Hokusai-VTE study suggests certain sub-groups of venous thromboembolism patients may need review

AMSTERDAM, The Netherlands – In the treatment of venous thromboembolism (VTE), the oral anticoagulant edoxaban resulted in equal efficacy and better safety compared to standard warfarin when either drug was used with initial low molecular weight heparin (LMWH), according to the results of the Hokusai-VTE trial.

In the landscape of new trials with oral anticoagulants, the Hokusai-VTE findings offer fresh insight into a previously under-represented subgroup of patients with pulmonary embolism (PE), suggesting that treatment for this group might need to be different than for other VTE patients, said lead investigator Harry R. Büller, MD, who presented the findings here at the European Society of Cardiology Congress.

"I think our findings are going to shake things up a little bit," said Dr. Büller, from the Department of Vascular Medicine at Academic Medical Center in Amsterdam.

"What makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE."

The Hokusai-VTE trial included a broader spectrum of VTE patients compared to those included in other recent oral anticoagulant trials, including a large subgroup (30%) of patients with PE and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.

In total, 4921 patients with deep-vein thrombosis and 3319 with pulmonary embolism received initial subcutaneous LMWH therapy and were then randomized to receive either 60 mg of edoxaban daily (30 mg for those at higher risk for bleeding, ie., creatinine clearance 30-50 mL/min or body weight below 60 kg), or warfarin (per standard of care) for 3 to 12 months.

For the primary efficacy endpoint of recurrent symptomatic venous thromboembolism, the study found that edoxaban was non-inferior to warfarin , with the primary endpoint of recurrent symptomatic VTE occurring in 3.2% vs 3.5% respectively (P<0.001 for noninferiority).

However, in the subgroup of patients with pulmonary embolism and evidence of right ventricular dysfunction, efficacy was superior with edoxaban (3.3% vs 6.2%, hazard ratio [HR] 0.52).

For the principal safety outcome of clinically relevant bleeding edoxaban was superior with a rate of 8.5% compared to 10.3% in the warfarin group, (P=0.004 for superiority). This included zero fatal and 5 non-fatal intracranial bleeds with edoxaban compared to 6 fatal and 12 non-fatal intracranial bleeds in the warfarin group.

And among the sub-group of patients ay high risk for bleeding, "by halving the daily dose of edoxaban to 30 mg, efficacy was maintained with significantly less bleeding than observed in the warfarin group," he said. In this high-risk subgroup clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin, while superior efficacy was maintained in the edoxaban arm (3.0% vs 4.2%).

Previous trials of oral anticoagulants have not identified these specific sub-groups, noted Dr. Büller.

"It was a nice and surprising finding that the combination of LMWH and edoxoban in the PE group resulted in a highly significant and clinically relevant reduction of about 50% in recurrent disease."

"Our findings are likely to be generalizable. In a global setting," he added. "We included patients with both provoked and unprovoked venous thromboembolism and treatment durations varied from 3 to 12 months at the discretion of the treating physician."

The success of edoxaban compared to warfarin is good news in the quest for simplified treatment of VTE, said Dr. Büller. "The problem with warfarin is that food and alcohol and many, many medications interfere with the level and so therefore you're obliged to do careful laboratory testing every 3 to 4 weeks or even more frequently to measure the INR (international normalised ratio) and adjust the dose," he said. "The great advantage of the new oral anticoagulants is they have very predictable kinetics and dynamics and therefore can be given in a fixed dose and do not need monitoring."

But, along with enthusiasm for oral anticoagulants, there is also growing hope in the field that injectable heparin might also be safely eliminated, thus switching 2 inconvenient therapies for one pill said Dr. Büller.

"Two previous oral anticoagulant studies have omitted LMWH altogether (EINSTEIN PE and AMPLIFY) and were applauded because of the simplicity of just giving pills, " said Dr. Büller, who was the lead author of one of those studies (N Engl J Med 2012; 366: 1287-97).

But, both EINSTEIN PE and AMPLIFY were criticized for under-representing the severely ill sub-groups that make up a large part of the Hokusai-VTE population, he said.

"The whole field was rushing to the conclusion that we could get rid of both heparin, and warfarin, but I think the findings of the Hokusai-VTE study show that in these subgroups it looks like it would be pretty unwise to omit heparin. Our study adjusts that thinking just a little bit, and may start us reconsidering."

SOURCES OF FUNDING: The study was supported by Daiichi Sankyo.

DISCLOSURES: Harry R. Büller chaired the Hokusai VTE study steering Committee and received compensation for his consultancy and advisory board membership from Daiichi Sankyo.

The European Society of Cardiology (ESC) represents more than 80 000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.

The ESC Congress is currently the world's premier conference on the science, management and prevention of cardiovascular disease. The spotlight of this year's event is "The Heart Interacting with Systemic Organs". ESC Congress 2013 takes place from 31 August to 4 September at the RAI centre in Amsterdam, Netherlands. More information is available from the ESC Press Office at press@escardio.org