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Biomarkers for detection of a thrombus in the left atrial appendage: the search for the grail?
  1. Christoph R Sinning
  1. Department of Cardiology, University Heart & Vascular Center Hamburg Eppendorf, Hamburg, Germany
  1. Correspondence to Dr Christoph R Sinning, General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, Hamburg 20251, Germany; c.sinning{at}uke.de

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Patients with atrial fibrillation (AF) undergoing either pulmonary vein isolation (PVI) or direct current cardioversion (DCCV) most commonly undergo transoesophageal echocardiography (TOE) for definite exclusion of a thrombus in the left atrial appendage (LAA).1 As TOE as a semi-invasive procedure is not without risk to the patient and during the current times with a still ongoing SARS-Cov-2 pandemic for the clinician, a definite exclusion of LAA thrombosis before a PVI or DCCV using a readily available biomarker would minimise the risk for the patient and clinician alike. However, as far as now the quest to identify such a biomarker is still ongoing.

D-dimer levels in the ADDIT-AF Study and identification of patients with LAA thrombus

In their manuscript Almorad et al 2 did compare two cut-offs of D-dimer to exclude LAA thrombus before DCCV. In their study patients did receive a transthoracic echocardiography 6 months before the TOE and D-dimer levels were measured at the day of the DCCV. Two cut-offs were used in the study, the first being 500 ng/mL as suggested by the manufacturer of the test and the second being an age-adjusted value 10 times the patients age.2 The main finding was that both cut-offs were able to identify the 13 patients with LAA thrombus whereby the age-adjusted cut-off had a higher specificity with 66.4% to 50.4% for the standard cut-off. From the data of the study the cut-off with the best sensitivity and specificity, being 100% and 86%, respectively, was 1344 ng/mL.2 In this study the list of exclusion criteria was extensive including a broad range of diseases known to influence D-dimer levels like inflammatory diseases, neoplasia, recent surgery, any known thrombosis irrespective of location and moderate-to-severe valvular heart disease.2

The definition of a biomarker in clinical medicine

To include a biomarker into clinical medicine the candidate has to fulfil certain criteria (box 1). The most commonly referred definition of a biomarker was made in 2001 by a National Institute of Health working group defining a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention.3 Although D-dimer in the study shows these criteria, a concern for the use of D-dimer is the performance of the biomarker in the described study. Although sensitivity was 100% for both D-dimer cut-offs, specificity of both cut-offs was low, implying that an increase in D-dimer levels above the cut-off is not exclusively related to the presence of an LAA thrombus.2

Box 1

Criteria for a biomarker

  1. Thorough methods must be used, and the marker should be evaluated across a wide range of patients using rigorous and contemporary statistical methods.

  2. Results should be easily obtained within a short period of time and provide acceptable level of accuracy-defined biological variation and low analytical imprecision.

  3. Results should reflect an important pathophysiological process in leftatrial appendage thrombus presence and progression.

  4. Results should provide clinical useful information beyond status quo.

D-dimer in the general population and in patients with AF and LAA thrombus

D-dimer is a high molecular weight fibrinogen derivative derived from the cleavage of cross-linked fibrin reflecting both thrombin production and activation of fibrinolysis.4 Thus, elevated D-dimer levels occur in all diseases with an activation of the coagulation system like inflammatory diseases, cancer or ischaemic cardiovascular disease.4 In the general population elevated D-dimer levels were associated with an increased risk of mortality.4 In this context patients with already identified LAA thrombus had no association of D-dimer levels and resolution of the thrombus.5 This study also supports the association of LAA thrombus and inflammation with D-dimer levels due to the fact that inflammation activates the coagulation system.5 6

Biomarker strategies in assessment of stroke risk in patients with AF

Despite the fact that currently no biomarker is described to improve the diagnosis of LAA thrombus in patients planned for PVI or DCCV, biomarkers have an important role in assessing the risk of patients with AF regarding the outcome of stroke or even mortality. The biomarkers troponin I/T and N-terminal fragment B-type natriuretic peptide (NT-proBNP) were the most common to be reported regarding the association with both adverse events.7 8 The biomarker troponin, mirroring myocyte damage and NT-proBNP adding aspects regarding myocardial wall stress and volume load did include more information regarding the outcome stroke and mortality as most of the clinical variables.7 8 Thus the added biomarker did add more information regarding subclinical cardiac dysfunction and in this setting most of the important risk factors such as hypertension, diabetes mellitus, congestive heart failure, and other cardiovascular diseases or sex, no longer carried any important incremental prognostic information.7 8 Thus, there is evidence that the biomarkers are important in the setting of AF and potential rule out of LAA thrombus in conjunction with the assessment of the stroke risk.

Important findings of the ADDIT-AF Study

The most important finding in the context of the Adjusted D-Dimer evaluation to exclude left atrial thrombus in atrial fibrillation patients (ADDIT-AF) Study was that patients with D-dimer levels below the defined and the age-adjusted cut-offs were safe to undergo DCCV only using the biomarker; further, if the selection process is according to the study the suggested algorithm can be used.2 However, the patients described might not reflect the ‘real world’ patient presenting to the emergency department with additional cardiovascular diseases, like severe mitral regurgitation, known cancer diagnosis or inflammatory diseases. Thus, although the approach is important in current times of increased risk for the physician due to diseases like SARS-Cov-2 regarding TOE examinations, the approach might not be commonly of use.

The quest continues

Studies as by Almorad et al, however, are an important step to identify a potential target or a combination of variables, like for the assessment of the stroke risk, which might in the end allow to rule out the presence of an LAA thrombus without performing TOE. However, on the other hand, the echocardiography before PVI or DCCV might help to identify additional cardiovascular diseases and should not be skipped as suggested.1 As of now the quest for the biomarker to reliably identify a thrombus in the LAA continues.

References

Footnotes

  • Contributors CRS is the sole author of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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