Electronic Letters to:

Arthroplasty: B. I. Eriksson, A. K. Kakkar, A. G. G. Turpie, M. Gent, T.-J. Bandel, M. Homering, F. Misselwitz, and M. R. Lassen Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement J Bone Joint Surg Br 2009; 91-B: 636-644 [Abstract] [Full text] [PDF]

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Bengt I, Eriksson, Ajay K Kakkar, Alexander G.G. Turpie, Michael Gent, and Michael R. Lassen   (10 July 2009)

Use of surrogate endpoints in studies of thromboprophylaxis

Robert A E Clayton, Paul Gaston, Colin R. Howie   (11 June 2009)

Authors' reply: 10 July 2009
Bengt I, Eriksson, Orthopaedic Surgeon Sahlgrenska University Hospital, Mölndal, Sweden, Ajay K Kakkar, Alexander G.G. Turpie, Michael Gent, and Michael R. Lassen Send letter to journal: Re: Authors' reply: bengteriksson27{at}gmail.com Bengt I, Eriksson, et al.	Sir, We thank Clayton et al for their interest in our paper. However, we have to correct a misinterpretation of our study: surrogate endpoints were not used in this analysis; only pre-specified symptomatic endpoints were included. The large patient numbers in our database allowed an analysis of the composite endpoint of symptomatic venous thromboembolism (VTE) and all-cause mortality. The clinical importance of symptomatic VTE complications should not be underestimated in terms of patient burden, economic cost and quality of life. Focusing on fatal pulmonary embolism only, as noted in the letter by Clayton et al, is scientifically and medically inaccurate. From a clinical perspective, symptomatic VTE can lead to prolonged hospitalisation, increased NHS costs and long-term sequelae such as recurrent VTE, post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension, which can affect morbidity, mortality and quality of life.1,2 Moreover, fatal pulmonary embolism is now a rare event in this population and, as Clayton et al discuss in their paper, clinical studies enrolling very large patient numbers would be required to demonstrate a significant reduction in fatal pulmonary embolism.3 The incidence of fatal pulmonary embolism is reported in our paper (0% with rivaroxaban, <0.01% with enoxaparin regimens). However, as clinicians are well aware, the reported incidence of fatal pulmonary embolism is not always accurate given the very low autopsy rate. Despite the differences noted in age profiles between our study and that of Cusick and Beverland,4 the patient demographics in the RECORD 1–3 analysis were representative of those seen in clinical practice, as supported by demographic data from the GLORY registry.5 Importantly, in our study there was no upper age limit, no weight limit and, although not a predominant subgroup, patients undergoing revision surgery were included. B.I. ERIKSSON, Orthopaedics Department, Sahlgrenska University Hospital, Mölndal, Sweden. A. KAKKAR, Barts and the London School of Medicine and Dentistry, London, UK. A.G.G. TURPIE, M. GENT, McMaster University, Hamilton, Ontario, Canada. M.R. LASSEN, Hørsholm Hospital, Hørsholm, Denmark. 1. No authors listed. House of Commons Health Committee, 2005. The prevention of venous thromboembolism in hospitalised patients. www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/9902.htm (date last accessed 10/07/2009) 2. Kahn SR, Ginsberg JS. The post-thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev 2002;16:155-65. 3. Clayton RA, Gaston P, Watts AC, Howie CR. Thromboembolic disease after total knee replacement: experience of 5100 cases. Knee 2009;16:18–21. 4. Cusick LA, Beverland DE. The incidence of fatal pulmonary embolism after primary hip and knee replacement in a consecutive series of 4253 patients. J Bone Joint Surg [Br] 2009;91-B:645–648. 5. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg [Br] 2007;89-B:799–807.
Use of surrogate endpoints in studies of thromboprophylaxis 11 June 2009
Robert A E Clayton, Specialist Registrar Royal Infirmary of Edinburgh, Paul Gaston, Colin R. Howie Send letter to journal: Re: Use of surrogate endpoints in studies of thromboprophylaxis raeclayton{at}onetel.com Robert A E Clayton, et al.	Sir, We read with interest the papers by Cusick and Beverland1 and by Eriksson et al2 in the May 2009 issue. In their study – funded by the manufacturers of rivaroxaban – Eriksson et al report a lower thromboembolic “event rate” with rivaroxaban than with enoxaparin. Their endpoint is a composite measure of thromboembolism and all cause mortality. This measure is a surrogate endpoint and they do not report the data for rates of fatal pulmonary embolism, which is arguably the only important endpoint when studying venous thromboembolism. It is also interesting to note the significantly different age profiles in the two studies, which look at different populations. This underlines the problem of the difference between efficacy - results in a controlled, limited, select but randomised, population - and effect - namely their translation into the general population. This was the subject of review by the NHS Health Technology Assessment report (HTA),3 which counsels against the use of such surrogate endpoints, stating that “reliance on surrogate outcomes can ultimately lead to harmful patient outcomes”. Cusick and Beverland report a rate of fatal pulmonary embolism of only three in 4253 (0.07%) cases of hip or knee arthroplasty. This rate is very similar to the rate of fatal pulmonary embolism of 0.06% observed in a series of 5100 total knee arthroplasty cases from our unit.4 Taking together these two independent, unfunded studies using hard clinical endpoints, we agree with the conclusion of Cusick and Beverland that, in patients without additional risk factors, arthroplasty surgery is not a high risk procedure for fatal pulmonary embolism. R.A.E. Clayton, Specialist Registrar, P. Gaston, C.R. Howie, Royal Infirmary of Edinburgh, Edinburgh, UK. 1. Cusick LA, Beverland DE. The incidence of fatal pulmonary embolism after primary hip and knee replacement in a consecutive series of 4253 patients. J Bone Joint Surg [Br] 2009;91-B:645-8. 2. Eriksson BI, Kakkar AK, Turpie AGG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg [Br] 2009;91-B:636-44. 3. Taylor RS, Elston J. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports. Health Technol Assess 2009;13:1-50. 4. Clayton RA, Gaston P, Watts AC, Howie CR. Thromboembolic disease after total knee replacement: experience of 5100 cases. Knee 2009;16:18-21.