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: https://doi.org/10.1136/bmj.e7498 (Published 13 November 2012) Cite this as: BMJ 2012;345:e7498All rapid responses
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We thank Dr Cudniff for his interest in our meta-analysis. We absolutely reject his demand to retract the manuscript. Retraction is warranted in cases of scientific fraud, plagiarism, gross incompetence or duplicate publication. None of these apply to our paper. Our meta-analysis compared conventional and 'novel' anticoagulants for the treatment of venous thromboembolism (VTE). Dr Cundiff's beliefs regarding the safety of conventional anticoagulation versus *placebo* for VTE are irrelevant to the subject of our paper and his linkage between the two issues is a non sequitur. We stand by our work and are grateful to the editors and reviewers of the BMJ for publishing it.
Competing interests: No competing interests
Call for retraction because conventional anticoagulants for VTE are ineffective and unsafe
In this meta-analysis of non-inferiority trials comparing warfarin with novel oral anticoagulants for venous thromboembolism (VTE),[1] the authors neglected to cite evidence of efficacy and safety of conventional anticoagulants (heparin and vitamin k inhibitors) for treatment of VTE.
To justify the efficacy and safety of conventional anticoagulants for VTE, this warfarin versus novel oral anticoagulants meta-analysis article stated,[1] “The mainstay of treatment has been initial use of parenteral anticoagulants followed by longer term use of oral vitamin K antagonists.[2] The reference is to the ACCP guidelines article on anticoagulants for VTE, which states, “The first and only trial that compared anticoagulant therapy with no anticoagulant therapy in patients with symptomatic DVT or PE was published in 1960 (Barritt and Jordan[3]).”[2] This statement is incorrect.
In a review that I led published in the Cochrane Database of Systematic Reviews titled, “Anticoagulants versus placebos or NSAIDs for venous thromboembolism,”[4] the authors, the editor, and the peer-reviewers all agreed that the Barritt and Jordan anticoagulants for pulmonary embolus trial was too flawed to provide evidence regarding the efficacy of using anticoagulants for VTE. For instance,
• The number of patients enrolled in the study (n = 35) was far too few to assess whether anticoagulants reduce the incidence of fatal PE.
• Modern chest imaging tests (lung scans, angiograms, CT scans, etc.) were not available to investigators in the 1950s. Anticoagulation experts didn’t learn until 1990 that a clinical suspicion of PE is confirmed by modern imaging tests to actually diagnose PE only about 25% of the time.[5]
• Autopsy descriptions of the patients in this study show that in 4 of the 5 deaths, severe underlying diseases (e.g., cerebral infarction and cavitary pneumonia with sepsis) caused the deaths, with PE only appearing as a contributing factor.
The data in my review in Cochrane[4] and my anticoagulants for VTE review in Medscape General Medicine[6] strongly suggest that standard anticoagulants don’t save lives and do cause major harm in VTE patients. In 3 published randomized trials in DVT patients comparing heparin and vitamin k inhibitors to placebos or NSAIDs, more people died that were treated with anticoagulants than were not anticoagulated (placebo or NSAIDs: 1/60 death versus heparin and vitamin k inhibitors: 6/66 deaths).[7-9] The 1 death in a placebo treated patient was due to an MI and not to a pulmonary embolus. These relevant articles and my reviews were not cited or discussed in this non-inferiority trial meta-analysis or the ACCP anticoagulants for VTE guidelines article that the authors cited to justify anticoagulants for VTE treatment.
At the invitation of regulators at the US Food and Drug Administration, I submitted the following citizen petition: “FDA should label anticoagulants “contraindicated” for venous thromboembolism.”[10] This petition further details the case against anticoagulants for VTE. The bleeding deaths of 1000 – 3500 anticoagulated VTE patients each year in the USA[6] and perhaps one-quarter that many bleeding deaths in VTE patients in the UK, make the evidence-basis of anticoagulants for VTE treatment especially important.
Please have the authors of this non-inferiority trials meta-analysis present their evidence supporting conventional anticoagulants as treatment for VTE. If no valid evidence is presented, please retract this meta-analysis.
Thank you.
