RIVAROXABAN TAB

Indications

• Atrial fibrillation/flutter (AF)
• Acute venous thromboembolism (VTE), or prevention of recurrent VTE
• Primary prophylaxis of VTE in patients undergoing hip or knee replacement surgery
• Other indication for anticoagulation (local adjudication required)

Exclusions

• Mechanical heart valve
• Moderate to severe rheumatic mitral valve stenosis (for AF/flutter only)
• Antiphospholipid syndrome (APS)
• Known significant liver disease (e.g., acute clinical hepatitis, cirrhosis [Child-Pugh C], or hepatic disease associated with coagulopathy)
• Pregnancy
• Breastfeeding

Pre-Treatment Assessment & Monitoring

• Assessment of renal function (CrCl) and hemoglobin, hematocrit, and platelets
• Consider liver function testing in patients with a history of or risk for hepatic insufficiency
• Provider must assess DOAC choice, dose, and duration considering patient’s age, renal function, liver function, concurrent medications, and indication
• Identify and address modifiable risk factors for bleeding (e.g., NSAIDs, antiplatelet therapy)
• Document the treatment plan including duration in the patient’s chart

Dosing & Administration Requirements

• For acute VTE: Administer 10 mg twice daily for 7 days as oral loading dose BEFORE starting maintenance doses
• Review drug dosing errors and drug-drug interactions, especially with new starts

Special Populations & Clinical Considerations

• Bioprosthetic heart valve placement in the past 3 months: Appropriate based on shared decision-making process between provider and patient
• Severe renal impairment (CrCl <25-30 ml/min) or hemodialysis: Individual evaluation of risks and benefits recommended; net clinical benefit unclear
• Apixaban may be the preferred DOAC when CrCl is less than 30 ml/min
• For patients who can become pregnant: Counsel on potential risks vs benefits of treatment and use of effective contraception during therapy

Clinical Indication & Context

• Low-dose (2.5 mg twice daily) rivaroxaban plus aspirin only for chronic, stable coronary artery disease (CAD)

Exclusion Criteria

• Indication for non-aspirin antiplatelet therapy including dual antiplatelet therapy (e.g., aspirin plus clopidogrel, ticagrelor, or prasugrel)
• Indication for therapeutic dose of an oral anticoagulant (e.g., atrial fibrillation, venous thromboembolism treatment, etc.)
• Recent stroke (within past 30 days) or any history of hemorrhagic stroke
• Heart failure (ejection fraction [EF] less than 40% or NYHA class III or IV symptoms)
• Estimated glomerular filtration rate (eGFR) less than 15 ml/min
• Known hepatic disease associated with coagulopathy
• Concurrent use of combined P-glycoprotein and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin)
• Concurrent use of combined P-glycoprotein and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir and ritonavir combinations, cobicistat)
• Pregnancy
• Breastfeeding
• High risk of bleeding per clinician discretion

Inclusion Criteria

• Prescribed low dose aspirin (75 to 100 mg) once daily as indicated for use with rivaroxaban LOW-DOSE (2.5 mg twice daily)
• One of the following must be met:
• Documented myocardial infarction in the past 20 years
• Multivessel coronary disease with symptoms or history of angina (stable or unstable)
• Multivessel percutaneous coronary intervention
• Multivessel coronary artery bypass graft (CABG) surgery
• One of the following must be met:
• Age 65 years or older
• Less than 65 years old with documented atherosclerosis or revascularization in two vascular beds (coronary vascular bed plus one additional vascular bed, e.g., aorta, brain, gastrointestinal tract, limbs, kidneys)
• Less than 65 years old with two or more risk factors: current smoker (within the last year), diabetes, renal impairment (estimated glomerular filtration rate [GFR] less than 60 mL/min), or atherosclerotic ischemic stroke at least one month ago

• Indication for therapeutic dose of an oral anticoagulant (e.g., atrial fibrillation, venous thromboembolism treatment, etc.)
• Indication for non-aspirin antiplatelet therapy including dual antiplatelet therapy (e.g., aspirin plus clopidogrel, ticagrelor, or prasugrel)
• Recent stroke (within the past 30 days) or any history of hemorrhagic stroke
• Estimated glomerular filtration rate (eGFR) less than 15 ml/min
• Known hepatic disease associated with coagulopathy
• Concurrent use of combined P-glycoprotein and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin)
• Concurrent use of combined P-glycoprotein and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir and ritonavir combinations, cobicistat)
• Pregnancy
• Breastfeeding
• High risk of bleeding per clinician discretion

