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Sent 6-20-07 Re: CJJ van Dongen, MR Mac Gillavry, MH Prins. Once versus twice daily LMWH for the initial treatment of venous thromboembolism. The Cochrane Database of Systematic Reviews 2005:Art. No.: CD003074.pub2. DOI: 10.1002/14651858. PVD

LMWHs have been approved by the U.S. Food and Drug Administration as safe and effective treatment for VTE based on RCTs with unfractionated heparin—no unanticoagulated controls. The validity of these noninferiority trials rests on the scientific validity of the randomized trials comparing heparin itself with a placebo, no treatment, or a platelet aggregation inhibitor. None of the three small RCTs with properly diagnosed VTE subjects that have been conducted with heparin versus no anticoagulation have shown clinical benefit with anticoagulants.^1-4 Consequently, twice daily LMWH is not a legitimate control therapy, and neither once daily nor twice daily LMWH is evidence-based to be safe and effective in VTE.

None an undisclosed financial conflict of interest with co-author Dr. Martin Prins. He 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.^{5, 6} Based on the results of these two non-inferiority RCTs comparing heparin with fondaparinux, 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.⁷ 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.⁸ Sanofi Winthrop provided him with research funding for a non-inferiority RCT comparing Fraxiparine with heparin.⁹

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.