December 4, 2010
Orlando, FL - The new oral anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is one of a number of new agents that could change the way that patients with deep vein thrombosis (DVT) and venous thromboembolism (VTE) are treated, attendees at the American Society of Hematology (ASH) meeting heard today.
During a press conference here, Dr Harry R Büller (Academic Medical Center, Amsterdam, the Netherlands) presented the findings of two studies that he has already reported previously, the EINSTEIN Acute-DVT study and EINSTEIN extension study. "This new treatment regimen of oral rivaroxaban can potentially make blood-clot therapy easier than the current standard treatment for both the patient and the physician with a single drug and simple fixed-dose approach," he noted.
Büller acknowledged: "There's nothing new as far as the data are concerned, except a little more detail on subgroups." But the two studies have been combined into one paper, appearing simultaneously in the New England Journal of Medicine , and this, he says, "has worked out well, in the sense of it tells you what to do initially if you are confronted with a patient with DVT and then if you've completed treatment for six to 12 months. It's the combined perspective that is important—how to interpret both studies together." Büller says he believes the EINSTEIN-Extension data "are being interpreted as really saying we shouldn't stop therapy after six to 12 months in that middle group of idiopathic patients."
But hematologist Dr Trevor P Baglin (Addenbrookes Hospital, Cambridge, UK), who was not involved in the EINSTEIN studies, said that EINSTEIN-Extension "is bizarre" and does not really add anything new to the debate about whether to continue anticoagulant therapy or not, because it compared ongoing rivaroxaban treatment with placebo. "The study that clinicians want to see is patients randomized to warfarin or a new anticoagulant," he says.
Dr Roy Silverstein (Cleveland Clinic, OH), also a hematologist, agrees: "EINSTEIN-Extension won't drive clinical practice that much because the control group was placebo," he commented. However, Silverstein says it does, at least, "show that rivaroxaban prevents recurrences if taken and that the bleeding risk of this drug is very low, so it could broaden the indication for extended therapy."
Trials where other new anticoagulants, such as the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) are being compared with warfarin for extended treatment of venous thromboembolism, are ongoing, Büller said.
Rivaroxaban looks good in EINSTEIN DVT, but cost an issue
Büller first presented the EINSTEIN Acute-DVT data at the European Society of Cardiology (ESC) meeting his summer; he told that the "ESC audience is not the audience you would expect to be terribly interested in DVT," so this was another reason for presenting the findings at ASH. "The fact that we need to treat someone with VTE in the beginning is obviously not new. Rivaroxaban—as a single-drug approach—just makes life easier and is at least as good as standard therapy," he says. This trial and others with competing agents in the same indication mean that the treatment of VTE will increasingly move out of the hospital into the community, he says.
Both Baglin and Silverstein agree that the EINSTEIN Acute-DVT data are informative. "There's no doubt that if you stick the two drugs side by side (warfarin and rivaroxaban) that you would use the new drug," says Baglin, "but the problem is cost." In the UK, it currently costs less than £100 a year to keep a patient on warfarin, he says, compared with the current cost of around £1500 a year for the newer anticoagulants. He acknowledges, however, that cost issues will be different in different markets.
Silverstein says the EINSTEIN Acute-DVT study "is a nice, encouraging study, well-done, that clearly shows noninferiority [to warfarin] and probably shows a clinically significant advantage [of rivaroxaban] in terms of major bleeding."
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. Now that both have phase 3 data on the treatment of DVT, it remains to be seen when they will be filed for approval in this indication.
Debate as to how much EINSTEIN-Extension adds to knowledge base
While the experts agree that the implications of EINSTEIN DVT are clear-cut, there is much more uncertainty and debate with regard to how long anticoagulant therapy should continue in patients who have had a thrombotic event.
Büller explains that in some patients, it is obvious treatment can stop—because, for example, they had a temporary risk factor such as thrombosis after orthopedic surgery—and in others, it is obvious treatment should be continued indefinitely—for example, cancer patients and those with multiple episodes of VTE. But "in the great majority of idiopathic patients, deciding who should stop therapy or who should continue is difficult, and the big question is, how long do you continue treatment?"
Both Büller and Baglin explain that the latest  guidelines that everybody follows—from the American College of Chest Physicians (ACCP)—now recommend continuing therapy for this group of "medium-risk" patients indefinitely. However, in practice, this decision is never clear-cut, they say, and must be made on an individual basis.
It is this group of "medium-risk" patients who were included in the EINSTEIN-Extension study. The results showed that recurrent VTE events occurred in 7.1% of the 594 patients treated with placebo, so "93% of patients did not have a recurrent event," compared with 1.3% of 602 patients taking rivaroxaban (82% reduction, p<0.001). Bleeding was minimal with the study drug: nonfatal major bleeding occurred in 0.7% of patients on rivaroxaban compared with none in the placebo group (p=0.11). Clinically relevant nonmajor bleeding occurred in 5.4% of rivaroxaban patients and 1.2% of placebo recipients, respectively.
Büller defends the decision to choose a placebo group as a comparator in EINSTEIN-Extension: "If, for whatever reason, you believe you have a reason to continue therapy, how would that go compared with doing nothing? That's basically what ENSTEIN Extension looked at."
But Baglin says, "EINSTEIN-Extension tells us that rivaroxaban stops thrombosis, but it doesn't tell us that it's better than warfarin at doing this." The threshold that is currently used, he says, is that "if the annual risk [of a recurrent thromboembolic event] is >5%, you should stay on therapy indefinitely, but if it's below that you should stop."
"Most of us struggle with how long we should treat, so in some sense, EINSTEIN-Extension does provide some information," Silverstein observes. "There is a very, very low incidence of bleeding [with rivaroxaban], so if this could be repeated in larger studies over longer periods, it could broaden the indication for extended therapy, because the reality is there is a continued risk of thrombosis in anyone who's had a DVT; it's just the issue of the risk of bleeding vs the risk of recurrence. The 5% cut-off relates to the risk of bleeding with warfarin, and that's really why clinicians tend to use that number.
"Having a drug on the shelf that we know is associated with a reasonably acceptable hemorrhage rate and is effective is good to know," Silverstein said, although he acknowledges "cost will be an issue."
VTE therapy will increasingly move into the community: Pros and cons
Also an issue, says Baglin, is the fact that treatment with these newer anticoagulants will reduce contact with patients, driving the treatment of VTE out into the community, into the hands of family practitioners. Büller says this has been his experience in the Netherlands: "Family doctors were not interested initially, but now the Dutch Federation of Family Physicians has drawn up guidelines on how to deal with this. That shift started with [low-molecular-weight heparin], but now we are moving toward simple pills and no lab control and no dose adjustments."
And while this might have some advantages, there are also drawbacks, says Baglin. "These patients won't be coming to specialized anticoagulant clinics anymore, so there won't be any reinforcement or reminders to take therapy, and they won't be followed up. Concordance and compliance will be real issues—they are already real issues with warfarin, and they will be real issues with newer anticoagulants."