Apixaban

May increase the risk of bleeding, including severe and potentially fatal bleeding. Concomitant use of drugs that affect hemostasis increases the risk of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. No specific antidote for apixaban reversal exists. Apixaban is highly protein-bound; therefore, hemodialysis is ineffective. Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending specific clinical scenario: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]).

Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. When used to prevent stroke in patients with nonvalvular atrial fibrillation, an increased risk of stroke was observed upon transition from apixaban to warfarin in clinical trials. If apixaban must be discontinued for reasons other than bleeding or completion of a course of therapy, consider the use of another anticoagulant. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a DOAC (eg, apixaban), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, non-disabling stroke and longer times for moderate-to-severe stroke) (AHA/ASA [Kernan 2014]). Disease-related concerns:

In a clinical trial evaluating the use of apixaban in addition to standard antiplatelet therapy to reduce the risk of recurrent ischemic events post-ACS, an increased incidence of major bleeding (including intracranial and fatal bleeding) without any significant clinical benefit was observed (Alexander 2011).

Use with caution in moderate impairment (Child-Pugh class B) as there is limited clinical experience in these patients; dosing recommendations cannot be provided. Use in severe hepatic impairment (Child-Pugh class C) is not recommended.

Systemic exposure increases with worsening renal function. Bleeding risk may be increased in severe renal impairment (CrCl 2.5 mg/dL or CrCl • Valvular disease: Safety and efficacy have not been established in patients with prosthetic heart valves or significant rheumatic heart disease (eg, mitral stenosis); use is not recommended. Non-valvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valve (AHA/ACC/HRS [January 2014]). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

In acutely ill patients (eg, heart failure, respiratory failure) at risk for venous thromboembolism (VTE) receiving apixaban for extended VTE prophylaxis, an increased incidence of major bleeding without greater efficacy was observed with extended apixaban therapy (eg, 30 days) versus low molecular weight heparin (enoxaparin) therapy for 1 to 2 weeks (Goldhaber 2011).

Systemic exposure is increased ~32% in patients >65 years of age; however, dose reductions are not required. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation who are ≥80 years of age and either weigh ≤60 kg or with a serum creatinine ≥1.5 mg/dL. Other warnings/precautions:

In hemodynamically unstable patients with acute PE or patients with PE requiring thrombolysis or pulmonary embolectomy, the use of apixaban is not recommended as an alternative to unfractionated heparin for initial treatment.

Systemic exposure may be increased by 20% to 30% in patients 120 kg; dosage reduction is recommended for patients with nonvalvular atrial fibrillation weighing ≤60 kg and either ≥80 years of age or with a serum creatinine ≥1.5 mg/dL.

Spinal or epidural hematomas resulting in long-term or permanent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal/epidural puncture; the risk is increased by the use of indwelling epidural catheters with concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, a history of spinal deformity or surgery, or if optimal timing between the administration of apixaban and neuraxial procedures is not known. Consider the potential benefit versus risk prior to neuraxial intervention in patients who are anticoagulated or scheduled to be anticoagulated for thromboprophylaxis. In patients who receive both apixaban and neuraxial anesthesia, avoid removal of epidural or intrathecal catheter for at least 24 hours following last apixaban dose; avoid apixaban administration for at least 5 hours following catheter removal. If traumatic puncture occurs, delay administration of apixaban for at least 48 hours. Monitor frequently for signs of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction). If neurologic impairment is noted, prompt treatment is necessary.