HAEMOSTASIS AND THROMBOSIS


Table 1. US Food and Drug Administration (FDA)-approved DiET clinical study performance data. Condition


Sensitivity (%)


DVT PE*


Stago 100% 97%


Competitor systems Stago 97.5/97.5 98/97


100 99.7


Negative predictive value (%) Competitor 99.6/99.1 99.7/99.6


Stago 55.2 75.5


Specificity (%)


Competitor 45.1/46.1 54.5/54.5


*Explanatory note on PE data for NPV and sensitivity: two patients in the negative D-dimer group had PE during the three-month follow-up, one related to being bedridden and hospitalised/atrial fibrillation and the second due to a suspected pre-analytical sample issue.


In the UK, upwards of 32,000 cases of hospital-associated VTE occur every year.2 and the annual incidence of diagnosed PE is said to be seven to eight per 10,000 people.3,4 As Thrombosis UK’s website points


out: “Taking proactive steps to mandate VTE best practice locally could help to reduce this burden; however, most health service providers appear to be unaware of what VTE is costing locally”. While full VTE-related costs to the


NHS are difficult to extract and can go undocumented, a 2016/17 survey of English Clinical Commissioning Groups (CCGs) asked about their recorded costs for VTE treatment, hospital bed days, sanctions and litigation, the average annual cost for that year was almost one million (£938,357) per commissioning group.


Choosing the right assay Stago’s most advanced exclusion assay, the STA-Liatest D-Di Plus evolved from the STA -Liatest D-Di, approved by the FDA to aid in the diagnosis of venous VTE.


Evidence on the assay’s overall cost benefits, can be seen in a recent independent health economics study.5 This shows that the use of the Stago assay in the patient care pathway can generate significant overall savings – between 7% and 45% – by removing the need for additional, costly tests that can cause the patient anxiety and are invasive. To help a laboratory make the decision on the choice of D-dimer assay, the CLSI guidelines also set down recommended analytical, operational and clinical criteria for selecting the safest method, as follows:


Analytical n Accurate test results around the


cut-off (low coefficient of variation [ CV] <7.5%)


n Clear unit to report the results – fibrinogen equivalent units (FEU) or D-dimer units (DDU).


Operational n Easy to use, with availability 24 hours/ seven days per week


n Rapid turnaround time (TAT)


Health technology assessment looks at the wider health economics of carrying out certain diagnostic protocols when faced with a potential DVT.


WWW.PATHOLOGYINPRACTICE.COM DECEMBER 2021


Clinical n Well-established diagnostic cut-off n Intended use of the product:


exclusionary claim versus aid in diagnosis.


Superior clinical performance D-dimer is a product of fibrin degradation (fibrinolysis) found at low levels in the blood of healthy people. As activated blood coagulation and consequent fibrinolysis are associated with increased plasma D-dimer concentration, D-dimer has become a clinically useful biomarker of thrombotic disease, with most commercial assays reporting a sensitivity of between 97% and 100%. Alongside the importance of negative predictive value (NPV), it is their differing specificity levels that affect their value as an exclusion assay.


Stago’s two-part international investigation, the ‘D-Dimer in the Exclusion of Venous Thromboembolism’ (DiET) Study’, demonstrated that the Stago assay used in combination with a pretest probability (PTP) assessment was able to exclude VTE safely without the need for imaging to provide further confirmation. The study also showed the assay’s superior clinical performance in a competitor analysis based on this higher specificity (Table 1).


To enhance its effectiveness, the D-Di Plus also includes a blocking agent to improve the analytical and diagnostic performance of the assay by minimising interferences to heterophilic antibodies, including rheumatoid factor (RF) and human anti-mouse antibodies (HAMA). For most patients, Stago recommends a validated D-dimer clinical threshold (cut-off) of 0.5 μg/mL measured in fibrinogen equivalent units.


While its main purpose was designed to demonstrate the ability of the Stago assay to safely exclude PE and deep vein thrombosis as part of the FDA approval process, it was recognised as the most robust international study ever to be undertaken to support the clinical utility of D-dimer in the management of patients suspected of having DVT. Until then, there was limited evidence for using a D-dimer assay to rule out PE and VTE, even on patients with low probability levels, because most commercial assays had not been considered sufficiently specific to be able to make an exclusion claim. There is still no standardisation to benchmark the diverse commercial D-dimer assays, so the comparability of results can be difficult, and this also affects patient outcomes and a hospital’s overall diagnostic costs.


Fewer false positives Higher specificity enables an assay to deliver fewer false-positive D-dimer results and therefore fewer unnecessary referrals for imaging studies that may increase the cost of patient care, increase length of stay and increase patient exposure to radiation and associated complications of imaging studies. The Stago assay exceeds the higher


CLSI requirements, delivering a specificity for PE of around 75% compared to competitors, which range from 43% and 55% – data that can be confirmed from the published validation studies for both Stago and competitor assays. The CLSI guidelines focused exclusively on an assay’s ability to exclude VTE. In 2011 the FDA’s original benchmarks of 95% (sensitivity) and 97% (NPV) for the efficacy of a D-dimer assay to aid in the diagnosis or exclusion of VTE


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