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Drug used for 35 days after THA reduced VTE rate by 80% vs. 12 days for enoxaparin
Researchers detailed results of the RECORD1 and 2 trials at the recent EFORT congress.
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Results of a multicenter, phase 3 study into pharmacological prevention of venous thromboembolic events after elective total hip arthroplasty showed that they could be reduced substantially without complication by extending use of a novel prophylactic regimen for 35 days when compared with 10-14 days prophylaxis with enoxaparin.
“In major venous thromboembolism (VTE) … it is associated with an 80% reduction in the frequency of symptomatic VTE, but there was no significant increase in bleeding complications associated with continuing prophylaxis for up to 35 days,” Ajay K. Kakkar, PhD, FRCS, said of treatment with rivaroxaban (Xarelto), an oral, direct inhibitor of Factor Xa being developed by Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research & Development LLC.
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Kakkar presented results of the RECORD2 trial (Regulation of Coagulation in Major Orthopaedic surgery reducing the Risk of DVT and PE) at the 9th European Federation of National Associations of Orthopaedics and Traumatology Congress in Nice.
During the same session, Kakkar’s co-author for the RECORD2 study, orthopaedist Bengt Eriksson, MD, of Gothenburg, presented results of a related trial, RECORD1. That study compared extended prophylaxis (35±4 days) with rivaroxaban following total hip arthroplasty (THA) to treatment with enoxaparin sodium (Lovenox, Sanofi) for the same extended time period.
Extended prophylaxis
Investigators for the double-blind RECORD2 trial involving 2,509 patients undergoing elective THA explored the merits of using extended prophylaxis to prevent patients from developing a VTE postoperatively. Based on previous studies, they hypothesized that extended prophylaxis (35±4 days) with the oral anticoagulant rivaroxaban might be more effective than short-term prophylaxis (10-14 days) with enoxaparin in preventing the occurrence of postoperative VTE.
Patients were randomized to receive rivaroxaban (10 mg once daily) starting 6 to 8 hours after surgery and continuing for 35 days (±4 days). Their results were compared to those of patients randomized to receive a subcutaneous injection of enoxaparin (40 mg once daily) for 12±2 postoperative days starting the night before surgery. Patients also received placebo tablets or injections matching the rivaroxaban or enoxaparin doses, respectively.
All patients underwent mandatory bilateral venography the day after the last dose of study medication and were followed for an additional 30-35 days.
Primary, secondary endpoints
Both trials used the same endpoints. The primary efficacy endpoint was total VTE, defined as the composite of any DVT, nonfatal PE, and all-cause mortality up to 35±6 days after surgery. Secondary efficacy endpoints were major VTE (composite of proximal DVT, nonfatal PE and VTE-related death), any DVT, and symptomatic VTE.
Bleeding events, both major and non-major, were the safety endpoints evaluated. In this trial, major bleeding was defined as a bleed that was fatal, went into a critical organ or required reoperation, and any extra surgical site bleeding associated with a drop in hemoglobin of >2 dl or bleeds requiring a transfusion of two or more units of whole blood.
“Compared to short-duration thromboembolic prophylaxis with only 12 days of enoxaparin followed by placebo, extended duration prophylaxis for up to 35 days was associated with a substantial reduction in the frequency of VTE events, a 79% reduction from 9.3% in the short-duration group to 2.0% in the extended-duration group,” Kakkar said.
For secondary endpoints, extended prophylaxis with rivaroxaban significantly reduced the incidence of major VTE by 88%, from 5.1% in the short-term enoxaparin group to 0.6% in the group that received extended rivaroxaban.
“But most importantly, if one looks at symptomatic events occurring before the time of venography, we can see a similar reduction in the frequency of events, an 80% reduction from a 1.2% symptomatic VTE rate some 35 days after operation reduced to 0.2%, a highly significant difference,” Kakkar said.
RECORD1 results
Eriksson presented the results of the RECORD1 trial, which involved 4,541 patients.
Total VTE rates (the primary efficacy endpoint) were 3.7% in patients treated with enoxaparin for 5 weeks, which compared favorably with the results from the other study, he said. “This was reduced to 1.1% with rivaroxaban and a significant P value and you can see a relative reduction risk of 70%,” Eriksson said.
The reduction in total VTE was consistent with the significant and substantial reduction seen in the incidence of major VTE. “It was reduced substantially by the rivaroxaban drug from 2.0% to 0.2%,” Eriksson said.
“This is the first study to compare extended prophylaxis for 35 days with rivaroxaban vs. enoxaparin. The primary endpoint was reduced by 70% with rivaroxaban compared to enoxaparin,” he said. “This was also consistent with the results seen for major VTE … and there was no indication of any compromise in safety.”
For more information:
- Ajay K. Kakkar, PhD, FRCS, can be reached at the Thrombosis Research Institute, Barts and the London School of Medicine and Dentistry, Emmanuel Kaye Building, Manresa Road, London SW3 6LR England; +44-171-35-8301; e-mail: akkakkar@tri-london.ac.ak. He received honoraria as a member of the Bayer Healthcare AG steering committee and is a consultant to Bayer Healthcare AG.
- Bengt Eriksson, MD, can be reached at the Department of Orthopaedics, Sahlgrenska University Hospital/Östra, SE-41685 Gothenburg, Sweden; +46-31-343-4408; e-mail: b.eriksson@orthop.gu.se. He received an honorarium as a member of the RECORD1 and RECORD2 Steering Committees and is a consultant to Bayer HealthCare AG.
References:
- Eriksson B, Borris L, Friedman R, et al. Comparison of oral rivaroxaban and subcutaneous enoxaparin for extended thromboprophylaxis following total hip replacement: RECORD1. Paper F2.
- Kakkar AK, Brenner B, Dahl O, et al. An evaluation of the efficacy and safety of extended thromboprophylaxis with oral rivaroxaban compared with short-term subcutaneous enoxaparin following total hip replacement (RECORD2: a phase III study). Paper F1. Both presented at the 9th European Federation of National Associations of Orthopaedics and Traumatology Congress. May 29-June 1, 2008. Nice.