Best wishes,
David K. Cundiff, MD
dkcundiff@whistleblowerdoctor.org
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 randomised controlled trials. BMJ 2012;345:e7498
2. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. Chest 2012;141(2 suppl):e419S-e94S
3. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism -- A controlled trial. Lancet 1960; 1:1309-12
4. Cundiff DK, Manyemba J, Pezzullo JC. Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism. The Cochrane Database of Systematic Reviews 2006(Issue 1)
5. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990;263(20):2753-9
6. Cundiff DK. Anticoagulation Therapy for Venous Thromboembolism. MedGenMed 2004;6(3)
7. Nielsen HK, Husted SE, Krusell LR, et al. Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis Research 1994;73(3-4):215-26
8. Ott P, Eldrup E, Oxholm P. The value of anticoagulant therapy in deep venous thrombosis in the lower limbs in elderly, mobilized patients. A double-blind, placebo-controlled investigation with open therapeutic guidance. Ugeskr Laeger 1988;150:218-21
9. Kakkar VV, Flanc C, O'Shea M, et al. Treatment of deep-vein thrombosis--a random trial. Br J Surg 1968;55(11):858
10. Cundiff DK. Citizen Petition: FDA should label anticoagulants “contraindicated” for venous thromboembolism. July 2, 2015. http://whistleblowerdoctor.org/2015/07/citizen-petition-fda-should-label....
Competing interests: I withdrew warfarin from a patient with lower-limb deep venous thrombosis, disseminated tuberculosis, alcoholism, liver failure, and anemia on the grounds that the risk for bleeding in the patient seemed to be greater than the benefit of anticoagulant treatment. The patient later died of pulmonary embolism. I lost my medical license because of this case. I had no previous disciplinary actions by any medical board in 25 years of practice. To prepare for my legal defense, I conducted a survey of anticoagulation specialists concerning the proper treatment of my patient with the DVT. An anonymous anticoagulation expert included on his/her survey form the reference to the randomized trial of conventional anticoagulants versus phenylbutazone for deep venous thrombosis by Nielsen, et al. This study reported 2/48 anticoagulated patients died and 0/42 phenylbutazone treated patients died. My research into the evidence basis of anticoagulant for VTE began at that point.
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: No competing interests
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.
References:
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: No competing interests
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: No competing interests
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.
References
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: No competing interests
Re: Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials
I thank Dr. Fox and his colleagues for their response to my call for a retraction of their article in the BMJ. My challenge to the appropriateness of publishing a meta-analysis of non-inferiority trials comparing warfarin (Coumadin) versus novel anticoagulants for venous thromboembolism concerns the lack of efficacy of heparin/warfarin (“standard anticoagulants”) for venous thromboembolism treatment. Dr. Fox and colleagues say that the efficacy of standard heparin/warfarin treatment of venous thromboembolism is irrelevant to comparing warfarin to newer drugs. I maintain that it is not ethical to conduct any non-inferiority trials of warfarin for venous thromboembolism versus various novel anticoagulants when current evidence shows that treatment with heparin and warfarin is not evidence-based to save lives.
We disagree.
I call on the BMJ editors to sort out this impasse by asking at least 5 evidence based medicine experts without financial ties to anticoagulant producing drug companies to independently adjudicate this dispute by submitting rapid responses to this meta-analysis of non-inferiority trials.
Firstly, they should state whether the evidence basis of standard anticoagulants for venous thromboembolism is or is not relevant to the ethical appropriateness and scientific merit of this meta-analysis of non-inferiority trials comparing treatment with warfarin versus novel anticoagulants. Secondly, the BMJ editors’ evidence based medicine experts should critique my Citizen Petition requesting that the US Food and Drug Administration withdraw FDA approval for anticoagulants for venous thromboembolism and have all anticoagulants labeled “contraindicated” for venous thromboembolism (http://www.regulations.gov/#!documentDetail;D=FDA-2015-P-2373-0001).
With thousands of bleeding deaths per year worldwide due to anticoagulants for venous thromboembolism, the powerful influence of the BMJ editors is needed here in the interest of public health and the integrity of the medical profession.
Competing interests: I withdrew warfarin from a patient with lower-limb deep venous thrombosis, disseminated tuberculosis, alcoholism, liver failure, and anemia on the grounds that the risk for bleeding in the patient seemed to be greater than the benefit of anticoagulant treatment. The patient later died of pulmonary embolism. I lost my medical license because of this case. I had no previous disciplinary actions by any medical board in 25 years of practice. To prepare for my legal defense, I conducted a survey of anticoagulation specialists concerning the proper treatment of my patient with the DVT. An anonymous anticoagulation expert included on his/her survey form the reference to the randomized trial of conventional anticoagulants versus phenylbutazone for deep venous thrombosis by Nielsen, et al. This study reported 2/48 anticoagulated patients died and 0/42 phenylbutazone treated patients died. My research into the evidence basis of anticoagulant for VTE began at that point.