Apixaban Approved in Europe for Use After Hip/Knee Surgery

May 20, 2011

May 20, 2011 (London, United Kingdom) — The oral direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) has been approved by the European Commission for use in the 27 countries of the EU for the prevention of venous-thromboembolic (VTE) events in adult patients who have undergone elective hip- or knee-replacement surgery [1]. This is the first approval of the drug worldwide.

The approval is based on the ADVANCE-2 and ADVANCE-3 clinical trials, in which apixaban given orally twice daily showed superior efficacy to enoxaparin 40 mg given once daily by injection in the prevention of VTE in total knee and total hip replacement, without increasing bleeding.

The recommended dosage for apixaban is 2.5 mg twice daily. The recommended duration of treatment is 32 to 38 days for patients undergoing hip-replacement surgery and 10 to 14 days for patients undergoing knee-replacement surgery.

Apixaban is one of a host of novel oral anticoagulants nearing or already on the market. Two of these new anticoagulants--another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim)--have been available for VTE prevention for some time in a number of countries.

Of the three oral anticoagulants now approved in Europe, both rivaroxaban in RECORD and apixaban in ADVANCE have been shown superior to enoxaparin, the current standard of care for VTE prevention post–orthopedic surgery. Expert in the field, Dr Alexander Turpie (McMaster University, Hamilton, ON), has previously told heartwire that, viewing these trials side by side, the efficacy results with rivaroxaban seemed slightly better, but the bleeding slightly worse than with apixaban. He attributed these differences to the timing of administration, as rivaroxaban was given six to eight hours after surgery in RECORD, whereas apixaban was given 18 hours after surgery in ADVANCE, and the closer to surgery these drugs are given, the better the outcome but the higher the bleeding risk.

Bristol-Myers Squibb and Pfizer are using the timing of apixaban in ADVANCE to claim: "Apixaban is the only oral anticoagulant with a 12- to 24-hour postsurgery initiation window, which may help physicians to observe and stabilize postsurgical patients before beginning treatment." Rivaroxaban has the advantage, however, of being the only one of these new oral anticoagulants to have a once-daily dosing.

Dabigatran has not shown quite such good results in the orthopedic setting, being shown noninferior to current standard of care in two studies but failing to meet noninferiority in other trials.

But dabigatran has the lead in the much larger indication of stroke prevention in atrial-fibrillation patients, having been approved in this indication in the US and Canada. Rivaroxaban has also shown promising results but has not yet gained approval for this indication.

Apixaban is also being investigated in phase 3 trials for the treatment of VTE, the prevention of VTE in hospitalized acutely ill medical patients, and the prevention of stroke and other thromboembolic events in patients with atrial fibrillation. Its development for acute coronary syndromes (ACS) was dropped after an unacceptable bleeding risk was seen in the APPRAISE-2 trial.

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