New Kids on the Block
The intention in development was to create “drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise,” says Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia. “When you look at the studies, actually they do reasonably well. It’s a pretty big step.” (For a list of major anticoagulant studies, see Figure 1, below.)
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Study: AVERROES
Conclusion: Apixaban superior to aspirin, with a number needed to treat of 47, in 5,600 patients not suitable for warfarin
Publication: N Engl J Med. 2011;364(9):806-817.
Topic: Venous thromboembolism prevention after orthopedic surgery
Study: Lassen et al
Conclusion: Apixaban equivalent to enoxaparin in total knee replacement
Publication: J Thromb Haemost. 2007;5(12):2368-2375.
Study: Lassen et al
Conclusion: Apixaban failed noninferiority against enoxaparin 30 mg every 12 hours in total knee replacement
Publication: N Engl J Med. 2009;361:594-604.
Study: ADVANCE-2
Conclusion: Apixaban superior to enoxaparin 40 mg once a day after total knee replacement
Publication: Lancet. 2010;375:807-815.
Rivaroxaban
Topic: Venous thromboembolism prevention after orthopedic surgery
Study: RECORD trials
Conclusion: Compared with enoxaparin in total hip and knee replacement patients, rivaroxaban was superior in all cases, even at an enoxaparin dose of 30 mg every 12 hours. The total VTE rate was 2% in the rivaroxaban group and 9.3% in the enoxaparin group; number needed to treat was 13.7.
Publication: Lancet. 2008;372(9632):31-39.
Dabigatran
Topic: Stroke prevention in nonvalvular atrial fibrillation
Study: RELY
Conclusion: When comparing dabigatran to warfarin in nonvalvular atrial fibrillation patients: 1.69% of patients had a stroke or systemic embolism in the warfarin group, compared with 1.53% for the 110-mg dabigatran group and 1.11% in the 150-mg dabigatran group. The major bleeding rates were 3.36% for warfarin, 2.71% for 110-mg dabigatran, and 3.11% for 150-mg dabigatran. The number needed to treat was 172.
Publication: N Engl J Med. 2009;361:1139-1151.
Topic: Venous thromboembolism prevention after orthopedic surgery
Study: BISTRO II
Conclusion: Various doses of dabigatran reduced VTE compared with enoxaparin 40 mg in total hip and total knee replacement patients
Publication: J Thromb Haemost. 2005;3(1):103-111.
Study: RE-NOVATE
Conclusion: 220 mg or 150 mg of dabigatran compared to enoxaparin for total hip replacement. Both doses were noninferior.
Publication: Lancet. 2007;370:949-956.
Study: RE-MODEL
Conclusion: 220 mg and 150 mg of dabigatran both noninferior in total knee replacement
Publication: J Thromb Haemost. 2007;5(11):2178-2185.
Study: RE-MOBILIZE
Conclusion: Dabigatran failed noninferiority to 30 mg of enoxaparin every 12 hours 30 q12, but dabigatran was started later
Publication: J Arthroplasty. 2009;24(1):1-9.
Topic: Acute venous thromboembolism
Study: RE-COVER
Conclusion: Dabigatran, 150 mg twice a day, was compared to warfarin after an average of a nine-day run-in with heparin in patents with acute venous thromboembolism. 60% of the time was spent with a therapeutic INR in the warfarin arm. VTE was recurrent in 2.4% of patients in the dabigatran arm and in 2.1% in the warfarin arm. Major bleeds were less common in the dabigatran arm, at 1.6% compared to 1.9%.
Publication: N Engl J Med. 2009;361:2342-2345.
Rivaroxaban, being developed jointly by Bayer Healthcare and Johnson & Johnson, has been submitted to the FDA for approval for stroke prevention in nonvalvular atrial fibrillation patients, which would put it in direct competition with dabigatran. And apixaban, being co-developed by the global alliance of Bristol-Myers Squibb and Pfizer, expects to submit for the same indication approval this year, Bristol-Myers Squibb spokeswoman Christina Trank says. (updated June 16)
All three are under study for other indications, including VTE prevention after hip and knee replacement surgeries, and clot prevention in the acutely ill.
The stakes are high for the companies: Manufacturers and analysts estimate that the market for anticoagulants will top $10 billion by 2015, with some estimates even higher. Dabigatran has been in development by Boehringer for about 15 years and studied in more than 19,000 patients, spokeswoman Anna Moses says.
