Hydra study

<p>Safety: Recurrent venous thromboembolism during three months follow-up in<br>patients with initially normal diagnostic tests.<br>Efficiency: Number of CTPA needed in each randomisation group.</p><p>An independent adjudication committee consisting of two thrombosis specialists not involved in the study will evaluate all new and recurrent suspected clinical events during the 90-day follow-up period. The events include DVT, PE or death (our primary endpoints), and MB.</p><p>Documentation required for the adjudication of suspected clinical events will be limited to clinical summaries, imaging reports, and other relevant findings, e.g., laboratory or physical exam. Requests for copies of films or images from objective tests will only be made when deemed necessary. Disagreements will be solved by discussion between the two specialists of the adjudication committee. If necessary, a third thrombosis specialist not involved in the study will be asked to resolve any persisting disagreements.<br>All deaths during follow-up will be adjudicated as to the likelihood that the death was related to PE using the International Society on Thrombosis and Haemostasis (ISTH) definition for PE-related death and classification of the cause of death [22]:<br>A.&nbsp;&nbsp;&nbsp;&nbsp;PE-related death (i.e., certainly / highly probable PE-related)</p><p>B.&nbsp;&nbsp;&nbsp;&nbsp;undetermined cause of death (i.e., possibly PE-related)</p><p>C.&nbsp;&nbsp;&nbsp;&nbsp;cause other than PE (i.e., PE-unrelated)*</p><p><br>For the main analysis assessing the safety and efficiency of both diagnostic strategies for ruling out PE, both category A (“PE-related death”) and category B (“undetermined cause of death”) will be considered PE-related.&nbsp;</p><p>&nbsp;</p><p>Interim analysis:<br>The study team has decided to perform an interim analysis in response to the higher-than anticipated all-cause mortality rate in both study arms. The objective of this interim analysis is to<br>account for the higher-than-anticipated mortality rate, which could be linked to a higher prevalence of PE resulting in PE-related death. This prompts a re-evaluation of the sample size and the predefined margin for defining non-inferiority.</p><p><br>The interim analysis aims to:<br>1. Assess the primary safety outcome (the diagnostic failure rate), defined as the proportion of<br>symptomatic VTE, PE-related mortality or mortality with undetermined cause of death during<br>the three month follow-up period in the subgroup of patients in whom PE was ruled out at<br>baseline (i.e., based on a negative results of the YEARS algorithm or a negative CTPA) and who<br>remained "untreated" with therapeutic anticoagulation.</p><p>2. Verify the power of our previous sample size calculation for the per-protocol non-inferiority<br>analysis and recalculate sample size on predefined margins for defining non-inferiority.</p><p>The interim analysis is planned to be conducted in March 2025 upon the adjudication of the<br>suspected clinical events by the adjudication committee. The recruitment of subjects will continue<br>during this process.<br>The interim analysis will be performed by an independent statistician for all patients included up to 25 July 2024. Based on the observed diagnostic failure rate, an adjusted alpha's for the interim andfinal analyses will be calculated using 0'Brien-Fleming alpha-spending<br>The calculated sample size will be adjusted to account for the number of patients who have been<br>enrolled and randomized but do not meet the criteria for the per-protocol analysis, resulting in the<br>final number of patients required for inclusion in the study.</p><p><br>&nbsp;</p>

<p>To evaluate the occurrence (timing, location and severity) of recurrent<br />
symptomatic VTE during follow-up in both study arms in order to better<br />
differentiate between missed PE diagnoses and new onset VTE<br />
To compare differences in the rate of isolated sub-segmental PE, defined as<br />
CTPA demonstrating an intraluminal filling defect in a sub-segmental artery<br />
with no filling defect visualized at more proximal artery levels, in both study<br />
arms<br />
To assess the occurrence of incidental VTE, defined as thromboembolism that was<br />
detected by means of imaging tests performed for reasons other than clinical<br />
suspicion of venous thromboembolism[18], during follow up in both study arms<br />
To evaluate contrast material induced complications (allergic reactions and<br />
contrast material induced nephropathy) in both study arms.<br />
To evaluate usage and safety of antithrombotic treatment in both study groups<br />
To evaluate practice patterns of anticoagulation therapy during end-of-life<br />
care in terminally ill patients with cancer.<br />
To evaluate quality of life in patients with PE at baseline or follow-up in<br />
this study by implementing the Pulmonary Embolism Quality of Life (PEmb-QoL)<br />
Questionnaire.<br />
To post-hoc evaluate the performance of the 4-Level Pulmonary Embolism Clinical<br />
Probability Score (4PEPS), in patients randomized for YEARS within the Hydra<br />
study.</p>

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