Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1 - RECORD1

Jun 28, 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:
Bayer HealthCare and Johnson & Johnson
Date Published:
01/01/2008
Date Updated:
06/28/2008
Original Posted Date:
06/28/2008
References

Description:

The goal of the trial was to evaluate treatment with the oral direct factor Xa inhibitor rivaroxaban compared with subcutaneous enoxaparin in patients undergoing hip arthroplasty.

Hypothesis:

Rivaroxaban will be more effective for thromboprophylaxis.

Study Design

  • Randomized
  • Blinded
  • Stratified

Patients Screened: 4,591
Patients Enrolled: 4,541
Mean Follow Up: 36 days
Mean Patient Age: Mean 63 years, range 18-93 years
Female: 55

Patient Populations:

Patients at least 18 years of age scheduled to undergo total hip arthroplasty

Exclusions:

• Need for bilateral total hip arthroplasty
• Pregnant or breast-feeding
• Active bleeding or high risk of bleeding
• Allergy or contraindication to one of the study medications
• Any condition preventing bilateral venography
• Severe liver disease
• Severe renal disease
• Use of protease inhibitors for treatment of human immunodeficiency virus
• Planned intermittent pneumatic compression
• Indication for anticoagulation that does not allow it to be terminated

Primary Endpoints:

• Composite of all-cause mortality, nonfatal PE, or any DVT (either symptomatic or asymptomatic thromboses detected by bilateral venography) up to 36 days
• Major bleeding: defined as fatal bleeding, serious bleeding (e.g., retroperitoneal, intracranial, intraocular, or intraspinal), bleeding that required reoperation, or obvious bleeding with a drop in hemoglobin of 2 g/dl or transfusion of 2 U of packed red bleed cells

Secondary Endpoints:

• Major VTE: defined as death from VTE, nonfatal PE, or proximal DVT
• Incidence of any DVT
• Incidence of symptomatic VTE during treatment and up to 35 days after study drug completion
• Death
• Minor bleeding
• Hemorrhagic wound complication
• Any bleeding after the first oral dose of rivaroxaban or placebo and up to 2 days after the last dose was given

Drug/Procedures Used:

Patients undergoing hip arthroplasty were randomized to 10 mg of oral rivaroxaban once daily beginning after surgery (n = 2,266) or 40 mg of subcutaneous enoxaparin once daily beginning the evening before surgery (n = 2,275). Study medications were administered for 35 days and bilateral venography was performed on the 36th day.

Principal Findings:

Study drugs were administered for a mean duration of 33.4 days for the rivaroxaban group and 33.7 days for the enoxaparin group. History of venous thromboembolism (VTE) (for rivaroxaban vs. enoxaparin) was 2.1% versus 2.5%, previous orthopedic surgery was 22.2% versus 22.5%, and the mean duration of surgery was 90.6 minutes versus 91.3 minutes.

The primary efficacy endpoint occurred in 1.1% of the rivaroxaban group and 3.7% of the enoxaparin group (p < 0.001). Major VTE was 0.2% versus 2.0% (p < 0.001), death during the treatment period was 0.3% versus 0.3% (p = 1.0), death during follow-up was 0.1% versus 0% (p = 1.0), nonfatal pulmonary embolism (PE) was 0.3% versus 0.1% (p = 0.37), any deep-vein thrombosis (DVT) was 0.8% versus 3.4% (p < 0.001), symptomatic VTE during treatment was 0.3% versus 0.5% (p = 0.22), and symptomatic VTE during follow-up was <0.1% versus 0.2% (p = 0.37), respectively for rivaroxaban versus enoxaparin.

Major bleeding occurred in 0.3% of the rivaroxaban group and 0.1% of the enoxaparin group (p = 0.18). Any bleeding during treatment was 6.0% versus 5.9% (p = 0.94), minor bleeding was 5.8% versus 5.8%, and hemorrhagic wound complication was 1.5% versus 1.7%, respectively.

Interpretation:

The use of oral rivaroxaban 10 mg daily for 5 weeks was superior to subcutaneous enoxaparin 40 mg daily for 5 weeks in preventing venous thromboembolic events after total hip replacement. Rivaroxaban reduced the composite outcome of death, nonfatal PE, or any DVT 36 days after surgery. This was driven by a reduction in distal and especially proximal DVT. The safety profile of rivaroxaban appeared favorable since there was no increase in major or minor bleeding, hemorrhagic wound complications, or other adverse events such as elevated liver enzymes.

Extended prophylaxis with enoxaparin for 5 weeks is more effective in preventing VTE after hip surgery than a shorter regimen of enoxaparin; however, this requires that a caregiver is able to administer this medication during this time. This phase 3 clinical trial shows the superior efficacy, similar safety, and ease of administration of oral rivaroxaban. This trial complements the findings of the RECORD2 and RECORD3 trials.

References:

Eriksson BI, Borris LC, Friedman RJ, et al., on behalf of the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75.

Keywords: Arthroplasty, Replacement, Hip, Follow-Up Studies, Morpholines, Pulmonary Embolism, Thiophenes, Venous Thromboembolism, Orthopedics, Caregivers, Complement System Proteins, Enoxaparin, Phlebography, Liver, Venous Thrombosis, Factor Xa


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