Safety and efficiency of the YEARS algorithm versus computed tomography pulmonary angiography alone for suspected pulmonary embolism in patients with malignancy - The Hydra Study

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent complication of malignancy[2]. Patients with malignancy were associated with a 4-fold risk of VTE compared patients without malignancy, where chemotherapy increased this risk to 6.5-fold[3]. The development of VTE is presumed to be due to the production of pro-coagulant molecules by malignant cells and to the pro-coagulant effect of these cells spread into the circulation[4]. Furthermore, many factors contribute to the thrombotic risk in malignancy patients, including classical thrombotic risk factors (i.e. age, bed-rest, history of VTE, and comorbid conditions) and risk factors typical of malignancy (i.e. type and stage of malignancy, anti-malignancy treatments)[3, 5, 6].
Diagnosing PE in patients with malignancy
Because of its diagnostic accuracy and wide availability, multi-row detector computed tomography pulmonary angiography (CTPA) is currently the imaging test of choice to confirm or exclude acute PE [7, 8]. However, this diagnostic test can yield useless or misleading test results if done without appropriate clinical indication [9]. Therefore, circulating D-dimer concentrations and clinical predictions rules were developed as complementary diagnostics steps.
The D-dimer is a biomarker that is routinely used in conjunction with clinical parameters in the initial assessment of suspected acute PE[10]. Although it is well documented that the D-dimer test is useful in the diagnostic workup of patients with suspected PE, it is thought that the D-dimer test is of less value in patients with malignancy due to often elevated levels in absence of thrombosis [11, 12]. According to previous studies, the incidence of normal D-dimer levels (cut off at 0.5μg/mL or age-adjusted) in patients with a malignancy and suspected PE may be as low as 10-15% [1, 13].
Several clinical decision rules (CDRs) have been developed for estimating the pre-test probability of PE. CDR can be combined with D-dimer testing to rule out PE in case of a non-high probability and a normal D-dimer test [14]. However, it is recognized that CDRs may not be as effective and safe in patients with malignancy. Recently, the YEARS study combined three elements of the Wells rule (i.e. clinical signs of deep vein thrombosis, hemoptysis, and whether pulmonary embolism is the most likely diagnosis) with D-dimer testing for exclusion of PE, of which the cut-off level is dependent whether YEARS items are absent or not. The study showed that CTPA could safely be avoided in an additional absolute 13% of patients compared with standard algorithms [1]. This reduction could be achieved, according to the worst case scenario, at an only 0.78% (95% CI 0.49-1.2) failure rate with regard to the 3-month incidence of recurrent venous thromboembolism. However, this algorithm showed highest failure rates (2.6%, 95%CI 1.3-5.2) in a relatively small subgroup of patients with malignancy (9.7% of the YEARS study population). Moreover, a recent meta-analysis demonstrated that the D-dimer test (cut off <0.5μg/mL), combined with the diagnostic Wells rule, resulted in a similar 2.6% (95% confidence interval (CI) 0.57-11) 3-month failure rate of diagnosing PE in patients with malignancy[13]. This was also highest among all subgroups.
As a consequence of unknown safety and efficacy of CDRs in patients with malignancy and presumed futility of D-dimer as a diagnostic test, clinicians-oncologists may often directly order a CTPA when suspecting PE. However, avoidance of CTPA use results in less radiation exposure, contrast material allergy and contrast material induced nephropathy, as well as leads to a reduction of irrelevant sub-segmental emboli detection and health care costs [15-17].

The YEARS algorithm is non-inferior to management by CTPA with regard to 3-month recurrent VTE rates and will reduce the rate of unnecessary CTPA in patients with clinically suspected PE and active malignancy.

Visit 1 (enrollment):
- Check for in- and exclusion criteria
- Obtain informed consent
- Randomization
- Medical history
- Demographic data
- Clinical examination
- Laboratory test (d dimer, renal function) (Part of clinical practice, no study proceedings)
- Decision of diagnostic method (management according to YEARS algorithm or CTPA alone)

Visit 2 (3 months follow up)
- Recording of death, adverse events, pulmonary embolism, deep vein thrombosis, major bleeding, re-hospitalization, anticoagulation therapy usage

Trial schedule:
The total duration of this study is expected to be 30 months.
Ethics approval in the primary research center is aimed to be achieved by second quarter of 2019 and by end of 2019 in the participating centers.
Subject recruitment is planned to start in June 2019 and end in February 2024.
The follow up-period will end in summer 2024, allowing for analysis of data and first assessment of results in autumn 2024.

The Hydra-study will be a randomized controlled, multicenter international trial with a non-inferiority analysis for the main safety outcome (rate of 3-month VTE); if non-inferiority has been demonstrated at secondary stage a superiority analysis for the efficiency judgment criterion (rate of unnecessary CTPA) will be performed. The two randomized arms will exist of diagnostic management according to the YEARS algorithm and diagnostic management by CTPA alone.