RE-NOVATE 2: Dabigatran "noninferior" to enoxaparin for VTE-event prophylaxis in setting of hip surgery

Becky McCall

June 15, 2010

Barcelona, Spain - In a randomized trial of patients undergoing total hip-replacement surgery, the oral anticoagulant dabigatran (Boehringer Ingelheim) was at least as effective as subcutaneous enoxaparin (Lovenox, Sanofi-Aventis) at preventing the primary end point of venous thromboembolism (VTE) or death (p<0.0001 for noninferiority).

In a secondary finding of the RE-NOVATE 2 trial, the patients who received dabigatran had about half the rate of major VTE or VTE-related death compared with those who received the low-molecular-weight heparin (p=0.03 for superiority).

The trial was reported here at the 2010 Congress of the European Hematology Association (EHA) by Dr Michael Huo (University of Texas Southwestern Medical Center, Dallas). It represents a follow-up to a phase 3 trial called RE-NOVATE, which, as previously reported by heartwire , found dabigatran to be noninferior to enoxaparin in the same clinical setting.

In an interview, Huo observed that the current trial's objective was to determine whether a higher dose of dabigatran—220 mg/day as compared to the 150-mg/day dose many patients in the earlier trial received—would be as safe and efficacious.

Patients were randomized to either oral dabigatran 220 mg once daily (n=1010) or 40 mg subcutaneous enoxaparin (n=1003) for an average of 32 days after total hip replacement.

Dabigatran was found to be as effective and safe as injected enoxaparin with respect to the trial's primary end point of total VTE and all-cause mortality, which occurred in 7.7% and 8.8% of patients, respectively. "This means a noninferiority margin with p<0.0001." It was not statistically significant for superiority. "However, the study was not designed to measure this," Huo observed.

Major VTE events included proximal deep-vein thrombosis, nonfatal pulmonary embolism, and VTE-related death. "The most important finding relates to major VTE and VTE-related death. The difference was 2.2% vs 4.2% in the dabigatran vs enoxaparin groups, respectively," Huo said.

Dabigatran is not approved by the FDA for use in the US, but according to Huo, dabigatran and similar-acting drugs have some distinct advantages. Notably, the oral form is more convenient and easier for patient compliance than subcutaneous administration of an anticoagulant.

Dr Anton Hagenbeek (University Medical Center, Utrecht, the Netherlands) commented that the findings are a major step forward for patients. "For the first time, instead of patients having to receive injections or even inject themselves, they [can] now take a simple pill. Monitoring of blood parameters is no longer required, thereby cutting costs, especially since thrombosis occurs very frequently."

Major bleeding events—classified as fatal, in a critical organ, or associated with a 20-mg/L fall in hemoglobin in excess of expected levels—were comparable between both treatment groups. Huo reported that 1.4% of patients in the dabigatran group vs 0.9% of those receiving enoxaparin had episodes of major bleeding (p=0.40).

Dr Johan Heemskerk (Maastricht University, the Netherlands) cautioned that despite some encouraging results with dabigatran, significant issues relating to bleeding remain. "The challenge is to find an anticoagulant that protects against venous thrombosis but has fewer side effects [than currently available agents]. This may be a step forward, but my understanding of the data suggests there are still further steps to be taken," he said.

RE- NOVATE 2 was sponsored by Boehringer Ingelheim. Huo has served as a consultant to Boehringer Ingelheim. Hagenbeek had no relevant financial disclosures and sits on the commu nication committee of the EHA. Heemskerk had no relevant financial disclosures.


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