Geert-Jan Geersing , Janneke M. T. Hendriksen, Nicolaas P. A. Zuithoff, Kit C. Roes, Ruud Oudega, Takada, Roger E. G. Schutgens, Karel G. M. Moons
Abstract
Background
Patients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3–6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care.
Introduction
Venous thromboembolism (VTE)—i.e., deep vein thrombosis (DVT) or pulmonary embolism (PE)—is a major healthcare burden [1]. An initial course of treatment for 3 to 6 months is recommended to prevent clot progression and VTE-related acute morbidity and mortality. After this initial phase, prolonging anticoagulant treatment reduces recurrence risk but at the price of increasing bleeding risk. Notably, patients with unprovoked VTE may benefit from prolonging treatment as it is widely appreciated that recurrence risk in them is highest [2]. However, both recurrent VTE events and major bleeding—reduced and induced by prolonged anticoagulation, respectively—carry a substantial mortality and morbidity risk. Clinically it is often difficult to balance both risks optimally on an individual level.
Methods
Trial design and ethical approval
VISTA was an investigator-initiated, multi-center, pragmatic, unblinded randomized trial. Patients were recruited by local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede). The trial was designed and overseen centrally at the University Medical Center Utrecht, the Netherlands. The study protocol was approved by the medical ethics research committee from the University Medical Center Utrecht, and the trial was registered in the Netherlands Trial Register (https://www.trialregister.nl) with registration number NTR2680. The protocol is available in S1 Text. The trial was performed in accordance with the principles of the Declaration of Helsinki. All participants provided written informed consent. Throughout this paper, we adhere to the CONSORT reporting guidelines for randomized controlled clinical trials (see S1 CONSORT Checklist) [5].
Discussion
Main findings
The randomized VISTA trial was primarily set up to determine whether applying a risk prediction model to estimate recurrence risk in patients with unprovoked VTE, with subsequent risk-based tailoring of prolonged anticoagulant treatment, would lower the risk of recurrence as compared to usual care. Our findings showed that we were unable to demonstrate such a reduction. In terms of predicting the risk of recurrent VTE, the VPM that we used showed good discriminative power and moderate to good calibration, in particular at the clinically relevant lower spectrum of predicted risk.
Acknowledgments
The authors would like to thank Anna E. C. Kingma for her help in data collection, as well as all patients and physicians, and the participating thrombosis services for their collaboration while conducting this trial.
Citation: Geersing G-J, Hendriksen JMT, Zuithoff NPA, Roes KC, Oudega R, Takada T, et al. (2020) Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial. PLoS Med 17(6): e1003142. https://doi.org/10.1371/journal.pmed.1003142
Academic Editor: Suzanne C. Cannegieter, Leiden University Medical Center, NETHERLANDS
Received: January 6, 2020; Accepted: June 3, 2020; Published: June 26, 2020
Copyright: © 2020 Geersing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data from this randomized controlled trial cannot be shared publicly because this study includes human research participant data and prior to sharing data, consulting an ethics committee is needed to ensure data are shared in accordance with participant consent and all applicable local laws. Data are available from the Institutional Data Access (contact via SecretariaatHAG-Onderzoek@umcutrecht.nl) for researchers who meet the criteria for access to confidential data, accompanied with a protocol describing the research questions aimed to answer.
Funding: The study received funding from the Netherlands Organisation for Health Research and Development (ZonMw grant number 171002214, KGMM was the receiving grant holder, URL: www.zonmw.nl). KGMM received a grant from The Netherlands Organization for Scientific Research (ZonMw 91810615 and 91208004; URL: www.zonmw.nl). GJG is supported by a VENI and VIDI grant from the Netherlands Organisation for Health Research and Development (ZonMw numbers 016.166.030 and 016.196.304; URL: www.zonmw.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CRNM, clinically relevant non-major; DVT, deep vein thrombosis; ISTH, International Society on Thrombosis and Haemostasis; ITT, intention to treat; NOAC, non-vitamin K antagonist oral anticoagulant; PE, pulmonary embolism; VPM, Vienna Prediction Model; VTE, venous thromboembolism
