Xarelto

Twenty-four young adult male Wistar Albino type rats of the same age, weighing 350 ± 50 g, were randomly divided into three groups. All animals were housed in an environment with 12-hour light and 12-hour dark cycles, 55% humidity, and 21 ± 2°C; they were fed with standard feed. All rats underwent a full-thickness surgical incision of the Achilles tendon, followed by primary repair (SA). After the procedure of the Achilles tendon, group 1 was determined as the control group and received no medication. Group 2 received 2.03 mg/kg rivaroxaban equal to 0.6 mg rivaroxaban/daily (Xarelto, Bayer HealthCare, Berlin, Germany) via gastric lavage once daily, for 28 days. The adjusted dose of rivaroxaban for rats was calculated according to the study of Nair and Jacob.
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Group 3 was given subcutaneous 114 IU AXa nadroparin calcium (Fraxiparine, Glaxo SmithKline, Canada) as low-molecular-weight heparin (LMWH), once daily for 28 days. The adjusted dose of nadroparin calcium for the rats was calculated according to the study of Nair and Jacob.
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The rats were given free access to food and water as well as free movement within their cages and the guidelines for the care and use of laboratory animals in biomedical research were closely followed.
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For dosing the rats, the original drug product (Xarelto, Bayer AG, Leverkusen, Germany) was crushed into powder and filled into the 9el gelatin capsules (Harvard Apparatus, Holliston, USA) as a reference formulation. Rivaroxaban content in one capsule was 4 mg.
In clinical studies, Xarelto® 20 mg film‐coated tablets (Bayer Pharma AG), were used as a reference product.
For the clinical study, the final granulates of all tested prototypes were filled into hypromellose capsules with rivaroxaban content in one capsule of 20 mg, while for the preclinical study, the final granulates of all tested prototypes were filled into 9el gelatin capsules with rivaroxaban contents of 4 mg per capsule.

Postoperative care incorporated a multimodal pain control programme. Urinary retention was systematically detected by bladder scan during the immediate postoperative period. Transfusion triggers were 8 g/dL Hb in patients with irrelevant cardiovascular comorbidities and 10 g/dL of Hb in patients with coronary artery disease. The rehabilitation protocol consisted of immediate hip mobilisation. Full weight-bearing was allowed postoperatively with the protection of crutches for one month.
Pharmacological venous thromboembolism (VTE) prophylaxis was started on the day of surgery, 6–10 hours after the closure of the skin. Two different anticoagulant molecules were used through successive periods for the immediate postoperative period: fondaparinux (Arixtra; GlaxoSmithKline, Marly-le-Roi, France) 2.5 mg once daily for nine days followed by subcutaneous pharmacologic VTE prophylaxis with 4,500 IU tinzaparine (Innohep, Leo Pharma, St-Quentin-en-Yvelines, France) once daily. Oral rivaroxaban (Xarelto; Bayer, Lille, France) was continued at 10 mg once daily for 35 days without platelet monitoring. NSAIDs were not used for prevention of heterotopic ossification. All patients underwent Doppler ultrasound of both lower limbs on postoperative Day 7, or earlier if there was any clinical suspicion of DVT.

An intermittent pneumatic foot vein pump and stretch socks were used. The patients were subcutaneously given enoxaparin sodium (Clexane, Sanofi Aventis) or orally given rivaroxaban (Xarelto, Bayer). In the first stage, enoxaparin sodium was given once a day, and the dosage was adjusted according to the patients’ weight. Some of the patients were subcutaneously given conventional doses (i.e. low-molecular-weight heparin) 12–24 h after TKA surgery (2–4 h after epidural catheter removal), and some were given half of the conventional doses 4–6 h after surgery, and the next day conventional doses were given. This process was generally repeated once every 24 h for 3–5 days. In the second stage, subcutaneous injection of low molecular weight heparin or oral administration of warfarin 10 mg once a day was used for 10–14 days after surgery.

Blood samples were obtained from patients aged 18–90 yr receiving rivaroxaban (Xarelto^®; Bayer, Germany). Exclusion criteria were pregnancy, non-compliance in taking medication, concomitant medication with an influence on rivaroxaban activity, or presence of haemophilia or an acquired or hereditary coagulation disorder.