Rivaroxaban non-inferieur aan enoxaparine/warfarine bij DVT

Rivaroxaban almost superior to usual care in treatment of DVT

August 31, 2010


Stockholm, Sweden - Results from the EINSTEIN-DVT study, showing that rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is noninferior to standard medical therapy for the treatment of acute symptomatic deep vein thrombosis (DVT), have been presented during a hot-line session at the European Society of Cardiology (ESC) 2010 Congress today by Dr Harry R Buller (Academic Medical Center, Amsterdam, the Netherlands). 

Buller said that rivaroxaban, an oral factor Xa inhibitor, was close to demonstrating superiority, although the trial was designed specifically to demonstrate noninferiority, because "the standard medical treatment is so good." But although usual care is effective, it is inconvenient, requiring initial subcutaneous injections of low-molecular-weight heparin (LMWH) followed by warfarin treatment, with its own attendant problems. "It's a nightmare to manage, for patients and physicians," he commented to heartwire.

American College of Cardiology president Dr Ralph Brindis (Kaiser-Permanente, San Francisco, CA), who was at the hot-line session press conference today, said: "This is a very important study. It increases our knowledge base regarding the safety and efficacy of factor Xa inhibitors, in this case in the management of DVT."

And the discussant of the EINSTEIN-DVT study, Dr Harald Darius (Vivantes Neukoelln Medical Center, Berlin, Germany), said: "I'm positive we are facing a new era of antithrombotic therapy in patients with DVT, but with some questions to be resolved. For example, what is the optimal duration of treatment? Is it three months, six months, 12 months, or even 24 months?" It also remains to be seen how other trials with similar new agents will compare, he noted.

The findings do appear to be in line with those of a study in the same indication with the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), Darius said. Dabigatran showed noninferiority over usual care in those with acute symptomatic venous thromboembolism (VTE) in the RECOVER trial, reported at the end of last year. However, while EINSTEIN-DVT showed a "definite trend" toward superiority, the RECOVER trial did not, although he acknowledged the difficulty of comparing findings across trials—different bleeding definitions were used in the two studies, for instance.

Whole host of new anticoagulants on the horizon

Both rivaroxaban and dabigatran are already approved for the prophylaxis of DVT and VTE in patients undergoing knee and hip surgery in the EU and some other markets, but neither has been cleared for marketing in the US. An FDA advisory committee did recommend approval of rivaroxaban for this same indication in March 2009, but the FDA has never approved the drug. Asked by heartwire if he had any insights as to why the FDA made this decision, Brindis said he did not: "The FDA has a tough job, they have a huge responsibility to our nation; it's not an easy role."

Now that both rivaroxaban and dabigatran have phase 3 data on the treatment of DVT, it remains to be seen when they will now be filed for approval in this indication. Buller told heartwire it's possible that, in Europe, they might be used off-label for this purpose, because they are already available: "I'm afraid this is going to happen, which we will not encourage, of course. We need to have the full data and try to educate people how to use these."

Trials with these new agents and others are also ongoing for stroke prevention in AF and in ACS patients. Dabigatran is due to be considered by an FDA advisory committee on September 20 for the prevention of stroke in patients with AF, based on the RE-LY megastudy presented a year ago. Rivaroxaban, too, is being looked at in the same indication in the ROCKET-AF study, another large trial in 14 000 patients, slated to be presented at the American Heart Association meeting in November. And a study with another new oral factor Xa inhibitor, apixaban (Bristol-Myers Squibb/Pfizer), vs aspirin to prevent strokes in patients with AF intolerant of warfarin has also just been reported here in Stockholm. Other oral factor Xa inhibitors in development include edoxaban (Daiichi-Sankyo) and betrixaban (Portola Pharmaceuticals/Merck).

The fact that there are a number of new agents nearing the market is good news for doctors and patients, say the experts, because it means there will be plenty of competition in the field, which, it is hoped, will have an effect on the price of the agents. Buller told heartwire: "You will have apixaban, you will have rivaroxaban, and they are going to compete. If a single company would have one of those drugs we would be in trouble, because then they'd have a monopoly, but in this case I'm optimistic."

Brindis agrees: "I am convinced that hopefully soon in the US we will be having that paradigm shift, switching to factor Xa drugs—patients have been begging for it and doctors too, because of the drug-drug interactions and the inconvenience. But when I get asked, 'Which one is going to win?' that question is impossible for me to answer, because there are no head-to-head trials, of course, between the agents. Each of them have different characteristics related to half-life and how they are metabolized; some of the medications are twice a day, some are once a day. The companies are going to look at the nuances between the drugs as a way of trying to differentiate their product in the marketplace."

Net clinical benefit of rivaroxaban "touched" significance

A brief announcement of the EINSTEIN-DVT findings was made by Bayer earlier this month to comply with legal requirements for firms in Germany, which, Buller explained, almost led to the cancellation of the presentation at the ESC meeting. However, the issue was resolved, and he said the ESC is going to meet with companies to discuss how to handle this kind of issue in the future.

In the trial, which was open label, 3449 patients were randomized to either standard DVT treatment—with around five days of subcutaneous injection with an LMWH, in this case enoxaparin (Lovenox, Sanofi-Aventis), followed by followed by a vitamin-K antagonist of either warfarin or acenocoumarol, titrated to maintain an international normalized ratio (INR) of 2.0 to 3.0—or rivaroxaban given as 15 mg twice a day for the first three weeks, followed by 20 mg once a day. This study design, with the twice-daily dose of rivaroxaban given for the first few weeks, came as a result of phase 2 studies, Buller said. The duration of treatment was left to the discretion of the treating physician but was three, six, or 12 months.

The primary efficacy outcome was the first symptomatic VTE event, which occurred in 2.1% of those on rivaroxaban (n=1731) compared with 3% of those on usual care (n=1718), with a hazard ratio of 0.68 (95% CI 0.44-1.04). This clearly met the criteria for noninferiority (p<0.0001), Buller said, and "was pretty close" to superiority.

The two regimens had comparable safety profiles, with the principal safety outcome—a composite of major and nonmajor clinically relevant bleeding events—being 8.1% in both treatment groups (p=0.77). "The only message I think we take from this in the long run is that the profile of bleeding of a full dose of warfarin targeting an INR of 2 to 3 and rivaroxaban are similar," Buller commented.

A combination of the primary efficacy outcome plus major bleeding was lower in those taking rivaroxaban, 2.9%, compared with usual care, 4.2%, for a hazard ratio of 0.67, Buller said. This demonstrates a net clinical benefit of rivaroxaban over standard treatment, which "touched" statistical significance, he said.

Buller also said there were no signs of liver toxicity with rivaroxaban and that the findings were consistent across a number of patient subgroups. "This single-drug regimen without monitoring will provide clinicians and patients with a simple approach to treatment of DVT and has the potential to improve the benefit/risk profile," he concluded.