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402 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 403

stroke or systemic embolism. Prophylactic rivaroxaban (10 mg once Following total knee replacement apixaban did not meet prespecified
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daily) significantly reduced rates of postoperative VTE compared to the noninferiority criteria in ADVANCE-1, where VTE rates were similar
LMWH Lovenox (40 mg once daily) following hip arthroplasty (1.1 in patients receiving apixaban (2.5 mg BID) and twice daily Lovenox
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percent vs, 3.7 percent, p<0.001) and knee arthroplasty (9.6 percent (30 mg BID) (9.0 percent vs. 8.8 percent), however in ADVANCE-2
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vs. 18.9 percent), and in hospitalized acutely medically ill patients was apixaban was proven to be noninferior to once daily Lovenox in pre-
noninferior to Lovenox for standard 10-day thromboprohylaxis. 86 vention of postoperative VTE following knee replacement. 99
The principal side effect of rivaroxaban therapy is bleeding. In a
pooled analysis of the EINSTEIN studies, major bleeding was less com- EDOXABAN
mon in patients receiving rivaroxaban compared to standard antico- Edoxaban is a direct oral factor Xa inhibitor with peak onset approxi-
agulation (1.0 percent vs. 1.7 percent, p = 0.002), and this includes a mately 1 to 2 hours after administration and a half-life of approximately
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significant reduction in intracranial bleeding. In another meta-analysis 8 hours. Like other direct Xa inhibitors, edoxaban is renally excreted.
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of phase III trials comparing rivaroxaban to standard anticoagulation, Multiple coagulation tests can be affected by edoxaban, but partial
rivaroxaban was associated with a reduced risk of fatal bleeding compli- thromboplastin time (PTT) and anti-Xa assay show the best correlation
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cations. There is no antidote for the anticoagulant effect of rivaroxaban. with drug levels.
Prothrombin complex concentrates partially reverse prolonged coagula- Edoxaban is effective in management of atrial fibrillation and acute
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tion times in healthy volunteers receiving rivaroxaban, and PCC and venous thromboembolism, and in the prevention of VTE following hip
recombinant activated factor VIIa improved bleeding times after rivarox- or knee arthroplasty. In the ENGAGE AF-TIMI trial, the annualized
aban treatment in animal studies. However, these agents have not been rate of stroke or systemic embolism in patients with nonvalvular atrial
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proven effective in managing rivaroxaban treated patients with bleeding fibrillation and moderate to high risk of thrombosis was 1.50 percent
complications.
with warfarin, 1.18 percent with high-dose edoxaban (P<0.001 for non-
inferiority), and 1.61 percent with low-dose edoxaban (P = 0.005 for
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APIXABAN noninferiority). Edoxaban-treated patients experienced significantly
fewer major bleeding events (3.43 percent with warfarin vs. 2.75 percent
Apixaban is an orally administered direct inhibitor of factor Xa which is with high-dose edoxaban and 1.61 percent with low-dose edoxaban). In
metabolized primarily by the hepatic cytochrome CYP3A4 enzyme. The the Hokusai-VTE study, edoxaban was noninferior to warfarin in pre-
onset of action and half-life are 3 hours and 12 hours respectively, and venting recurrent VTE in patients with acute PE or DVT (3.2 percent vs.
approximately 25 percent is excreted by the kidney. Apixaban affects 3.4 percent), and bleeding complications were reduced in the edoxaban
standard anticoagulation assays less than rivaroxaban, and the effect is treated group (8.5 percent vs. 10.3 percent). 102
variable for different reagents within an assay group. In general the PT
is more sensitive than aPTT, and chromogenic apixaban specific anti-Xa
assays display the most accurate linear correlation across a therapeutic FIBRINOLYTIC THERAPY
dose range. There is no antidote for reversal of apixaban. In animal Fibrinolytic therapy is administered by infusing high doses of a plas-
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studies recombinant activated factor VIIa but not PCCs reduced bleed- minogen activator to accelerate the conversion of plasminogen to the
ing times in apixaban-treated animals. 92 active fibrinolytic enzyme plasmin, which proteolytically degrades
Apixaban, like rivaroxaban and dabigatran, has been studied in fibrin (Chap. 135). The specific biochemical and pharmacologic proper-
several clinical settings. Two large phase III randomized clinical tri- ties of different agents are important determinants of the administration
als with slightly different designs led to the approval of apixaban for regimen, the efficacy of clot lysis, and the nature of adverse effects. For
management of nonvalvular atrial fibrillation. In the ARISTOTLE example, some fibrinolytic drugs are bacterial products that are anti-
trial, patients with nonvalvular atrial fibrillation and a risk for stroke genic and can cause allergic responses, whereas others are recombinant
were randomized to apixaban (5 mg BID) or dose-adjusted warfarin. human proteins. Some agents activate plasminogen prominently, both
Apixaban was superior to warfarin in reducing the rate of embolic or in blood and at the clot surface, and induce a systemic fibrinolytic state
hemorrhagic stroke and systemic embolism (1.27 percent vs. 1.6 per- in addition to accelerating clot lysis. In contrast, the activity of other
cent per year, p = 0.01), and fewer patients experienced major bleeding agents is more specifically limited to the clot surface with fewer sys-
complications (2.13 percent vs. 3.09 percent, p<0.001). The AVER- temic effects. Fibrinolytic therapy is used for treatment of both venous
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ROES trial was terminated early because of a clear reduction in stroke and arterial thrombosis and represents standard treatment for many
and systemic embolism in patients with nonvalvular atrial fibrillation patients presenting with acute myocardial infarction because it accel-
deemed unsuitable or unwilling to take vitamin K antagonists random- erates reperfusion, decreases mortality, and reduces morbidity (Chap.
ized to apixaban versus aspirin (1.6 percent vs. 3.7 percent, p<0.001). 135). Thrombolytic therapy has also become standard for many patients
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Interestingly, there was no difference in major bleeding or intracranial presenting with thrombosis of peripheral arteries, bypass grafts, and
bleeding between apixaban and aspirin. Apixaban (10 mg BID for 7 catheters. It is used for treatment of selected patients with thrombotic
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days then 5 mg BID) has also been shown to be noninferior to standard stroke. Fibrinolytic therapy improves outcome in selected patients with
anticoagulation (LMWH then dose-adjusted warfarin) in initial man- large pulmonary emboli (Chap. 135).
agement of acute VTE, and effective for secondary VTE prevention
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in patients treated for an extended time following acute VTE. Major
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bleeding rates were significantly lower with apixaban compared to stan- STREPTOKINASE
dard anticoagulation in the initial period after acute VTE (0.6 percent Streptokinase was the first plasminogen activator used clinically. It is
vs. 1.8 percent, p<0.001), and rates of major bleeding were equivalent derived from β-hemolytic streptococci and has a unique indirect mech-
in patients receiving extended thromboprophylactic dosing of apix- anism of action. By itself, streptokinase has no enzymatic activity, but
aban compared to placebo (0.1 percent in the 5-mg apixaban group, it combines with plasminogen to form an equimolar streptokinase–
0.2 percent in the 2.5-mg apixaban group, 0.5 percent in the placebo plasminogen complex that can then convert other plasminogen mole-
group). Prophylactic apixaban (2.5 mg BID) is better than Lovenox (40 cules to plasmin. Additionally, the streptokinase–plasminogen complex
mg daily) at preventing postoperative VTE following hip replacement. can undergo proteolytic cleavage itself, resulting in activation. When
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