Apixaban better than European enoxaparin regimen for preventing VTE

March 04, 2010

Copenhagen, Denmark - The investigational anticoagulant apixaban (Bristol-Myers Squibb/Pfizer) is more effective than the dose of enoxaparin (Lovenox, Sanofi-Aventis) commonly used in Europe for preventing venous thromboembolism (VTE) in those undergoing knee replacement, a new study shows [1]. Dr Michael Rud Lassen (University of Copenhagen, Denmark) and colleagues report their findings in the March 6, 2010 issue of the Lancet.

In the trial, called ADVANCE-2, apixaban, an oral factor Xa inhibitor, was given at a dose of 2.5 mg twice daily starting 12 to 24 hours after surgery and was compared with the standard "European" regimen of enoxaparin (given subcutaneously 40 mg once daily). There was no difference in bleeding events between the two agents.

Lassen, an orthopedic surgeon, told heart wire that the dosing schedule of apixaban, whereby it is initiated after surgery, "is a great advantage for anesthesiologists and surgeons because they don't have to worry about bleeding during the procedure." He added, "Apixaban was better than the European enoxaparin regimen, and although we were not able to show a significant difference in bleeding, there was a trend to lower bleeding with apixaban; it appears to be safer than the European regimen of enoxaparin."

Apixaban is also being studied in acute coronary syndrome (ACS) and for the treatment of VTE in ongoing trials, Lassen notes, which are "completely different situations, where the dose will be different." A phase 2 trial with apixaban in ACS, APPRAISE-1, has shown promising results. Another factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is also being studied in a phase 3 trial in ACS.

Second study for a "small indication"

In ADVANCE-1, an earlier trial of the same regimen of apixaban compared with the US regimen of enoxaparin (where it is given 30 mg sc twice daily), also in knee-replacement surgery, apixaban failed to show a benefit over the low-molecular-weight heparin (LMWH) in terms of preventing VTE but was associated with significantly less bleeding

Apixaban has the potential of better safety [than enoxaparin] , and surgeons are really, really keen on that; they are really nervous about postoperative bleeding.

Lassen told heart wire he does not believe that Bristol-Myers Squibb and Pfizer will invest any more in trying to determine a new dose of apixaban for prevention of VTE in orthopedic surgery, "because it's rather a small indication," but he believes they have sufficient data with the two ADVANCE trials to submit a new drug application. "Apixaban has the potential of better safety [than enoxaparin], and surgeons are really, really keen on that; they are really nervous about postoperative bleeding and complications. This package—ADVANCE-1 and ADVANCE-2—can really show surgeons they now have a drug that can prevent deep vein thrombosis [DVT] with less bleeding than enoxaparin.

"Apixaban adds another chapter to the future of handling this type of patient," he commented. "It's easy to use, it has a short half-life and very predictable pharmacokinetics," and all of these newer oral anticoagulants are "quite nice things to work with," he added.

Another new oral anticoagulant: How will they compare?

If apixaban is approved for the prevention of VTE in orthopedic indications, it will compete with at least two other new agents, including rivaroxaban and the thrombin inhibitor dabigatran (Boehringer Ingelheim). The latter two are approved for use in the prevention of VTE in orthopedic-surgery patients in Europe and in Canada.

Dabigatran suffered a similar fate to apixaban in that it failed to show a benefit when compared with the US regimen of enoxaparin in the RE-MOBILIZE study in knee surgery, so the company did not file for approval of dabigatran for this indication in the US. A new North American trial in hip-replacement patients with dabigatran is now under way (RE-NOVATE 2), but it is using the European enoxaparin 40-mg once-daily dose as a comparison.

Dabigatran has also recently shown noninferiority to warfarin, with less bleeding, in the landmark RE-LY trial in patients with atrial fibrillation (AF). And another investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested in a phase 3 trial in more than 16 000 patients with AF.

Meanwhile, the approval of rivaroxaban for prevention of VTE during orthopedic surgery in the US is currently on hold; despite an FDA advisory committee recommending the drug for approval in March last year, the agency later said it was seeking "further information."

