Phase 3 results for new oral anticoagulants in DVT prevention

July 12, 2007

Geneva, Switzerland - Phase 3 results with the new oral anticoagulants rivaroxaban (Johnson & Johnson/Bayer) and dabigatran (Boehringer Ingelheim) in prevention of deep vein thrombosis (DVT) in orthopedic-surgery patients were presented at the 2007 Congress of the International Society on Thrombosis and Hemostasis (ISTH) earlier this week.

Rivaroxaban and dabigatran are the first of a host of potential new oral anticoagulants in development that could become the long-sought-after replacement for warfarin that will not need regular monitoring. They are being developed for the prevention and treatment of DVT as well as for prevention of stroke in atrial-fibrillation patients and the treatment of acute coronary syndromes.

The first major phase 3 study of rivaroxaban to be reported, RECORD 3, suggested superior efficacy in the prevention of venous thromboembolism (VTE), with similar bleeding rates compared with enoxaparin (the current standard of care) in patients undergoing knee-replacement surgery[1].

Two phase 3 trials were reported with dabigatran in hip/knee-replacement surgery. In the RE-NOVATE trial, dabigatran showed similar results to enoxaparin 40 mg[2], while in the North American RE-MOBILIZE study, dabigatran failed to show equivalence to a higher dose of enoxaparin (60 mg)[3].

Lead RECORD 3 investigator Dr Michael Lassen (University of Copenhagen, Denmark) commented to heartwire : "Both these agents are an improvement over what we have at the moment, as they can be given orally, and both agents appear to be working well. From the trials presented here, rivaroxaban, a factor Xa inhibitor, showed better efficacy rates than enoxaparin without increasing bleeding, whereas dabigatran, a factor IIa inhibitor, showed roughly similar efficacy and bleeding rates to enoxaparin. But we can't say from these results that rivaroxaban is better than dabigatran, as we would need a head-to-head trial to do that." Lassen himself believes that factor Xa may be a better target than factor IIa for new anticoagulants. "Factor Xa seems to me to be right molecule to inhibit. You need a lot less drug to inhibit the coagulation system at this point. By the time you get to factor IIa, the intensity of thrombin generation has been upregulated, and there are 800 times more molecules to inhibit," he said.

Of the new oral agents in development, dabigatran appears to be closest to the market, having already been filed for approval in Europe. Rivaroxaban is not too far behind, with approval applications expected for the prevention of VTE in orthopedic surgery in late 2007 in Europe and in 2008 in the US. Rivaroxaban will be marketed in the US by Scios and Ortho-McNeil and in the rest of the world by Bayer Schering.

Rivaroxaban RECORD 3 trial

The RECORD 3 study randomized 2531 patients undergoing knee-replacement surgery to rivaroxaban (10 mg orally once daily started six to eight hours after surgery) or enoxaparin (40 mg subcutaneously once daily started the evening before surgery). Both regimens were continued for 10 to 14 days. The primary efficacy end point of the study was the composite of DVT, as diagnosed by mandatory venography, nonfatal pulmonary embolism (PE), and all-cause mortality, which was significantly reduced in the rivaroxaban group. Significant reductions were also shown for the end points of major VTE and symptomatic VTE. No difference in bleeding rates was seen between the two groups.

RECORD 3: Major efficacy end points

End point Rivaroxaban (%) Enoxaparin (%) Relative risk reduction (%) p
DVT, nonfatal PE, all-cause mortality 9.6 18.9 49 <0.001
Major VTE (proximal DVT, nonfatal PE, and VTE-related death) 1.0 2.6 62 0.01
RECORD 3: Major safety end points
Outcome Rivaroxaban (%) Enoxaparin (%) p
Major bleed 0.6 0.5 NS
Any bleed 4.9 4.8 NS

As the earlier oral anticoagulant, ximelagatran, had to be withdrawn because of liver toxicity, this side effect will be scrutinized with the new agents in development. Lassen noted that liver-enzyme elevations occurred in 1.7% of patients in both groups in RECORD 3, and two additional patients in the rivaroxaban group showed an increase in bilirubin, but all these changes normalized as treatment progressed. He said these results were "reassuring" and that he has not seen any signal of liver toxicity with rivaroxaban so far.

Other rivaroxaban trials to be reported at ASH

The RECORD 1 and 2 trials of rivaroxaban in the prevention of DVT in total hip-replacement surgery are expected to be reported at the American Society of Hematology meeting in December. Results of an additional North American trial of rivaroxaban vs enoxaparin in knee-surgery patients are expected next year. The drug is also in phase 3 trials in the treatment of DVT and in the prevention of stroke in atrial-fibrillation patients and in phase 2 trials in the treatment of acute coronary syndromes.

