Rivaroxiban studies presented at American Society of Hematology
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C. Michael Gibson M.S., M.D. December 10, 2007.
Atlanta, Georgia: The results of the RECORD 1 trial were presented by Dr. Bengt I. Eriksson, MD, PhD, Sahlgrenska University Hospital/Östra, Goteborg, Sweden at the American Society of Hematology. RECORD 1 demonstrates that the investigational agent rivaroxaban when administered once daily in a fixed oral dose for 4 weeks is significantly more effective than subcutaneous enoxaparin, the current standard of care, in reducing the risk of venous thromboembolism after total hip replacement surgery. In addition, these efficacy benefits came without any increase in the risk of bleeding. Rivaroxiban caries the brand name Xarelto, and is an oral factor Xa inhibitor.
At a press briefing discussing the results doctor Eriksson,principal investigator of the study, stated "It's very exciting to be here today to present very positive results, because we showed the superiority of rivaroxaban over the low molecular weight heparin -- enoxaparin -- and in spite of this increased superiority it was possible to maintain safety regarding the risk of bleeding."
RECORD 1
RECORD 1 is an acronym for the Regulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE (RECORD1). RECORD1 was an international, randomized, double-blind, double-dummy Phase-3 trial evaluating the efficacy and safety of oral rivaroxaban versus enoxaparin for thromboprophylaxis following total hip replacement. The trial randomized a total of 4,541 patients to either enoxaparin 40 mg once daily (beginning the evening before surgery and restarting 6 to 8 hours after surgery) or rivaroxaban 10 mg (initiated 6 to 8 hours after surgery and then once a day thereafter). Both drugs were continued for 5 weeks after total hip replacement.
The primary efficacy endpoint in RECORD 1 was the composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality. The incidence of the primary endpoint was 1.1% with rivaroxaban compared with 3.7% with enoxaparin (RRR 70%, p <.001). Likewise, the incidence of the secondary endpoint (major venous thromboembolism and symptomatic VTE) was reduced from 2% with enoxaparin to 0.2% with rivaroxaban (RRR 88%, p <.001).
Despite these differences in efficacy, there was no excess in the trial's main efficacy endpoint, the rates of major bleeding: the rate of major bleeding associated with Rivaroxaban was 0.27% which did not differ from that of enoxaparin at 0.09% (p =.178). The incidence of non-major bleeding was identical for both drugs (5.8%). There was no hepatotoxicity associated with rivaroxaban administration.
Data from the RECORD 2 (total hip relacement) and RECORD 3 (total knee replacement) studies were also presented at the 49th Annual Meeting of the American Society of Hematology.
Highlights from RECORD 2 and 3 are as follows:
- RECORD 2 (n=2,509), which demonstrated a 79% RRR (p<0.001) in total VTE when compared with enoxaparin, again with an 88% RRR (p<0.001) in major VTE
- RECORD 3 (n=2,531), which demonstrated a 49% RRR (p<0.001) in total VTE when compared with enoxaparin, and a 62% RRR (p=0.016) in major VTE
- Major bleeding rates were similar for both drugs (≤0.6%) and differences were not statistically significant
- No routine blood monitoring was required in the Phase III RECORD program at the 10mg dose, based on the Phase II data and pharmacokinetic profile
RECORD 2 (Abstract #307)
The RECORD2 study evaluated the safety and efficacy of rivaroxaban compared with enoxaparin and placebo. The duration of thromboprophylaxis in patients undergoing total hip replacement was 35+/-4 days (extended prophylaxis) for rivaroxaban or 10–14 days for those receiving enoxaparin, followed by placebo. The primary and secondary endpoints were the same as for RECORD1 with a 79% RRR (p<0.001) in total VTE and an 88% RRR (p<0.001) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated a similar rate of major bleeding compared to enoxaparin (0.1% and 0.1%, respectively, p=0.980), despite the greater treatment duration with rivaroxaban in this study.
RECORD 3 (Abstract #308)
The RECORD3 trial compared the safety and efficacy of rivaroxaban with enoxaparin in patients undergoing total knee replacement surgery. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban was initiated 6–8 hours after surgery; both treatments were continued for 10–14 days. Primary and secondary endpoints were the same as for RECORD1 and there was a 49% RRR (p<0.001) in total VTE and a 62% RRR (p=0.016) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated similar rates of major bleeding to enoxaparin (0.6% and 0.5%, respectively, p=0.774).
Copies of the abstracts may be viewed online at the ASH website: [www.hematology.org/meetings/abstracts.cfm]
“In RECORD1, 2 and 3 we have three Phase III trials showing unprecedented results in major orthopedic surgery for the prevention of VTE, and this is genuinely exciting,” said Dr. A.G.G. Turpie, Principal Investigator in the RECORD program, Professor of Medicine, McMaster University, Canada. “In three different trials across large patient populations, we have seen rivaroxaban outperform the current standard of care, enoxaparin, without compromising on safety. This is strong clinical evidence that we are making a major leap forward in oral anticoagulation in orthopedic surgery.”
A key secondary endpoint of the study measuring the reduction of symptomatic VTE, also showed clinically meaningful results in favor of rivaroxaban. For this endpoint, the trials showed an RRR of 45% (p=0.222) in RECORD1, an 80% RRR (p=0.004) in RECORD2 and a 66% RRR (p=0.005) in RECORD3, compared to the standard regimen.
“The symptomatic VTE findings in the RECORD trials are extraordinary,” added Dr. Turpie. “Previous trials were successful in identifying trends towards reducing symptomatic VTE, but with RECORD2 and 3 we are seeing clinically relevant reductions in symptomatic VTE for the first time in orthopedic surgery. These results are a major milestone in the evolution of anticoagulation therapy.”
Unmet Needs in Venous Thromboembolism (VTE)
VTE, a disease process that begins with a blood clot in a vein, includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients undergoing major orthopedic surgery are at risk for VTE because, during the surgery the large veins of the leg that carry blood back to the heart can be damaged, significantly increasing the risk of coagulation and thrombosis.
Each year approximately 700,000 people elect to have hip and knee replacement surgeries in the U.S. and a blood clot is the most common cause of re-hospitalization for this patient group. In fact, VTE is considered the most frequent preventable serious and potentially fatal complication following major orthopedic surgery. But the threat stretches beyond orthopedic surgeries. Blood clots are one of the leading causes of global mortality and a concern for many patient populations, including those with atrial fibrillation at risk for stroke; those at risk for acute myocardial infarction (heart attack); those undergoing major orthopedic surgery; and acutely medically ill patients.
Rivaroxiban is being developed jointly by Bayer and Johnson & Johnson. On Oct 31 Bayer filed an application with the European Agency for the Evaluation of Medicinal Products for rivaroxiban folloping positive results in other RECORD studies of venous thrombosis. Bayer and Johnson & Johnson plan to file for approval of rivaroxaban in the US in 2008.
Disclosure: The author of this article, C. Michael Gibson M.S., M.D. has received research grant support from Johnson & Johnson and Bayer the sponsors of the RECORD 1 study.
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Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
