Apixaban

Apixaban is an orally active anticoagulant with the molecular formula C25H25N5O4, which has been approved since 2011 for the prophylaxis of venous thromboembolism following elective orthopaedic surgery. Apixaban is approved in the EU for the prevention of ischaemic stroke and systemic embolism in adults with non-valvular atrial fibrillation and is also approved for the treatment and prevention of recurrent pulmonary embolism and deep vein thrombosis.

Apixaban has a half-life of 9 to 14 hours. The substance is well absorbed in the gastrointestinal tract. Its bioavailability is 50 %. Apixaban is metabolised in the liver. Cytochrome P450 plays a minor role in this metabolism. Elimination takes place in 75 % via the bile and 25 % via the kidney.

• highly effective, oral, reversible, direct, highly selective inhibitor of the centre of factor Xa
• independent of AT III
• inhibits the activity of free and clot-bound factor Xa
• no direct effect on platelet aggregation, but indirect inhibition by thrombin

The ADVANCE-2 study (Lassen MR et al. 2010) investigated the effectiveness of thrombosis prophylaxis after implantation of a knee joint prosthesis. Therapy with Apixaban was started 12-24 hours after completion of the operation, with enoxaparin 12 hours before the operation. A superiority of Apixaban (2 × 2.5 mg/day) over therapy with enoxaparin (1x 40 mg/d) was demonstrated.

A similar study result was shown in the ADVANCE-3 study (Lassen MR et al. 2010). Here, the prophylaxis of thrombosis in patients undergoing hip joint replacement was compared. Start of therapy and dose were applied as in the ADVANCE 2 study. Bleeding complications were not more frequent under therapy with Apixaban.

AMPLIFY: This Phase III study compared Apixaban (2 × 10 mg/day for 7 days, followed by 2 × 5 mg/day for 6 months) to standard enoxaparin followed by warfarin (bridging therapy) in 5395 patients with acute deep vein thrombosis and/or acute pulmonary embolism. The result of the study is a non-inferiority of Apixaban compared to conventional therapy. There was significantly less bleeding (Agnelli G et al. 2013)

A rare indication is livedovasculopathy (Livedoid vasculopathy - Osada SI et al. 2019; Yamaguchi Y et al. 2017).

Pregnancy & Breastfeeding:

• Pregnancy: use of Eliquis is not recommended
• Lactation period: Data from animal experiments show transition to breast milk, risk for newborns and children cannot be excluded

Nature of the application:

• with water, can be taken independently from meals
• can also be crushed and dissolved in water, 5% dextrose in water or apple juice or mixed with apple sauce and taken immediately
• can also be administered via stomach tube, crushed and dissolved in 60ml water or 5% dextrose in water
• crushed Eliquis tablets are stable in water, 5% dextrose in water, apple juice or applesauce up to 4 hours

Dosages:

• Prophylaxis of strokes and system. Embolisms in Pat with NVAF: 2 x 5mg per day; dose adjustment required for at least 2 of the following criteria: age >/= 80 years, body weight </=60kg, serum creatinine >/=1.5 mg/dl . Reduction to 2 x 2.5mg per day
• Treatment of acute DVT and LE: initially 2 x 10 mg per day for 7 days, then 2 x 5 mg per day for at least 3 months. Afterwards, a decision on continuation must be made on an individual basis in accordance with the guidelines, depending on the existing risk profile.
• Prophylaxis of recurrent DVT and LE: 2 x 2.5mg per day (only after completion of a 6-month acute therapy)

Discount adjustments:

• restricted kidney function --> dose adjustment necessary
• restricted liver function with coagulopathy and clinically relevant risk of bleeding --> contraindication
• body weight --> no dose adjustment necessary
• Gender --> no dose adjustment necessary
• Age --> no dose adjustment necessary as long as the Krietrein requirements for dose adjustment for NAVF are not met, see above
• Cardioversion --> Apixaban can still be used

children and adolescents --> safety and efficacy not yet proven for persons <18 years, no data available

acute, clinically relevant bleeding, liver parenchyma damage (pathological liver values).

lesions or clinical situations with/as a significant risk factor for heavy bleeding

simultaneous use of other anticoagulants

Precautions: Monitor the risk of bleeding, do not perform routine laboratory monitoring, if necessary use calibrated quantitative anti-factor Xa test to assess efficacy (e.g. emergency surgery, especially overdose)

The potential for interaction with other drugs is estimated to be low. W1 interactions:

• including other anticoagulants, antiplatelet aggregation inhibitors, NSAIDs, fibrinolytics, inhibitors and inducers of CYP3A4 and P-gp, digoxin, naproxen, atenolol, activated carbon

Common to all new oral anticoagulants are the following contraindications:

• acute, clinically relevant bleeding
• lesions or clinical situations that are considered a significant risk factor for major bleeding
• simultaneous use of other anticoagulants such as heparins or vitamin K antagonists (with a few exceptions)
• A kidney dysfunction can also be a contraindication.

Eliquis®

For all new oral anticoagulants such as apixaban, dabigatran etexilate and rivaroxaban, there is a significant risk of severe bleeding events, including death.

Surgery and invasive procedures:

• Apixaban should be discontinued at least 48 hours before the planned surgery/intervention with medium or high risk of bleeding
• Apixaban should be discontinued at least 24 hours before the planned surgery/low bleeding procedure

For further details and updates see the respective valid technical information!

1. Agnelli G et al (2013) Oral apixaban for the treatment of acute venous thromboembolism. In: The New England J Med 369: 799-808
2. Alexander JH et al (2009) Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 119:2877-2885,
3. Connolly SJ (2011) Apixaban in patients with atrial fibrillation. The New England J Med 364: 806-817,
4. Let MR et al (2010) Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 375: 807-815, doi:10.1016/S0140-6736(09)62125-5. PMID 20206776.
5. Let MR et al (2010) Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. The New England J Med 363: 2487-2498
6. Nasir UB et al (2018) Apixaban Causing Leukocytoclastic Vasculitis. J Allergy Clin Immunol Pract 6:1744-1745.
7. Osada SI et al. (2019) Prevention of recurrent ulceration of livedoid vasculopathy with long-term apixaban monotherapy. JDermatol 46:e142-e143.
8. Yamaguchi Y et al. (2017) Rapid remission of severe pain from livedoid vasculopathy with long-term apixaban monotherapy J Eur Acad Dermatol Venereol 31:e45-e46.