Dabigatran trials

Two new phase 3 trials of dabigatran in hip/knee-replacement surgery were also reported at the ISTH meeting. In one (RE-NOVATE), dabigatran showed similar results to enoxaparin 40 mg, while in the other (RE-MOBILIZE), dabigatran failed to show equivalence to a higher dose of enoxaparin (60 mg).

The RE-NOVATE trial randomized 3494 hip-replacement-surgery patients to one of two doses of dabigatran (150 mg or 220 mg orally once daily) or enoxaparin (40 mg by subcutaneous injection once daily) for an average of 33 days. The primary efficacy end point of total VTE and death from all causes was similar among the three groups, as was major bleeding. The incidence of liver-enzyme elevations and acute coronary events during the treatment or during the follow-up period also did not differ significantly between the groups.

RE-NOVATE: Major results

End point Dabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin 40 mg (%)
Total VTE and death from all causes 8.6 6.0 6.7
Major bleeding 1.3 2.0 1.6

In the North American knee-replacement trial (RE-MOBILIZE), due to North American labeling requirements, the enoxaparin dosage was increased to 60 mg daily, and the primary end point of equivalence for a composite of proximal DVT, distal DVT, PE, and all-cause mortality was missed. But differences were said to be predominantly due to asymptomatic distal DVTs, since major (clinically relevant) VTE occurred at similar rates in all treatment groups. Although bleeding rates were not statistically different between treatment groups, there were twice as many major bleeding events in the enoxaparin group as in the dabigatran groups, Boehringer reports in a press release.


End point Dabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin 60 mg (%)
Proximal DVT, distal DVT, PE, and all-cause mortality (primary end point) 33.7 31.1 25.3

Also presented at the ISTH meeting was a prespecified pooled analysis of major VTE and VTE-related death after major orthopedic surgery across more than 8000 randomized patients included in the phase 3 primary VTE prevention program for dabigatran (including the RE-MODEL, RE-MOBILIZE and RE-NOVATE studies)[4]. This analysis concluded that dabigatran was comparable to enoxaparin in the prevention of major VTE and VTE-related mortality after both knee and hip replacement. In addition, elevations of liver enzymes and treatment-emergent ACS events were infrequent and comparable across treatment groups.

Combined analysis of dabigatran trials

End point Dabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin (%)
Major VTE and VTE-related death 3.8 3.0 3.3
Major bleeding 1.1 1.4 1.4

Dabigatran is also being studied in a phase 3 trial (RE-LY) for stroke prevention in atrial fibrillation and in the RE-COVER and RE-MEDY trials for acute treatment and secondary prevention of venous thromboembolism.

Portola's factor Xa inhibitor

Phase 2 results with another oral factor Xa inhibitor (PRT054021, Portola Pharmaceuticals) were also reported at the ISTH meeting[5]. The EXPERT study randomized 215 US and Canadian patients undergoing total-knee-replacement surgery to receive one of two oral doses of PRT054021 (15 mg or 40 mg twice daily) or enoxaparin (30 mg twice daily by subcutaneous injection) for 10 to 14 days. The primary efficacy end point was the incidence of VTE through day 10 or 14 measured by venography.

EXPERT results

End point PRT054021 15 mg (n=87) (%) PRT054021 40 mg (n=84) (%) Enoxaparin (n=43) (%)
VTE (95% CI) 20 (12-32) 15 (8-27) 10 (3-23)
Major bleeds 0 0 2.3 (1 patient)
Significant nonmajor bleeds 0 2.4 (2 patients) 4.7 (2 patients)

Portola notes that in recent comparable controlled trials the VTE rate for enoxaparin has been between 15% and 20%.


A phase 2 study with another oral factor Xa inhibitor, apixaban (Bristol-Myers Squibb/Pfizer), focused on the treatment of acute symptomatic DVT[6]. In this study, presented by Dr Harry Buller (Academic Medical Center, Amsterdam, Netherlands), apixaban at three doses showed comparable safety and efficacy to a low-molecular-weight heparin or fondaparinux followed by a vitamin-K antagonist. Phase 3 trials are now under way, with a US approval application scheduled for 2009.

Lassen says he is a consultant for most companies developing new antithrombotics, including Bayer, Sanofi-Aventis, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim.


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