Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 3 - RECORD3

Jun 27, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Johnson & Johnson Pharmaceutical Research & Development and Bayer HealthCare AG
Date Presented:
01/01/2007
Date Published:
01/01/2008
Date Updated:
06/27/2008
Original Posted Date:
06/27/2008
References

Description:

The goal of the trial was to evaluate treatment with rivaroxaban, a novel direct factor Xa inhibitor, compared with enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee replacement surgery.

Hypothesis:

Rivaroxaban will be more effective in preventing VTE.

Study Design

  • Randomized
  • Blinded

Patients Screened: 2,556
Patients Enrolled: 2,531
Mean Follow Up: 42 days
Mean Patient Age: 68 years
Female: 68

Patient Populations:

Age ≥18 years old and scheduled for elective total knee replacement

Exclusions:

Active bleeding or high risk of bleeding contraindicating treatment with low molecular weight heparin; contraindication listed in the labeling or conditions precluding subject treatment with enoxaparin or requiring dose adjustment (e.g., severe renal impairment); conditions prohibiting bilateral venography (e.g., amputation of one leg, allergy to contrast media); use of human immunodeficiency virus protease inhibitors; or anticoagulant therapy that could not be stopped

Primary Endpoints:

Composite of DVT, nonfatal PE, and all-cause mortality

Secondary Endpoints:

Major VTE, defined as the composite of proximal DVT, nonfatal PE, and VTE-related death

Drug/Procedures Used:

Patients were randomized in a double-blind manner to rivaroxaban (10 mg orally per day; n = 1,254) or enoxaparin (40 mg subcutaneous per day; n = 1,277). The rivaroxaban was started 6-8 hours after surgery and the enoxaparin was started 12 hours before surgery. Both were continued for 10-14 days. Patients underwent bilateral venography to evaluate for deep vein thrombosis (DVT) after the study drug was discontinued.

Principal Findings:

At study entry, 4% of patients had a history of VTE and 29% had a prior orthopedic surgery. The majority of patients were females (68%). Median weight was 80 kg and median body mass index was 29 kg/m2.

The primary composite endpoint of DVT, pulmonary embolism (PE), or death was significantly lower in the rivaroxaban group compared with the enoxaparin group (9.6% vs. 18.9%, relative risk reduction [RRR] 49%; p < 0.001), driven by a reduction in DVT (9.6% vs. 18.2%, p < 0.001; proximal DVT 1.1% vs. 2.3%, p = 0.068; distal DVT only 8.5% vs. 15.9%, p < 0.001). Among the components, PE was infrequent, but occurred less frequently in the rivaroxaban group (0 vs. 0.5%, p = 0.06); there was no difference in death (0 vs. 0.2%).

The secondary endpoint of major VTE was also significantly lower in the rivaroxaban group (1.0% vs. 2.6%, RRR 62%, p = 0.01). Symptomatic VTE occurred less frequently in the rivaroxaban group (0.7% vs. 2.0%, p = 0.005).

Among the safety cohort, there was no difference in major bleeding between the rivaroxaban and enoxaparin groups (0.6% vs. 0.5%, p = 0.77). Any bleeding occurred in 4.9% of the rivaroxaban group and 4.8% of the enoxaparin group. Alanine aminotransferase >3x upper limit of normal on day 1 occurred in 1.7% of each group. The frequency of drug-related adverse events was similar between groups (12.0% of the rivaroxaban group and 13.0% of the enoxaparin group).

Interpretation:

Among patients undergoing elective total knee replacement surgery, treatment with the novel direct factor Xa inhibitor rivaroxaban was associated with a reduction in DVT compared with treatment with enoxaparin.

In conclusion, DVT and major VTE were reduced in the rivaroxaban group, without an increase in bleeding or adverse events. This trial complements the findings of RECORD1 and RECORD2.

Other studies with rivaroxaban are underway in the settings of acute coronary syndromes and atrial fibrillation. While RECORD3 provided information on rivaroxaban in the venous system, these ongoing trials will provide insight into rivaroxaban in the arterial system.

References:

Presented by Dr. Michael R. Lassen at the XXI International Society on Thrombosis and Haemostasis (ISTH) Congress, Geneva, Switzerland, July 2007.

Lassen MR, Ageno W, Borris LC, et al., on behalf of the RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-86.

Keywords: Risk, Acute Coronary Syndrome, Arthroplasty, Replacement, Knee, Morpholines, Pulmonary Embolism, Thiophenes, Venous Thromboembolism, Orthopedics, Complement System Proteins, Body Mass Index, Enoxaparin, Phlebography, Venous Thrombosis, Factor Xa


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