This information is intended for healthcare professionals based in Ireland.

ADVANCE-2

ADVANCE-2: Phase III trial for the efficacy and safety of ELIQUIS® (apixaban 2.5 mg tablets) vs. enoxaparin 40 mg once daily (OD) for prevention of venous thromboembolic events (VTE) in patients undergoing total knee replacement surgery1

Overview

ADVANCE-2 was a phase III, randomised, double-blind study comparing the efficacy and safety of ELIQUIS® vs enoxaparin for the prevention of VTE in patients undergoing total knee replacement surgery.

ADVANCE-2 Study Design

In this multi-centre, randomised, double-blind trial, patients received either ELIQUIS® 2.5 mg BD, starting 12–24 hours after surgery, or enoxaparin 40 mg OD starting 12 (+/-3) hours before the procedure. 1528 patients were randomised to ELIQUIS®; 1529 were randomised to enoxaparin.

Subjects underwent either unilateral or same-day bilateral elective knee replacement. Treatment was continued for 10–14 days after surgery.

In hospital all patients were assessed daily for symptomatic Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) as well as bleeding complications. Bilateral venographic studies were scheduled 10–14 days after surgery. All venograms were adjudicated by an independent central adjudication committee.

For primary efficacy analysis, 976 patients in the ELIQUIS group and 997 in the enoxaparin 40 mg OD dosing group were eligible.

The primary efficacy endpoint was the Total VTE/all-cause death (composite of asymptomatic and symptomatic VTE, non-fatal PE and all-cause death), whereas the secondary efficacy endpoint was the major VTE (composite of asymptomatic and symptomatic proximal DVT, non-fatal PE and VTE-related death).

ADVANCE-2 Efficacy Results

ELIQUIS® demonstrated superior efficacy vs. enoxaparin 40 mg OD following total knee replacement1

In ADVANCE-2, the incidence of symptomatic VTE or VTE-related death with ELIQUIS® was low and similar to enoxaparin1:

  • 7/1528 patients (0.46%) in the ELIQUIS® group vs. 7/1529 patients (0.46%) in the enoxaparin group

ADVANCE-2 Trial: ELIQUIS® superior efficacy in Total VTE and Major VTE1

advance 2 eliquis (apixaban) trial superior efficacy in total vte and major vte image

RRR: relative risk reduction
ARR: absolute risk reduction
NNT: number needed to treat
Total VTE/all cause death measured at days 10-14 was a composite of asymptomatic or symptomatic DVT, non-fatal PE and death from any cause.
Major VTE was a composite of asymptomatic and symptomatic proximal DVT, non fatal PE and VTE-related death

ADVANCE-2 Safety Endpoints

ELIQUIS® provided no increased bleeding vs. enoxaparin 40 mg once daily following total knee replacement.1

Primary Safety Endpoint—Bleeding during treatment (major; clinically relevant non-major [CRNM]; minor; composite of major and CRNM).1

ADVANCE-2 Trial: treatment period bleeding rates1

advance 2 eliquis (apixaban) trial treatment period bleeding rates image

Adapted from reference 1
Results include all events occurring after the first dose of enoxaparin (pre-surgery).

Comprehensive bleeding definitions1,2

  • Major Bleeding:

    Acute, clinically overt bleeding accompanied by at least one of the following criteria:
    • A decrease in haemoglobin of 20 g/L or more over a 24-hour period
    • Transfusion of 2 or more units of packed red blood cells
    • Bleeding occurring in one or more critical sites (intracranial, intraspinal, intraocular, pericardial or retroperitoneal)
    • Bleeding into the operated joint needing re-operation or intervention (surgical site bleeding)
    • Intramuscular bleeding with compartment bleeding
    • Fatal bleeding
  • CRNM Bleeding:

    Acute, clinically overt bleeding that does not satisfy criteria for major bleeding and meets at least one of the following criteria:
    • Wound haematoma
    • Bruising or ecchymosis
    • Gastrointestinal bleeding
    • Haemoptysis
    • Haematuria
    • Epistaxis
  • All the bleeding criteria included surgical site bleeding
  • Surgical site bleeding included haematoma, haemarthrosis (with or without intervention), bruising or ecchymosis, and other surgical site bleeds

ADVANCE-2 Surgical Site Bleeding

ELIQUIS® provided similar rates of surgical site bleeding vs. enoxaparin 40 mg OD following total knee replacement.1

Surgical site bleeding was included in the bleeding definition in the ELIQUIS® Phase III trials in major orthopaedic surgery.1,2

The occurrence of surgical bleeds may be associated with an increased risk of infection.3

ADVANCE-2 Trial: Surgical Site Bleeding Incidence1

advance 2 eliquis (apixaban) surgical site bleeding incidence chart image

Adapted from reference 1
Results were based on investigator reports. Not powered to detect statistically significant differences.

Risk Minimisation Materials

The Eliquis (apixaban) Prescriber Guide and Patient Alert Card are risk minimisation materials developed for all indications as an aid to prescribing, in particular they are aimed at increasing awareness about the potential risk of bleeding during treatment with apixaban and providing guidance on how to manage that risk. Printed copies of these educational materials may be obtained by contacting the Bristol-Myers Squibb Medical Information Department (telephone: 1800 749 749; e-mail: medical.information@bms.com). Alternatively, electronic copies can be accessed via the HPRA website at http://www.hpra.ie/homepage/medicines/medicines-information/find-a-medicine.

References:

  1. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815.
  2. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498.
  3. Lieberman JR, Hsu WK. Prevention of venous thromboembolic disease after total hip and knee arthroplasty. J Bone Joint Surg Am. 2005;87(9):2097-2112.