Primary Inclusion Criteria

• Prescribed low dose aspirin (75 to 100 mg) once daily as indicated for use with rivaroxaban LOW-DOSE (2.5 mg twice daily)
• Additional Inclusion Criteria (Patient must fulfill at least one of the following)
• Current or prior revascularization procedure for the treatment of PAD
• History of limb or foot amputation due to PAD
• Symptomatic PAD, including history of intermittent claudication or critical limb threatening ischemia with objective clinical confirmation (i.e., ankle-brachial index ratio measures, peripheral angiography)

Indication & Administration Parameters

• Use is restricted to low-dose rivaroxaban (2.5 mg twice daily) combined with aspirin ONLY in the setting of PAD
• Concomitant clopidogrel may be used for a finite period of time (e.g., 30 days and up to 6 months) following a lower-extremity revascularization procedure

General Principles & Supportive Care

• Reversal agents considered ONLY for severe, life-threatening bleeding where potential risk of thromboembolism is deemed less than consequences of continued bleeding.
• DOACs have relatively short half-lives; bleeding often managed by temporarily discontinuing anticoagulant and providing supportive care.
• Supportive care includes: discontinuing anticoagulant, maintaining adequate diuresis, compression, surgical repair, fluid and/or blood replacement, hemodynamic support (hemodialysis for dabigatran).
• Consider activated charcoal for known recent DOAC ingestion within past 2-4 hours.
• Consider presence of other antithrombotic drugs (e.g., antiplatelet agents) and discontinue as appropriate.
• Use reversal agents reserved for patients with known recent exposure to a DOAC.
• Restart anticoagulant therapy as soon as medically appropriate due to elevated risk of thromboembolism.

Idarucizumab (Praxbind) Criteria

• Indication: Reversal of dabigatran in setting of bleeding or emergent surgery/urgent procedures.
• Inclusion Criteria (ALL required):
• Patient taking dabigatran with provider reasonably certain therapeutic anticoagulant levels are present.
• Life-threatening or critical site bleeding (e.g., ICH) OR need for truly emergent procedure that cannot be delayed ≥8 hours requiring normal hemostasis.
• Standard measures for bleeding management (e.g., discontinuing anticoagulant, compression, surgical repair, fluid/blood replacement, hemodynamic support) are insufficient.
• Patient’s risk of thromboembolism deemed less than consequences of continued bleeding or delay of procedure/surgery.
• Safety & Considerations:
• Specific for dabigatran only; will not reverse effects of other anticoagulants including Factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban).
• Thromboembolic events reported (4.8% within 30-day follow-up in REVERSE-AD); consider restarting anticoagulant as soon as medically appropriate (dabigatran can be started 24 hours after administration).
• Hypersensitivity reactions reported.
• Hereditary fructose intolerance due to sorbitol excipient (4g per dose) requires consideration of combined metabolic load.
• Re-elevation of coagulation parameters observed in limited patients; safety/effectiveness of repeat doses not established.

4-Factor Prothrombin Complex Concentrate (4F-PCC/KCetra) Criteria

• Indication: DOAC-associated life-threatening bleeding or need for emergent surgery/urgent procedures (Off-label).
• Exclusion Criteria (ANY present = NOT receive):
• Known anaphylactic or severe systemic reaction to 4F-PCC or components (heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III, human albumin).
• Disseminated intravascular coagulation.
• History of heparin-induced thrombocytopenia (contains heparin).
• Inclusion Criteria (ALL required):
• Patient taking a DOAC with provider reasonably certain therapeutic anticoagulant levels are present.
• Specific reversal agent FDA approved for patient’s condition is not readily available.
• Life-threatening or critical site bleeding (e.g., ICH) OR need for truly emergent procedure that cannot be delayed requiring normal hemostasis.
• Standard measures for bleeding management are insufficient.
• Patient’s risk of thromboembolism deemed less than consequences of continued bleeding or delay of procedure/surgery.
• Safety & Considerations:
• Boxed warning for arterial and venous thromboembolic complications; higher thromboembolic events vs plasma in VKA trials, especially with history of thromboembolism.
• Not suitable for patients with thromboembolic events in prior 3 months.
• Hypersensitivity reactions observed.
• Risk of transmitting infection from human blood source.
• No FDA-approved products indicated for reversal of apixaban, rivaroxaban, or edoxaban; use of nonspecific agent such as 4F-PCC may be considered though evidence is limited. If 4F-PCC unavailable, activated PCC (aPCC/FEIBA) may be considered.

