Safety

ADVANCE-2: A study of VTE prevention in patients undergoing elective TKR2

Apixaban was comparable to enoxaparin across the three bleeding outcomes2

Eliquis® was comparable to enoxaparin across three bleeding outcomes3

‡12 patients in the apixaban group and 16 in the enoxaparin group had major or clinically relevant non-major bleeding events that occurred before the first postsurgery dose of study drug.2
§Seven patients in the apixaban group and 11 in the enoxaparin group had clinically relevant non-major bleeding events that occurred before the first postsurgery dose of study drug.2
ǁFive patients in the apixaban group and five in the enoxaparin group had major bleeding events that occurred before the first postsurgery dose of study drug.2

Major bleeding2

Acute, clinically overt bleeding accompanied by at least one of the following criteria:

  • A decrease in haemoglobin of 2 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
  • Intramuscular bleeding with compartment syndrome
  • Fatal bleeding

CRNM bleeding2

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
  • GI bleeding
  • Haemoptysis
  • Haematuria
  • Epistaxis

Study Design

In ADVANCE-2, a multicentre, randomised, double-blind phase III study, patients undergoing elective unilateral or bilateral TKR  were randomly allocated through an interactive central telephone system to receive oral apixaban 2.5 mg BID (n=1,528) or SC  enoxaparin 40 mg once daily(n=1529). Apixaban was started 12–24 hours after wound closure and enoxaparin 12 hours before surgery;  both drugs were continued for 10-14 days, when bilateral ascending venography was scheduled. Primary outcome was the  composite of asymptomatic and symptomatic DVT, non-fatal PE, and all-cause death during treatment.2

 

ADVANCE-2: Apixaban versus Enoxaparin for Thromboprophylaxis after Knee Replacement; BID: twice daily; CRNM: clinically  relevant non-major bleeding; DVT: deep-vein thrombosis; GI: gastrointestinal; NS: non-significant; PE: pulmonary embolism;  QD: once daily; SC: subcutaneous; TKR: total knee replacement; VTE: venous thromboembolism.

References: 1 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban  versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. 2. Lassen MR, Raskob GE, Gallus A, Pineo  G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement  (ADVANCE-2): a randomized double-blind trial. Lancet. 2010;375(9717):807-815. 

#Ruff CT, et al. Lancet. 2014;383(9921):955-62, Hur et al, Acta Orthopaedica 2017; 88 (6): 634–641, Cohen AT et al. Adv Ther 2014;31:473-93

ADVANCE-3: A study of VTE prevention in patients undergoing elective THR2

Apixaban was comparable to enoxaparin across the three bleeding outcomes2

Eliquis® was comparable to enoxaparin across three bleeding outcomes2

*Patients could be counted in more than one category of bleeding events.

Major bleeding2:

Major bleeding was defined as acute clinically overt bleeding accompanied by one or more of the  following: a decrease in blood haemoglobin concentration of 20 g/dl or more during 24 hours; transfusion  of two or more units of packed red blood cells; critical site bleeding (including intracranial, intraspinal,  intraocular, pericardial or retroperitoneal bleeding); bleeding into the operated joint needing reoperation  or intervention; intramuscular bleeding with compartment syndrome; or fatal bleeding.

Clinically relevant non-major (CRNM) bleeding2:

Included acute clinically overt episodes such as wound haematoma, bruising or ecchymosis, GI bleeding,  haemoptysis, haematuria or epistaxis that did not meet criteria for major efficacy outcome for non-inferiority using a prespecified margin in which the upper limit of the 95% CI for RR should not exceed 1.5, and if this occurred to then test for superiority.

Study Design

In this double-blind, double-dummy study, we randomly assigned 5407 patients undergoing total hip replacement to receive apixaban at a dose of 2.5 mg orally twice daily or enoxaparin at a dose of 40 mg subcutaneously every 24 hours. Apixaban therapy was initiated 12 to 24 hours after closure of the surgical wound; enoxaparin therapy was initiated 12 hours before surgery. Prophylaxis was continued for 35 days after surgery, followed by bilateral venographic studies. The primary efficacy outcome was the composite of asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause during the treatment period. Patients were followed for an additional 60 days after the last intended dose of study medication.2

 

ADVANCE-3: Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement; BID: twice daily; CI: confidence  interval; CRNM: clinically relevant non-major bleeding; DVT: deep-vein thrombosis; GI: gastrointestinal; NS: non-significant;  PE: pulmonary embolism; QD: once daily; RR: relative risk; SC: subcutaneous; THR: total hip replacement; VTE: venous  thromboembolism.

References: 1 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban  versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. 2. Lassen MR, Gallus A, Raskob GE, Pineo  G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.  N Engl J Med. 2010;363(26):2487-2498.

#Ruff CT, et al. Lancet. 2014;383(9921):955-62, Hur et al, Acta Orthopaedica 2017; 88 (6): 634–641, Cohen AT et al. Adv Ther 2014;31:473-93

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