Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7498 (Published 13 November 2012)
Cite this as: BMJ 2012;345:e7498

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We thank Mara N. Villanueva for correcting an error in the paper.

In the EINSTEIN studies cited, patients randomized to rivaroxaban received 15mg bid for three weeks followed by 20mg qd.

Competing interests: None declared

Benjamin D Fox, Visiting Professor

McGill University, Jewish General Hospital, Montreal

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The meta-analysis by Fox and colleagues provides an overview of the pivotal trials evaluating the use of novel oral anticoagulants for the treatment of acute venous thromboembolism; however, it appears that the doses used in some of these trials have been reported erroneously.[1]

According to Table 1, rivaroxaban was studied at a dose of 20 mg four times a day after the initial 3 weeks of treatment with 15 mg twice a day; based on the Einstein-PE and Einstein-DVT trials, the patients were actually given 20 mg daily, not four times a day, after the initial 3 weeks of treatment.[2,3] This error is also found in the Results section on page 3, under “Study Characteristics: Rivaroxaban.” Similarly, in the Einstein-Dose study, patients received 20 mg, 30 mg, or 40 mg daily, not four times a day.[4] In the ODIXa trial, patients received 10 mg, 20 mg, or 30 mg twice daily or 40 mg daily, not 10-40 mg four times a day.[5] In the Boticelli DVT study, patients received apixaban at a dose of 5 mg or 10 mg twice daily or 20 mg daily, not 5-20 mg four times a day.[6]

While the dosing information provided for the other agents is accurate, this is a substantial error which may be misleading to a reader who is unfamiliar with the standard dosing of rivaroxaban and apixaban.

1. Fox BD, Kahn SR, Langleben D, et al. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomized controlled trials. BMJ. 2012;345:e7498.
2. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-510.
3. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-97.
4. Buller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study. Blood. 2008;112:2242-7.
5. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa inhibitor BAY 59-7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation. 2007;116:180-7.
6. Buller H, Deitchman D, Prins M, et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost. 2008;6:1313-8.

Competing interests: None declared

Mara N. Villanueva, PGY-2 Drug Information Resident, Pharmacist

Evelyn R. Hermes-DeSantis, Pharm.D., BCPS

Rutgers, The State University of NJ, Robert Wood Johnson University Hospital, New Brunswick, NJ

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Since these four novel drugs are either factor Xa inhibitors or Direct thrombin inhibitors, it would be interesting to know the methods used to neutralize/control the antithrombotic effects of these drugs.

Competing interests: None declared

Shree Jamdar, Student - Clinical Research

St. Xavier's College (Mumbai), 5, Mahapalika Marg, Mumbai, Maharashtra 400 001

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The meta-analysis by Fox and colleagues focussed on the risk of recurrence and bleeding with the new oral anticoagulants in comparison with vitamin K antagonists with no worse profile for any of the newer agents [1]. However, the bigger safety issue with these agents is likely to be related to the lack of compliance. Data published from trials are based on strict surveillance of drug intake and continuous feedback from the participants. Also the selection process for the trials warrants good compliance with these medications. The real-world issue is likely to be completely different. In this regard, the need for no monitoring proposed by the pharmaceutical companies as the significant benefit for the new drugs itself can be the biggest headache.

Poor adherence to medications is a well-known cause of inadequate drug effectiveness. This is especially true with respect to the drugs, which are required to be taken long-term, like anti-hypertensives. Since one of the common indications for the new oral anticoagulants is atrial fibrillation, these will soon belong to the drug cupboards of many individuals. However, unlike the other routine drugs, the short half-life of these newer drugs would mean rebound thrombotic risk even after missing a day’s tablet. This ‘adverse effect’ is seen much less commonly with warfarin whose half-life is much longer and missing one or two doses do not lead to complete washout of the drug from the circulation. Also, visits to the anticoagulation department provide an additional checkpoint to ensure the compliance of vitamin K antagonists and a place for regular advice about the importance of anticoagulant therapy. In this regard, it is highly important that, despite the lack of laboratory monitoring required, regular follow-up visits are arranged to educate and ensure compliance of these new agents.


1. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ. 2012 Nov 13;345:e7498.

Competing interests: None declared

Jecko Thachil, Consultant Haematologist

Manchester Royal Infirmary, Oxford road

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