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Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism

CJJ Dongen, AGM Belt, MH Prins, AWA Lensing

DOI:10.1002/14651858.CD001100.pub2

Dr Haren Kumar
Date received: February 10, 2003
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9000#9000

Iam interested in knowing the source from which these Heparin are produced.This may have relevance to their efficacy.

I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.

Dr Haren Kumar.
Date received: February 8, 2003
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=8999#8999

Can you provide me the information regarding the source of heparin,either porcine or bovine.

Thanks.

I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.

David K. Cundiff
Date received: June 20, 2001
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=8813#8813

I will comment on aspects of this review according to section.

Abstract background:

1. "Low molecular weight heparins have been shown to be effective and safe for prevention of venous thromboembolism." -- Using the surrogate endpoint of venographically diagnosed DVTs (mostly asymptomatic), LMWHs reduce the development of DVT from about 50% with placebos to about 10-20%. However, there is no evidence that this reduction with LMWH prophylaxis translates into reduced deaths from pulmonary emboli (PE).

2. " There is accumulating evidence that these new anticoagulants are also effective and safe for treatment of venous thromboembolism." -- No placebo-controlled trials of LMWHs as treatment of VTE have been published. Evidence of efficacy of LMWHs in treatment of VTE depends on RCTs comparing LMWHs with heparin. For DVT patients, there are no placebo-controlled RCTs versus heparin and vitamin K antagonists. The only RCT of heparin and a vitamin K antagonist versus phenylbutazone showed no efficacy of anticoagulants. 1, 2 The only RCT of anticoagulants versus placebo as treatment of patients with PE was flawed and should be disregarded. 3 Failure to mention and discuss these two RCTs in this review was a major omission, profoundly influencing the conclusions.

Abstract conclusion:

1. "Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism." -- This is irrelevant since unfractionated heparin itself has not been shown to reduce the morbidity or mortality of VTE.

2. A reduction in the incidence of major hemorrhage of LMWH versus unfractionated heparin is of no advantage if neither has been shown to reduce mortality.

Body of Article Background:

1. "Therefore, increasingly they (DVT and PE) are referred to as one disease, and are treated with comparable anticoagulant regimens." -- This unreferenced statement suggests that RCTs support the efficacy of anticoagulant treatment over placebo or NSAIDs in both patients with DVT and PE which they do not.

2. "Anticoagulant therapy is the treatment of choice for most patients with venous thromboembolism (Hirsh 1991). -- The reference is a review article by Jack Hirsh, MD. It documents that standard treatment of VTE is with anticoagulants based on the opinion of an authority on VTE. It does not represent an evidence-based finding. Dr. Hirsh is a career investigator, specializing in prevention and treatment of VTE with anticoagulants. This represents a potential conflict of interest since his research funding depends on the efficacy of anticoagulants in clinical medicine.

3. "Heparin is administered by either continuous intravenous infusion or twice daily subcutaneous injection (Hull 1986; Gallus 1986; Hull 1990)." -- The titles of these referenced articles are as follows:

? "Continuous intravenous heparin compared with intermittent subcutaneous heparin in the treatment of proximal-vein thrombosis."

? "Heparin for 5 days as compared with 10 days in the initial treatment of proximal-vein thrombosis."

? "Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism."

None of these articles addresses the question of whether the morbidity and/or mortality of VTE is reduced by heparin given in any manner.

4. " The evidence supporting initial treatment with heparin comes from a placebo-controlled randomized trial which demonstrated that a regimen of intravenous heparin plus oral anticoagulants is more effective in preventing recurrence than oral anticoagulants alone (Brandjes 1992)." -- This is not a placebo-controlled trial. The control group received warfarin. Warfarin by itself has never been shown to be effective in a placebo-controlled trial. Warfarin has complex and variable effects of the coagulation cascade, including the potential for increased clotting in some people. In this small trial, there was no mortality in either group, so it doesn't prove that heparin reduces PE mortality.

5. "Although most experience with low molecular weight heparins has been in the prevention of venous thromboembolism, where they have been shown to be safe and effective (Nurmohamed 1992). . ." -- This meta-analysis compares RCTs of thromboprophylaxis with heparin versus LMWH, using surrogate endpoints not morbidity and mortality. This does not show that either is safe or effective.

Reviewers' conclusions:

1. "This systematic review suggests that low molecular weight heparin treatment can safely be adopted as the standard therapy in patients with deep venous thrombosis." -- This conclusion is not warranted because neither heparin or LMWHs have been shown to reduce morbidity or mortality of VTE when compared in RCTs to unanticoagulated controls.

Potential conflict of interest: "None."

1. The issue of financial conflict of interest arises in two of the reviewers in this analysis. Anthonie W. A. Lensing has been funded by Sanofi Winthrop for a study of nadroparine, a LMWH, 4 and Leo Laboratories for a comparison of LMWHs, Tinzaparin and Enoxaparin. 5 Martin H. Prins received funding from Sanofi Winthrop for a study comparing Fraxiparine, a LMWH, with unfractionated heparin. 6

2. The implications for research states, "Further studies are required in patients with pulmonary embolism comparing low molecular weight heparin with unfractionated heparin. In patients with deep venous thrombosis of the leg, the individual low molecular weight heparins could be compared with each other and new drugs should now be compared with low molecular weight heparin." -- Drs. Lensing and Prins stand to receive the research contracts to conduct those studies.

Thank you for considering these comments regarding your review.

Sincerely,

David K. Cundiff

1. Nielsen HK, Husted SE, Krusell LR, et al. Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis Research 1994; 73:215-26.

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. Journal of Internal Medicine 1994; 235:457-61.

3. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism -- A controlled trial. Lancet 1960; 1:1309.

4. Hamulyak K, Lensing AW, van der Meer J, Smid WM, van Ooy A, Hoek JA. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group. Thromb Haemost 1994; 74:1428-31.

5. Planes A, Samama MM, Lensing AW, et al. Prevention of deep vein thrombosis after hip replacement--comparison between two low-molecular heparins, tinzaparin and enoxaparin. Thromb Haemost 1999; 81:22-5.

6. Koopman MM, Prandoni P, Piovella F, Prins MH, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. New England Journal of Medicine 1996; 334:682-7.

I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms