ADVANCE Analysis: Apixaban Effective, Safe for VTE Prevention Following Hip/Knee Surgery

December 08, 2010

December 8, 2010 (Orlando, Florida) — Pooled data from the ADVANCE clinical-trial program shows that apixaban (Bristol-Myers Squibb/Pfizer), a novel factor Xa inhibitor, is more effective than enoxaparin (Lovenox, Sanofi-Aventis) for the prevention of major venous thromboembolism (VTE) in patients undergoing hip- or knee-replacement surgery.

"The findings show that major venous thromboembolism, clots in the large veins in the thigh or those that have already moved to the lungs and caused symptoms, was reduced by a little over half, from 1.5% in the enoxaparin group to 0.7% in the apixaban group," according to lead investigator Dr Gary Raskob (University of Oklahoma Health Sciences Center, Oklahoma City). "The absolute reduction of 0.76%, or about eight patients per 1000 treated, means that for every 125 patients treated with apixaban, by comparison with enoxaparin, we would prevent one episode of major venous thromboembolism."

Presenting the results during a press conference here at the American Society of Hematology 2010 Annual Meeting, Raskob pointed out that the treatment benefit did not come at an increased cost of excess bleeding with apixaban. Overall, rates of major bleeding were low and similar in both treatment arms, with major bleeding occurring in 0.74% of patients in the apixaban group and 0.77% in the enoxaparin-treated group. In addition, major bleeding at the surgical site occurred in 26 of the apixaban patients and in 27 of the enoxaparin patients.

The lack of an increased risk of bleeding with apixaban is particularly reassuring, given that Bristol-Myers Squibb and Pfizer stopped the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome (ACS) because of increased bleeding that would not be offset by reductions in ischemic events. As reported by heartwire , the data and safety monitoring board (DSMB) recommended that the trial be halted a few weeks ago.

During the press conference, Raskob pointed out that the APPRAISE-2 trial differed significantly from the ADVANCE studies. In APPRAISE-2, the ACS patients were randomized to apixaban 5.0 mg twice daily or to placebo, in addition to one or two other antiplatelet agents. In contrast, the ADVANCE hip/knee-replacement patients were treated with a lower dose of apixaban and were not treated with other anticoagulants.

"The studies are independent studies, with entirely different patient populations evaluated for different indications for the medication," said Raskob. "What it might mean is that we have to use different regimens of anticoagulants in different situations."

The ADVANCE Trials

Briefly, the data presented this week were from a pooled analysis of the ADVANCE-2 and -3 studies, a cohort of 8464 patients undergoing hip- and knee-replacement surgery. The purpose of the analysis, explained Raskob, was to focus only on major venous thromboembolism, or serious blood clots in the large veins of the thigh or lungs, excluding blood clots in the veins of calf muscles, as these are not deemed as clinically important. Patients were treated with 2.5-mg apixaban twice daily 12 to 24 hours after surgery (average 19 hours), whereas those in the enoxaparin arm received 40 mg of the drug 12 hours prior to the operation followed by a resumption of medication following surgery.

Overall, major venous thromboembolism occurred in 0.68% of the patients treated with apixaban and in 1.5% of patients in the enoxaparin group, a statistically significant difference. As noted, rates of major bleeding were not statistically different between the two treatment regimens. Adverse events, including elevation in hepatic enzymes, were also similar in both treatment arms.

Raskob said the apixaban regimen represents a convenient form of thromboprophylaxis because it can be given orally and postoperatively, and he expects it to be of benefit given the significant number of hip and knee replacements performed annually. Overall, the emergence of other anticoagulants, on top of the traditionally used low-molecular-weight heparin and warfarin, is good news for surgeons and clinical hematologists treating these patients.

"In terms of the impact, this is a significant issue in healthcare in the United States," he said. "There are about 700 000 operations of hip and knee replacement each year, and the American Academy of Orthopedic Surgeons expects that that will double within the next 10 years."

Recently, the AVERROES trial, reported by heartwire from the European Society of Cardiology 2010 Congress in Stockholm, Sweden, showed that atrial-fibrillation patients unable to take warfarin who are treated with apixaban had a significantly lower risk of stroke and systemic embolic events compared with patients treated with aspirin. That study paves the way for the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial, a comparison of apixaban 5.0 mg twice daily vs warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. The trial is currently under way, and results are expected in April 2011.

Raskob reports consulting for or being on a board of directors or advisory committee for Bristol-Myers Squibb, Pfizer, Johnson & Johnson, Sanofi-Aventis, Daiichi Sankyo, and GlaxoSmithKline and consulting for Takeda R&D and Boehringer Ingelheim. Disclosures for the coauthors are listed in the abstract.

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