Blood, 15 January 2002, Vol. 99, No. 2, pp. 723-724
CORRESPONDENCE
To the editor:
Reconsidering anticoagulant therapy in venous
thromboembolism
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
David K. Cundiff
Correspondence: 319 Grand Ave, Long Beach, CA 90814
References
1.
Streiff MB.
Vena caval filters: a comprehensive review.
Blood.
2000;95:3669-3677[Abstract/Free Full Text].
2.
Nielsen HK, Husted SE, Krusell LR, Fasting H, Charles P, Hansen HH.
Silent pulmonary embolism in patients with deep venous thrombosis: incidence and fate in a randomized, controlled trial of anticoagulation versus no anticoagulation.
J Intern Med.
1994;235:457-461[Medline]
[Order article via Infotrieve].
3.
Nielsen HK, Husted SE, Krusell LR, et al.
Anticoagulant therapy in deep venous thrombosis: a randomized controlled study.
Thromb Res.
1994;73:215-226[CrossRef][Medline]
[Order article via Infotrieve].
4. Cundiff DK. FDA approved anticoagulants that don't work. Available at
http://hometown.aol.com/~dkcundiff/home.htm.
Response:
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 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.2 Equivalency studies must be designed in accordance with strict methodologic criteria in order for their conclusions to have any statistical validity.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.4 The task at the present is to identify
safer and more effective antithrombotic agents, not to revisit the past.
Michael B. Streiff
Correspondence: Department of Medicine, Johns Hopkins
University School of Medicine, 1025 Ross Building, 720 Rutland Ave,
Baltimore, MD 21205
References
1.
Streiff MB.
Vena caval filters: a comprehensive review.
Blood.
2000;95:3669-3677.
2.
Nielsen HK, Husted SE, Krusell LR, et al.
Anticoagulant therapy in deep venous thrombosis: a randomized controlled study.
Thromb Res.
1994;73:215-226.
3.
Rohmel J.
Therapeutic equivalence investigations: statistical considerations.
Stat Med.
1998;17:1703-1714[CrossRef][Medline]
[Order article via Infotrieve].
4.
Barritt DW, Jordan SC.
Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial.
Lancet.
1960;1:1309-1312[CrossRef][Medline]
[Order article via Infotrieve].
