New Oral Anticoagulants

The NOACs are new oral anticoagulants, or sometimes called non-vitamin K antagonist (VKA) oral anticoagulants (since they are no longer that new).

Oral anticoagulants are widely used for long-term prevention and treatment of venous and arterial thromboembolism. Until recently, vitamin K antagonists, such as warfarin, were the only available oral anticoagulants. This situation changed with the recent introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban.

Designed to overcome the limitations of warfarin, the NOACs have revolutionized oral anticoagulation because they are at least as effective as warfarin, but are more convenient to administer because the NOACs can be given in fixed doses without routine coagulation monitoring. Moreover, as a class, the NOACs are associated with significantly less intracranial bleeding than warfarin. This is an important advantage because bleeding into the brain is the most feared complication of anticoagulation therapy.

In the United States, rivaroxaban and apixaban are licensed for prevention of venous thromboembolism (VTE) after elective hip or knee replacement surgery and dabigatran, rivaroxaban, apixaban, and edoxaban are approved for treatment of VTE and for stroke prevention in patients with atrial fibrillation (AF). Although not approved in the United States for this indication, rivaroxaban is licensed in Europe for the prevention of recurrent ischemia in stabilized patients with acute coronary syndrome (ACS).

Comparison between Warfarin and NOACs

Warfarin inhibits vitamin K epoxide reductase, thereby attenuating the reduction of oxidized vitamin K in the liver. Without reduced vitamin K as a cofactor for hepatic γ-carboxylase, functional levels of the vitamin K–dependent clotting proteins, factors II, VII, IX, and X decrease. This results in attenuated thrombin generation regardless of whether clotting is triggered via the extrinsic, intrinsic, or common pathway of coagulation. Because of its indirect mechanism of action, the onset and offset of action of warfarin are delayed for several days, a phenomenon that often necessitates bridging with a rapidly acting parenteral anticoagulant when initiating warfarin therapy, and complicates periprocedural management.

In contrast to warfarin, the NOACs directly inhibit a single clotting enzyme; dabigatran inhibits thrombin, whereas rivaroxaban, apixaban, and edoxaban inhibit factor Xa. As direct inhibitors, these agents have a rapid onset of action such that peak plasma levels are achieved 1 to 4 hours after oral administration. With half-lives of ≈12 hours, the NOACs also have a rapid offset of action.

Although warfarin is predominantly cleared through nonrenal mechanisms, the NOACs are excreted, at least in part, via the kidneys. The extent of renal clearance varies; ≈80% of absorbed dabigatran is cleared unchanged by the kidneys, whereas 50%, 33%, and 27% of absorbed edoxaban, rivaroxaban, and apixaban, respectively, are cleared unchanged via the renal route. Consequently, the drugs can accumulate in patients with renal impairment, thereby potentially placing them at risk for bleeding. To avoid this complication, NOACs should be used with caution in patients with a creatinine clearance <30 mL/min, and they should not be used if the creatinine clearance is <15 mL/min.

The dose of warfarin varies between patients reflecting differences in dietary vitamin K intake, multiple drug-drug interactions, and common polymorphisms that affect warfarin metabolism or pharmacodynamics. Warfarin has a narrow therapeutic window; thus, under anticoagulation can lead to recurrent thrombosis, whereas excessive anticoagulation can cause bleeding. Consequently, frequent coagulation monitoring and dose adjustments are necessary to ensure that the international normalized ratio (INR) remains within the therapeutic range. In contrast, because the NOACs produce a more predictable anticoagulant response, they can be given in fixed doses without routine monitoring, thereby simplifying therapy.

Although there are few clinically important drug-drug interactions with the NOACs, potent inhibitors or inducers of CYP 3A4 and p-glycoprotein can be problematic with rivaroxaban and apixaban, whereas potent inhibitors of p-glycoprotein may increase exposure with dabigatran and edoxaban. Dietary vitamin K intake does not influence the NOACs and there are no dietary restrictions except that therapeutic doses of rivaroxaban should be administered with a meal to maximize its absorption.

Indications and Doses for the NOACs:

The recommended doses for the NOACs for each approved indication are provided in the table. In general, the doses used for thromboprophylaxis are half those used for VTE treatment or for stroke prevention in AF. When used for stroke prevention, the doses of the NOACs are reduced based on important patient characteristics to maximize the benefit-to-risk profile.

Reversal of Anticoagulation:

Vitamin K is the antidote for warfarin. When given orally or by slow intravenous infusion, vitamin K restores the INR to baseline levels, but this can take 12 to 24 hours. Rapid warfarin reversal can be achieved with 4-factor prothrombin complex concentrate (PCC). Fresh frozen plasma is an alternative to PCC, but it produces incomplete restoration of the INR to baseline levels, its infusion takes longer than administration of PCC and large volumes of plasma are often needed, which can be problematic for patients with compromised cardiopulmonary function. For these reasons, guidelines recommend PCC over fresh frozen plasma for patients who require urgent warfarin reversal.

There are no specific antidotes for the NOACs, but as outlined by Crowther et al, these are under development. Although nonactivated or activated PCC may be effective for reversal of the anticoagulant effects of the NOACs, clinical data in patients with serious bleeding are limited.

Andexxa (andexanet alfa) works by acting as a decoy for Factor Xa inhibitors in the blood, thereby preventing them from inhibiting the activity of native Factor Xa. As a result, the native Factor Xa is available to participate in the coagulation process and restore hemostasis (normal clotting).

Andexxa is specifically indicated for patients treated with rivaroxaban and apixaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

 

Andexxa is supplied as a lyophilized powder for solution for intravenous injection. Dose Andexxa based on the specific FXa inhibitor, the dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor. Administer as an intravenous (IV) bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. There are two dosing regimens: Low Dose: Initial IV Bolus: 400 mg at a target rate of 30 mg/min. Follow-On IV Infusion: 4mg/min for up to 120 minutes. High Dose: Initial IV Bolus: 800 mg at a target rate of 30 mg/min. Follow-On IV Infusion: 8mg/min for up to 120 minutes.

References:

Calvin H. Yeh, Kerstin Hogg, and Jeffrey I. Weitz. Overview of the New Oral Anticoagulants | Arteriosclerosis, Thrombosis, and Vascular Biology. https://www.ahajournals.org/doi/10.1161/ATVBAHA.115.303397

Kim On, Lan-Anh Hunter, and Ross J Hunter. Ten top tips – NOACs. http://www.pulsetoday.co.uk/clinical/clinical-specialties/cardiovascular/ten-top-tips-noacs/20034760.article

Messerschmidt C, Friedman RJ. Clinical experience with novel oral anticoagulants for thromboprophylaxis after elective hip and knee arthroplasty. Arterioscler Thromb Vasc Biol. 2015; 35:771–778.

Bacchus F, Schulman S. Clinical experience with the new oral anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2015; 35:513–519.

Carreras ET, Mega JL. Role of oral anticoagulants in patients after an acute coronary syndrome. Arterioscler Thromb Vasc Biol. 2015; 35:520–524.