Boehringer Ingelheim has now published the encouraging Phase III data from the RE-NOVATE trial with its once-daily oral direct thrombin inhibitor, Rendix (dabigatran), that were presented last July at the XXI Congress of the International Society on Thrombosis and Haemostasis in Geneva.

As previously reported, the double-blind study of 3,494 patients undergoing total hip replacement showed that dabigatran exexilate, taken once-daily for an average of 33 days, was as effective and well tolerated as injections of the standard treatment, Sanofi-Aventis’ Lovenox (enoxaparin), in preventing venous thromboembolism (VTE) after orthopaedic surgery.

In the trial led by Dr Bengt Eriksson from Sahlgrenska University Hospital in Gothenburg, Sweden, patients were randomised to either dabigatran 220mg once daily, dabigatran 150mg once daily or a subcutaneous injection of enoxaparin 40mg once daily. The primary efficacy outcome was a composite of total venous thromboembolism (blood clots, venographic or symptomatic) and death from all causes.

Among the 3,494 patients, 880 in the dabigatran 220mg group, 874 in the dabigatran 150mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis. The main reasons for exclusion in all three groups were lack of adequate venographic data, the researchers noted in The Lancet (2007; 370:949-956). .

The primary efficacy outcome occurred in 53 of the 880 available patients (6.0%) in the dabigatran 220mg group, 75 of 874 patients (8.6%) in the dabigatran 150mg group and 60 of 897 patients (6.7%) in the enoxaparin group. There was no significant difference in major bleeding rates with either dabigatran dose compared with enoxaparin, nor in the frequency of either acute coronary events or increases in liver enzyme concentrations.

“Our results show that oral dabigatran etexilate, 220 mg or 150 mg once daily, given for a median of 33 days, was non-inferior to enoxaparin for reducing the risk of total venous thromboembolism and all-cause mortality after total hip replacement surgery,” the authors concluded.

“These findings, in conjunction with other results from the large, Phase 3 development programme in total hip and knee replacement surgery, will help define the optimum dosage regimen for dabigatran etexilate,” they added. Rendix has already been filed for approval in Europe for the prevention of deep-vein thrombosis in conjunction with hip or knee joint replacements.

One of the other study authors, Simon Frostick, Professor of Orthopaedics at the University of Liverpool in the UK, commented: “Given the trend for shorter hospital stays following joint replacement surgery and longer duration of thromboprophylaxis, it is becoming increasingly important to have anticoagulant treatments available which are well tolerated and easy to use in an outpatient setting. Based on the encouraging results demonstrated in the RE-NOVATE trial, once daily oral dabigatran exexilate may be an attractive alternative to other thromboprophylaxis regimens currently used to prevent VTE in patients undergoing elective hip replacement surgery.”

Warning note

There was a warning note, though, from Dr John Norrie of the Centre for Healthcare Randomised Trials at the University of Aberdeen in Scotland. In an accompanying comment in The Lancet, he suggested that the RE-NOVATE trial results might be compromised by methodological flaws.

Typically, Dr Norrie pointed out, VTE trials with venographically determined primary outcomes end in one in three patients not having any data, either because venography is not performed or the results are unreadable. “The bottom line is that the effect of these missing data is unknown,” he commented.

In future, VTE trials should be designed with safety analyses in mind, Dr Norrie said, adding: “Even in a mature research area such as treatments for venous thromboembolism, there is still important methodological work to be done to improve design and so ensure the highest quality of evidence to inform the management of these conditions.”