Title: The development and evaluation of a prognostic model and clinical decision rule to help decide on cessation of anticoagulant therapy in patients with idiopathic venous thromboembolism (VTE)
Funder: Department of Health (England)

Abstract: Design and Review/Modelling Strategy: A summary of the methods for each objective is given in (a) to (d) below.(a) Objectives 1 and 2 - Systematic Review and meta-analysis of prognostic factors studies: A pragmatic systematic review of existing systematic reviews randomised controlled trials cohort and registry studies to identify factors that have been examined as predictors of (i) risk of VTE recurrence post-treatment and/or (ii) risk of adverse outcomes will be undertaken as well as to identify parameters required for the economic model. This will be undertaken using standard systematic review methodology (as per the Cochrane Handbook) driven by a pre-specified protocol. A meta-analysis of the prognostic and predictive ability of individual factors identified will be undertaken where appropriate. Existing prognostic models and decision rules will be identified and summarised.(b) Objectives 3 and 4 - Identification of prognostic factors in the three databases: Univariable and multivariable survival modelling will be undertaken to identify those factors available in the databases that are (independently) prognostic for VTE recurrence or adverse events. For example in RIETE a mainly Spanish database 15041 patients with first idiopathic VTE are available with 6291 with extended follow-up post-treatment and factors to examine for their prognostic/predictive ability include age gender site of VTE therapeutic control concomitant illness (eg: cancer) known thrombophlia d-dimer at diagnosis and d-dimer post treatment. Similar variables are available in Douketis database of 7 trials (1863 patients) and MEGA cohort database (1218 patients). (c) Objectives 5 and 6 - Development of prognostic model: Four trials within the Douketis database (containing about 900 patients and 145 recurrences) will be used to develop a prognostic model based on the key factors of age gender body mass index site of VTE and D-dimer post treatment. Cox regression or flexible parametric survival regression models will be used with continuous variables examined on their original scale and fractional polynomial methods used to model non-linear trends if necessary; multiple imputation will be used to deal with the small amount of missing data available and clustering of patients within trials will be accounted for. The models performance will be examined through discrimination and calibration statistics and plots. The decision rule will utilise an individuals risk score from the prognostic model and a threshold value above which the risk of recurrence is considered too high to stop treatment. The choice of threshold will be informed by predictive accuracy and economic modelling (described further below).(d) Objectives 7 and 8 - External validation and comparison: The performance of the prognostic model and decision rule will be validated in new data: the three remaining trials from Douketis the REITE database and the MEGA database. Existing models/rules identified in part (a) will also be compared to our model/rule if possible at this stage.Expected Output: If we can prospectively identify patients in whom it is safe to stop anticoagulation after conventional therapy and conversely those patients in whom it would be beneficial to continue anticoagulation it will inform clinical practice and be adapted into clinical guidelines. Findings may be equivocal which would suggest primary research is warranted. The efficacy of a derived decision rule will need be demonstrated in routine practice ideally by multisite randomised control trial(s). Expertise: The team combines leading methodological (DM JD RR DL SJ CH) and clinical (DF TB PR MM GL) expertise. The team currently collaborates on 3 HTA systematic reviews. RR co-leads the Cochrane Prognosis Methods Group.Timetable: 21 months comprising 3 month study start up 9 month systematic review univariate analysis modelling and derivation of decision rule 6 months validation of decision rule 3 months write up.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR