Feedback from David K. Cundiff, MD Sent 2-14-07

 

J van der Heijden, B Hutten, H Büller, MH Prins. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. The Cochrane Database of Systematic Reviews 2001: Art. No.: CD002001. DOI: 10.1002/14651858. PVD

 

Dear Drs. Fowkes and van der Heijden,

 

I will comment on aspects of this review according to section. Thank you for considering these criticisms regarding your review.

 

Sincerely,

 

David K. Cundiff, MD

 

Abstract

Background

 

“People with venous thromboembolism (VTE) are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) followed by three months of vitamin K antagonists treatment……."

Comment: The implied evidence of proof of efficacy is lacking. None of the only three RCTs of heparin and vitamin K antagonists with un-anticoagulated controls showed any benefit with anticoagulants.1-6

 

Objective

 

“To evaluate the efficacy and safety of long-term treatment of VTE with low-molecular-weight heparins compared to vitamin K antagonists.”

Comment: Neither has been shown to be effective compared with un-anticoagulated controls, so this review evaluates the efficacy and safety of neither.

 

Reviewers' conclusions

 

" Low-molecular-weight heparins are possibly as effective as vitamin K antagonists in preventing symptomatic VTE after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with LMWH is significantly safer than treatment with vitamin K antagonists and is possibly a safe alternative in some patients….."

Comment: This is a moot issue in the absence of demonstrated efficacy of any anticoagulant therapy for VTE patients.

 

Main Article

Background

 

" …Patients are usually treated with an initial course of unfractionated heparin or low-molecular-weight heparin (for approximately five to seven days) and vitamin K antagonist therapy, which is started simultaneously and continued for a period of at least three months thereafter.”

Comment: The implication is that anticoagulants reduce the mortality and/or morbidity of DVT. This is not proven in randomized trials with un-anticoagulated controls.5, 6

 

Implications for research

 

Comment: Since anticoagulants are not evidence-based to reduce morbidity or mortality of VTE, the stated implications for research are not valid. The only RCT indicated might be a non-inferiority trial comparing an NSAID with LMWH or heparin and a vitamin K antagonist.

 

Potential conflict of interest

 

"None."

Comment: The issue of financial conflict of interest arises in two of the reviewers in this analysis. Harry R. Buller, MD received honoraria and grants from Sanofi-Synthe´labo, NV Organon (fondaparinux and enoxaparin),7 and research funding from Leo Laboratories for a comparison of tinzaparin and enoxaparin.8 Fondaparinux now competes with heparin and LMWH as a initial anticoagulant treatment of VTE. AstraZeneca LP; Aventis Pharmaceuticals; Bristol-Myers Squibb/Sanofi-Syntholabo Partnership; GlaxoSmithKline; Organon Sanofi-Synthelabo LLC supported his review of Antithrombotic Therapy for Venous Thromboembolic Disease for the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.9

 

Martin H. Prins, MD participated on the steering committees and in obtaining funding from Santofi-Synthelabo and NV Organon drug companies for trials of fondaparinux (Aristra®) in treatment of DVT and PE.7, 10 Based on the results of these two studies, the FDA approved fondaparinux for the treatment of DVT and PE on May 28, 2004. Anticipating this approval, Sanofi-Synthelabo announced the sale of Arixtra® and nadroparine (Fraxiparine®) on April 13, 2004 to GlaxoSmithKline for about $360 million.11 AstraZeneca LP; Aventis Pharmaceuticals; Bristol-Myers Squibb/Sanofi-Syntholabo Partnership; GlaxoSmithKline; Organon Sanofi-Synthelabo LLC supported his review of Antithrombotic Therapy for Venous Thromboembolic Disease for the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.9 Sanofi Winthrop provided him with research funding for a study comparing Fraxiparine with heparin.12

 

1.         Nielsen HK, Husted SE, Krusell LR, et al. Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis Research. 1994;73(3-4):215-226.

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(5):457-461.

3.         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;150:218-221.

4.         Kakkar VV, Flanc C, O'Shea M, Flute P, Howe CT, Clarke MB. Treatment of deep-vein thrombosis--a random trial. Br J Surg. 1968;55(11):858.

5.         Cundiff DK. Review Article - Anticoagulation Therapy for Venous Thromboembolism. Medscape General Medicine. September 9, 2004;6(3):http://www.medscape.com/viewarticle/487577.

6.         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. Art. No.: CD003746. DOI: 10.1002/14651858.CD003746.pub2.

7.         Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial. Ann Intern Med. June 1, 2004;140(11):867-873 http://www.annals.org/cgi/reprint/140/811/867.pdf.

8.         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(1):22-25.

9.         Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic Therapy for Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. September 1, 2004 2004;126(3_suppl):401S-428.

10.       The Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. 0.1056/NEJMoa035451. N Engl J Med. October 30, 2003;349(18):1695-1702.

11.       Sanofi-Synthelabo to Sell to GlaxoSmithKline Arixtra(R), Fraxiparine(R) and Notre Dame de Bondeville Plant. PRNewswire-FirstCall. April 13, 2004. Accessed July 29, 2006.

12.       Koopman MM, Prandoni P, 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(11):682-687.

 

http://www.cochranefeedback.com/cf/cda/feedback.do?DOI=10.1002/14651858.CD002001&reviewGroup=HM-PVD

NA 9-21-07