Ah, D-dimers, the exposed crosslink fragments resulting from the cleaving of fibrin mesh by plasmin. They predict everything – and nothing, with poor positive likelihood ratios for scads of pathologic diagnoses, and limited negative likelihood ratios for others. Little wonder, then, routine D-dimer assays were part of the PESIT trial taking the diagnosis of syncope off the rails. Now, does the YEARS study threaten to make a similar kludge out of the diagnosis of pulmonary embolism?
On the surface, this looks like a promising study. We are certainly inefficient at the diagnosis of PE. Yield for CTPA in the U.S. is typically below 10%, and some of these diagnoses are likely insubstantial enough to be false positives. This study implements a standardized protocol for the evaluation of possible PE, termed the YEARS algorithm. All patients with possible PE are tested using D-dimer. Patients are also risk-stratified for pretest likelihood of PE by three elements: clinical signs of deep vein thrombosis, hemoptysis, or “pulmonary embolism the most likely diagnosis”. Patients with none of those “high risk” elements use a D-dimer cut-off of 1000 ng/mL to determine whether they proceed to CTPA or not. If a patient has one of more high-risk features, a traditional D-dimer cut-off of 500 ng/mL is used. Of note, this study was initiated prior to age-adjusted D-dimer becoming commonplace.
Without going into interminable detail regarding their results, their strategy works. Patients ruled out solely by the the D-dimer component of this algorithm had similar 3 month event rates to those ruled out following a negative CTPA. Their strategy, per their discussion, reduces the proportion managed without CTPA by 14% over a Wells’-based strategy (CTPA in 52% per-protocol, compared to 66% based on Wells’) – although less-so against Wells’ plus age-adjusted D-dimer. Final yield for PE per-protocol with YEARS was 29%, which is at the top end of the range for European cohorts and far superior, of course, to most U.S. practice.
There are a few traps here. Interestingly, physicians were not blinded to the D-dimer result when they assigned the YEARS risk-stratification items. Considering the subjectivity of the “most likely” component, foreknowledge of this result and subsequent testing assignment could easily influence the clinician’s risk assessment classification. The “most likely” component also has a great deal of inter-physician and general cultural variation that may effect the performance of this rule. The prevalence of PE in all patients considered for the diagnosis was 14% – a little lower than the average of most European populations considered for PE, but easily twice as high as those considered for possible PE in the U.S. It would be quite difficult to generalize any precise effect size from this study to such disparate settings. Finally, considering the D-dimer assay continuous likelihood ratios, we know the +LR for a test result of 1000 ± ~500 is probably around 1. This suggests using a cut-off of 1000 may hinge a fair bit of management on a test result representing zero informational value.
This ultimately seems as though the algorithm might have grown out of a need to solve a problem of their own creation – too many potentially actionable D-dimer results being produced from an indiscriminate triage-ordering practice. I remain a little wary the effect of poisoning clinical judgment with the D-dimer result, and expect it confounds the overall generalizability of this study. As robust as this trial was, I would still recommend waiting for additional prospective validation prior to adoption.
“Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study”