Lassen says: "Fiddling around with anticoagulation in the postsurgical setting is always a question of balance." Rivaroxaban—which he describes as a sibling drug to apixaban—has "better efficacy because it's given in a total daily dose of 10 mg, but it also has more bleeding than apixaban," although he noted that the bleeding is generally "gastrointestinal" rather than major bleeding in the operative site.

He said the whole Copenhagen area where he works "has changed to rivaroxaban from LMWH as a standard procedure." But other Danish centers are using dabigatran, he noted, with many actually maintaining use of LMWH around the time of surgery and then switching to dabigatran at discharge. There are also many situations where LMWHs are still used "because there are quite a lot of indications where you can't use these new oral anticoagulants," he noted.

A 40% reduction in primary end point with apixaban in ADVANCE-2

In the newly published ADVANCE-2 study, just over 3000 patients undergoing elective single or double knee replacement were randomly allocated to receive either oral apixaban 2.5 mg twice daily (n=1528) or sc enoxaparin 40 mg once daily (n=1529). Apixaban was started 12 to 24 hours after wound closure and enoxaparin 12 hours before surgery; both drugs were continued for 10 to 14 days when bilateral ascending venography was scheduled.

The primary outcome was the composite of asymptomatic and symptomatic DVT, nonfatal pulmonary embolism (PE), and all-cause death during treatment. Only 1973 of the 3057 patients allocated to treatment were eligible for analysis, because patients whose venography was suboptimum or not done were excluded. In practice, this was unlikely to have affected the results, because the percentage of patients excluded was similar in both drug groups, the researchers note.

The primary end point was reported in 146 (15%) of 976 apixaban patients and 243 (24%) of 997 enoxaparin patients (relative risk 0.62; p<0.0001; absolute risk reduction 9.3%).

Major or clinically relevant nonmajor bleeding occurred in 53 (4%) of patients receiving apixaban and 72 (5%) of those treated with enoxaparin (p=0.09).

In an editorial accompanying the publication of the study [2], Drs Jawed Fareed (Loyola University Medical Center, Maywood, IL) and Russell Hull (University of Calgary, AB) say: "The outcomes in ADVANCE-2 suggest that the apixaban regimen was more efficacious than the parenteral comparator [enoxaparin] and as safe."

No signs of hepatotoxicity with newer anticoagulants

But there will be a need for long-term safety analysis, especially for hepatic toxic effects, say the editorialists. Few patients in ADVANCE-2 had raised liver-function enzymes during or after treatment, but there was one multifactorial death after apixaban exposure, which was accompanied by abnormal results of liver tests, so a contribution by the study drug "remains possible," the researchers note.

However, Lassen maintains that none of the newer oral anticoagulants show any signal of hepatoxicity, which he says "is reassuring" following the experience with ximelagatran (Exanta, AstraZeneca), a direct thrombin inhibitor that had to be withdrawn from a number of European and other countries in 2006 due to hepatoxicity (it was never approved in the US). It now seems that this was a one-off, Lassen says. "There was something about ximelagatran, about how it was metabolized by the hepatic system, although the full explanation has never really been revealed."

The editorialists also discuss the other newly available agents, rivaroxaban and dabigatran, and the relative risks and benefits of each of these. But they say that it is hard to compare bleeding outcomes across trials of the different agents, because each uses a slightly different definition of major bleeding. A general consensus is needed on a single, standard measure of bleeding, they note.

ADVANCE-2 was funded by Bristol-Myers Squibb and Pfizer. Lassen has received consulting fees from Bristol-Myers Squibb, Pfizer, Bayer, Johnson & Johnson, GlaxoSmithKline, and Sanofi-Avent is. Disclosures for the co authors are listed in the paper . Fareed has been a consultant to Mitsubishi Pharma, King Pharma, Sanofi- Aventis , and Gentium. Hull has been a consultant to Sanofi- Aventis , Bayer, Pfizer, Boehringer Ingelheim , and Portola.


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