ATLANTA, Georgia — New data from a pooled analysis of theEINSTEIN-DVT and EINSTEIN-PE in the treatment of deep venous thrombosis (DVT) or pulmonary embolism suggests thatrivaroxaban (Xarelto, Bayer/ Janssen) is similarly effective in preventing recurrence of venous thromboembolism (VTE) asenoxaparin followed by a vitamin-K antagonist and may be associated with less bleeding.
In addition, subgroup analysis showed reassuring results in specific high-risk populations such as elderly, fragile patients, those with cancer, and those with large clots.
The data was presented at the American Society of Hematology (ASH) 2012 Annual Meeting by Dr Harry Buller (Academic Medical Center, Amsterdam, the Netherlands).
He noted that the EINSTEIN-DVT and EINSTEIN-PE trials had identical noninferiority designs comparing oral rivaroxaban (15 mg twice daily for three weeks then 20 mg once daily thereafter for up to 12 months) with enoxaparin for five to 10 days followed by an oral vitamin-K antagonist. In total, 8282 patients were enrolled into the two trials. The mean age was 57 in both treatment groups, and 50% of the patients were male.
Results of the pooled analysis showed a similar efficacy rate with the two treatments. The primary safety end point--major or nonmajor clinically relevant bleeding--was also similar in the two arms. But major bleeding alone appeared to be significantly reduced with rivaroxaban
Main Results From EINSTEIN Databases Combined
| Outcome | Rivaroxaban (%) | Enoxaparin/vitamin-K antagonist (%) | HR (95% CI) |
| Recurrence of thromboembolism | 2.1 | 2.3 | 0.89 (0.66–1.19) |
| Major or nonmajor clinically relevant bleeding | 9.4 | 10.0 | 0.93 (0.81–1.06) |
| Major bleeding | 1.0 | 1.7 | 0.54 (0.37–0.79) |
Buller commented: "We have clear evidence of noninferiority with regard to recurrence of thromboembolism and a large reduction in major bleeding compared with the current standard of care. And this is with a much more convenient oral drug that does not need monitoring."
Focus on High-Risk Subgroups
Buller noted that while doctors seem to be welcoming the new oral anticoagulants for use in younger, more robust patients, there is the usual caution over use of a new drug in more fragile patients such as the elderly, those with cancer, and others at a high bleeding risk. Also, physicians are generally reluctant to use new agents in patients with a particularly large clot. "We wanted to look at these groups in this large database of the two EINSTEIN trials combined."
First of all, fragile patients--those who were elderly (over 75 years), had a body weight under 50 kg, or those with renal failure (creatinine clearance <50 mL/min)--were investigated, with around 790 such patients in each treatment arm. There was a trend in favor of rivaroxaban in effectiveness and a significant reduction in major bleeding in this group, Buller reported. He commented: "From these data, you would be wrong not to use rivaroxaban in fragile patients. It appears much safer than standard therapy."
EINSTEIN Databases Combined: Results in Fragile Patients
| Outcome | Rivaroxaban (%) | Enoxaparin/vitamin-K antagonist (%) | HR (95% CI) |
| Recurrence of thromboembolism | 2.7 | 3.8 | 0.68 (0.39–1.18), |
| Major bleeding | 1.3 | 4.5 | 0.27 (0.13–0.54) |
The second group of interest included those with cancer, who made up about 200 patients in each treatment arm. Buller said "The numbers in this analysis are small and so need to be interpreted with caution, but again they look reassuring, with no evidence of an increase in bleeding with rivaroxaban."
EINSTEIN Databases Combined: Results in Cancer Patients
| Outcome | Rivaroxaban (%) | Enoxaparin/vitamin K antagonist (%) | HR (95% CI) |
| Recurrence of thromboembolism | 2.6 | 4.0 | 0.62 (0.22–1.8), |
| Major bleeding | 2.6 | 4.1 | 0.61 (0.21–1.77) |
The last subgroup focused on were patients with a large clot. About this group, Buller commented: "Results show no indication that rivaroxaban isn't just as effective as low-molecular-weight heparin followed by a vitamin-K antagonist in patients with a large clot. I think we can use it with confidence in these patients."
Recurrence of Thromboembolism in Patients With Different Categories of Clot
| Category of clot | Rivaroxaban (%) | Enoxaparin/vitamin-K antagonist (%) | p |
| Limited | 1.4 | 2.3 | NS |
| Intermediate | 2.4 | 2.6 | NS |
| Extensive | 2.3 | 2.1 | NS |
Buller acts as a consultant and/or receives research funding from Bayer, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Pfizer, Sanofi, Roche, Isis, and Thrombogenics.
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