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July 31, 2014

RECORD trials with Xarelto

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Xarelto Reduces Symptomatic VTE and Death Following Knee or Hip Replacement Surgery Compared to Enoxaparin.


Last November Bayer Schering Pharma launched Xarelto (rivaroxaban), an orally active direct factor Xa inhibitor approved for the prevention of venous blood clots in adult patients undergoing elective (planned) hip or knee replacement surgery. EU marketing approval for Xarelto was received following an analysis of three Phase III trials from the extensive RECORD clinical program.
Pooled results from all RECORD trials (including a fourth one), involving more than 12,500 patients undergoing elective hip or knee replacement surgery, have recently been presented at the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco (USA).
RECORD is the largest clinical trial program ever conducted of an oral anticoagulant in the prevention of venous thromboembolism (VTE) after such surgeries.
Study Design
The RECORD studies evaluated Xarelto (10mg given as one tablet, once-daily) in the prevention of VTE following elective total knee or hip replacement surgery against enoxaparin at various doses and treatment durations. The pooled analysis had a primary composite efficacy endpoint of symptomatic VTE (symptomatic deep vein thrombosis and symptomatic non-fatal pulmonary embolism) and all-cause mortality, which was analysed at three different time points: (1) total study duration (day 42 post- knee arthroplasty and day 65 post- hip arthroplasty, including a 30-day follow-up period after study drug discontinuation); (2) total treatment duration (12±2 days following knee arthroplasty and 35±4 days following hip arthroplasty, including 5 weeks rivaroxaban treatment in RECORD2 compared to 2 weeks enoxaparin treatment followed by placebo for 3 weeks); (3) after 12±2 days head-to head treatment post surgery.
Symptomatic VTE and Death reduced by More than 50% with Xarelto compared to Enoxaparin
At all three time points, patients treated with rivaroxaban demonstrated a statistically significant reduction of more than 50% in the composite primary efficacy endpoint of symptomatic VTE and death compared to patients treated with enoxaparin. Specifically, there was 52% and 51% relative risk reductions in those treated with rivaroxaban vs. those treated with enoxaparin at 12.2 days and at total study duration respectively. The relative risk reduction was 58% at total treatment duration (0.6% vs. 1.3%, respectively, p<0.001).
These findings confirm the results of the four individual RECORD studies, which demonstrated the superior efficacy of Xarelto for preventing total VTE, both in head-to-head comparisons with enoxaparin (RECORD1, 3 and 4) as well as when comparing extended-duration (5 weeks) Xarelto with short-duration (2 weeks) enoxaparin in RECORD2.
Low bleeding rates with Xarelto
In all four trials, Xarelto and enoxaparin had similar safety profiles. In the pooled analysis, emergent bleeding safety endpoints were assessed at two time points: total treatment duration and 12±2 days post surgery. Xarelto demonstrated low bleeding rates, which were not significantly different in comparison to enoxaparin for major bleeding, major bleeding including surgical site bleeding, and any bleeding. In particular, rates of any bleeding at total treatment duration were 7.0% vs. 6.5% (p=0.255) and at 12±2 days were 6.6% vs. 6.2% (p=0.376) for Xarelto and enoxaparin, respectively.
Major and clinically relevant non-major bleeding (another safety endpoint) were also low but statistically significantly different for the total treatment duration time period – 3.2% for Xarelto vs. 2.5% for enoxaparin (p=0.039). However, the rates were not statistically significantly different at 12±2 days, which included the majority of reported bleeding cases in these criteria – 2.8% for Xarelto vs. 2.5% for enoxaparin (p=0.186).
Conclusion
“Swelling in the leg and shortness of breath are symptoms that can herald venous thromboembolism, which, in turn, can result in long-term complications or death,” said Dr. A.G.G. Turpie, Principal Investigator for the RECORD program. “As a physician, one of my goals is to reduce patients’ risk of complications, and these data show that Xarelto has the ability to reduce the composite of symptomatic VTE and all cause mortality by half when compared to enoxaparin.” He added: “All the results reported from the RECORD program strengthen my belief that direct Factor Xa inhibition with Xarelto has the potential to revolutionise the way we prevent the formation of dangerous blood clots.”
More than 60,000 patients are expected to be enrolled into the Xarelto clinical development program, which will evaluate the product in the prevention and treatment of a broad range of acute and chronic blood-clotting disorders including VTE treatment, stroke prevention in patients with atrial fibrillation and VTE prevention in hospitalised, medically ill patients.
Full prescribing information and references available from Bayer Schering Pharma. Telephone: (01) 2999313. MIMS Ireland Copyright®