Dosing & Administration

• Idarucizumab: Single dose 5 gm (2 vials x 2.5 gm). Administered IV as 2 consecutive infusions or bolus injection. Requires refrigeration.
• 4F-PCC: Doses vary: single dose 25-50 units/kg or fixed dose 2,000 units IV. Dosing calculated based on quantity of factor IX in product. Administered by IV infusion at rate up to 8.4 ml/min (~210 units/min). Supplied in 500 or 1000 unit vials requiring reconstitution; store at 2-25°C.

FDA Approved Adult Indications

• Non-valvular atrial fibrillation
• Treatment of DVT and PE (after 5-10 days of parenteral anticoagulant)
• Reduction in the risk of recurrent DVT and PE following initial therapy
• Post-surgical VTE prophylaxis following hip replacement surgery
• Post-surgical VTE prophylaxis following knee replacement surgery

Oversight & Initiation

• Chronic DOAC therapy requires initial assessment, education, and follow-up by locally designated staff (e.g., anticoagulation management program or other designees).
• Facilities should utilize decision support tools and/or anticoagulation staff for upfront review to verify appropriate candidate selection, agent choice, and dosing upon initiation.
• Short-term treatment (e.g., post-surgical VTE prophylaxis) or very low dose regimens should follow education/monitoring protocols similar to alternative agents in that setting.

Laboratory Monitoring

• Baseline: Serum creatinine (SCr) to estimate creatinine clearance (CrCl); CrCl estimated using Cockcroft-Gault equation with actual body weight for apixaban trials. Hemoglobin, hematocrit, and platelets required. Liver function tests may be considered for patients with history/risk of hepatic insufficiency. PT/aPTT may be obtained for emergency reference. Baseline values drawn within 1-3 months are acceptable per provider clinical judgment based on age/health status/comorbidities.
• Follow-up: SCr monitored at least annually (more frequently if CrCl < 60 ml/min, concomitant illness worsening renal function, or age ≥ 75 years). Hemoglobin, hematocrit, and platelets monitored at least annually or as clinically dictated. Liver function testing considered for underlying liver disease or clinical indication.

Patient Education

• Initial and periodic education must cover: capsule/tablet identification, proper storage, therapy indication, risks/benefits, anticipated duration, daily dose/dosing changes (e.g., loading doses), administration considerations, drug interactions, monitoring requirements, adherence importance, management of missed/extra doses, signs/symptoms of bleeding/thromboembolic events, avoidance of major bleeding risk medications (e.g., NSAIDs, antiplatelets) unless instructed, non-bleeding adverse events, fall risks/mitigation, medication supply acquisition, pre-procedure provider notification for peri-procedural management, anticoagulation provider contact information, and gender-specific considerations for women of childbearing age (menstrual difficulties, pregnancy, contraception).

Adherence Monitoring

• Monitor adherence, refill history, and medication tolerance, especially at therapy initiation.
• Utilize population management tools, telephone follow-up, face-to-face visits, secure messaging, or combinations based on site resources.

Follow-up Care

• Initial: Within 2-4 weeks of initiation (or sooner if clinically indicated) to assess tolerance, bleeding, thromboembolic events, other adverse events (e.g., GI intolerance), adherence, correct dosing (e.g., transition from high-intensity initiation dosing for acute VTE), duplicate therapy, and reinforce education.
• Periodic/Long-term: Reassess adherence, screen for drug interactions, monitor labs as needed. Time points, methods, and responsible staff determined locally per VHA Directive 1108.16(1).

Quality Assurance

• Incorporate DOACs into ongoing quality assurance plans per VHA Directive 1108.16(1).
• Report adverse events per local protocols and P&T Committee; enter into VA ADERS.