Blood readers should be aware of the omission of crucial information in a meta-analysis by Michael B. Streiff, which stated, “Although anticoagulation remains the primary therapy for venous thromboembolism, vena caval filters are an important alternative when anticoagulants are contraindicated.” 1(p3669) Dr Streiff and the researchers in the articles that he referenced did not mention or discuss a randomized controlled trial by Nielsen et al, comparing heparin and a phenprocoumon anticoagulation with phenylbutazone in patients with deep venous thrombosis (DVT).2 3 This is the only published randomized controlled trial of treatment of DVT patients with unanticoagulated controls, as opposed to standard anticoagulation controls. It was a negative study with 1 of 48 anticoagulated patients dying of pulmonary embolisms (PEs) and 0 of 42 phenylbutazone patients with fatal PEs.
Heparin and vitamin K antagonists became standard treatment for DVT and PE patients in the 1940s before the advent of randomized controlled trials to prove efficacy. The FDA allowed them to be “grandfathered in” as standard treatment of DVT and PE in the early 1960s when proof of efficacy became required for FDA approval. Low-molecular-weight heparins (LMWH) have been granted indications for treatment of DVT and PE by virtue of randomized controlled trials showing equivalence with heparin in trials that do not include unanticoagulated controls.
I am not suggesting that Dr Streiff intentionally neglected to cite this crucial study. None of the other major reviews of the treatment of venous thromboembolism (VTE) and none of the published trials of LMWH in VTE treatment mention the Nielsen study. Last year, I spoke with Lilia Talarico, chief of the Coagulation and GI Drug section of the FDA's Center for Drug Evaluation and Research (CDER), who did not know then of the Nielsen study. But based on this important trial and an overall review of the data, Janet Woodcock, chief of CDER; Robert Temple, director of FDA's Office of Medical Policy; and Dr Talarico are considering the withdrawal of the indication for anticoagulants (heparin, LMWH, and vitamin K antagonists) in prophylaxis and treatment of VTE.
For the articles and FDA correspondence detailing the case for withdrawing the indications for anticoagulants (heparin, LMWHs, and vitamin K antagonists) in prophylaxis and treatment of VTE, please see Cundiff.4
A significant omission in vena caval filters: a comprehensive review of phenylbutazone for venous thromboembolic disease
The purpose of my review was to examine the evidence supporting the efficacy and safety of vena caval filters in the prevention of venous thromboembolic disease (VTED).1-1 The study mentioned by Dr Cundiff was not included because it did not examine the use of vena caval filters in VTED, the focus of my article. But I would caution him not to conclude from the Nielsen study that there is no difference between standard anticoagulation and phenylbutazone in the treatment of VTED. The lack of a significant difference between the treatment groups in this study does not mean that they are necessarily equivalent treatments. With only 90 participants, the study has insufficient power to permit any valid statement on the equivalence of the treatments, a weakness acknowledged by the authors in the final sentence of their manuscript.1-2Equivalency studies must be designed in accordance with strict methodologic criteria in order for their conclusions to have any statistical validity.1-3 The unambiguous outcome of the Barritt and Jordan study and the totality of subsequent medical literature and clinical experience clearly indicate that additional placebo-controlled clinical trials in the treatment of VTED would be highly unethical.1-4 The task at the present is to identify safer and more effective antithrombotic agents, not to revisit the past.
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