94 CHAPTER 6 After one month, the intervention itself (i.e. switching treatment from a VKA to a NOAC) will be completed, and NOAC treatment will be taken over by the treating physician as part of usual care, given the pragmatic setting of this trial. Control arm and observational arm Subjects randomised to the control arm and those in the observational arm continue to receive care as usual, that is, VKA treatment (in the Netherlands either acenocoumarol or phenprocoumon) aiming at an INR target value between 2.0 and 3.0, with monitoring by the Dutch thrombosis services. Outcomes of patients in the observational arm are not included in the primary comparison of outcomes between both randomised treatment arms, but will be included in a secondary analysis exploring potential predictors of bleeding, as explained below in the section on data analysis. Neither switch to NOAC treatment in the control or observational arm, nor switch back to VKA treatment in the intervention arm are contraindicated. Hence, it is likely that some form of crossover (i.e. patients randomised to a NOAC who switch back to a VKA, and vice versa) between both randomised treatment arms will occur; this will probably also happen in general clinical practice, and is therefore permitted in this pragmatic trial. Study outcome assessment Primary and secondary outcomes (see Supplementary file S2) are collected after one, three, six, nine, and twelve months of follow-up using a standardised questionnaire administered to the patient by telephone.26,27 If necessary, additional information on outcomes is obtained from the patient’s treating physician. Data are collected on medication use and on the primary composite outcome of major or CRNM bleeding complications, based on the definition of the International Society on Thrombosis and Haemostasis (ISTH).26,27 Accordingly, major bleeding is defined as fatal bleeding, and/or bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with compartment syndrome), and/or bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells.26 CRNM bleeding is defined as any sign or symptom of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH-definition of major bleeding but does meet at least one of the following criteria: bleeding requiring medical intervention by a healthcare professional, and/or leading to hospitalisation or increased level of care, and/or prompting a face-to-face (i.e. not just a telephone or electronic communication) evaluation.27 Secondary outcomes are 1) major bleeding complications (separate from CRNM bleeding complications), 2) CRNM bleeding complications (separate from major bleeding complications), 3) minor bleeding complications (i.e. all bleeding complications that are not classified as major or CRNM bleeding complication according
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