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Proefschrift-Banne-Nemeth.Pdf Stellingen behorende bij het proefschrift Venous thrombosis following lower-leg cast immobilization and knee arthroscopy From a population-based approach to individualized therapy 1. A prophylactic regimen of low-molecular-weight-heparin for eight days after knee arthroscopy or during the complete immobilization period in patients with casting of the lower leg is not efective for the prevention of symptomatic venous thromboembolism. -this thesis- 2. For patients with a history of venous thromboembolism who are undergoing surgery or are treated with a lower leg cast, the risk of recurrent venous thromboembolism is high. -this thesis- 3. Estimating the risk of venous thromboembolism risk following lower leg cast immobilization or following knee arthroscopy is feasible by using a risk prediction model. -this thesis- 4. A targeted approach, by identifying high-risk patients who may beneft from a higher dose or longer duration of thromboprophylactic therapy, is a promising next step to prevent symptomatic VTE following lower leg cast immobilization or knee arthroscopy. -this thesis- 5. The best treatment strategy to prevent symptomatic venous thromboembolism following lower leg cast immobilization or following knee arthroscopy is yet to be determined. 6. Prognostic models are meant to assist and not to replace clinicians’ decisions. Accurate estimation of risks of outcomes can enhance informed decision making with the patient. -Adapted from PLoS Med 10(2): e1001381- 7. The frst developed prediction model is not the last. 8. Voor de dagelijkse klinische praktijk is het essentieel dat onderzoeksresultaten op de juiste manier worden geïnterpreteerd en toegepast. Om dit te waarborgen is een intensievere samenwerking tussen epidemiologen en dokters aan te raden. 9. Allereerst, niet schaden. Geef geen tromboseprofylaxe wanneer dit niet efectief is. -Adapted from Eed van Hippocrates- 10. Een bloedstollende flm is niet alleen maar eng. -Adapted from BMJ 2015;351:h6367- Venous thrombosis following lower-leg cast immobilization and knee arthroscopy From a population-based approach to individualized therapy Banne Németh Venous thrombosis following lower-leg cast immobilization and knee arthroscopy From a population-based approach to individualized therapy Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnifcus prof. mr. C.J.J.M. Stolker, Colophon volgens besluit van het College voor Promoties The research described in this thesis was performed at the Department of Clinical te verdedigen op woensdag 2 september 2020 Epidemiology and the Department of Orthopaedic Surgery, Leiden University Medical klokke 16.15 uur Center, Leiden, The Netherlands. Cover: Antony Nguyen door Lay-out and print: Gildeprint ISBN: 978-94-6402-463-0 Banne Németh geboren te Alphen aan den Rijn © 2020 B. Németh. All rights reserved. No part of this thesis may be reproduced, stored or in 1987 transmitted in any form or by any means without prior permission of the copyright owner. Financial support by the Federatie van Nederlandse Trombosediensten, ChipSoft, Nederlandse Orthopaedische Vereniging, Anna Fonds, Pfzer, Daiichi Sankyo and Boehringer Ingelheim, for the publication of this thesis is gratefully acknowledged. Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Promotores TABLE OF CONTENTS Prof. dr. S.C. Cannegieter Prof. dr. R.G.H.H. Nelissen Chapter 1 General introduction and outline of this thesis 7 Chapter 2 Thromboprophylaxis after knee arthroscopy and lower-leg 15 Leden promotiecommissie casting Prof. dr. F.R. Rosendaal Chapter 3 No indication for thromboprophylactic therapy following knee 39 Prof. dr. R.W. Poolman arthroscopy or lower-leg casting Prof. dr. H.R. Büller (Amsterdam UMC) Chapter 4 High risk of recurrent venous thrombosis in patients with 49 Prof. A.B. Pedersen (Aarhus University, Aarhus, Denmark) lower-leg cast immobilization Chapter 5 Risk and risk factors associated with recurrent venous 61 thromboembolism following surgery in patients with history of venous thromboembolism Chapter 6 Venous thrombosis risk after cast immobilization of the lower 83 extremity: derivation and validation of a clinical prediction score, L-TRiP(cast), in three population-based case–control studies Chapter 7 Venous thromboembolism risk stratifcation for patients with 111 nonsurgical lower-limb trauma requiring immobilization: a consensus decision-making aid, clinical model designed using the Delphi method Chapter 8 Individualized thromboprophylaxis in patients with lower-leg 131 cast immobilization – a validation and subgroup analysis in the POT-CAST trial Chapter 9 Venous thrombosis risk after arthroscopy of the knee: 153 derivation and validation of the L-TRiP(ascopy) score Chapter 10 Predicting venous thromboembolism risk after immobilization 173 of the lower-limb for trauma: update and validation of a clinical risk assessment model, the TRiP(cast) score Chapter 11 Venous thrombosis following lower-leg cast immobilization 195 and knee arthroscopy: from a population-based approach to individualized therapy Chapter 12 Summary and general discussion 235 Nederlandse samenvatting 245 Dankwoord 255 List of publications 261 Curriculum vitae 271 1 General introduction and outline of this thesis Introduction and outline GENERAL INTRODUCTION 1 Venous Thrombosis Hemostasis is a physiological process that prevents bleeding once vessel damage occurs. By the formation of a blood clot, a regulatory blood fow in the circulatory system is maintained. Blood clot formation (thrombolysis) and clot break down (fbrinolysis) act synergistically and are mechanically closely intertwined. Once this balance gets disturbed, either Venous Thrombosis (VT) or bleeding occurs. VT is a clotting disease which mainly afects the deep veins in the leg, known as Deep Vein Thrombosis (DVT) or the pulmonary arteries, known as Pulmonary Embolism (PE). In the general population, annually, 1.5 per 1000 persons develop VT and the incidence steeply increases with age.[1] Many risk factors for VT have been identifed of which orthopaedic surgery is recognized to be a major cause. This can partially be explained by the extensive iatrogenic tissue damage and immobilization due to surgery. Therefore, to prevent post-operative VT, thromboprophylaxis is indicated in the vast majority of patients who undergo orthopaedic surgery.[2] Whereas the efectiveness of thromboprophylaxis has been established in many trials following major orthopaedic surgery (e.g. total hip or knee replacement), it is unclear whether patients treated with lower-leg cast immobilization or those who undergo arthroscopic knee surgery also beneft from this strategy. Effectiveness of thromboprophylaxis using a population-based approach Patients treated with lower-leg cast immobilization have an increased risk for the development of VT which was already noted in 1944.[3] Since then, many observational studies have shown an increased VT risk following lower-leg cast immobilization and it has been shown that lower-leg cast is associated with a 56-fold increased risk for VT within 3-months of its application (corresponding to an incidence within 3-months of approximately 2.0%).[4-7] To evaluate prevention of VT following cast application, prior to this thesis, 6 randomized trials have been performed to study whether thromboprophylaxis (during cast immobilization) is an efective treatment.[8-13] The results across these trials did not uniformly suggest efectiveness of thromboprophylaxis. Moreover, as many trials had methodological shortcomings (i.e. underpowered to establish efcacy on prevention of symptomatic VTE, high rates of loss to follow-up, limited validity due to strict selection of high-risk patients and many post-randomisation exclusions) most guidelines are reluctant to state efectiveness of thromboprophylaxis following lower-leg cast immobilization. Therefore, a new large randomized controlled trial to investigate the efectiveness of thromboprophylaxis was highly needed. 9 Chapter 1 Introduction and outline In knee arthroscopy patients, a similar pattern and body of evidence exists. The risk for VT Following identifcation of high-risk groups based on single risk factors, we focus on risk is estimated to be 18-fold increased within 3-months following arthroscopy (corresponding prediction. Chapter 6 encompasses the development of a prediction model for VT 1 to an absolute risk of approximately 1.0% within 3-months).[14-17]. Five randomized trials following lower-limb cast immobilization using data from a large population-based case- have been performed, all studying the efectiveness of Low-Molecular-Weight-Heparin control study, the MEGA (Multiple Environmental and Genetic Assessment) study, which (LMWH) versus no treatment for VT prevention.[18-22] A Cochrane review in 2008 aimed to identify risk factors for a frst VT. In addition, the added value of biomarker concluded that thromboprophylaxis in knee arthroscopy was efective for the prevention of assessment for risk prediction is examined. In Chapter 7, an analogous model is developed asymptomatic VTE with a relative risk of 0.16 (95%CI 0.05 – 0.52).[23] However, when as part of an international collaboration using the Delphi method. For patients undergoing the authors only included symptomatic events, the meta-analysis failed to show a protective knee arthroscopy, a diferent prediction model for VT is developed of which results are efect for anticoagulant therapy (RR 0.42,
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