© 2014, Bayer AS
Siste oppdatering 14 april 2014
L.NO.03.2014.0926

RECORD Studies in Total Knee Replacement (TKR)

RECORD3: Xarelto® versus enoxaparin in TKR

RECORD3 compared one 10 mg tablet of once-daily Xarelto® with the low-molecular-weight heparin (LMWH) enoxaparin 40 mg administered subcutaneously.4
The American College of Chest Physicians (ACCP) Antithrombotic and Thrombolytic Therapy Guidelines (8th edition) recommend that patients undergoing TKR receive routine thromboprophylaxis for at least 10 days.
This recommendation is graded 1A (strong recommendation based on high-quality evidence, defined as consistent evidence from randomised controlled studies without important limitations).6, 22

Study design

RECORD3 was a randomised, double-blind, double-dummy, head-to-head trial in 2,531 patients undergoing TKR. The enrolled patients were randomly assigned to one of the following regimens:
  • Xarelto® 10 mg tablet starting 6–8 hours after wound closure and continued once daily, plus subcutaneous placebo initiated 12 hours before surgery and continued 6–8 hours after wound closure and once daily thereafter
  • Subcutaneous enoxaparin 40 mg 12 hours before surgery and continued 6–8 hours after wound closure and once daily thereafter, plus oral placebo given 6–8 hours after wound closure and continued once daily
Both study drugs and placebos were given for 12±2 days after surgery. The patients underwent mandatory bilateral venography 1 day after the last dose of the study drug and returned for a follow-up visit 30 (+5) days after the last dose.4


 

Patient demographics: a broad range of patient types

In the RECORD3 study, a broad patient population including patients with a prior history of venous thromboembolism (VTE) was enrolled. There was a wide range of patient ages (28 to 91 years) and weights (41 to 157 kg). As in the entire RECORD programme, the patients enrolled in RECORD3 reflect a typical patient population seen in clinical practice.4

 

Primary efficacy endpoint

Prevention with Xarelto® resulted in a significant relative risk reduction of 49% (P < 0.001) in total VTE (the composite of deep vein thrombosis [DVT], pulmonary embolism [PE], and all-cause mortality) compared to treatment with enoxaparin.4

 

Secondary efficacy endpoint

Prophylaxis with Xarelto® showed superior efficacy over enoxaparin for the reduction of major VTE (proximal DVT, PE, and VTE-related death). Xarelto® achieved a relative risk reduction of 62% (P = 0.01).4
Furthermore, there was a significant 66% relative risk reduction (P = 0.005) for symptomatic VTE for patients on Xarelto® compared with enoxaparin.4
This is the first time since the introduction of unfractionated heparins (UFHs) that prophylaxis with an anticoagulant has led to significant reduction in symptomatic VTE after major orthopaedic surgery on the lower limb.6


 

Reassuring safety



The superior efficacy demonstrated by Xarelto® was associated with a low and similar incidence of major bleeding (0.6% in the Xarelto® arm and 0.5% in the enoxaparin arm). Non-major bleeding was also similar in both groups.4

 
During the treatment period, there were no deaths or known pulmonary emboli in the Xarelto® group and 2 unexplained deaths and 4 known pulmonary emboli in the enoxaparin group; during the follow-up period, there were 4 unexplained deaths in the enoxaparin group.4

The overall occurrence of any adverse events, including serious drug-related adverse events, was similar in the Xarelto® arm (803 patients) and the enoxaparin arm (882 patients).

 

There was no evidence of drug-induced liver injury attributable to Xarelto®. Extensive monitoring throughout the clinical study was performed, which provides a solid basis for assessing the liver safety profile.4

 

RECORD4: Xarelto® versus US regimen of enoxaparin in TKR

RECORD4 compared 10 mg Xarelto® once daily with subcutaneous enoxaparin 30 mg twice daily (the enoxaparin regimen approved in the US for TKR).21
Xarelto® demonstrated a 31% relative risk reduction (P = 0.012) in total VTE in patients undergoing TKR surgery compared to enoxaparin, with a similar safety profile.9

Study design

RECORD4 was a double-blind, double-dummy, head-to-head study in 3,148 randomised patients undergoing elective TKR surgery. The patients were assigned to receive either:
  • Xarelto® 10 mg tablet starting 6–8 hours after wound closure and continued once daily, plus subcutaneous injections of placebo initiated 12–24 hours after surgery and twice daily thereafter
  • Subcutaneous enoxaparin 30 mg 12–24 hours after wound closure and twice daily thereafter, plus oral placebo given 6–8 hours after surgery and continued once daily
The therapy with both study drugs and placebos was continued for 12±2 days after surgery. One day after the last dose of the study drug, the patients underwent a mandatory bilateral venography. The patients returned for a follow-up visit 42 (+5) days after the last dose.21


 

  • 4 - Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
  • 6 - Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):381S-453S.
  • 22 - Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schünemann HJ. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):123S-131S.
  • 21 - RECORD 4 Study: REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE: a Controlled, Double-Blind, Randomized Study of BAY 59-7939 in the Prevention of VTE in Subjects Undergoing Elective Total Knee Replacement. Available at http://clinicaltrials.gov/ct2/show/NCT00362232. Accessed 13 August 2008.
  • 9 - International Congress on Thrombosis: Rivaroxaban is first novel oral anticoagulant to significantly reduce the composite outcome of symptomatic VTE and death [press release]. Leverkusen, Germany: Bayer HealthCare AG; June 30, 2008.
Thromboprophylaxis
Preventative treatment for blood clotting.
Subcutaneous
Introduced beneath the skin.
Venous thromboembolism
A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
Relative Risk Reduction
Proportion of the control group experiencing a given outcome minus the proportion of the treatment group experiencing the outcome, divided by the proportion of the control group experiencing the outcome.
Thrombosis
Formation of a clot inside a blood vessel.
Efficacy
The ability of a drug to produce the desired effect.
Deep vein thrombosis
A blood clot in a deep vein, usually resulting from damage to the vein or blood flow slowing down or stopping. Usually DVTs are found in the leg, but can also be in the arm. Distal DVTs are found in deep veins of the calf, and are the most common type of DVT. Proximal DVTs are found in the legs above the calf muscle up to the waist.
Pulmonary embolism
A potentially fatal condition caused by a blood clot blocking a vessel in the lung: usually the clot originates from a DVT in the legs. PE can result in permanent lung damage.
Major orthopaedic surgery
Major operations on the bones or joints including total hip or knee replacement surgery.

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