angioplasty, as an adjunct to streptokinase in acute myocardial the CYP enzyme system and it produces a predictable anticoagulant
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infarction, and in preventing venous thrombosis after orthopedic sur- response, which allows therapy without the need for monitoring.
gery and in patients with HIT. However, these indications have not been Dabigatran prolongs several coagulation assays. The PT, aPTT, and ACT
approved by the FDA. The most common adverse effect is bleeding, and lack sensitivity for therapeutic drug levels, while the dilute thrombin
no specific antidote is available. The infusion should be discontinued in time and ecarin clotting time appear to correlate well across a broad
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patients with bleeding complications and blood levels monitored with range of drug levels. None of these tests have been shown to predict
the aPTT or other coagulation parameters. Antibivalirudin antibodies clinical outcomes such as thrombosis or bleeding.
have not been detected following therapy. The major side effect of dabigatran is hemorrhage. No specific
antidote is currently available, although such antidotes are in develop-
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ment. Consequently, bleeding complications are managed symptom-
ARGATROBAN atically. Although not well studied, there are published case reports
Argatroban is a small-molecule arginine derivative that reversibly and showing that dialysis or hemoperfusion likely removes this compound
directly inhibits thrombin by binding to the active catalytic site of the from the circulation. In animal models the administration of various
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enzyme with a K of 3.9 × 10 mol/L. Because of its small size, arga- coagulation factor concentrates or recombinant activated factor VII
i
troban is an effective inhibitor of thrombin, both bound to surfaces and (factor VIIa) improved prolonged bleeding times, although these agents
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in solution. The anticoagulant effect can be assessed with either the did not cause correlative changes in anticoagulation tests. 77
aPTT or ACT, and both correlate with plasma concentrations of the Dabigatran etexilate, and the other novel oral anticoagulants, are
drug. Argatroban is approximately 50 percent protein bound and has effective in various clinical settings (Table 25–5). Dabigatran is now FDA
a volume of distribution of 0.2 L/kg and an elimination half-life of 39 approved for management of VTE and prevention of stroke and systemic
to 51 minutes. Metabolism is primarily hepatic, and the clearance and embolism in nonvalvular atrial fibrillation. In the RE-LY trial, patients
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half-life are prolonged in patients with hepatic functional abnormalities with nonvalvular atrial fibrillation and a risk of stroke were randomized
requiring dose reduction. Renal function has less effect on argatroban to dabigatran etexilate (110 mg BID or 150 mg BID) or dose-adjusted
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pharmacokinetics. warfarin. In this noninferiority trial, rates of stroke or systemic embo-
Argatroban is approved for treatment and prophylaxis of HIT lism were 1.69 percent per year with warfarin, 1.53 percent per year with
and for percutaneous interventions in patients with HIT. It also shows dabigatran etexilate 110 mg (relative risk [RR] 0.91, p<0.001 for nonin-
some benefit in patients with thrombotic stroke in clinical trials. For feriority) and 1.11 percent per year with dabigatran etexilate 150 mg (RR
treatment of HIT, argatroban is administered at 2 mcg/kg per hour and 0.66, p<0.001 for superiority). The rates of major bleeding in the RE-LY
adjusted to maintain the aPTT at 1.5 to 3 times baseline. For patients trial were similar between higher dose dabigatran and warfarin, but sig-
with HIT who are undergoing percutaneous coronary interventions, the nificantly lower for low-dose dabigatran compared to warfarin. The rate
drug is administered as a bolus of 350 mcg/kg followed by a continuous of intracranial bleeding was lower for both doses of dabigatran com-
infusion of 15 to 400 mcg/kg per minute for a target ACT of 300 to 450 pared to warfarin. The RE-COVER trial was a randomized double-blind

Kaushansky_chapter 25_p0393-0408.indd 399 9/19/15 12:19 AM