Original articles   

International Angiology 2008 February;27(1):60-7

Copyright © 2008 EDIZIONI MINERVA MEDICA

language: English

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use

Dahl O. E. ¹, Borris L. C. ², Bergqvist D. ³, Schnack Rasmussen M. ⁴, Eriksson B. I. ⁵, Kakkar A. K. ⁶, Colwell C. W. ⁷, Caprini J. A. ⁸, Fletcher J. ⁹, Friedman R. J. ¹⁰, Lassen M. R. ¹¹, Frostick S. P. ¹², Sakon M. ¹³, Kwong L. M. ¹⁴, Kakkar V. V. ¹⁵

¹ International Surgical Thrombosis Forum (ISTF), Thrombosis Research Institute, London, UK 2 Department of Orthopaedic Surgery, Århus University Hospital, Århus, Denmark 3 Department of Vascular Surgery and Surgical Science, Uppsala, Sweden 4 Department of Surgery, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark 5 Department of Orthopaedic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden 6 St. Barts Hospital, School of Medicine, London, UK 7 Center for Orthopaedic Research at Scripps Clinic, La Jolla, CA, USA 8 Department of Surgery, Evanston IL and Northwestern University Feinberg School of Medicine, Chicago, IL, USA 9 Department of Surgery, Westmead Hospital, University of Sydney, Sydney, Australia 10 Department of Orthopaedics, Medical University of South Carolina, Charleston, SC, USA 11 Department of Orthopaedics, Hillerød Hospital, University of Copenhagen, Copenhagen, Denmark 12 Department of Musculoskeletal Science, Royal Liverpool University Hospital, Liverpool, UK 13 Department of Surgery, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan 14 Department of Orthopaedic Surgery, Harbor-UCLA Medical Center, Torrance, CA, USA 15 Thrombosis Research Institute, London, UK and Bangalore, India

Aim. Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events.
Methods. First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compaired drugs and technical procedure.
Results. The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated.
Conclusion. Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.