ADVANCE-3: Apixaban superior to enoxaparin in reducing VTE after hip-replacement surgery

December 22, 2010

Copenhagen, Denmark - Treating patients undergoing elective hip-replacement surgery with apixaban (Bristol-Myers Squibb/Pfizer) is more effective than standard treatment with enoxaparin (Lovenox, Sanofi-Aventis) for reducing the risk of venous thromboembolism (VTE), without a significant increase in bleeding, according to results of the ADVANCE-3 study [1].

Publishing the study in the December 23, 2010 issue of the New England Journal of Medicine, lead investigator Dr Michael Rud Lassen (University of Copenhagen, Denmark) and colleagues report that apixaban prevented one episode of VTE for every 147 patients treated.

In an editorial accompanying the study [2], Dr Elaine Hylek (Boston University School of Medicine, MA) said the potential impact of apixaban, an oral factor Xa inhibitor, and other drugs like it, including rivaroxaban (Xarelto, Johnson & Johnson) and e doxaban (Daiichi Sankyo), as well as other drugs in development, will be substantial, especially in other clinical settings where patients are intolerant of warfarin.

"Currently, millions of people worldwide are relegated to receiving no therapy or therapy that has been proven to be ineffective, because they lack access to the monitoring expertise needed to safely and effectively administer warfarin," writes Hylek. "It is conceivable that the oral factor Xa inhibitors, as compared with warfarin, will prove to be safer in clinical practice because they are administered in fixed doses, do not interfere with diet, and have fewer interactions with other drugs."

Recently, the ADVANCE-2 trial showed that apixaban was more effective than the dose of enoxaparin commonly used in Europe for VTE in patients undergoing knee replacement, and pooled data from the ADVANCE trials showed apixaban was more effective than enoxaparin for the prevention of major VTE in patients undergoing hip- or knee-replacement surgery.

Benefit in reducing VTE without a bleeding risk

The ADVANCE-3 trial is a double-blind, double-dummy study that included patients undergoing total hip replacement treated with oral apixaban 2.5 mg twice daily given 12 to 24 hours following surgery and patients treated with enoxaparin 40 mg per day started the evening before surgery. The primary efficacy outcome was the composite of adjudicated asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause during the intended treatment period, a time from randomization to 32 to 38 days or within two days of when the study drug was last administered.

Overall, the primary efficacy end point occurred in 27 of 1949 patients treated with apixaban (1.4%) and in 74 of the 1917 patients treated with enoxaparin (3.9%), a difference that reached statistical significance for noninferiority and superiority. Major VTE occurred in 0.5% of patients treated with apixaban and 1.1% of patients treated with enoxaparin. During the follow-up treatment period, assessed out to 60 days after the last dose of the study drug was given, symptomatic VTE/death occurred in none of the apixaban-treated patients and in six patients treated with enoxaparin.

Rates of clinically adjudicated major bleeding were similar in both treatment arms, occurring in 0.8% of patients treated with apixaban and 0.7% of patients treated with enoxaparin. The composite of major and clinically relevant nonmajor bleeding occurred in 4.8% of the apixaban-treated patients and in 5.0% of patients treated with enoxaparin, a difference that did not achieve statistical significance.

ADVANCE-3 efficacy outcomes

End point
Apixaban , n= 1949 (%)
Enox a parin, n= 1917 (%)
Relative risk (95% CI)
Absolute difference (95% CI)
V TE and death from any causes
0.36 (0.22-0.54)
-2.5 (-3.5 to -1.5)
Major VTE
0.40 (0.15- 0.80)
-0.7 (-1.3 to -0.2)
Symptomatic VTE and de ath from venous thromboembolism
0.40 (0.01-1.28)
-0.2 (-0.6 to 0.06)

ADVANCE-3: Safety end points

End point
Apixaban (n=2673), n (%)
Enoxaparin (n=2659), n (%)
Adjudicated major bleeding
22 (0.8)
18 (0.7)
Adjudicated clinically relevant nonmajor bleeding
109 (4.1)
120 (4.5)
Adjudicated major or clinically relevant nonmajor bleeding
129 (4.8)
134 (5.0)
All bleeding
313 (11.7)
334 (12.6)

The researchers point out that the primary efficacy end point was adjudicated by venography and that patients were not included in the efficacy analyses if the quality of the venogram was suboptimal or if venography was not performed, such as in patients who withdrew consent. Overall, 28% of patients in the apixaban arm and 29% of patients in the enoxaparin arm were not included in the primary efficacy analysis.

"These proportions are unlikely to have biased the observed results," state Lassen and colleagues. "Because the patients in the two study groups who could not be evaluated had similar baseline demographic characteristics and similar reasons for not having assessable venograms, it is probable that the between-group differences in the rates of venous thromboembolism would remain similar."

Future trials coming soon in AF

In her editorial, Hylek notes that each of the oral factor Xa inhibitors is being tested in large-scale trials in the atrial-fibrillation setting. These studies include ROCKET-AF with rivaroxaban, where the drug was shown to be noninferior to warfarin with regard to all-cause stroke and non-central nervous system embolism, and AVERROES with apixaban, stopped early because of significant reductions in the risk of stroke with the drug compared with aspirin-treated patients. Other studies with warfarin as the active comparator, including ARISTOTLE with apixaban and ENGAGE-AF TIMI 48 with edoxaban, are also expected in 2011 and 2012, respectively.

"If these novel, breakthrough, oral anticoagulant drugs prove to be effective across the broad spectrum of patients in routine care and are conscientiously priced, the worldwide impact will be huge," writes Hylek. She points out, however, that patients in the ADVANCE-3 trial were 60 years old and 89% had normal renal function, factors that will be important when attempting to take these results into the real world. The critical role of baseline risk, and particularly concomitant therapy, were highlighted in the APPRAISE-2 acute coronary syndrome trial, a study that was stopped early due to bleeding risks in patients taking single or dual antiplatelet therapy and randomized to apixaban.

"Translating the efficacy and safety that have been shown in clinical trials to real-world practice is often a challenge because, as compared with patients in real-world practices, participants in trials are usually younger, have less medically complex illnesses, are more likely to be adherent, and have been specifically selected on the basis of having a lower risk of bleeding," writes Hylek.

The ADVANCE-3 trial was sponsored by Bristol-Myers Squibb and Pfizer. Lassen reports receiving consulting fees from Bristol-Myers Squibb, Pfizer, Sanofi-Aventis, Astellas Pharma Europe, GlaxoSmithKline, and Bayer HealthCare and payment for development of educational materials from Bayer HealthCare. Hylek has served as a consultant to Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Merck, and Daiichi Sankyo a nd is a member of the ARISTOTLE executive steering committee.


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